Sexually transmitted infections (STIs) continue to be a significant public health problem with potentially serious complications.¹ The incidence of new STIs, including viral STIs, in the United States is estimated at 19 million cases per year.²Chlamydia trachomatis remains the most common bacterial STI with an estimated annual incidence of 2.8 million cases in the United States and 50 million worldwide. Second in prevalence is gonococcal infection. Herpes simplex virus is one of the most common viral STIs, but the incidence of human papillomavirus virus (HPV), which is associated with cervical cancer, has steadily increased worldwide.³ Young persons age 15 to 24 are at the highest risk of acquiring new STIs with almost 50% of new cases reported among this age group.⁴

STIs can have serious complications and sequelae. For example, 20% to 40% of women who have chlamydia infections and 10% to 20% of women who have gonococcal infections develop pelvic inflammatory disease (PID),² which increases the risk for ectopic pregnancy, infertility, and chronic pelvic pain.

Patients with mental illness are at high risk of acquiring STIs. In the United States, the prevalence of HIV among patients with psychiatric illness is 10 to 20 times higher than in the general population.^4,5 Factors contributing to increased vulnerability to STIs among psychiatric patients include:

• impaired autonomy
• increased impulsivity
• increased susceptibility to coerced sex.⁶
  

Furthermore, a higher incidence of poverty, placement in risky environments, and overall poor health and medical care also contribute to the high prevalence of STIs and their complications in this population (Table 1). Because of risk factors specific to psychiatric illness, standard STI prevention interventions are not always successful and novel and innovative behavioral approaches are necessary.⁷

Case Abdominal pain and fever

Ms. K, age 25, has a history of bipolar disorder treated with lithium and presents to the community psychiatrist with lower abdominal pain. She recently recovered from a manic episode and has started to reintegrate with the community mental health team. She refuses to see her primary care physician and is adamant that she wishes to see her psychiatrist, who is the only doctor she has rapport with.

Ms. K reports lower abdominal pain for 3 or 4 days and fever for 1 day. The pain is dull in character. She denies diarrhea, vomiting, or urinary symptoms, but on further questioning describes new-onset, foul-smelling vaginal discharge without vaginal bleeding. Her menstrual cycle usually is regular, but her last menstrual period occurred 2 months ago. Her medical history includes an appendectomy at age 10 and she is a current cigarette smoker. Chart notes taken during her manic episode describe high-risk behavior, including having unprotected sexual intercourse with several partners. On examination, she is febrile and tachycardic with a tender lower abdomen.

Diagnosing STIs

To diagnose an STI, first a clinician must consider its likelihood. Taking a thorough sexual history allows assessment of the need for further investigation and provides an opportunity to discuss risk reduction. In accordance with recent guidelines,⁸ all health care providers are encouraged to consider the sexual history a routine aspect of the clinical encounter. The Centers for Disease Control and Prevention’s (CDC’s) “Five Ps” approach (Table 2) is an excellent tool for guiding investigation and counseling.⁹

The Figure provides health care providers with an algorithm to guide testing for STIs among psychiatric patients. Note that chlamydia, gonorrhea, syphilis, chancroid, viral hepatitis, and HIV must be reported to state public health agencies and the CDC.

Modern laboratory techniques make diagnosing STIs easier. Analysis of urine or serum reduces the need for invasive sampling. If swabs are required for diagnosis, patient self-collection of urethral, vulvovaginal, rectal, or pharyngeal specimens is as accurate as clinician collected samples and is better tolerated.⁸ Because of variation in diagnostic assays, we recommend contacting the laboratory before sending non-standard samples to ensure accurate collection and analysis.

Guidelines for preventing and screening for STIs

There are no prevention guidelines for STIs specific to the psychiatric population, although there is a clear need for focused intervention in this vulnerable patient group.¹⁰ Rates of STI screening generally are low in the psychiatric setting,¹¹ which results in a considerable burden of disease. All psychiatric patients should be encouraged to engage with STI screening programs that are in line with national guidelines. In the inpatient psychiatric or medical environment, clinicians have a responsibility to ensure that STI screening is considered for each patient.

Patients with mental illness should be assumed to be sexually active, even if they do not volunteer this information to clinicians. Employ a low threshold for recommending safer sex practices including condom use. Encourage women to develop a relationship with a family practitioner, internist, or gynecologist. Advise men who have sex with men (MSM) to visit a doctor regularly for screening of HIV and rectal, anal, and oral STIs as behavior and symptoms dictate.

HPV. Routine HPV screening is not recommended; however, 2 vaccines are available to prevent oncogenic HPV (types 16 and 18). All females age 13 to 26 should receive 3 doses of HPV vaccine over a 6-month period. The quadrivalent vaccine (Gardasil) also protects against HPV types 6 and 11, which cause 90% of genital warts and is preferred when available. Males age 9 to 26 also can receive the vaccine, although ideally it should be administered before sexual activity begins.¹⁵ Women still should attend routine cervical cancer screening even if they have the vaccine because 30% of cervical cancers are not caused by HPV 16/18. However, this means that 70% of cervical cancers are associated with HPV 16/18, making screening and the vaccine an important public health initiative. There also is a link between HPV and oral cancers.

Treating STIs among mentally ill individuals

Treatment of STIs among mentally ill individuals is important to prevent medical complications and to reduce transmission. Here are a few additional questions to keep in mind when treating a patient with psychiatric illness:

Does the patient have a primary psychiatric disorder, or is the patient’s current psychiatric presentation a result of the infection?
Some STIs can manifest with psychiatric symptoms—for example, neurosyphilis and HIV-associated neurocognitive disorders—and pose a diagnostic challenge. Obtaining a longitudinal history of the patient’s mental health, age of onset, and family history can help clarify the cause.

Are there any psychiatric adverse effects of STI treatment?

Most drugs used for treating common STIs are not known to cause psychiatric adverse effects (See the American Psychiatric Association¹⁶ and Sockalingham et al¹⁷ for a thorough discussion of HIV and hepatitis C treatment). The exception is fluoroquinolones, which could be prescribed for PID if cephalosporin therapy is not feasible. CNS effects of fluoroquinolones include insomnia, restlessness, confusion, and, in rare cases, mania and psychosis.

What are possible medication interactions to keep in mind when treating a psychiatric patient?
Nonsteroidal anti-inflammatory drugs (NSAIDs), other than sulindac, could increase serum lithium levels. Although NSAIDs are not contraindicated in patients taking lithium, other pain relievers, such as acetaminophen, may be preferred as a first-line choice.

Carbamazepine could lower serum levels of doxycycline.¹⁸
Azithromycin and other macrolides, as well as fluoroquinolones, could have QTc prolonging effects and has been associated with torsades de pointes.¹⁹ Several psychiatric medications, in particular, atypical antipsychotics, also could prolong the QTc interval. This could be a consideration in patients with underlying long QT intervals at baseline or a family history of sudden cardiac death.

Psychiatric patients might refuse or not adhere to their medication. Refusals could be the result of grandiose delusions (“I don’t need treatment”) or paranoia (“The doctor is trying to poison me”). Consider 1-time doses of antibiotics that can be given in the clinic for uncomplicated infections when adherence is an issue. Because psychiatric patients are at higher risk for acquiring STIs, education and counseling—especially substance abuse counseling—are vital as both primary and secondary prevention strategies. Treatment of STIs should be accompanied by referrals to the social work team or a therapist when appropriate.

Finally, as with any proposed treatment, it is important to consider whether the patient has capacity to consent to or refuse treatment. To assess for capacity, a patient must be able to:

• communicate a choice
• understand the relevant information
• appreciate the medical consequences of the decision
• demonstrate the ability to reason about treatment choices.²⁰

Case continued

In the emergency department, Ms. K’s vital signs are: temperature 39.5°C; pulse 110 beats per minute; blood pressure 96/67 mm Hg; and breathing 20 respirations per minute. She complains of nausea and has 2 episodes of emesis. She allows clinicians to perform a complete physical examination, including pelvic exam. Her cervix is inflamed, and she is noted to have adnexal and cervical motion tenderness.

Labs and imaging confirm a diagnosis of PID due to gonorrhea and she is admitted to the hospital for IV antibiotics. She continues to experience nausea and vomiting, but also complains of dizziness and diarrhea. Her speech is slurred and a coarse tremor is noticed in her hands. Renal function tests show slight impairment, probably due to dehydration. A pregnancy test is negative.

Lithium is held. Her nausea, vomiting, and diarrhea resolve quickly, and Ms. K asks to leave. When she is told that she is not ready for discharge, Ms. K becomes upset and rips out her IV yelling, “I don’t need treatment from you guys!” A psychiatry consult is called to assess for her capacity to refuse treatment. The team determines that she has capacity, but she becomes agreeable to remaining in the hospital after a phone conversation with her community mental health team.

Ms. K improves with antibiotic treatment. HIV and syphilis serology tests are negative. Before discharge, both the community psychiatrist and her primary care physicians are informed her lithium was held during hospitalization and restarted before discharge. Ms. K also is educated about the signs and symptoms of lithium toxicity, as well as common STIs.

Clinical considerations

• Physicians should have a low threshold of suspicion for PID in a sexually active young woman who presents with abdominal pain and shuffling gait, which is a natural attempt to reduce cervical irritation and is associated with PID.
• Ask about sexual history and symptoms of STIs.
• Rule out STIs in men presenting with urinary tract infections.
• If chlamydia is diagnosed, treatment for gonorrhea also is essential, and vice versa.
• Always think about HIV and hepatatis B and C in a patient with a STI.
• Treatment with single-dose medications can be effective.
• Risk of STIs is higher during episodes of mania or psychosis.
• Consider hospitalization if medically indicated or if you suspect non-adherence to therapy. It is important to remember that all kinds of systemic infections—including PID—can result in dehydration and alter renal metabolism leading to lithium accumulation.
• Mentally ill patients might require placement under involuntary commitment if they are found to be a danger to themselves or others. It is important to liaise with both the community psychiatry team and primary care physician both during hospitalization and before discharge to ensure a smooth transition.

Sexually transmitted infections (STIs) continue to be a significant public health problem with potentially serious complications.¹ The incidence of new STIs, including viral STIs, in the United States is estimated at 19 million cases per year.²Chlamydia trachomatis remains the most common bacterial STI with an estimated annual incidence of 2.8 million cases in the United States and 50 million worldwide. Second in prevalence is gonococcal infection. Herpes simplex virus is one of the most common viral STIs, but the incidence of human papillomavirus virus (HPV), which is associated with cervical cancer, has steadily increased worldwide.³ Young persons age 15 to 24 are at the highest risk of acquiring new STIs with almost 50% of new cases reported among this age group.⁴

STIs can have serious complications and sequelae. For example, 20% to 40% of women who have chlamydia infections and 10% to 20% of women who have gonococcal infections develop pelvic inflammatory disease (PID),² which increases the risk for ectopic pregnancy, infertility, and chronic pelvic pain.

Patients with mental illness are at high risk of acquiring STIs. In the United States, the prevalence of HIV among patients with psychiatric illness is 10 to 20 times higher than in the general population.^4,5 Factors contributing to increased vulnerability to STIs among psychiatric patients include:

• impaired autonomy
• increased impulsivity
• increased susceptibility to coerced sex.⁶
  

Furthermore, a higher incidence of poverty, placement in risky environments, and overall poor health and medical care also contribute to the high prevalence of STIs and their complications in this population (Table 1). Because of risk factors specific to psychiatric illness, standard STI prevention interventions are not always successful and novel and innovative behavioral approaches are necessary.⁷

Case Abdominal pain and fever

Ms. K, age 25, has a history of bipolar disorder treated with lithium and presents to the community psychiatrist with lower abdominal pain. She recently recovered from a manic episode and has started to reintegrate with the community mental health team. She refuses to see her primary care physician and is adamant that she wishes to see her psychiatrist, who is the only doctor she has rapport with.

Ms. K reports lower abdominal pain for 3 or 4 days and fever for 1 day. The pain is dull in character. She denies diarrhea, vomiting, or urinary symptoms, but on further questioning describes new-onset, foul-smelling vaginal discharge without vaginal bleeding. Her menstrual cycle usually is regular, but her last menstrual period occurred 2 months ago. Her medical history includes an appendectomy at age 10 and she is a current cigarette smoker. Chart notes taken during her manic episode describe high-risk behavior, including having unprotected sexual intercourse with several partners. On examination, she is febrile and tachycardic with a tender lower abdomen.

Diagnosing STIs

To diagnose an STI, first a clinician must consider its likelihood. Taking a thorough sexual history allows assessment of the need for further investigation and provides an opportunity to discuss risk reduction. In accordance with recent guidelines,⁸ all health care providers are encouraged to consider the sexual history a routine aspect of the clinical encounter. The Centers for Disease Control and Prevention’s (CDC’s) “Five Ps” approach (Table 2) is an excellent tool for guiding investigation and counseling.⁹

The Figure provides health care providers with an algorithm to guide testing for STIs among psychiatric patients. Note that chlamydia, gonorrhea, syphilis, chancroid, viral hepatitis, and HIV must be reported to state public health agencies and the CDC.

Modern laboratory techniques make diagnosing STIs easier. Analysis of urine or serum reduces the need for invasive sampling. If swabs are required for diagnosis, patient self-collection of urethral, vulvovaginal, rectal, or pharyngeal specimens is as accurate as clinician collected samples and is better tolerated.⁸ Because of variation in diagnostic assays, we recommend contacting the laboratory before sending non-standard samples to ensure accurate collection and analysis.

Guidelines for preventing and screening for STIs

There are no prevention guidelines for STIs specific to the psychiatric population, although there is a clear need for focused intervention in this vulnerable patient group.¹⁰ Rates of STI screening generally are low in the psychiatric setting,¹¹ which results in a considerable burden of disease. All psychiatric patients should be encouraged to engage with STI screening programs that are in line with national guidelines. In the inpatient psychiatric or medical environment, clinicians have a responsibility to ensure that STI screening is considered for each patient.

Patients with mental illness should be assumed to be sexually active, even if they do not volunteer this information to clinicians. Employ a low threshold for recommending safer sex practices including condom use. Encourage women to develop a relationship with a family practitioner, internist, or gynecologist. Advise men who have sex with men (MSM) to visit a doctor regularly for screening of HIV and rectal, anal, and oral STIs as behavior and symptoms dictate.

HPV. Routine HPV screening is not recommended; however, 2 vaccines are available to prevent oncogenic HPV (types 16 and 18). All females age 13 to 26 should receive 3 doses of HPV vaccine over a 6-month period. The quadrivalent vaccine (Gardasil) also protects against HPV types 6 and 11, which cause 90% of genital warts and is preferred when available. Males age 9 to 26 also can receive the vaccine, although ideally it should be administered before sexual activity begins.¹⁵ Women still should attend routine cervical cancer screening even if they have the vaccine because 30% of cervical cancers are not caused by HPV 16/18. However, this means that 70% of cervical cancers are associated with HPV 16/18, making screening and the vaccine an important public health initiative. There also is a link between HPV and oral cancers.

Treating STIs among mentally ill individuals

Treatment of STIs among mentally ill individuals is important to prevent medical complications and to reduce transmission. Here are a few additional questions to keep in mind when treating a patient with psychiatric illness:

Does the patient have a primary psychiatric disorder, or is the patient’s current psychiatric presentation a result of the infection?
Some STIs can manifest with psychiatric symptoms—for example, neurosyphilis and HIV-associated neurocognitive disorders—and pose a diagnostic challenge. Obtaining a longitudinal history of the patient’s mental health, age of onset, and family history can help clarify the cause.

Are there any psychiatric adverse effects of STI treatment?

Most drugs used for treating common STIs are not known to cause psychiatric adverse effects (See the American Psychiatric Association¹⁶ and Sockalingham et al¹⁷ for a thorough discussion of HIV and hepatitis C treatment). The exception is fluoroquinolones, which could be prescribed for PID if cephalosporin therapy is not feasible. CNS effects of fluoroquinolones include insomnia, restlessness, confusion, and, in rare cases, mania and psychosis.

What are possible medication interactions to keep in mind when treating a psychiatric patient?
Nonsteroidal anti-inflammatory drugs (NSAIDs), other than sulindac, could increase serum lithium levels. Although NSAIDs are not contraindicated in patients taking lithium, other pain relievers, such as acetaminophen, may be preferred as a first-line choice.

Carbamazepine could lower serum levels of doxycycline.¹⁸
Azithromycin and other macrolides, as well as fluoroquinolones, could have QTc prolonging effects and has been associated with torsades de pointes.¹⁹ Several psychiatric medications, in particular, atypical antipsychotics, also could prolong the QTc interval. This could be a consideration in patients with underlying long QT intervals at baseline or a family history of sudden cardiac death.

Psychiatric patients might refuse or not adhere to their medication. Refusals could be the result of grandiose delusions (“I don’t need treatment”) or paranoia (“The doctor is trying to poison me”). Consider 1-time doses of antibiotics that can be given in the clinic for uncomplicated infections when adherence is an issue. Because psychiatric patients are at higher risk for acquiring STIs, education and counseling—especially substance abuse counseling—are vital as both primary and secondary prevention strategies. Treatment of STIs should be accompanied by referrals to the social work team or a therapist when appropriate.

Finally, as with any proposed treatment, it is important to consider whether the patient has capacity to consent to or refuse treatment. To assess for capacity, a patient must be able to:

• communicate a choice
• understand the relevant information
• appreciate the medical consequences of the decision
• demonstrate the ability to reason about treatment choices.²⁰

Case continued

In the emergency department, Ms. K’s vital signs are: temperature 39.5°C; pulse 110 beats per minute; blood pressure 96/67 mm Hg; and breathing 20 respirations per minute. She complains of nausea and has 2 episodes of emesis. She allows clinicians to perform a complete physical examination, including pelvic exam. Her cervix is inflamed, and she is noted to have adnexal and cervical motion tenderness.

Labs and imaging confirm a diagnosis of PID due to gonorrhea and she is admitted to the hospital for IV antibiotics. She continues to experience nausea and vomiting, but also complains of dizziness and diarrhea. Her speech is slurred and a coarse tremor is noticed in her hands. Renal function tests show slight impairment, probably due to dehydration. A pregnancy test is negative.

Lithium is held. Her nausea, vomiting, and diarrhea resolve quickly, and Ms. K asks to leave. When she is told that she is not ready for discharge, Ms. K becomes upset and rips out her IV yelling, “I don’t need treatment from you guys!” A psychiatry consult is called to assess for her capacity to refuse treatment. The team determines that she has capacity, but she becomes agreeable to remaining in the hospital after a phone conversation with her community mental health team.

Ms. K improves with antibiotic treatment. HIV and syphilis serology tests are negative. Before discharge, both the community psychiatrist and her primary care physicians are informed her lithium was held during hospitalization and restarted before discharge. Ms. K also is educated about the signs and symptoms of lithium toxicity, as well as common STIs.

Clinical considerations

• Physicians should have a low threshold of suspicion for PID in a sexually active young woman who presents with abdominal pain and shuffling gait, which is a natural attempt to reduce cervical irritation and is associated with PID.
• Ask about sexual history and symptoms of STIs.
• Rule out STIs in men presenting with urinary tract infections.
• If chlamydia is diagnosed, treatment for gonorrhea also is essential, and vice versa.
• Always think about HIV and hepatatis B and C in a patient with a STI.
• Treatment with single-dose medications can be effective.
• Risk of STIs is higher during episodes of mania or psychosis.
• Consider hospitalization if medically indicated or if you suspect non-adherence to therapy. It is important to remember that all kinds of systemic infections—including PID—can result in dehydration and alter renal metabolism leading to lithium accumulation.
• Mentally ill patients might require placement under involuntary commitment if they are found to be a danger to themselves or others. It is important to liaise with both the community psychiatry team and primary care physician both during hospitalization and before discharge to ensure a smooth transition.

Sexually transmitted infections (STIs) continue to be a significant public health problem with potentially serious complications.¹ The incidence of new STIs, including viral STIs, in the United States is estimated at 19 million cases per year.²Chlamydia trachomatis remains the most common bacterial STI with an estimated annual incidence of 2.8 million cases in the United States and 50 million worldwide. Second in prevalence is gonococcal infection. Herpes simplex virus is one of the most common viral STIs, but the incidence of human papillomavirus virus (HPV), which is associated with cervical cancer, has steadily increased worldwide.³ Young persons age 15 to 24 are at the highest risk of acquiring new STIs with almost 50% of new cases reported among this age group.⁴

STIs can have serious complications and sequelae. For example, 20% to 40% of women who have chlamydia infections and 10% to 20% of women who have gonococcal infections develop pelvic inflammatory disease (PID),² which increases the risk for ectopic pregnancy, infertility, and chronic pelvic pain.

Patients with mental illness are at high risk of acquiring STIs. In the United States, the prevalence of HIV among patients with psychiatric illness is 10 to 20 times higher than in the general population.^4,5 Factors contributing to increased vulnerability to STIs among psychiatric patients include:

• impaired autonomy
• increased impulsivity
• increased susceptibility to coerced sex.⁶
  

Furthermore, a higher incidence of poverty, placement in risky environments, and overall poor health and medical care also contribute to the high prevalence of STIs and their complications in this population (Table 1). Because of risk factors specific to psychiatric illness, standard STI prevention interventions are not always successful and novel and innovative behavioral approaches are necessary.⁷

Case Abdominal pain and fever

Ms. K, age 25, has a history of bipolar disorder treated with lithium and presents to the community psychiatrist with lower abdominal pain. She recently recovered from a manic episode and has started to reintegrate with the community mental health team. She refuses to see her primary care physician and is adamant that she wishes to see her psychiatrist, who is the only doctor she has rapport with.

Ms. K reports lower abdominal pain for 3 or 4 days and fever for 1 day. The pain is dull in character. She denies diarrhea, vomiting, or urinary symptoms, but on further questioning describes new-onset, foul-smelling vaginal discharge without vaginal bleeding. Her menstrual cycle usually is regular, but her last menstrual period occurred 2 months ago. Her medical history includes an appendectomy at age 10 and she is a current cigarette smoker. Chart notes taken during her manic episode describe high-risk behavior, including having unprotected sexual intercourse with several partners. On examination, she is febrile and tachycardic with a tender lower abdomen.

Diagnosing STIs

To diagnose an STI, first a clinician must consider its likelihood. Taking a thorough sexual history allows assessment of the need for further investigation and provides an opportunity to discuss risk reduction. In accordance with recent guidelines,⁸ all health care providers are encouraged to consider the sexual history a routine aspect of the clinical encounter. The Centers for Disease Control and Prevention’s (CDC’s) “Five Ps” approach (Table 2) is an excellent tool for guiding investigation and counseling.⁹

The Figure provides health care providers with an algorithm to guide testing for STIs among psychiatric patients. Note that chlamydia, gonorrhea, syphilis, chancroid, viral hepatitis, and HIV must be reported to state public health agencies and the CDC.

Modern laboratory techniques make diagnosing STIs easier. Analysis of urine or serum reduces the need for invasive sampling. If swabs are required for diagnosis, patient self-collection of urethral, vulvovaginal, rectal, or pharyngeal specimens is as accurate as clinician collected samples and is better tolerated.⁸ Because of variation in diagnostic assays, we recommend contacting the laboratory before sending non-standard samples to ensure accurate collection and analysis.

Guidelines for preventing and screening for STIs

There are no prevention guidelines for STIs specific to the psychiatric population, although there is a clear need for focused intervention in this vulnerable patient group.¹⁰ Rates of STI screening generally are low in the psychiatric setting,¹¹ which results in a considerable burden of disease. All psychiatric patients should be encouraged to engage with STI screening programs that are in line with national guidelines. In the inpatient psychiatric or medical environment, clinicians have a responsibility to ensure that STI screening is considered for each patient.

Patients with mental illness should be assumed to be sexually active, even if they do not volunteer this information to clinicians. Employ a low threshold for recommending safer sex practices including condom use. Encourage women to develop a relationship with a family practitioner, internist, or gynecologist. Advise men who have sex with men (MSM) to visit a doctor regularly for screening of HIV and rectal, anal, and oral STIs as behavior and symptoms dictate.

HPV. Routine HPV screening is not recommended; however, 2 vaccines are available to prevent oncogenic HPV (types 16 and 18). All females age 13 to 26 should receive 3 doses of HPV vaccine over a 6-month period. The quadrivalent vaccine (Gardasil) also protects against HPV types 6 and 11, which cause 90% of genital warts and is preferred when available. Males age 9 to 26 also can receive the vaccine, although ideally it should be administered before sexual activity begins.¹⁵ Women still should attend routine cervical cancer screening even if they have the vaccine because 30% of cervical cancers are not caused by HPV 16/18. However, this means that 70% of cervical cancers are associated with HPV 16/18, making screening and the vaccine an important public health initiative. There also is a link between HPV and oral cancers.

Treating STIs among mentally ill individuals

Treatment of STIs among mentally ill individuals is important to prevent medical complications and to reduce transmission. Here are a few additional questions to keep in mind when treating a patient with psychiatric illness:

Does the patient have a primary psychiatric disorder, or is the patient’s current psychiatric presentation a result of the infection?
Some STIs can manifest with psychiatric symptoms—for example, neurosyphilis and HIV-associated neurocognitive disorders—and pose a diagnostic challenge. Obtaining a longitudinal history of the patient’s mental health, age of onset, and family history can help clarify the cause.

Are there any psychiatric adverse effects of STI treatment?

Most drugs used for treating common STIs are not known to cause psychiatric adverse effects (See the American Psychiatric Association¹⁶ and Sockalingham et al¹⁷ for a thorough discussion of HIV and hepatitis C treatment). The exception is fluoroquinolones, which could be prescribed for PID if cephalosporin therapy is not feasible. CNS effects of fluoroquinolones include insomnia, restlessness, confusion, and, in rare cases, mania and psychosis.

What are possible medication interactions to keep in mind when treating a psychiatric patient?
Nonsteroidal anti-inflammatory drugs (NSAIDs), other than sulindac, could increase serum lithium levels. Although NSAIDs are not contraindicated in patients taking lithium, other pain relievers, such as acetaminophen, may be preferred as a first-line choice.

Carbamazepine could lower serum levels of doxycycline.¹⁸
Azithromycin and other macrolides, as well as fluoroquinolones, could have QTc prolonging effects and has been associated with torsades de pointes.¹⁹ Several psychiatric medications, in particular, atypical antipsychotics, also could prolong the QTc interval. This could be a consideration in patients with underlying long QT intervals at baseline or a family history of sudden cardiac death.

Psychiatric patients might refuse or not adhere to their medication. Refusals could be the result of grandiose delusions (“I don’t need treatment”) or paranoia (“The doctor is trying to poison me”). Consider 1-time doses of antibiotics that can be given in the clinic for uncomplicated infections when adherence is an issue. Because psychiatric patients are at higher risk for acquiring STIs, education and counseling—especially substance abuse counseling—are vital as both primary and secondary prevention strategies. Treatment of STIs should be accompanied by referrals to the social work team or a therapist when appropriate.

Finally, as with any proposed treatment, it is important to consider whether the patient has capacity to consent to or refuse treatment. To assess for capacity, a patient must be able to:

• communicate a choice
• understand the relevant information
• appreciate the medical consequences of the decision
• demonstrate the ability to reason about treatment choices.²⁰

Case continued

In the emergency department, Ms. K’s vital signs are: temperature 39.5°C; pulse 110 beats per minute; blood pressure 96/67 mm Hg; and breathing 20 respirations per minute. She complains of nausea and has 2 episodes of emesis. She allows clinicians to perform a complete physical examination, including pelvic exam. Her cervix is inflamed, and she is noted to have adnexal and cervical motion tenderness.

Labs and imaging confirm a diagnosis of PID due to gonorrhea and she is admitted to the hospital for IV antibiotics. She continues to experience nausea and vomiting, but also complains of dizziness and diarrhea. Her speech is slurred and a coarse tremor is noticed in her hands. Renal function tests show slight impairment, probably due to dehydration. A pregnancy test is negative.

Lithium is held. Her nausea, vomiting, and diarrhea resolve quickly, and Ms. K asks to leave. When she is told that she is not ready for discharge, Ms. K becomes upset and rips out her IV yelling, “I don’t need treatment from you guys!” A psychiatry consult is called to assess for her capacity to refuse treatment. The team determines that she has capacity, but she becomes agreeable to remaining in the hospital after a phone conversation with her community mental health team.

Ms. K improves with antibiotic treatment. HIV and syphilis serology tests are negative. Before discharge, both the community psychiatrist and her primary care physicians are informed her lithium was held during hospitalization and restarted before discharge. Ms. K also is educated about the signs and symptoms of lithium toxicity, as well as common STIs.

Clinical considerations

• Physicians should have a low threshold of suspicion for PID in a sexually active young woman who presents with abdominal pain and shuffling gait, which is a natural attempt to reduce cervical irritation and is associated with PID.
• Ask about sexual history and symptoms of STIs.
• Rule out STIs in men presenting with urinary tract infections.
• If chlamydia is diagnosed, treatment for gonorrhea also is essential, and vice versa.
• Always think about HIV and hepatatis B and C in a patient with a STI.
• Treatment with single-dose medications can be effective.
• Risk of STIs is higher during episodes of mania or psychosis.
• Consider hospitalization if medically indicated or if you suspect non-adherence to therapy. It is important to remember that all kinds of systemic infections—including PID—can result in dehydration and alter renal metabolism leading to lithium accumulation.
• Mentally ill patients might require placement under involuntary commitment if they are found to be a danger to themselves or others. It is important to liaise with both the community psychiatry team and primary care physician both during hospitalization and before discharge to ensure a smooth transition.

Snake venom is deadly but is being used to treat some cancers,¹ because it produces contortrostatin, a protein that “paralyzes” cancer cells and prevents them from migrating. Venoms from spiders are being investigated as a treatment to slow the progression of muscular dystrophy by preventing muscle cells from deteriorating. Venom from tarantulas can relieve chronic pain, and those from centipedes help rodents tolerate thermal, chemical, or acid pain. Scorpion venom can cause cancer cells to glow under a flashlight, enabling surgeons to locate and remove them. Anemones toxin could be used to treat autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus.

Vaccines are an excellent example of how deadly pathogens can be transformed into life-saving therapies. Billions of people have been protected from polio, smallpox, tetanus, diphtheria, measles, mumps, rubella, influenza, pneumococcus, hepatitis A and B, rabies, shingles, typhoid, meningitis, or cholera. Turning killers into saviors is one of the most remarkable miracles of medical research.²

The mind-boggling transformation of mind-altering drugs

In psychiatry, psychedelic drugs have been repurposed into useful therapies for mental illness. As recently as a decade ago, psychiatric practitioners—physicians and nurse practitioners—regarded hallucinogens as dangerous, “must-avoid” drugs of abuse that could trigger or exacerbate serious psychiatric disorders. Then, thanks to ongoing research, the psychedelic “caterpillars” transformed into therapeutic “butterflies,” and the despised drugs of abuse became welcome adjuncts for treating some stubborn psychopathologies. Such paradoxical developments are emblematic of how one can always find a silver lining.

Consider the following transformations of various psychedelics and hallucinogens—also called “entheogens”—into novel pharmacotherapies. Note that in most cases, the application of these mind-altering drugs into useful medications is still a work in progress.

 

 

LSD

Lysergic acid diethylamide (LSD) was used extensively for treating mood disorders in the pre-antidepressant era, before it was prohibited in the late 1960s. A review of 19 studies—many uncontrolled—concluded that approximately 80% of patients improved, according to the treating physicians.³ However, research on LSD was halted for several decades after it became illegal, and resumed in 2010. Neuropsychiatrists and neuroscience researchers are now employing advanced techniques, such as neuroimaging, molecular pharmacology, and connectomics, to study its therapeutic effects.⁴ LSD is not only being used for treatment-resistant depression but also anxiety, alcoholism, autism, and even schizophrenia. However, despite its potential uses for treating alcoholism and anxiety, enhancing creativity, or caring for terminally ill patients, using LSD requires expertise, caution, and adherence to ethical standards.⁵

In healthy individuals, the effects of LSD include visual hallucinations, audiovisual synesthesia, depersonalization and derealization, and a sense of well-being, happiness, closeness to others, and trust.

Biologic effects include increased heart rate and blood pressure, elevated temperature, dilated pupils, and increased serum cortisol, prolactin, oxytocin, and epinephrine. All effects subside within 3 days.⁶

Psilocybin

Psilocybin, a component of some mushrooms that is known for its use during rituals in some cultures, has been discovered to have antidepressant, anxiolytic, and anti-addictive effects.⁷ Recent controlled studies at Johns Hopkins University reported that a single dose of psilocybin can relieve anxiety or depression for up to 6 months, which, if replicated, could lead to a remarkable paradigm shift in treating mood and anxiety disorders, especially if patients do not respond to standard antidepressants.³ Other emerging uses of both psilocybin and LSD are in treating addictions⁸ where psychiatry is desperately looking for innovative new therapies.

Ecstasy

MDMA (3,4-methylenedioxymethamphetamine), also known as ecstasy, is widely regarded as a harmful party drug that produces euphoria, but not hallucinations. However, it has emerged as a useful treatment for posttraumatic stress disorder (PTSD). In one study of female sexual abuse victims, 80% of the patients who received MDMA with psychotherapy no longer met diagnostic criteria for PTSD after 2 months.⁹ Other studies showed no effects. Despite persistent skepticisms by many, the Multidisciplinary Association for Psychedelics Studies organization is investing millions of dollars into studying MDMA for PTSD in several countries.^9,10 One hurdle is that it is difficult to conduct truly blind studies with psychedelic drugs because of their profound effects. MDMA releases cortisol, oxytocin—which are known to facilitate psychotherapy—and testosterone, but the debate about the risk–benefit ratio will continue.¹¹ MDMA also is being studied for treating social anxiety in adults with autism.¹²

Ketamine

Ketamine is a weaker cousin of the potent psychotogenic phencyclidine (approximately one-fiftieth the potency) and is a well-known drug of abuse that causes dissociation and hallucinations. It is used as an anesthetic in veterinary medicine and in children undergoing surgical procedures. Until recently, its only use in psychiatry has been as an anesthetic during electroconvulsive therapy. However, over the past few years, IV ketamine has been in the spotlight as a breakthrough, rapid-onset antidepressant and anti-suicidal agent in several controlled studies.¹³ This drug is revolutionizing the management of treatment-resistant depression and suicidal ideation and generating new insights into the neurobiology of depression.

Cannabis

Last, but certainly not least, is marijuana, which is more widely used than all the other psychedelics combined, and is currently at the center of a national debate about its legalization. Although the director of the National Institute on Drug Abuse highlighted the many risk of marijuana,¹⁴ studies have pointed to the myriad medical uses of Cannabis.^15,16 An editorial in Nature Medicine recently urged that regulators reconsider the tight constraints on marijuana research.¹⁷ Some of the medical applications of marijuana include:

• psychiatry (anxiety, PTSD)
• neurology (severe epilepsy, tremors in Parkinson’s disease, traumatic brain injury, pain of multiple sclerosis, muscle spasms, and progression of Alzheimer’s disease)
• oncology (nausea and pain of chemotherapy, reduction of metastasis)
• ophthalmology (decrease of intraocular pressure in glaucoma)
• autoimmune disorders (rheumatoid arthritis, Crohn’s disease, lupus).

However, as a schizophrenia researcher, I am wary about marijuana’s high risk of triggering psychosis in young adults with a family history of schizophrenia spectrum disorders.¹⁸

The above are examples of how psychiatry is finally recognizing the therapeutic value inherent in traditionally “evil” street drugs that we euphemistically refer to as “recreational drugs.” Even methamphetamine, the universally condemned and clearly harmful drug, was recently reported to be neuroprotective at low dosages!¹⁹ Could our field have suffered from a blind eye to the benefits of these hallucinogens and ignored the possibility that some persons with addiction who use these “recreational drugs” may have been self-medicating to alleviate their un-diagnosed psychiatric disorder? We need to reconceptualize the pejorative term “mind-altering drug” because of its implicitly negative connotation. After all, alteration may indicate a favorable, not just a deleterious, outcome.

Snake venom is deadly but is being used to treat some cancers,¹ because it produces contortrostatin, a protein that “paralyzes” cancer cells and prevents them from migrating. Venoms from spiders are being investigated as a treatment to slow the progression of muscular dystrophy by preventing muscle cells from deteriorating. Venom from tarantulas can relieve chronic pain, and those from centipedes help rodents tolerate thermal, chemical, or acid pain. Scorpion venom can cause cancer cells to glow under a flashlight, enabling surgeons to locate and remove them. Anemones toxin could be used to treat autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus.

Vaccines are an excellent example of how deadly pathogens can be transformed into life-saving therapies. Billions of people have been protected from polio, smallpox, tetanus, diphtheria, measles, mumps, rubella, influenza, pneumococcus, hepatitis A and B, rabies, shingles, typhoid, meningitis, or cholera. Turning killers into saviors is one of the most remarkable miracles of medical research.²

The mind-boggling transformation of mind-altering drugs

In psychiatry, psychedelic drugs have been repurposed into useful therapies for mental illness. As recently as a decade ago, psychiatric practitioners—physicians and nurse practitioners—regarded hallucinogens as dangerous, “must-avoid” drugs of abuse that could trigger or exacerbate serious psychiatric disorders. Then, thanks to ongoing research, the psychedelic “caterpillars” transformed into therapeutic “butterflies,” and the despised drugs of abuse became welcome adjuncts for treating some stubborn psychopathologies. Such paradoxical developments are emblematic of how one can always find a silver lining.

Consider the following transformations of various psychedelics and hallucinogens—also called “entheogens”—into novel pharmacotherapies. Note that in most cases, the application of these mind-altering drugs into useful medications is still a work in progress.

 

 

LSD

Lysergic acid diethylamide (LSD) was used extensively for treating mood disorders in the pre-antidepressant era, before it was prohibited in the late 1960s. A review of 19 studies—many uncontrolled—concluded that approximately 80% of patients improved, according to the treating physicians.³ However, research on LSD was halted for several decades after it became illegal, and resumed in 2010. Neuropsychiatrists and neuroscience researchers are now employing advanced techniques, such as neuroimaging, molecular pharmacology, and connectomics, to study its therapeutic effects.⁴ LSD is not only being used for treatment-resistant depression but also anxiety, alcoholism, autism, and even schizophrenia. However, despite its potential uses for treating alcoholism and anxiety, enhancing creativity, or caring for terminally ill patients, using LSD requires expertise, caution, and adherence to ethical standards.⁵

In healthy individuals, the effects of LSD include visual hallucinations, audiovisual synesthesia, depersonalization and derealization, and a sense of well-being, happiness, closeness to others, and trust.

Biologic effects include increased heart rate and blood pressure, elevated temperature, dilated pupils, and increased serum cortisol, prolactin, oxytocin, and epinephrine. All effects subside within 3 days.⁶

Psilocybin

Psilocybin, a component of some mushrooms that is known for its use during rituals in some cultures, has been discovered to have antidepressant, anxiolytic, and anti-addictive effects.⁷ Recent controlled studies at Johns Hopkins University reported that a single dose of psilocybin can relieve anxiety or depression for up to 6 months, which, if replicated, could lead to a remarkable paradigm shift in treating mood and anxiety disorders, especially if patients do not respond to standard antidepressants.³ Other emerging uses of both psilocybin and LSD are in treating addictions⁸ where psychiatry is desperately looking for innovative new therapies.

Ecstasy

MDMA (3,4-methylenedioxymethamphetamine), also known as ecstasy, is widely regarded as a harmful party drug that produces euphoria, but not hallucinations. However, it has emerged as a useful treatment for posttraumatic stress disorder (PTSD). In one study of female sexual abuse victims, 80% of the patients who received MDMA with psychotherapy no longer met diagnostic criteria for PTSD after 2 months.⁹ Other studies showed no effects. Despite persistent skepticisms by many, the Multidisciplinary Association for Psychedelics Studies organization is investing millions of dollars into studying MDMA for PTSD in several countries.^9,10 One hurdle is that it is difficult to conduct truly blind studies with psychedelic drugs because of their profound effects. MDMA releases cortisol, oxytocin—which are known to facilitate psychotherapy—and testosterone, but the debate about the risk–benefit ratio will continue.¹¹ MDMA also is being studied for treating social anxiety in adults with autism.¹²

Ketamine

Ketamine is a weaker cousin of the potent psychotogenic phencyclidine (approximately one-fiftieth the potency) and is a well-known drug of abuse that causes dissociation and hallucinations. It is used as an anesthetic in veterinary medicine and in children undergoing surgical procedures. Until recently, its only use in psychiatry has been as an anesthetic during electroconvulsive therapy. However, over the past few years, IV ketamine has been in the spotlight as a breakthrough, rapid-onset antidepressant and anti-suicidal agent in several controlled studies.¹³ This drug is revolutionizing the management of treatment-resistant depression and suicidal ideation and generating new insights into the neurobiology of depression.

Cannabis

Last, but certainly not least, is marijuana, which is more widely used than all the other psychedelics combined, and is currently at the center of a national debate about its legalization. Although the director of the National Institute on Drug Abuse highlighted the many risk of marijuana,¹⁴ studies have pointed to the myriad medical uses of Cannabis.^15,16 An editorial in Nature Medicine recently urged that regulators reconsider the tight constraints on marijuana research.¹⁷ Some of the medical applications of marijuana include:

• psychiatry (anxiety, PTSD)
• neurology (severe epilepsy, tremors in Parkinson’s disease, traumatic brain injury, pain of multiple sclerosis, muscle spasms, and progression of Alzheimer’s disease)
• oncology (nausea and pain of chemotherapy, reduction of metastasis)
• ophthalmology (decrease of intraocular pressure in glaucoma)
• autoimmune disorders (rheumatoid arthritis, Crohn’s disease, lupus).

However, as a schizophrenia researcher, I am wary about marijuana’s high risk of triggering psychosis in young adults with a family history of schizophrenia spectrum disorders.¹⁸

The above are examples of how psychiatry is finally recognizing the therapeutic value inherent in traditionally “evil” street drugs that we euphemistically refer to as “recreational drugs.” Even methamphetamine, the universally condemned and clearly harmful drug, was recently reported to be neuroprotective at low dosages!¹⁹ Could our field have suffered from a blind eye to the benefits of these hallucinogens and ignored the possibility that some persons with addiction who use these “recreational drugs” may have been self-medicating to alleviate their un-diagnosed psychiatric disorder? We need to reconceptualize the pejorative term “mind-altering drug” because of its implicitly negative connotation. After all, alteration may indicate a favorable, not just a deleterious, outcome.

Snake venom is deadly but is being used to treat some cancers,¹ because it produces contortrostatin, a protein that “paralyzes” cancer cells and prevents them from migrating. Venoms from spiders are being investigated as a treatment to slow the progression of muscular dystrophy by preventing muscle cells from deteriorating. Venom from tarantulas can relieve chronic pain, and those from centipedes help rodents tolerate thermal, chemical, or acid pain. Scorpion venom can cause cancer cells to glow under a flashlight, enabling surgeons to locate and remove them. Anemones toxin could be used to treat autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus.

Vaccines are an excellent example of how deadly pathogens can be transformed into life-saving therapies. Billions of people have been protected from polio, smallpox, tetanus, diphtheria, measles, mumps, rubella, influenza, pneumococcus, hepatitis A and B, rabies, shingles, typhoid, meningitis, or cholera. Turning killers into saviors is one of the most remarkable miracles of medical research.²

The mind-boggling transformation of mind-altering drugs

In psychiatry, psychedelic drugs have been repurposed into useful therapies for mental illness. As recently as a decade ago, psychiatric practitioners—physicians and nurse practitioners—regarded hallucinogens as dangerous, “must-avoid” drugs of abuse that could trigger or exacerbate serious psychiatric disorders. Then, thanks to ongoing research, the psychedelic “caterpillars” transformed into therapeutic “butterflies,” and the despised drugs of abuse became welcome adjuncts for treating some stubborn psychopathologies. Such paradoxical developments are emblematic of how one can always find a silver lining.

Consider the following transformations of various psychedelics and hallucinogens—also called “entheogens”—into novel pharmacotherapies. Note that in most cases, the application of these mind-altering drugs into useful medications is still a work in progress.

 

 

LSD

Lysergic acid diethylamide (LSD) was used extensively for treating mood disorders in the pre-antidepressant era, before it was prohibited in the late 1960s. A review of 19 studies—many uncontrolled—concluded that approximately 80% of patients improved, according to the treating physicians.³ However, research on LSD was halted for several decades after it became illegal, and resumed in 2010. Neuropsychiatrists and neuroscience researchers are now employing advanced techniques, such as neuroimaging, molecular pharmacology, and connectomics, to study its therapeutic effects.⁴ LSD is not only being used for treatment-resistant depression but also anxiety, alcoholism, autism, and even schizophrenia. However, despite its potential uses for treating alcoholism and anxiety, enhancing creativity, or caring for terminally ill patients, using LSD requires expertise, caution, and adherence to ethical standards.⁵

In healthy individuals, the effects of LSD include visual hallucinations, audiovisual synesthesia, depersonalization and derealization, and a sense of well-being, happiness, closeness to others, and trust.

Biologic effects include increased heart rate and blood pressure, elevated temperature, dilated pupils, and increased serum cortisol, prolactin, oxytocin, and epinephrine. All effects subside within 3 days.⁶

Psilocybin

Psilocybin, a component of some mushrooms that is known for its use during rituals in some cultures, has been discovered to have antidepressant, anxiolytic, and anti-addictive effects.⁷ Recent controlled studies at Johns Hopkins University reported that a single dose of psilocybin can relieve anxiety or depression for up to 6 months, which, if replicated, could lead to a remarkable paradigm shift in treating mood and anxiety disorders, especially if patients do not respond to standard antidepressants.³ Other emerging uses of both psilocybin and LSD are in treating addictions⁸ where psychiatry is desperately looking for innovative new therapies.

Ecstasy

MDMA (3,4-methylenedioxymethamphetamine), also known as ecstasy, is widely regarded as a harmful party drug that produces euphoria, but not hallucinations. However, it has emerged as a useful treatment for posttraumatic stress disorder (PTSD). In one study of female sexual abuse victims, 80% of the patients who received MDMA with psychotherapy no longer met diagnostic criteria for PTSD after 2 months.⁹ Other studies showed no effects. Despite persistent skepticisms by many, the Multidisciplinary Association for Psychedelics Studies organization is investing millions of dollars into studying MDMA for PTSD in several countries.^9,10 One hurdle is that it is difficult to conduct truly blind studies with psychedelic drugs because of their profound effects. MDMA releases cortisol, oxytocin—which are known to facilitate psychotherapy—and testosterone, but the debate about the risk–benefit ratio will continue.¹¹ MDMA also is being studied for treating social anxiety in adults with autism.¹²

Ketamine

Ketamine is a weaker cousin of the potent psychotogenic phencyclidine (approximately one-fiftieth the potency) and is a well-known drug of abuse that causes dissociation and hallucinations. It is used as an anesthetic in veterinary medicine and in children undergoing surgical procedures. Until recently, its only use in psychiatry has been as an anesthetic during electroconvulsive therapy. However, over the past few years, IV ketamine has been in the spotlight as a breakthrough, rapid-onset antidepressant and anti-suicidal agent in several controlled studies.¹³ This drug is revolutionizing the management of treatment-resistant depression and suicidal ideation and generating new insights into the neurobiology of depression.

Cannabis

Last, but certainly not least, is marijuana, which is more widely used than all the other psychedelics combined, and is currently at the center of a national debate about its legalization. Although the director of the National Institute on Drug Abuse highlighted the many risk of marijuana,¹⁴ studies have pointed to the myriad medical uses of Cannabis.^15,16 An editorial in Nature Medicine recently urged that regulators reconsider the tight constraints on marijuana research.¹⁷ Some of the medical applications of marijuana include:

• psychiatry (anxiety, PTSD)
• neurology (severe epilepsy, tremors in Parkinson’s disease, traumatic brain injury, pain of multiple sclerosis, muscle spasms, and progression of Alzheimer’s disease)
• oncology (nausea and pain of chemotherapy, reduction of metastasis)
• ophthalmology (decrease of intraocular pressure in glaucoma)
• autoimmune disorders (rheumatoid arthritis, Crohn’s disease, lupus).

However, as a schizophrenia researcher, I am wary about marijuana’s high risk of triggering psychosis in young adults with a family history of schizophrenia spectrum disorders.¹⁸

The above are examples of how psychiatry is finally recognizing the therapeutic value inherent in traditionally “evil” street drugs that we euphemistically refer to as “recreational drugs.” Even methamphetamine, the universally condemned and clearly harmful drug, was recently reported to be neuroprotective at low dosages!¹⁹ Could our field have suffered from a blind eye to the benefits of these hallucinogens and ignored the possibility that some persons with addiction who use these “recreational drugs” may have been self-medicating to alleviate their un-diagnosed psychiatric disorder? We need to reconceptualize the pejorative term “mind-altering drug” because of its implicitly negative connotation. After all, alteration may indicate a favorable, not just a deleterious, outcome.

Ms. C, age 44, has a history of hypertension, chronic shoulder pain associated with a motor vehicle accident almost 2 decades ago, and major depressive disorder (MDD). Her medication regimen includes losartan, 100 mg/d; atenolol, 25 mg/d; gabapentin, 100 mg, 3 times a day; sertraline, 100 mg/d; and naproxen, 500 mg, twice a day as needed for pain. She does not take opioids for pain control because she had a poor response when used in the past. Ms. C denies muscle pain or tenderness but describes pain in nonspecific areas of her arm, shoulder, neck, and chest. Ms. C reports poor quality of sleep and early morning awakenings, which she attributes to her unmanaged pain. Her last appointment with a psychiatrist was “many, many months ago.”

A reciprocal relationship exists between depression and pain. A 2-year, population-based, prospective, observational study of 3,654 patients showed that pain at baseline was an independent predictor of depression and a depression diagnosis was a predictor of developing pain within 2 years.¹ Patients with MDD might complain of physical symptoms, such as constipation, generalized aches, frequent headache, and fatigue, many of which overlap with chronic pain disorders. Therefore, a thorough symptom assessment and history is vital for an accurate diagnosis. To decrease polypharmacy and pill burden, optimal treatment should employ agents that treat both conditions.

Using antidepressants to treat pain disorders

Several antidepressants have been studied for managing pain disorders including:

• fibromyalgia
• diabetic neuropathy
• neuropathic pain
• postherpetic neuralgia
• migraine prophylaxis
• chronic musculoskeletal pain.

Antidepressants that treat both depression and chronic neuropathic pain include tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (Table).^2-12 Notably, most antidepressants studied for pain management are used off-label; duloxetine is the only medication with an FDA indication for MDD and pain disorders.

TCAs used to treat comorbid depression and pain conditions include amitriptyline, nortriptyline, imipramine, and desipramine.¹⁴ TCAs are cost-effective medications for managing neuropathy and headache; however, the dosages used for pain tend to be lower than those typically used for depression.

TCAs are not commonly prescribed for depression because of their side-effect profile and poor tolerability. TCAs are contraindicated in patients with cardiac conduction abnormalities, epilepsy, and narrow-angle glaucoma. Common adverse effects include dry mouth, sweating, dizziness, orthostatic hypotension, sedation, weight gain, urinary retention, and constipation. These adverse effects limit their use and have organizations, such as the American Geriatric Society, to caution against their use in geriatric patients.

SNRIs that have been studied for pain disorders include venlafaxine, duloxetine, and milnacipran.² Of note, milnacipran is not FDA-approved for MDD, but its L-enantiomer, levomilnacipran, is. Unlike duloxetine and venlafaxine, both milnacipran and levomilnacipran are not available as a generic formulation, therefore they have a higher patient cost. The SNRI dosages used for pain management tend to be similar to those used for MDD, indicating that the target dosage may be effective for both depressive and pain symptoms.

Selective serotonin reuptake inhibitors (SSRIs). Compared with data available supporting the use of TCAs and SNRIs for pain management, the data for SSRI are sparse. Studies have evaluated fluoxetine, paroxetine, and citalopram for pain, with the most promising data supporting fluoxetine.² Fluoxetine, 10 to 80 mg/d, has been evaluated in randomized, placebo-controlled trials for pain conditions, including fibromyalgia (n = 3), painful diabetic neuropathy (n = 1), and facial pain (n = 1). Fluoxetine was more effective than placebo at controlling pain in 2 fibromyalgia studies (dosage range, 10 to 80 mg/d) and 1 facial pain study (dosage, 20 mg/d).²

CASE CONTINUED

When evaluating potential treatment options, it is noted that Ms. C is prescribed sertraline, 200 mg/d, but has been taking a lower dosage. Ms. C states that she has been taking sertraline, 100 mg every morning, for months, and noticed some minor initial improvements in mood, but still has days when she don’t feel like doing anything. She fills out a depression rating scale classifying her current depression as moderately severe. Today she rates her pain as 7 out of 10. Suboptimal control of her depression may require a dosage increase; however, perhaps a change in therapy is warranted. It may be prudent to switch Ms. C to an SNRI, such as duloxetine, an agent that can address her depression and provide additional benefits of pain control.

Switching from a SSRI to duloxetine has been shown to be effective when targeting pain symptoms in patients with comorbid MDD. In addition, improvements in pain scores have been seen after a switch to duloxetine in patients with depression with nonresponse or partial response to a SSRI.¹⁵

Studies support the decision to change Ms. C’s medication from sertraline to duloxetine, despite an inadequate therapeutic trial of the SSRI.

 

 

Using pain medication to treat depression

Conversely, the use of pain medications to treat depression also has been studied. The most notable data supports the use of ketamine, an anesthetic. IV ketamine is well documented for treating pain and, in recent years, has been evaluated for MDD in several small studies. Results show that IV ketamine, 0.5 mg/kg, produced a rapid response in depressed patients.¹⁶ For pain conditions studies support the use of ketamine as an IV push, continuous infusion, intermittent infusion, as well as oral administration, for many conditions, including acute and postoperative pain, chronic regional pain, and neuropathic pain. However, there is little evidence evaluating ketamine’s effect on both pain scores and depression symptoms in patients such as Ms. C.

Ms. C, age 44, has a history of hypertension, chronic shoulder pain associated with a motor vehicle accident almost 2 decades ago, and major depressive disorder (MDD). Her medication regimen includes losartan, 100 mg/d; atenolol, 25 mg/d; gabapentin, 100 mg, 3 times a day; sertraline, 100 mg/d; and naproxen, 500 mg, twice a day as needed for pain. She does not take opioids for pain control because she had a poor response when used in the past. Ms. C denies muscle pain or tenderness but describes pain in nonspecific areas of her arm, shoulder, neck, and chest. Ms. C reports poor quality of sleep and early morning awakenings, which she attributes to her unmanaged pain. Her last appointment with a psychiatrist was “many, many months ago.”

A reciprocal relationship exists between depression and pain. A 2-year, population-based, prospective, observational study of 3,654 patients showed that pain at baseline was an independent predictor of depression and a depression diagnosis was a predictor of developing pain within 2 years.¹ Patients with MDD might complain of physical symptoms, such as constipation, generalized aches, frequent headache, and fatigue, many of which overlap with chronic pain disorders. Therefore, a thorough symptom assessment and history is vital for an accurate diagnosis. To decrease polypharmacy and pill burden, optimal treatment should employ agents that treat both conditions.

Using antidepressants to treat pain disorders

Several antidepressants have been studied for managing pain disorders including:

• fibromyalgia
• diabetic neuropathy
• neuropathic pain
• postherpetic neuralgia
• migraine prophylaxis
• chronic musculoskeletal pain.

Antidepressants that treat both depression and chronic neuropathic pain include tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (Table).^2-12 Notably, most antidepressants studied for pain management are used off-label; duloxetine is the only medication with an FDA indication for MDD and pain disorders.

TCAs used to treat comorbid depression and pain conditions include amitriptyline, nortriptyline, imipramine, and desipramine.¹⁴ TCAs are cost-effective medications for managing neuropathy and headache; however, the dosages used for pain tend to be lower than those typically used for depression.

TCAs are not commonly prescribed for depression because of their side-effect profile and poor tolerability. TCAs are contraindicated in patients with cardiac conduction abnormalities, epilepsy, and narrow-angle glaucoma. Common adverse effects include dry mouth, sweating, dizziness, orthostatic hypotension, sedation, weight gain, urinary retention, and constipation. These adverse effects limit their use and have organizations, such as the American Geriatric Society, to caution against their use in geriatric patients.

SNRIs that have been studied for pain disorders include venlafaxine, duloxetine, and milnacipran.² Of note, milnacipran is not FDA-approved for MDD, but its L-enantiomer, levomilnacipran, is. Unlike duloxetine and venlafaxine, both milnacipran and levomilnacipran are not available as a generic formulation, therefore they have a higher patient cost. The SNRI dosages used for pain management tend to be similar to those used for MDD, indicating that the target dosage may be effective for both depressive and pain symptoms.

Selective serotonin reuptake inhibitors (SSRIs). Compared with data available supporting the use of TCAs and SNRIs for pain management, the data for SSRI are sparse. Studies have evaluated fluoxetine, paroxetine, and citalopram for pain, with the most promising data supporting fluoxetine.² Fluoxetine, 10 to 80 mg/d, has been evaluated in randomized, placebo-controlled trials for pain conditions, including fibromyalgia (n = 3), painful diabetic neuropathy (n = 1), and facial pain (n = 1). Fluoxetine was more effective than placebo at controlling pain in 2 fibromyalgia studies (dosage range, 10 to 80 mg/d) and 1 facial pain study (dosage, 20 mg/d).²

CASE CONTINUED

When evaluating potential treatment options, it is noted that Ms. C is prescribed sertraline, 200 mg/d, but has been taking a lower dosage. Ms. C states that she has been taking sertraline, 100 mg every morning, for months, and noticed some minor initial improvements in mood, but still has days when she don’t feel like doing anything. She fills out a depression rating scale classifying her current depression as moderately severe. Today she rates her pain as 7 out of 10. Suboptimal control of her depression may require a dosage increase; however, perhaps a change in therapy is warranted. It may be prudent to switch Ms. C to an SNRI, such as duloxetine, an agent that can address her depression and provide additional benefits of pain control.

Switching from a SSRI to duloxetine has been shown to be effective when targeting pain symptoms in patients with comorbid MDD. In addition, improvements in pain scores have been seen after a switch to duloxetine in patients with depression with nonresponse or partial response to a SSRI.¹⁵

Studies support the decision to change Ms. C’s medication from sertraline to duloxetine, despite an inadequate therapeutic trial of the SSRI.

 

 

Using pain medication to treat depression

Conversely, the use of pain medications to treat depression also has been studied. The most notable data supports the use of ketamine, an anesthetic. IV ketamine is well documented for treating pain and, in recent years, has been evaluated for MDD in several small studies. Results show that IV ketamine, 0.5 mg/kg, produced a rapid response in depressed patients.¹⁶ For pain conditions studies support the use of ketamine as an IV push, continuous infusion, intermittent infusion, as well as oral administration, for many conditions, including acute and postoperative pain, chronic regional pain, and neuropathic pain. However, there is little evidence evaluating ketamine’s effect on both pain scores and depression symptoms in patients such as Ms. C.

Ms. C, age 44, has a history of hypertension, chronic shoulder pain associated with a motor vehicle accident almost 2 decades ago, and major depressive disorder (MDD). Her medication regimen includes losartan, 100 mg/d; atenolol, 25 mg/d; gabapentin, 100 mg, 3 times a day; sertraline, 100 mg/d; and naproxen, 500 mg, twice a day as needed for pain. She does not take opioids for pain control because she had a poor response when used in the past. Ms. C denies muscle pain or tenderness but describes pain in nonspecific areas of her arm, shoulder, neck, and chest. Ms. C reports poor quality of sleep and early morning awakenings, which she attributes to her unmanaged pain. Her last appointment with a psychiatrist was “many, many months ago.”

A reciprocal relationship exists between depression and pain. A 2-year, population-based, prospective, observational study of 3,654 patients showed that pain at baseline was an independent predictor of depression and a depression diagnosis was a predictor of developing pain within 2 years.¹ Patients with MDD might complain of physical symptoms, such as constipation, generalized aches, frequent headache, and fatigue, many of which overlap with chronic pain disorders. Therefore, a thorough symptom assessment and history is vital for an accurate diagnosis. To decrease polypharmacy and pill burden, optimal treatment should employ agents that treat both conditions.

Using antidepressants to treat pain disorders

Several antidepressants have been studied for managing pain disorders including:

• fibromyalgia
• diabetic neuropathy
• neuropathic pain
• postherpetic neuralgia
• migraine prophylaxis
• chronic musculoskeletal pain.

Antidepressants that treat both depression and chronic neuropathic pain include tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (Table).^2-12 Notably, most antidepressants studied for pain management are used off-label; duloxetine is the only medication with an FDA indication for MDD and pain disorders.

TCAs used to treat comorbid depression and pain conditions include amitriptyline, nortriptyline, imipramine, and desipramine.¹⁴ TCAs are cost-effective medications for managing neuropathy and headache; however, the dosages used for pain tend to be lower than those typically used for depression.

TCAs are not commonly prescribed for depression because of their side-effect profile and poor tolerability. TCAs are contraindicated in patients with cardiac conduction abnormalities, epilepsy, and narrow-angle glaucoma. Common adverse effects include dry mouth, sweating, dizziness, orthostatic hypotension, sedation, weight gain, urinary retention, and constipation. These adverse effects limit their use and have organizations, such as the American Geriatric Society, to caution against their use in geriatric patients.

SNRIs that have been studied for pain disorders include venlafaxine, duloxetine, and milnacipran.² Of note, milnacipran is not FDA-approved for MDD, but its L-enantiomer, levomilnacipran, is. Unlike duloxetine and venlafaxine, both milnacipran and levomilnacipran are not available as a generic formulation, therefore they have a higher patient cost. The SNRI dosages used for pain management tend to be similar to those used for MDD, indicating that the target dosage may be effective for both depressive and pain symptoms.

Selective serotonin reuptake inhibitors (SSRIs). Compared with data available supporting the use of TCAs and SNRIs for pain management, the data for SSRI are sparse. Studies have evaluated fluoxetine, paroxetine, and citalopram for pain, with the most promising data supporting fluoxetine.² Fluoxetine, 10 to 80 mg/d, has been evaluated in randomized, placebo-controlled trials for pain conditions, including fibromyalgia (n = 3), painful diabetic neuropathy (n = 1), and facial pain (n = 1). Fluoxetine was more effective than placebo at controlling pain in 2 fibromyalgia studies (dosage range, 10 to 80 mg/d) and 1 facial pain study (dosage, 20 mg/d).²

CASE CONTINUED

When evaluating potential treatment options, it is noted that Ms. C is prescribed sertraline, 200 mg/d, but has been taking a lower dosage. Ms. C states that she has been taking sertraline, 100 mg every morning, for months, and noticed some minor initial improvements in mood, but still has days when she don’t feel like doing anything. She fills out a depression rating scale classifying her current depression as moderately severe. Today she rates her pain as 7 out of 10. Suboptimal control of her depression may require a dosage increase; however, perhaps a change in therapy is warranted. It may be prudent to switch Ms. C to an SNRI, such as duloxetine, an agent that can address her depression and provide additional benefits of pain control.

Switching from a SSRI to duloxetine has been shown to be effective when targeting pain symptoms in patients with comorbid MDD. In addition, improvements in pain scores have been seen after a switch to duloxetine in patients with depression with nonresponse or partial response to a SSRI.¹⁵

Studies support the decision to change Ms. C’s medication from sertraline to duloxetine, despite an inadequate therapeutic trial of the SSRI.

 

 

Using pain medication to treat depression

Conversely, the use of pain medications to treat depression also has been studied. The most notable data supports the use of ketamine, an anesthetic. IV ketamine is well documented for treating pain and, in recent years, has been evaluated for MDD in several small studies. Results show that IV ketamine, 0.5 mg/kg, produced a rapid response in depressed patients.¹⁶ For pain conditions studies support the use of ketamine as an IV push, continuous infusion, intermittent infusion, as well as oral administration, for many conditions, including acute and postoperative pain, chronic regional pain, and neuropathic pain. However, there is little evidence evaluating ketamine’s effect on both pain scores and depression symptoms in patients such as Ms. C.

What is a GI hospitalist?

A GI hospitalist is a gastroenterologist that primarily provides inpatient care. Their main professional focus is the acute management of gastrointestinal conditions occurring in the hospital setting.

How prevalent are subspecialty hospitalists?

The rise of hospitalists has changed the landscape of medicine. The hospitalist is now the central inpatient provider responsible for patient care and day-to-day housestaff education. From 1995 to 2016, the number of hospitalists increased from 500 to over 50,000.¹ While the majority of hospitalists are generalists from the fields of internal medicine, pediatrics, and obstetrics/gynecology, some come in the form of specialists. In a recent survey, up to 10% of internal medicine subspecialists already consider themselves “hospitalists.”² However, most of these self-described hospitalists only do so part of the time. For example, many group practices have one of their members manage all the hospitalized patients for the group for certain periods of time. It is rare to find full-time subspecialist hospitalists, but there has been an emergence in this new model of GI practice. Many people are unaware of this system of care nor understand how it may influence hospital-based care.

What is the role of a GI hospitalist?

While my primary responsibility is to care for inpatients whom require GI consults, I have outpatient and administrative responsibilities. Generally speaking, I am the de facto consult attending for the year.
 

How did you decide to become a GI hospitalist?

Upon graduation from my GI fellowship, I wanted an academic job where I could work closely with fellows and manage a wide breadth of complex, high-acuity patients. During fellowship, I enjoyed all areas of gastroenterology and hepatology and did not “sub-subspecialize.” As such, I wanted a job where I would see the full spectrum of GI and liver disease. Additionally, I enjoyed seeing the sickest patients, because I felt I could make the most dramatic differences with my care.

When I was searching for jobs, I spoke with the chief of GI at the hospital where I completed my residency about how I could fill a niche. We conceived of a model that would merge my personal interests and help the division provide consistent teaching for fellows and increase inpatient billing. Prior to my arrival, attendings that staffed the consult service were expected to continue their research and outpatient clinical workload while finding time to come to the hospital. Not surprisingly, attending rounds was erratic. The fellows were left to manage patients independently, scrambled to run cases by whomever happened to be around, or waited until they could reach the attending the next day. Unsurprisingly, billing by attendings was sparse.
 

What is a typical day like in your life as a GI hospitalist?

My day starts at 7:30 a.m. either with my outpatient office hours, endoscopy session, or GI Grand Rounds. Each week, I have two morning outpatient office sessions, one morning endoscopy session, and one morning session supervising fellows’ endoscopy.

At noon, I round with a team of GI fellows, medical students, and housestaff rotators for 2 hours. After we see the new consults, the remainder of my afternoon is spent seeing the follow-up patients. For two afternoons throughout the week, I have outpatient endoscopy sessions. I typically conclude my day at 5 p.m.

For night coverage, I take emergency calls for my own patients, and share general call duties with the other members of my division. On average, I take calls for one weekday a month and five weekends per year.

Typically, GI hospitalists only cover inpatients during the daytime. All nights and weekends are covered by partners and nonemergent overnight consults are saved until the next day. They have no office work.
 

What is the most challenging part of being a GI hospitalist?

As the perpetual “GI Consult Attending,” there is the threat of burnout when confronted with a high volume of sick, complex patients. Many of the patients have multiple comorbidities and require a multidisciplinary approach. On average, we have five new consults a day and the number of active follow-up patients is 10. Nonetheless, the nature of the inpatient service makes the volume of work unpredictable. When the service is busy and the census swells, the numbers of patients requiring staffing and notes can become overwhelming.

Mike Powell/Thinkstock

How are you paid?

My compensation is based on a base salary with an incentivized system based on my RVUs and collections. For the dedicated hospitalist for a group practice, there is typically a base salary and productivity-based income. Additionally, there should be a path to partnership. Lastly, in balancing the ledger, the diminished inpatient revenue stream is offset by the lack of overhead.

What are the benefits of a GI hospitalist system?

Our system benefits the workflow for the GI fellows. Since I have started, the GI consultation rounds start at a consistent time. During these rounds, we discuss relevant GI literature and make timely plans on all patients. Oftentimes, I am able to supervise the fellows so they can fit in a scope before the end of the workday. Ultimately, the fellows know they can find me and discuss patients throughout the day. The fellows consistently have told me that the since the implementation of the hospitalist system, there has been a dramatic difference. Collectively, they feel both their education and patient care have improved.

In terms of consult efficiency, one study demonstrated that the transition to a GI hospitalist system resulted in a mean decrease in consult to urgent esophagogastroduodenoscopy (EGD) time from approximately 24 to 14 hours.³ However, this occurred in the context of a lower inpatient consult volume and only covered 2 months. Furthermore, the time from admission to EGD did not change. Nonetheless, further studies are needed to examine the impact of this model shift.

In terms of a financial benefit, at our institution the total gross inpatient charges increased more than $850,000 for the year. This was largely attributable to the 79% increase in the gross charges from follow-up notes.

For group practices, the hospitalist system makes more efficient use of physician’s time. Physicians can either focus on outpatients or inpatients without worrying about going between the office, ambulatory surgical center, and the hospital. In general, inpatients require a disproportionate amount of time relative to the revenue collected. Furthermore, by eliminating the need for group physicians to go to the hospital, they can carve out 1-2 hours of office time to increase billing.

When there is one point-person whom handles all inpatient GI, communication is facilitated among primary teams and other services. The GI hospitalist develops working relationships with surgeons, radiologists, anesthesiologists, intensivists, etc. Teams can often just text or call me directly, instead of looking for the covering attending or going through the office phone service.
 

What are drawbacks to the GI hospitalist model?

Since there is only one gastroenterologist in the hospitalist model, if that person is not doing a good job, it affects the management of GI conditions for the entire hospital.

There is a loss of continuity-of-care. When GI patients get admitted, the gastroenterologists responsible for their care will not be the person with whom they have a long-term relationship. Furthermore, when the patient gets discharged, the primary gastroenterologists will not be fully aware of the inpatient course.

Also, when outpatient and inpatient gastroenterologists become segregated based on hospital setting, they each lose out of learning the intricacies of managing patients in a different context.
 

What do you like most about being a GI hospitalist?

The GI hospitalist position creates a great opportunity for gastroenterologists to make a remarkable, immediate impact on interesting, high acuity patients. The nature of the job also has the advantage of providing reasonable hours. This may be attractive to many whom want a better work-life balance.

Dr. Wan is assistant professor of medicine, associate program director, GI Fellowship Program, New York Presbyterian/Weill Cornell Medical Center, New York, N.Y.

References

1. Wachter R.M., Goldman L. Zero to 50,000 – The 20th Anniversary of the Hospitalist. N Engl J Med. 2016 Sep 15;375[11]:1009-11.

2. Estimating the Number and Characteristics of Hospitalist Physicians in the United States and Their Possible Workforce Implications. Analysis in Brief. Available at: https://www.aamc.org/download/300620/data/aibvol12_no3-hospitalist.pdf. Accessed May 1st, 2016.

3. Mahadev S., Lebwohl B., Ramirez I., Garcia-Carrasquillo R.J., Freedberg, D.E. Transition to a GI Hospitalist System is Associated with Expedited Upper Endoscopy. Gastroenterology. 2016;150[4]:S639-40.
 

What is a GI hospitalist?

A GI hospitalist is a gastroenterologist that primarily provides inpatient care. Their main professional focus is the acute management of gastrointestinal conditions occurring in the hospital setting.

How prevalent are subspecialty hospitalists?

The rise of hospitalists has changed the landscape of medicine. The hospitalist is now the central inpatient provider responsible for patient care and day-to-day housestaff education. From 1995 to 2016, the number of hospitalists increased from 500 to over 50,000.¹ While the majority of hospitalists are generalists from the fields of internal medicine, pediatrics, and obstetrics/gynecology, some come in the form of specialists. In a recent survey, up to 10% of internal medicine subspecialists already consider themselves “hospitalists.”² However, most of these self-described hospitalists only do so part of the time. For example, many group practices have one of their members manage all the hospitalized patients for the group for certain periods of time. It is rare to find full-time subspecialist hospitalists, but there has been an emergence in this new model of GI practice. Many people are unaware of this system of care nor understand how it may influence hospital-based care.

What is the role of a GI hospitalist?

While my primary responsibility is to care for inpatients whom require GI consults, I have outpatient and administrative responsibilities. Generally speaking, I am the de facto consult attending for the year.
 

How did you decide to become a GI hospitalist?

Upon graduation from my GI fellowship, I wanted an academic job where I could work closely with fellows and manage a wide breadth of complex, high-acuity patients. During fellowship, I enjoyed all areas of gastroenterology and hepatology and did not “sub-subspecialize.” As such, I wanted a job where I would see the full spectrum of GI and liver disease. Additionally, I enjoyed seeing the sickest patients, because I felt I could make the most dramatic differences with my care.

When I was searching for jobs, I spoke with the chief of GI at the hospital where I completed my residency about how I could fill a niche. We conceived of a model that would merge my personal interests and help the division provide consistent teaching for fellows and increase inpatient billing. Prior to my arrival, attendings that staffed the consult service were expected to continue their research and outpatient clinical workload while finding time to come to the hospital. Not surprisingly, attending rounds was erratic. The fellows were left to manage patients independently, scrambled to run cases by whomever happened to be around, or waited until they could reach the attending the next day. Unsurprisingly, billing by attendings was sparse.
 

What is a typical day like in your life as a GI hospitalist?

My day starts at 7:30 a.m. either with my outpatient office hours, endoscopy session, or GI Grand Rounds. Each week, I have two morning outpatient office sessions, one morning endoscopy session, and one morning session supervising fellows’ endoscopy.

At noon, I round with a team of GI fellows, medical students, and housestaff rotators for 2 hours. After we see the new consults, the remainder of my afternoon is spent seeing the follow-up patients. For two afternoons throughout the week, I have outpatient endoscopy sessions. I typically conclude my day at 5 p.m.

For night coverage, I take emergency calls for my own patients, and share general call duties with the other members of my division. On average, I take calls for one weekday a month and five weekends per year.

Typically, GI hospitalists only cover inpatients during the daytime. All nights and weekends are covered by partners and nonemergent overnight consults are saved until the next day. They have no office work.
 

What is the most challenging part of being a GI hospitalist?

As the perpetual “GI Consult Attending,” there is the threat of burnout when confronted with a high volume of sick, complex patients. Many of the patients have multiple comorbidities and require a multidisciplinary approach. On average, we have five new consults a day and the number of active follow-up patients is 10. Nonetheless, the nature of the inpatient service makes the volume of work unpredictable. When the service is busy and the census swells, the numbers of patients requiring staffing and notes can become overwhelming.

Mike Powell/Thinkstock

How are you paid?

My compensation is based on a base salary with an incentivized system based on my RVUs and collections. For the dedicated hospitalist for a group practice, there is typically a base salary and productivity-based income. Additionally, there should be a path to partnership. Lastly, in balancing the ledger, the diminished inpatient revenue stream is offset by the lack of overhead.

What are the benefits of a GI hospitalist system?

Our system benefits the workflow for the GI fellows. Since I have started, the GI consultation rounds start at a consistent time. During these rounds, we discuss relevant GI literature and make timely plans on all patients. Oftentimes, I am able to supervise the fellows so they can fit in a scope before the end of the workday. Ultimately, the fellows know they can find me and discuss patients throughout the day. The fellows consistently have told me that the since the implementation of the hospitalist system, there has been a dramatic difference. Collectively, they feel both their education and patient care have improved.

In terms of consult efficiency, one study demonstrated that the transition to a GI hospitalist system resulted in a mean decrease in consult to urgent esophagogastroduodenoscopy (EGD) time from approximately 24 to 14 hours.³ However, this occurred in the context of a lower inpatient consult volume and only covered 2 months. Furthermore, the time from admission to EGD did not change. Nonetheless, further studies are needed to examine the impact of this model shift.

In terms of a financial benefit, at our institution the total gross inpatient charges increased more than $850,000 for the year. This was largely attributable to the 79% increase in the gross charges from follow-up notes.

For group practices, the hospitalist system makes more efficient use of physician’s time. Physicians can either focus on outpatients or inpatients without worrying about going between the office, ambulatory surgical center, and the hospital. In general, inpatients require a disproportionate amount of time relative to the revenue collected. Furthermore, by eliminating the need for group physicians to go to the hospital, they can carve out 1-2 hours of office time to increase billing.

When there is one point-person whom handles all inpatient GI, communication is facilitated among primary teams and other services. The GI hospitalist develops working relationships with surgeons, radiologists, anesthesiologists, intensivists, etc. Teams can often just text or call me directly, instead of looking for the covering attending or going through the office phone service.
 

What are drawbacks to the GI hospitalist model?

Since there is only one gastroenterologist in the hospitalist model, if that person is not doing a good job, it affects the management of GI conditions for the entire hospital.

There is a loss of continuity-of-care. When GI patients get admitted, the gastroenterologists responsible for their care will not be the person with whom they have a long-term relationship. Furthermore, when the patient gets discharged, the primary gastroenterologists will not be fully aware of the inpatient course.

Also, when outpatient and inpatient gastroenterologists become segregated based on hospital setting, they each lose out of learning the intricacies of managing patients in a different context.
 

What do you like most about being a GI hospitalist?

The GI hospitalist position creates a great opportunity for gastroenterologists to make a remarkable, immediate impact on interesting, high acuity patients. The nature of the job also has the advantage of providing reasonable hours. This may be attractive to many whom want a better work-life balance.

Dr. Wan is assistant professor of medicine, associate program director, GI Fellowship Program, New York Presbyterian/Weill Cornell Medical Center, New York, N.Y.

References

1. Wachter R.M., Goldman L. Zero to 50,000 – The 20th Anniversary of the Hospitalist. N Engl J Med. 2016 Sep 15;375[11]:1009-11.

2. Estimating the Number and Characteristics of Hospitalist Physicians in the United States and Their Possible Workforce Implications. Analysis in Brief. Available at: https://www.aamc.org/download/300620/data/aibvol12_no3-hospitalist.pdf. Accessed May 1st, 2016.

3. Mahadev S., Lebwohl B., Ramirez I., Garcia-Carrasquillo R.J., Freedberg, D.E. Transition to a GI Hospitalist System is Associated with Expedited Upper Endoscopy. Gastroenterology. 2016;150[4]:S639-40.
 

What is a GI hospitalist?

A GI hospitalist is a gastroenterologist that primarily provides inpatient care. Their main professional focus is the acute management of gastrointestinal conditions occurring in the hospital setting.

How prevalent are subspecialty hospitalists?

The rise of hospitalists has changed the landscape of medicine. The hospitalist is now the central inpatient provider responsible for patient care and day-to-day housestaff education. From 1995 to 2016, the number of hospitalists increased from 500 to over 50,000.¹ While the majority of hospitalists are generalists from the fields of internal medicine, pediatrics, and obstetrics/gynecology, some come in the form of specialists. In a recent survey, up to 10% of internal medicine subspecialists already consider themselves “hospitalists.”² However, most of these self-described hospitalists only do so part of the time. For example, many group practices have one of their members manage all the hospitalized patients for the group for certain periods of time. It is rare to find full-time subspecialist hospitalists, but there has been an emergence in this new model of GI practice. Many people are unaware of this system of care nor understand how it may influence hospital-based care.

What is the role of a GI hospitalist?

While my primary responsibility is to care for inpatients whom require GI consults, I have outpatient and administrative responsibilities. Generally speaking, I am the de facto consult attending for the year.
 

How did you decide to become a GI hospitalist?

Upon graduation from my GI fellowship, I wanted an academic job where I could work closely with fellows and manage a wide breadth of complex, high-acuity patients. During fellowship, I enjoyed all areas of gastroenterology and hepatology and did not “sub-subspecialize.” As such, I wanted a job where I would see the full spectrum of GI and liver disease. Additionally, I enjoyed seeing the sickest patients, because I felt I could make the most dramatic differences with my care.

When I was searching for jobs, I spoke with the chief of GI at the hospital where I completed my residency about how I could fill a niche. We conceived of a model that would merge my personal interests and help the division provide consistent teaching for fellows and increase inpatient billing. Prior to my arrival, attendings that staffed the consult service were expected to continue their research and outpatient clinical workload while finding time to come to the hospital. Not surprisingly, attending rounds was erratic. The fellows were left to manage patients independently, scrambled to run cases by whomever happened to be around, or waited until they could reach the attending the next day. Unsurprisingly, billing by attendings was sparse.
 

What is a typical day like in your life as a GI hospitalist?

My day starts at 7:30 a.m. either with my outpatient office hours, endoscopy session, or GI Grand Rounds. Each week, I have two morning outpatient office sessions, one morning endoscopy session, and one morning session supervising fellows’ endoscopy.

At noon, I round with a team of GI fellows, medical students, and housestaff rotators for 2 hours. After we see the new consults, the remainder of my afternoon is spent seeing the follow-up patients. For two afternoons throughout the week, I have outpatient endoscopy sessions. I typically conclude my day at 5 p.m.

For night coverage, I take emergency calls for my own patients, and share general call duties with the other members of my division. On average, I take calls for one weekday a month and five weekends per year.

Typically, GI hospitalists only cover inpatients during the daytime. All nights and weekends are covered by partners and nonemergent overnight consults are saved until the next day. They have no office work.
 

What is the most challenging part of being a GI hospitalist?

As the perpetual “GI Consult Attending,” there is the threat of burnout when confronted with a high volume of sick, complex patients. Many of the patients have multiple comorbidities and require a multidisciplinary approach. On average, we have five new consults a day and the number of active follow-up patients is 10. Nonetheless, the nature of the inpatient service makes the volume of work unpredictable. When the service is busy and the census swells, the numbers of patients requiring staffing and notes can become overwhelming.

Mike Powell/Thinkstock

How are you paid?

My compensation is based on a base salary with an incentivized system based on my RVUs and collections. For the dedicated hospitalist for a group practice, there is typically a base salary and productivity-based income. Additionally, there should be a path to partnership. Lastly, in balancing the ledger, the diminished inpatient revenue stream is offset by the lack of overhead.

What are the benefits of a GI hospitalist system?

Our system benefits the workflow for the GI fellows. Since I have started, the GI consultation rounds start at a consistent time. During these rounds, we discuss relevant GI literature and make timely plans on all patients. Oftentimes, I am able to supervise the fellows so they can fit in a scope before the end of the workday. Ultimately, the fellows know they can find me and discuss patients throughout the day. The fellows consistently have told me that the since the implementation of the hospitalist system, there has been a dramatic difference. Collectively, they feel both their education and patient care have improved.

In terms of consult efficiency, one study demonstrated that the transition to a GI hospitalist system resulted in a mean decrease in consult to urgent esophagogastroduodenoscopy (EGD) time from approximately 24 to 14 hours.³ However, this occurred in the context of a lower inpatient consult volume and only covered 2 months. Furthermore, the time from admission to EGD did not change. Nonetheless, further studies are needed to examine the impact of this model shift.

In terms of a financial benefit, at our institution the total gross inpatient charges increased more than $850,000 for the year. This was largely attributable to the 79% increase in the gross charges from follow-up notes.

For group practices, the hospitalist system makes more efficient use of physician’s time. Physicians can either focus on outpatients or inpatients without worrying about going between the office, ambulatory surgical center, and the hospital. In general, inpatients require a disproportionate amount of time relative to the revenue collected. Furthermore, by eliminating the need for group physicians to go to the hospital, they can carve out 1-2 hours of office time to increase billing.

When there is one point-person whom handles all inpatient GI, communication is facilitated among primary teams and other services. The GI hospitalist develops working relationships with surgeons, radiologists, anesthesiologists, intensivists, etc. Teams can often just text or call me directly, instead of looking for the covering attending or going through the office phone service.
 

What are drawbacks to the GI hospitalist model?

Since there is only one gastroenterologist in the hospitalist model, if that person is not doing a good job, it affects the management of GI conditions for the entire hospital.

There is a loss of continuity-of-care. When GI patients get admitted, the gastroenterologists responsible for their care will not be the person with whom they have a long-term relationship. Furthermore, when the patient gets discharged, the primary gastroenterologists will not be fully aware of the inpatient course.

Also, when outpatient and inpatient gastroenterologists become segregated based on hospital setting, they each lose out of learning the intricacies of managing patients in a different context.
 

What do you like most about being a GI hospitalist?

The GI hospitalist position creates a great opportunity for gastroenterologists to make a remarkable, immediate impact on interesting, high acuity patients. The nature of the job also has the advantage of providing reasonable hours. This may be attractive to many whom want a better work-life balance.

Dr. Wan is assistant professor of medicine, associate program director, GI Fellowship Program, New York Presbyterian/Weill Cornell Medical Center, New York, N.Y.

References

1. Wachter R.M., Goldman L. Zero to 50,000 – The 20th Anniversary of the Hospitalist. N Engl J Med. 2016 Sep 15;375[11]:1009-11.

2. Estimating the Number and Characteristics of Hospitalist Physicians in the United States and Their Possible Workforce Implications. Analysis in Brief. Available at: https://www.aamc.org/download/300620/data/aibvol12_no3-hospitalist.pdf. Accessed May 1st, 2016.

3. Mahadev S., Lebwohl B., Ramirez I., Garcia-Carrasquillo R.J., Freedberg, D.E. Transition to a GI Hospitalist System is Associated with Expedited Upper Endoscopy. Gastroenterology. 2016;150[4]:S639-40.
 

Historical perspective

The term “pancreas” derives its name from the Greek words pan (all) and kreas (flesh). Understanding pancreas physiology was first attempted in the 17th century by Regnier de Graaf^1. Giovanni Morgagni is credited with the first description of the syndrome of acute pancreatitis (AP) in 1761². Reginald Huber Fitz proposed the first classification of AP into hemorrhagic, gangrenous, and suppurative types in 1889³. The distinction of acute from chronic pancreatitis was not well described until the middle of the 20th century when Mandred W. Comfort gave a detailed account of chronic relapsing pancreatitis in 1946⁴.

Diagnosis and classification of severity

The diagnosis of AP is based on the presence of two of the three following criteria: typical abdominal pain (severe, upper abdominal pain frequently radiating to the back), serum amylase and/or lipase levels greater than 3 times the upper limit of normal, and/or characteristic imaging findings.

The original 1992 Atlanta classification provided the first blueprint to standardize how severity of AP was defined⁵. Over the years, better understanding of AP pathophysiology and its complications led to a greater focus on local and systemic determinants of severity⁶ and eventually the Revised Atlanta Classification (RAC) in 2013 (Table 1).
 

Management of acute pancreatitis

Prevention

Determination of etiology

The most common causes of AP are gallstones and alcohol, accounting for more than two-thirds of all cases¹³. Other etiologies include hypertriglyceridemia, ERCP, drugs induced, familial/hereditary, and post-traumatic. Initial work up includes a thorough history to quantify alcohol consumption and assess for recently started medications, measurement of liver injury tests¹⁴ and triglyceride levels, and performance of a transabdominal ultrasound to evaluate for biliary dilation, chole- and choledocholithiasis¹⁵.

Assessment of disease severity

Fluid resuscitation

Despite extensive research and trials using medications such as ulinastatin, octreotide, pentoxifylline, gabexate, N-acetyl cysteine, steroids, IL-10, and antibiotics²⁰, no pharmacologic agent has been shown to significantly alter the clinical course/outcomes of AP.

Adequate intravenous hydration remains the cornerstone of early management in AP²¹. Studies have demonstrated that increased intestinal permeability, secondary to reduced intestinal capillary microcirculation, leads to bacterial translocation and development of SIRS²². Intestinal microcirculation does not become as readily impaired, and there is a certain “latency” to its onset, from the insult that triggers pancreatitis. This gives rise to the concept of a “golden window” of 12-24 hours from the insult to potentially reverse such changes and prevent organ dysfunction. It has been shown that patients who are adequately resuscitated with intravenous fluids have lower risk for local and systemic complications²³.

Patients with predicted severe AP or those with persistent SIRS despite initial fluid resuscitation should be managed in a closely monitored unit, ideally an ICU. Patients with impending respiratory failure require mechanical ventilation, renal failure complicated by metabolic acidosis and/or hyperkalemia requires hemodialysis, and cardiovascular shock requires the initiation of vasopressors and continuous monitoring of blood pressure via an arterial line. A special entity that requires ICU level care is hypertriglyceridemia (HTG)-induced severe AP. HTG should be considered as the etiology of AP in certain clinical scenarios²⁸: previous history of HTG, poorly controlled diabetes mellitus, history of significant alcohol use, third trimester of pregnancy, and use of certain medications associated with HTG such as oral estrogens, tamoxifen, and propofol. Levels of triglyceride greater than 1000 mg/dL strongly point toward HTG being the etiology.

Plasmapheresis, which filters and removes triglycerides from plasma, has been reported as an efficient treatment in such patients based on case series^29,30. At this time its use may only be justified in patients with predicted severe AP from HTG, preferably within the first 24 hours of presentation.


Urgent ERCP

Nutrition

Recovery of the gut function is often delayed for several days or weeks in patients with severe AP. Studies have shown that prolonged fasting in such circumstances leads to malnutrition and worse prognosis^33,34. Enteral nutrition via a nasogastric (NG) or nasojejunal (NJ) tube is the preferred route of nutritional support, as it is associated with lower risk of infection, multi-organ failure, and mortality when compared to total parenteral nutrition³³.

The question of whether NJ feeding offers any additional advantages over NG feeding has not been clearly answered with a recent randomized trial showing NG feeds not to be inferior to NJ feeds³⁵. In regards to the timing of initiation of enteral nutrition, early nasoenteric feeding within 24 hours from presentation was found not to be superior compared to on-demand feeding in patients with predicted severe AP³⁶.


Strategies to decrease risk of recurrent attacks

Management of peripancreatic fluid collections

Patients with AP frequently develop peripancreatic fluid collections (PFCs). Based on the revised Atlanta classification, those are categorized into four types (Table 2, Figures 1-4).

The majority of acute PFCs in patients without evidence of pancreatic necrosis regress within a few weeks and thus intervention is not indicated early in the disease course. Current literature supports delaying the drainage/debridement of such collections for several weeks. The mortality from interventions decreases as the time to intervention from onset of symptoms increases⁴¹. Delaying intervention gives more time for recovery from systemic complications and allows the encapsulating wall and contents to organize further.

While surgery is still an option for patients with symptomatic mature PFCs, endoscopic ultrasound-guided drainage in expert hands has been shown to be cost effective, with shorter hospital stay and even decreased risk of cyst recurrence compared with surgical cyst-gastrostomy creation⁴⁴. Ultrasound or computed tomography-guided drainage of such collections with a percutaneous catheter is an equally efficacious option when compared to the endoscopic approach. However, patients undergoing endotherapy require fewer procedures and imaging studies and shorter length of stay⁴⁵ when compared with radiological interventions.

Although this topic has generated much debate, the majority of available evidence shows no clinical benefit from using prophylactic antibiotics to prevent infection in pancreatic necrosis⁴⁶.

Vascular complications

Vascular complications such as splanchnic vein thrombosis can occur in up to a quarter of AP patients⁴⁹. Anticoagulation is not usually indicated unless thrombosis is extensive and causes bowel ischemia. Arterial pseudoaneurysms are rare but life threatening complications of AP. They typically require interventional radiology guided coil embolization to prevent massive bleeding⁵⁰.

Abdominal compartment syndrome

Abdominal compartment syndrome is an end result of third spacing of fluid into the abdominal cavity secondary to inflammation and fluid resuscitation in severe pancreatitis. Abdominal pressure in patients can be monitored by measuring bladder pressures. Intra-abdominal hypertension is defined as a sustained pressure greater than 12 mm Hg, while abdominal compartment syndrome is defined as sustained intra-abdominal pressure greater than 20 mm Hg with new organ failure⁵¹. Intra-abdominal hypertension (IAH) is present in up to 75% of patients with severe AP. While all conservative measures to prevent development or worsening of IAH should be implemented (adequate sedation, decompression of bowel in patients with ileus, etc.), current guidelines do not recommend aggressive interventions to treat it. On the other hand, abdominal compartment syndrome is a life-threatening complication that requires urgent intervention to decrease intra-abdominal pressure, such as percutaneous drain placement or surgical fasciotomy^52,53.

Conclusion

The key principles in the management of acute pancreatitis are aggressive hydration and preventing development of end organ failure. In the last two decades there has been a paradigm shift in the guidelines for management of peripancreatic fluid collections and pancreatic necrosis. When feasible, drainage of these collections should be delayed and be performed using minimally invasive interventions. There is still an urgent need for developing and testing disease-specific treatments targeting control of the inflammatory response in the early phase of acute pancreatitis and prevention of development of severe disease with end-organ dysfunction.

Dr. Gulati is a gastroenterology and hepatology fellow at Allegheny Health Network, Pittsburgh, and Dr. Papachristou is professor of medicine, University of Pittsburgh School of Medicine, Pittsburgh.

References

1. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Chapter 55, 923-33.

2. Morgagni G.B. [Fie Books on the Seats and Causes of Diseases as Discovered by the Anatomist]. Venice, Italy: Typographia Remondiniana;1761.

3. Fitz R.H. Boston Med Surg J. 1889;120:181-8.

4. Comfort M., Gambill E., Baggesnstoss A. Gastroenterology. 1946;6:238-76.

5. Bollen T.L., van Santvoort H.C., Besselink M.G., et al. Br J Surg. 2008;95:6–21.

6. Dellinger E.P., Forsmark C.E., Layer P., et al. Ann Surg. 2012 Dec;256[6]:875-80.

7. Kochar B., Akshintala V.S., Afghani E., et al. Gastrointest Endosc. 2015 Jan;81[1]:143-9.

8. Choudhary A., Bechtold M.L., Arif M., et al. Gastrointest Endosc. 2011 Feb;73[2]:275-82.

9. Shi Q.Q., Ning X.Y., Zhan L.L., Tang G.D., Lv X.P. World J Gastroenterol. 2014 Jun 14;20[22]:7040-8.

10. Elmunzer B.J., Waljee A.K., Elta G.H., Taylor J.R., Fehmi S.M., Higgins P.D. Gut. 2008 Sep;57[9]:1262-7.

11. Sethi S., Sethi N., Wadhwa V., Garud S., Brown A. Pancreas. 2014 Mar;43[2]:190-7. 
12. Elmunzer B.J., Serrano J., Chak A., et al. Trials. 2016 Mar 3;17[1]:120.

13. Lowenfels A.B., Maisonneuve P., Sullivan T. Curr Gastroenterol Rep. 2009;11:97-103.

14. Agarwal N., Pitchumoni C.S., Sivaprasad A.V. Am J Gastroenterol. 1990;85:356-66.

15. Tenner S., Baillie J., DeWitt J. Vege S.S. Am J Gastroenterol. 2013;108:1400-15.

16. Papachristou G.I., Muddana V., Yadav D., et al. Am J Gastroenterol. 2010;105:435-41.

17. Mounzer R., et al. Gastroenterology 2012;142:1476-82.

18. Working Group IAP/APA Acute Pancreatitis Guidelines. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

19. Koutroumpakis E., Wu B.U., Bakker O.J., et al. Am J Gastroenterol. 2015 Dec;110[12]:1707-16.

20. Bang U.C., Semb S., Nojgaard C., Bendtsen F. World J Gastroenterol. 2008 May 21;14[19]:2968-76.

21. Warndorf M.G., Kurtzman J.T., Bartel M.J., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:705-9.

22. Hotz H.G., Foitzik T., Rohweder J., et al. J Gastrointest Surg. 1998 Nov-Dec;2[6]:518-25.

23. Brown A., Baillargeon J.D., Hughes M.D., et al. Pancreatology 2002;2:104-7.

24. Wu B.U., Hwang J.Q., Gardner T.H., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:710-7.

25. Forsmark C.E., Baillie J., AGA Institute Clinical Practice and Economics Committee, AGA Institute Governing Board. Gastroenterology. 2007 May;132[5]:2022-44.

26. Lankisch P.G., Mahlke R., Blum T., et al. Am J Gastroenterol. 2001;96:2081-5.

27. Wu B.U., Johannes R.S., Sun X., et al. Gastroenterology 2009;137:129-35.

28. Scherer J., Singh V.P., Pitchumoni C.S., Yadav D. J Clin Gastroenterol. 2014 Mar;48[3]:195-203.

29. Gubensek J., Buturovic-Ponikvar J., Romozi K., Ponikvar R. PLoS One. 2014 Jul 21;9[7]:e102748.

30. Chen J.H., Yeh J.H., Lai H.W., Liao C.S. World J Gastroenterol. 2004 Aug 1;10[15]:2272-4.

31. Tse F., Yuan Y. Cochrane Database Syst Rev. 2012 May 16;[5]:CD009779.

32. Folsch U.R., Nitsche R., Ludtke R., et al. N Engl J Med. 1997;336:237-42.

33. Al-Omran M., Albalawi Z.H., Tashkandi M.F., Al-Ansary L.A. Cochrane Database Syst Rev. 2010 Jan 20;[1]:CD002837.

34. Li J.Y., Yu T., Chen G.C., et al. PLoS One. 2013;8[6]:e64926.

35. Singh N., Sharma B., Sharma M., et al. Pancreas. 2012 Jan;41[1]:153-9.

36. Bakker O.J., van Brunschot S., van Santvoort H.C., et al. N Engl J Med. 2014 Nov 20;371[21]:1983-93.

37. Van Baal M.C., Besselink M.G., Bakker O.J., et al. Ann Surg. 2012;255:860–6.

38. Nealon W.H., Bawduniak J., Walser E.M. Ann Surg. 2004 Jun;239[6]:741-9.

39. Sanjay P., Yeeting S., Whigham C., Judson H., Polignano F.M., Tait I.S. Surg Endosc. 2008 Aug;22[8]:1832-7.

40. Nordback I., Pelli H., Lappalainen-Lehto R., Järvinen S., Räty S., Sand J. Gastroenterology. 2009 Mar;136[3]:848-55.

41. Besselink M.G., Verwer T.J., Schoenmaeckers E.J., et al. Arch Surg. 2007;142:1194-201.

42. Besselink M., van Santvoort H., Freeman M. et al. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

43. Hjalmar C., van Santvoort, H., Besselink M.G., et al. N Engl J Med. 2010;362:1491-502.

44. Varadarajulu S., Bang J.Y., Sutton B.S., et al. Gastroenterology. 2013;145:583-90.e1.

45. Akshintala V.S., Saxena P., Zaheer A., et al. Gastrointest Endosc. 2014 Jun;79[6]:921-8.

46. Jiang K, Huang W, Yang XN., et al. World J Gastroenterol. 2012;18:279–84.

47. Dervenis C., Smailis D., Hatzitheoklitos E. J Hepatobiliary Pancreat Surg. 2003;10[6]:415Y418.

48. Gloor B., Muller C.A., Worni M., et al. Arch Surg. 2001;136[5]:592Y596.

49. Nadkarni N.A., Khanna S., Vege S.S. Pancreas. 2013 Aug;42[6]:924-31.

50. Marshall G.T., Howell D.A., Hansen B.L., Amberson S.M., Abourjaily G.S., Bredenberg C.E. Arch Surg. 1996 Mar;131[3]:278-83.

51. Malbrain M.L., Cheatham M.L., Kirkpatrick A., et al. Intensive Care Med. 2006 Nov;32[11]:1722-32.

52. De Waele J.J. Leppaniemi A.K. World J Surg. 2009;33:1128-33.

53. Kirkpatrick A.W., Roberts D.J., De W.J., et al. Intensive Care Med. 2013 Jul;39[7]1190-206.
 

Historical perspective

The term “pancreas” derives its name from the Greek words pan (all) and kreas (flesh). Understanding pancreas physiology was first attempted in the 17th century by Regnier de Graaf^1. Giovanni Morgagni is credited with the first description of the syndrome of acute pancreatitis (AP) in 1761². Reginald Huber Fitz proposed the first classification of AP into hemorrhagic, gangrenous, and suppurative types in 1889³. The distinction of acute from chronic pancreatitis was not well described until the middle of the 20th century when Mandred W. Comfort gave a detailed account of chronic relapsing pancreatitis in 1946⁴.

Diagnosis and classification of severity

The diagnosis of AP is based on the presence of two of the three following criteria: typical abdominal pain (severe, upper abdominal pain frequently radiating to the back), serum amylase and/or lipase levels greater than 3 times the upper limit of normal, and/or characteristic imaging findings.

The original 1992 Atlanta classification provided the first blueprint to standardize how severity of AP was defined⁵. Over the years, better understanding of AP pathophysiology and its complications led to a greater focus on local and systemic determinants of severity⁶ and eventually the Revised Atlanta Classification (RAC) in 2013 (Table 1).
 

Management of acute pancreatitis

Prevention

Determination of etiology

The most common causes of AP are gallstones and alcohol, accounting for more than two-thirds of all cases¹³. Other etiologies include hypertriglyceridemia, ERCP, drugs induced, familial/hereditary, and post-traumatic. Initial work up includes a thorough history to quantify alcohol consumption and assess for recently started medications, measurement of liver injury tests¹⁴ and triglyceride levels, and performance of a transabdominal ultrasound to evaluate for biliary dilation, chole- and choledocholithiasis¹⁵.

Assessment of disease severity

Fluid resuscitation

Despite extensive research and trials using medications such as ulinastatin, octreotide, pentoxifylline, gabexate, N-acetyl cysteine, steroids, IL-10, and antibiotics²⁰, no pharmacologic agent has been shown to significantly alter the clinical course/outcomes of AP.

Adequate intravenous hydration remains the cornerstone of early management in AP²¹. Studies have demonstrated that increased intestinal permeability, secondary to reduced intestinal capillary microcirculation, leads to bacterial translocation and development of SIRS²². Intestinal microcirculation does not become as readily impaired, and there is a certain “latency” to its onset, from the insult that triggers pancreatitis. This gives rise to the concept of a “golden window” of 12-24 hours from the insult to potentially reverse such changes and prevent organ dysfunction. It has been shown that patients who are adequately resuscitated with intravenous fluids have lower risk for local and systemic complications²³.

Patients with predicted severe AP or those with persistent SIRS despite initial fluid resuscitation should be managed in a closely monitored unit, ideally an ICU. Patients with impending respiratory failure require mechanical ventilation, renal failure complicated by metabolic acidosis and/or hyperkalemia requires hemodialysis, and cardiovascular shock requires the initiation of vasopressors and continuous monitoring of blood pressure via an arterial line. A special entity that requires ICU level care is hypertriglyceridemia (HTG)-induced severe AP. HTG should be considered as the etiology of AP in certain clinical scenarios²⁸: previous history of HTG, poorly controlled diabetes mellitus, history of significant alcohol use, third trimester of pregnancy, and use of certain medications associated with HTG such as oral estrogens, tamoxifen, and propofol. Levels of triglyceride greater than 1000 mg/dL strongly point toward HTG being the etiology.

Plasmapheresis, which filters and removes triglycerides from plasma, has been reported as an efficient treatment in such patients based on case series^29,30. At this time its use may only be justified in patients with predicted severe AP from HTG, preferably within the first 24 hours of presentation.


Urgent ERCP

Nutrition

Recovery of the gut function is often delayed for several days or weeks in patients with severe AP. Studies have shown that prolonged fasting in such circumstances leads to malnutrition and worse prognosis^33,34. Enteral nutrition via a nasogastric (NG) or nasojejunal (NJ) tube is the preferred route of nutritional support, as it is associated with lower risk of infection, multi-organ failure, and mortality when compared to total parenteral nutrition³³.

The question of whether NJ feeding offers any additional advantages over NG feeding has not been clearly answered with a recent randomized trial showing NG feeds not to be inferior to NJ feeds³⁵. In regards to the timing of initiation of enteral nutrition, early nasoenteric feeding within 24 hours from presentation was found not to be superior compared to on-demand feeding in patients with predicted severe AP³⁶.


Strategies to decrease risk of recurrent attacks

Management of peripancreatic fluid collections

Patients with AP frequently develop peripancreatic fluid collections (PFCs). Based on the revised Atlanta classification, those are categorized into four types (Table 2, Figures 1-4).

The majority of acute PFCs in patients without evidence of pancreatic necrosis regress within a few weeks and thus intervention is not indicated early in the disease course. Current literature supports delaying the drainage/debridement of such collections for several weeks. The mortality from interventions decreases as the time to intervention from onset of symptoms increases⁴¹. Delaying intervention gives more time for recovery from systemic complications and allows the encapsulating wall and contents to organize further.

While surgery is still an option for patients with symptomatic mature PFCs, endoscopic ultrasound-guided drainage in expert hands has been shown to be cost effective, with shorter hospital stay and even decreased risk of cyst recurrence compared with surgical cyst-gastrostomy creation⁴⁴. Ultrasound or computed tomography-guided drainage of such collections with a percutaneous catheter is an equally efficacious option when compared to the endoscopic approach. However, patients undergoing endotherapy require fewer procedures and imaging studies and shorter length of stay⁴⁵ when compared with radiological interventions.

Although this topic has generated much debate, the majority of available evidence shows no clinical benefit from using prophylactic antibiotics to prevent infection in pancreatic necrosis⁴⁶.

Vascular complications

Vascular complications such as splanchnic vein thrombosis can occur in up to a quarter of AP patients⁴⁹. Anticoagulation is not usually indicated unless thrombosis is extensive and causes bowel ischemia. Arterial pseudoaneurysms are rare but life threatening complications of AP. They typically require interventional radiology guided coil embolization to prevent massive bleeding⁵⁰.

Abdominal compartment syndrome

Abdominal compartment syndrome is an end result of third spacing of fluid into the abdominal cavity secondary to inflammation and fluid resuscitation in severe pancreatitis. Abdominal pressure in patients can be monitored by measuring bladder pressures. Intra-abdominal hypertension is defined as a sustained pressure greater than 12 mm Hg, while abdominal compartment syndrome is defined as sustained intra-abdominal pressure greater than 20 mm Hg with new organ failure⁵¹. Intra-abdominal hypertension (IAH) is present in up to 75% of patients with severe AP. While all conservative measures to prevent development or worsening of IAH should be implemented (adequate sedation, decompression of bowel in patients with ileus, etc.), current guidelines do not recommend aggressive interventions to treat it. On the other hand, abdominal compartment syndrome is a life-threatening complication that requires urgent intervention to decrease intra-abdominal pressure, such as percutaneous drain placement or surgical fasciotomy^52,53.

Conclusion

The key principles in the management of acute pancreatitis are aggressive hydration and preventing development of end organ failure. In the last two decades there has been a paradigm shift in the guidelines for management of peripancreatic fluid collections and pancreatic necrosis. When feasible, drainage of these collections should be delayed and be performed using minimally invasive interventions. There is still an urgent need for developing and testing disease-specific treatments targeting control of the inflammatory response in the early phase of acute pancreatitis and prevention of development of severe disease with end-organ dysfunction.

Dr. Gulati is a gastroenterology and hepatology fellow at Allegheny Health Network, Pittsburgh, and Dr. Papachristou is professor of medicine, University of Pittsburgh School of Medicine, Pittsburgh.

References

1. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Chapter 55, 923-33.

2. Morgagni G.B. [Fie Books on the Seats and Causes of Diseases as Discovered by the Anatomist]. Venice, Italy: Typographia Remondiniana;1761.

3. Fitz R.H. Boston Med Surg J. 1889;120:181-8.

4. Comfort M., Gambill E., Baggesnstoss A. Gastroenterology. 1946;6:238-76.

5. Bollen T.L., van Santvoort H.C., Besselink M.G., et al. Br J Surg. 2008;95:6–21.

6. Dellinger E.P., Forsmark C.E., Layer P., et al. Ann Surg. 2012 Dec;256[6]:875-80.

7. Kochar B., Akshintala V.S., Afghani E., et al. Gastrointest Endosc. 2015 Jan;81[1]:143-9.

8. Choudhary A., Bechtold M.L., Arif M., et al. Gastrointest Endosc. 2011 Feb;73[2]:275-82.

9. Shi Q.Q., Ning X.Y., Zhan L.L., Tang G.D., Lv X.P. World J Gastroenterol. 2014 Jun 14;20[22]:7040-8.

10. Elmunzer B.J., Waljee A.K., Elta G.H., Taylor J.R., Fehmi S.M., Higgins P.D. Gut. 2008 Sep;57[9]:1262-7.

11. Sethi S., Sethi N., Wadhwa V., Garud S., Brown A. Pancreas. 2014 Mar;43[2]:190-7. 
12. Elmunzer B.J., Serrano J., Chak A., et al. Trials. 2016 Mar 3;17[1]:120.

13. Lowenfels A.B., Maisonneuve P., Sullivan T. Curr Gastroenterol Rep. 2009;11:97-103.

14. Agarwal N., Pitchumoni C.S., Sivaprasad A.V. Am J Gastroenterol. 1990;85:356-66.

15. Tenner S., Baillie J., DeWitt J. Vege S.S. Am J Gastroenterol. 2013;108:1400-15.

16. Papachristou G.I., Muddana V., Yadav D., et al. Am J Gastroenterol. 2010;105:435-41.

17. Mounzer R., et al. Gastroenterology 2012;142:1476-82.

18. Working Group IAP/APA Acute Pancreatitis Guidelines. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

19. Koutroumpakis E., Wu B.U., Bakker O.J., et al. Am J Gastroenterol. 2015 Dec;110[12]:1707-16.

20. Bang U.C., Semb S., Nojgaard C., Bendtsen F. World J Gastroenterol. 2008 May 21;14[19]:2968-76.

21. Warndorf M.G., Kurtzman J.T., Bartel M.J., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:705-9.

22. Hotz H.G., Foitzik T., Rohweder J., et al. J Gastrointest Surg. 1998 Nov-Dec;2[6]:518-25.

23. Brown A., Baillargeon J.D., Hughes M.D., et al. Pancreatology 2002;2:104-7.

24. Wu B.U., Hwang J.Q., Gardner T.H., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:710-7.

25. Forsmark C.E., Baillie J., AGA Institute Clinical Practice and Economics Committee, AGA Institute Governing Board. Gastroenterology. 2007 May;132[5]:2022-44.

26. Lankisch P.G., Mahlke R., Blum T., et al. Am J Gastroenterol. 2001;96:2081-5.

27. Wu B.U., Johannes R.S., Sun X., et al. Gastroenterology 2009;137:129-35.

28. Scherer J., Singh V.P., Pitchumoni C.S., Yadav D. J Clin Gastroenterol. 2014 Mar;48[3]:195-203.

29. Gubensek J., Buturovic-Ponikvar J., Romozi K., Ponikvar R. PLoS One. 2014 Jul 21;9[7]:e102748.

30. Chen J.H., Yeh J.H., Lai H.W., Liao C.S. World J Gastroenterol. 2004 Aug 1;10[15]:2272-4.

31. Tse F., Yuan Y. Cochrane Database Syst Rev. 2012 May 16;[5]:CD009779.

32. Folsch U.R., Nitsche R., Ludtke R., et al. N Engl J Med. 1997;336:237-42.

33. Al-Omran M., Albalawi Z.H., Tashkandi M.F., Al-Ansary L.A. Cochrane Database Syst Rev. 2010 Jan 20;[1]:CD002837.

34. Li J.Y., Yu T., Chen G.C., et al. PLoS One. 2013;8[6]:e64926.

35. Singh N., Sharma B., Sharma M., et al. Pancreas. 2012 Jan;41[1]:153-9.

36. Bakker O.J., van Brunschot S., van Santvoort H.C., et al. N Engl J Med. 2014 Nov 20;371[21]:1983-93.

37. Van Baal M.C., Besselink M.G., Bakker O.J., et al. Ann Surg. 2012;255:860–6.

38. Nealon W.H., Bawduniak J., Walser E.M. Ann Surg. 2004 Jun;239[6]:741-9.

39. Sanjay P., Yeeting S., Whigham C., Judson H., Polignano F.M., Tait I.S. Surg Endosc. 2008 Aug;22[8]:1832-7.

40. Nordback I., Pelli H., Lappalainen-Lehto R., Järvinen S., Räty S., Sand J. Gastroenterology. 2009 Mar;136[3]:848-55.

41. Besselink M.G., Verwer T.J., Schoenmaeckers E.J., et al. Arch Surg. 2007;142:1194-201.

42. Besselink M., van Santvoort H., Freeman M. et al. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

43. Hjalmar C., van Santvoort, H., Besselink M.G., et al. N Engl J Med. 2010;362:1491-502.

44. Varadarajulu S., Bang J.Y., Sutton B.S., et al. Gastroenterology. 2013;145:583-90.e1.

45. Akshintala V.S., Saxena P., Zaheer A., et al. Gastrointest Endosc. 2014 Jun;79[6]:921-8.

46. Jiang K, Huang W, Yang XN., et al. World J Gastroenterol. 2012;18:279–84.

47. Dervenis C., Smailis D., Hatzitheoklitos E. J Hepatobiliary Pancreat Surg. 2003;10[6]:415Y418.

48. Gloor B., Muller C.A., Worni M., et al. Arch Surg. 2001;136[5]:592Y596.

49. Nadkarni N.A., Khanna S., Vege S.S. Pancreas. 2013 Aug;42[6]:924-31.

50. Marshall G.T., Howell D.A., Hansen B.L., Amberson S.M., Abourjaily G.S., Bredenberg C.E. Arch Surg. 1996 Mar;131[3]:278-83.

51. Malbrain M.L., Cheatham M.L., Kirkpatrick A., et al. Intensive Care Med. 2006 Nov;32[11]:1722-32.

52. De Waele J.J. Leppaniemi A.K. World J Surg. 2009;33:1128-33.

53. Kirkpatrick A.W., Roberts D.J., De W.J., et al. Intensive Care Med. 2013 Jul;39[7]1190-206.
 

Historical perspective

The term “pancreas” derives its name from the Greek words pan (all) and kreas (flesh). Understanding pancreas physiology was first attempted in the 17th century by Regnier de Graaf^1. Giovanni Morgagni is credited with the first description of the syndrome of acute pancreatitis (AP) in 1761². Reginald Huber Fitz proposed the first classification of AP into hemorrhagic, gangrenous, and suppurative types in 1889³. The distinction of acute from chronic pancreatitis was not well described until the middle of the 20th century when Mandred W. Comfort gave a detailed account of chronic relapsing pancreatitis in 1946⁴.

Diagnosis and classification of severity

The diagnosis of AP is based on the presence of two of the three following criteria: typical abdominal pain (severe, upper abdominal pain frequently radiating to the back), serum amylase and/or lipase levels greater than 3 times the upper limit of normal, and/or characteristic imaging findings.

The original 1992 Atlanta classification provided the first blueprint to standardize how severity of AP was defined⁵. Over the years, better understanding of AP pathophysiology and its complications led to a greater focus on local and systemic determinants of severity⁶ and eventually the Revised Atlanta Classification (RAC) in 2013 (Table 1).
 

Management of acute pancreatitis

Prevention

Determination of etiology

The most common causes of AP are gallstones and alcohol, accounting for more than two-thirds of all cases¹³. Other etiologies include hypertriglyceridemia, ERCP, drugs induced, familial/hereditary, and post-traumatic. Initial work up includes a thorough history to quantify alcohol consumption and assess for recently started medications, measurement of liver injury tests¹⁴ and triglyceride levels, and performance of a transabdominal ultrasound to evaluate for biliary dilation, chole- and choledocholithiasis¹⁵.

Assessment of disease severity

Fluid resuscitation

Despite extensive research and trials using medications such as ulinastatin, octreotide, pentoxifylline, gabexate, N-acetyl cysteine, steroids, IL-10, and antibiotics²⁰, no pharmacologic agent has been shown to significantly alter the clinical course/outcomes of AP.

Adequate intravenous hydration remains the cornerstone of early management in AP²¹. Studies have demonstrated that increased intestinal permeability, secondary to reduced intestinal capillary microcirculation, leads to bacterial translocation and development of SIRS²². Intestinal microcirculation does not become as readily impaired, and there is a certain “latency” to its onset, from the insult that triggers pancreatitis. This gives rise to the concept of a “golden window” of 12-24 hours from the insult to potentially reverse such changes and prevent organ dysfunction. It has been shown that patients who are adequately resuscitated with intravenous fluids have lower risk for local and systemic complications²³.

Patients with predicted severe AP or those with persistent SIRS despite initial fluid resuscitation should be managed in a closely monitored unit, ideally an ICU. Patients with impending respiratory failure require mechanical ventilation, renal failure complicated by metabolic acidosis and/or hyperkalemia requires hemodialysis, and cardiovascular shock requires the initiation of vasopressors and continuous monitoring of blood pressure via an arterial line. A special entity that requires ICU level care is hypertriglyceridemia (HTG)-induced severe AP. HTG should be considered as the etiology of AP in certain clinical scenarios²⁸: previous history of HTG, poorly controlled diabetes mellitus, history of significant alcohol use, third trimester of pregnancy, and use of certain medications associated with HTG such as oral estrogens, tamoxifen, and propofol. Levels of triglyceride greater than 1000 mg/dL strongly point toward HTG being the etiology.

Plasmapheresis, which filters and removes triglycerides from plasma, has been reported as an efficient treatment in such patients based on case series^29,30. At this time its use may only be justified in patients with predicted severe AP from HTG, preferably within the first 24 hours of presentation.


Urgent ERCP

Nutrition

Recovery of the gut function is often delayed for several days or weeks in patients with severe AP. Studies have shown that prolonged fasting in such circumstances leads to malnutrition and worse prognosis^33,34. Enteral nutrition via a nasogastric (NG) or nasojejunal (NJ) tube is the preferred route of nutritional support, as it is associated with lower risk of infection, multi-organ failure, and mortality when compared to total parenteral nutrition³³.

The question of whether NJ feeding offers any additional advantages over NG feeding has not been clearly answered with a recent randomized trial showing NG feeds not to be inferior to NJ feeds³⁵. In regards to the timing of initiation of enteral nutrition, early nasoenteric feeding within 24 hours from presentation was found not to be superior compared to on-demand feeding in patients with predicted severe AP³⁶.


Strategies to decrease risk of recurrent attacks

Management of peripancreatic fluid collections

Patients with AP frequently develop peripancreatic fluid collections (PFCs). Based on the revised Atlanta classification, those are categorized into four types (Table 2, Figures 1-4).

The majority of acute PFCs in patients without evidence of pancreatic necrosis regress within a few weeks and thus intervention is not indicated early in the disease course. Current literature supports delaying the drainage/debridement of such collections for several weeks. The mortality from interventions decreases as the time to intervention from onset of symptoms increases⁴¹. Delaying intervention gives more time for recovery from systemic complications and allows the encapsulating wall and contents to organize further.

While surgery is still an option for patients with symptomatic mature PFCs, endoscopic ultrasound-guided drainage in expert hands has been shown to be cost effective, with shorter hospital stay and even decreased risk of cyst recurrence compared with surgical cyst-gastrostomy creation⁴⁴. Ultrasound or computed tomography-guided drainage of such collections with a percutaneous catheter is an equally efficacious option when compared to the endoscopic approach. However, patients undergoing endotherapy require fewer procedures and imaging studies and shorter length of stay⁴⁵ when compared with radiological interventions.

Although this topic has generated much debate, the majority of available evidence shows no clinical benefit from using prophylactic antibiotics to prevent infection in pancreatic necrosis⁴⁶.

Vascular complications

Vascular complications such as splanchnic vein thrombosis can occur in up to a quarter of AP patients⁴⁹. Anticoagulation is not usually indicated unless thrombosis is extensive and causes bowel ischemia. Arterial pseudoaneurysms are rare but life threatening complications of AP. They typically require interventional radiology guided coil embolization to prevent massive bleeding⁵⁰.

Abdominal compartment syndrome

Abdominal compartment syndrome is an end result of third spacing of fluid into the abdominal cavity secondary to inflammation and fluid resuscitation in severe pancreatitis. Abdominal pressure in patients can be monitored by measuring bladder pressures. Intra-abdominal hypertension is defined as a sustained pressure greater than 12 mm Hg, while abdominal compartment syndrome is defined as sustained intra-abdominal pressure greater than 20 mm Hg with new organ failure⁵¹. Intra-abdominal hypertension (IAH) is present in up to 75% of patients with severe AP. While all conservative measures to prevent development or worsening of IAH should be implemented (adequate sedation, decompression of bowel in patients with ileus, etc.), current guidelines do not recommend aggressive interventions to treat it. On the other hand, abdominal compartment syndrome is a life-threatening complication that requires urgent intervention to decrease intra-abdominal pressure, such as percutaneous drain placement or surgical fasciotomy^52,53.

Conclusion

The key principles in the management of acute pancreatitis are aggressive hydration and preventing development of end organ failure. In the last two decades there has been a paradigm shift in the guidelines for management of peripancreatic fluid collections and pancreatic necrosis. When feasible, drainage of these collections should be delayed and be performed using minimally invasive interventions. There is still an urgent need for developing and testing disease-specific treatments targeting control of the inflammatory response in the early phase of acute pancreatitis and prevention of development of severe disease with end-organ dysfunction.

Dr. Gulati is a gastroenterology and hepatology fellow at Allegheny Health Network, Pittsburgh, and Dr. Papachristou is professor of medicine, University of Pittsburgh School of Medicine, Pittsburgh.

References

1. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Chapter 55, 923-33.

2. Morgagni G.B. [Fie Books on the Seats and Causes of Diseases as Discovered by the Anatomist]. Venice, Italy: Typographia Remondiniana;1761.

3. Fitz R.H. Boston Med Surg J. 1889;120:181-8.

4. Comfort M., Gambill E., Baggesnstoss A. Gastroenterology. 1946;6:238-76.

5. Bollen T.L., van Santvoort H.C., Besselink M.G., et al. Br J Surg. 2008;95:6–21.

6. Dellinger E.P., Forsmark C.E., Layer P., et al. Ann Surg. 2012 Dec;256[6]:875-80.

7. Kochar B., Akshintala V.S., Afghani E., et al. Gastrointest Endosc. 2015 Jan;81[1]:143-9.

8. Choudhary A., Bechtold M.L., Arif M., et al. Gastrointest Endosc. 2011 Feb;73[2]:275-82.

9. Shi Q.Q., Ning X.Y., Zhan L.L., Tang G.D., Lv X.P. World J Gastroenterol. 2014 Jun 14;20[22]:7040-8.

10. Elmunzer B.J., Waljee A.K., Elta G.H., Taylor J.R., Fehmi S.M., Higgins P.D. Gut. 2008 Sep;57[9]:1262-7.

11. Sethi S., Sethi N., Wadhwa V., Garud S., Brown A. Pancreas. 2014 Mar;43[2]:190-7. 
12. Elmunzer B.J., Serrano J., Chak A., et al. Trials. 2016 Mar 3;17[1]:120.

13. Lowenfels A.B., Maisonneuve P., Sullivan T. Curr Gastroenterol Rep. 2009;11:97-103.

14. Agarwal N., Pitchumoni C.S., Sivaprasad A.V. Am J Gastroenterol. 1990;85:356-66.

15. Tenner S., Baillie J., DeWitt J. Vege S.S. Am J Gastroenterol. 2013;108:1400-15.

16. Papachristou G.I., Muddana V., Yadav D., et al. Am J Gastroenterol. 2010;105:435-41.

17. Mounzer R., et al. Gastroenterology 2012;142:1476-82.

18. Working Group IAP/APA Acute Pancreatitis Guidelines. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

19. Koutroumpakis E., Wu B.U., Bakker O.J., et al. Am J Gastroenterol. 2015 Dec;110[12]:1707-16.

20. Bang U.C., Semb S., Nojgaard C., Bendtsen F. World J Gastroenterol. 2008 May 21;14[19]:2968-76.

21. Warndorf M.G., Kurtzman J.T., Bartel M.J., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:705-9.

22. Hotz H.G., Foitzik T., Rohweder J., et al. J Gastrointest Surg. 1998 Nov-Dec;2[6]:518-25.

23. Brown A., Baillargeon J.D., Hughes M.D., et al. Pancreatology 2002;2:104-7.

24. Wu B.U., Hwang J.Q., Gardner T.H., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:710-7.

25. Forsmark C.E., Baillie J., AGA Institute Clinical Practice and Economics Committee, AGA Institute Governing Board. Gastroenterology. 2007 May;132[5]:2022-44.

26. Lankisch P.G., Mahlke R., Blum T., et al. Am J Gastroenterol. 2001;96:2081-5.

27. Wu B.U., Johannes R.S., Sun X., et al. Gastroenterology 2009;137:129-35.

28. Scherer J., Singh V.P., Pitchumoni C.S., Yadav D. J Clin Gastroenterol. 2014 Mar;48[3]:195-203.

29. Gubensek J., Buturovic-Ponikvar J., Romozi K., Ponikvar R. PLoS One. 2014 Jul 21;9[7]:e102748.

30. Chen J.H., Yeh J.H., Lai H.W., Liao C.S. World J Gastroenterol. 2004 Aug 1;10[15]:2272-4.

31. Tse F., Yuan Y. Cochrane Database Syst Rev. 2012 May 16;[5]:CD009779.

32. Folsch U.R., Nitsche R., Ludtke R., et al. N Engl J Med. 1997;336:237-42.

33. Al-Omran M., Albalawi Z.H., Tashkandi M.F., Al-Ansary L.A. Cochrane Database Syst Rev. 2010 Jan 20;[1]:CD002837.

34. Li J.Y., Yu T., Chen G.C., et al. PLoS One. 2013;8[6]:e64926.

35. Singh N., Sharma B., Sharma M., et al. Pancreas. 2012 Jan;41[1]:153-9.

36. Bakker O.J., van Brunschot S., van Santvoort H.C., et al. N Engl J Med. 2014 Nov 20;371[21]:1983-93.

37. Van Baal M.C., Besselink M.G., Bakker O.J., et al. Ann Surg. 2012;255:860–6.

38. Nealon W.H., Bawduniak J., Walser E.M. Ann Surg. 2004 Jun;239[6]:741-9.

39. Sanjay P., Yeeting S., Whigham C., Judson H., Polignano F.M., Tait I.S. Surg Endosc. 2008 Aug;22[8]:1832-7.

40. Nordback I., Pelli H., Lappalainen-Lehto R., Järvinen S., Räty S., Sand J. Gastroenterology. 2009 Mar;136[3]:848-55.

41. Besselink M.G., Verwer T.J., Schoenmaeckers E.J., et al. Arch Surg. 2007;142:1194-201.

42. Besselink M., van Santvoort H., Freeman M. et al. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

43. Hjalmar C., van Santvoort, H., Besselink M.G., et al. N Engl J Med. 2010;362:1491-502.

44. Varadarajulu S., Bang J.Y., Sutton B.S., et al. Gastroenterology. 2013;145:583-90.e1.

45. Akshintala V.S., Saxena P., Zaheer A., et al. Gastrointest Endosc. 2014 Jun;79[6]:921-8.

46. Jiang K, Huang W, Yang XN., et al. World J Gastroenterol. 2012;18:279–84.

47. Dervenis C., Smailis D., Hatzitheoklitos E. J Hepatobiliary Pancreat Surg. 2003;10[6]:415Y418.

48. Gloor B., Muller C.A., Worni M., et al. Arch Surg. 2001;136[5]:592Y596.

49. Nadkarni N.A., Khanna S., Vege S.S. Pancreas. 2013 Aug;42[6]:924-31.

50. Marshall G.T., Howell D.A., Hansen B.L., Amberson S.M., Abourjaily G.S., Bredenberg C.E. Arch Surg. 1996 Mar;131[3]:278-83.

51. Malbrain M.L., Cheatham M.L., Kirkpatrick A., et al. Intensive Care Med. 2006 Nov;32[11]:1722-32.

52. De Waele J.J. Leppaniemi A.K. World J Surg. 2009;33:1128-33.

53. Kirkpatrick A.W., Roberts D.J., De W.J., et al. Intensive Care Med. 2013 Jul;39[7]1190-206.
 

AGA’s focus on young GIs

The AGA Trainee and Early Career Committee (formerly Trainee and Young GI Committee) is composed of 12 trainee and early-career AGA members and meets twice a year to develop programs and events specifically targeted to trainees and gastroenterologists (GIs) in their first five years out of fellowship training. The committee was formed by the AGA in February 2013 to address the specific needs of early-career GI professionals and to develop programs to expose younger members to all that the AGA has to offer. The new committee also became a creative space to organize efforts to increase membership among early-career GIs. Trainee and Early Career Committee members are selected for 2-year terms and represent fellowship training programs, universities, and practices from around the nation. Each committee member serves simultaneously on one other AGA committee, which gives young GIs additional opportunities for leadership roles. The committee meets regularly with AGA staff and a governing board liaison to discuss committee goals and the issues most relevant to physicians during and directly after GI fellowship training. The committee also provides feedback to other committees about how programs and initiatives might involve or impact GI fellows and recent graduates. The result is a unique focus group where young GIs from all over the country work collectively to improve the young GI experience through flagship programs like the Regional Practice Skills Workshop, the Young Delegates Program, and Trainee and Early Career events at Digestive Disease Week (DDW)®.

AGA Regional Practice Skills Workshops

The workshop agenda is similar across locations and includes sessions on career options in research and clinical practice, how to evaluate a job, contract negotiation, health care reform, financial planning, and work-life balance. The program is geared toward second- and third-year fellows, recent fellowship graduates, and those considering a job or career change. All workshops include catered meals and are free to both AGA members and non-members. Those interested in attending one of the workshops can find more information at http://www.gastro.org/trainees. The Trainee and Early Career committee is also looking to expand to additional cities in future years so that more trainees and early-career GIs can participate in these workshops.
 

The AGA Young Delegates program

The AGA highly values the efforts of our Young Delegates, and the Trainee and Early Career Committee considers them a talent pool from which we can elicit input, select committee members, and find future leaders. More importantly, we hope that the program allows young AGA members to increasingly engage with the AGA to refresh, improve, and strengthen the society. To become a Young Delegate, please visit www.gastro.org/youngdelegates to provide us with your information.
 

Trainee and early career GIs at DDW

The Trainee and Early Career Committee sponsors several events at DDW to bring together fellows and early-career GIs from all over the country. Each year, our committee hosts a DDW Trainee and Early Career symposium to provide practical advice for early-career GIs from all practice settings. Our DDW 2016 symposium was entitled “Surviving The First Years in Clinical Practice – Roundtable with the Experts,” and featured prominent leaders who shared career perspectives with attendees through formal presentations and more casual discussion. Attendees gained insider tips on how to design and run a fiscally prosperous practice, coding and documentation, and building and maintaining a clinical practice referral base from expert AGA leaders. We are now in the process of planning the DDW 2017 Trainee and Early Career symposium that will focus on “The Road to Leadership in GI.”

Come join us!

The success of the AGA depends on the 16,000 members who volunteer their time for committees, councils, and the governing board. Since its inception, the Trainee and Early Career Committee has allowed young GIs to have a role in the AGA as well as benefit from all of the resources that the AGA has to offer in leadership training, networking, and career preparation. In the past three years, participation of young GIs in the Trainee and Early Career Committee events has been on the rise, which we hope is a reflection of our efforts to address the educational needs of early GIs and the transition from fellowship to practice. We would love to see more fellows and early-career GIs involved!

For more information about the Trainee and Early Career committee, becoming a committee member, and our programs, please visit http://www.gastro.org/trainees. If you have any ideas that you think the committee should consider, please let us know at trainees@gastro.org.
 

Dr. Liang is an instructor in the division of gastroenterology, New York University School of Medicine, New York, and an attending physician in the VA New York Harbor Healthcare System, New York. Dr. Kushner is a transplant hepatology fellow in the division of gastroenterology, University of California, San Francisco. Dr. May is assistant professor in the division of digestive diseases, David Geffen School of Medicine, University of California, Los Angeles, and an attending physician in the department of gastroenterology in the VA Greater Los Angeles Healthcare System, Los Angeles.

AGA’s focus on young GIs

The AGA Trainee and Early Career Committee (formerly Trainee and Young GI Committee) is composed of 12 trainee and early-career AGA members and meets twice a year to develop programs and events specifically targeted to trainees and gastroenterologists (GIs) in their first five years out of fellowship training. The committee was formed by the AGA in February 2013 to address the specific needs of early-career GI professionals and to develop programs to expose younger members to all that the AGA has to offer. The new committee also became a creative space to organize efforts to increase membership among early-career GIs. Trainee and Early Career Committee members are selected for 2-year terms and represent fellowship training programs, universities, and practices from around the nation. Each committee member serves simultaneously on one other AGA committee, which gives young GIs additional opportunities for leadership roles. The committee meets regularly with AGA staff and a governing board liaison to discuss committee goals and the issues most relevant to physicians during and directly after GI fellowship training. The committee also provides feedback to other committees about how programs and initiatives might involve or impact GI fellows and recent graduates. The result is a unique focus group where young GIs from all over the country work collectively to improve the young GI experience through flagship programs like the Regional Practice Skills Workshop, the Young Delegates Program, and Trainee and Early Career events at Digestive Disease Week (DDW)®.

AGA Regional Practice Skills Workshops

The workshop agenda is similar across locations and includes sessions on career options in research and clinical practice, how to evaluate a job, contract negotiation, health care reform, financial planning, and work-life balance. The program is geared toward second- and third-year fellows, recent fellowship graduates, and those considering a job or career change. All workshops include catered meals and are free to both AGA members and non-members. Those interested in attending one of the workshops can find more information at http://www.gastro.org/trainees. The Trainee and Early Career committee is also looking to expand to additional cities in future years so that more trainees and early-career GIs can participate in these workshops.
 

The AGA Young Delegates program

The AGA highly values the efforts of our Young Delegates, and the Trainee and Early Career Committee considers them a talent pool from which we can elicit input, select committee members, and find future leaders. More importantly, we hope that the program allows young AGA members to increasingly engage with the AGA to refresh, improve, and strengthen the society. To become a Young Delegate, please visit www.gastro.org/youngdelegates to provide us with your information.
 

Trainee and early career GIs at DDW

The Trainee and Early Career Committee sponsors several events at DDW to bring together fellows and early-career GIs from all over the country. Each year, our committee hosts a DDW Trainee and Early Career symposium to provide practical advice for early-career GIs from all practice settings. Our DDW 2016 symposium was entitled “Surviving The First Years in Clinical Practice – Roundtable with the Experts,” and featured prominent leaders who shared career perspectives with attendees through formal presentations and more casual discussion. Attendees gained insider tips on how to design and run a fiscally prosperous practice, coding and documentation, and building and maintaining a clinical practice referral base from expert AGA leaders. We are now in the process of planning the DDW 2017 Trainee and Early Career symposium that will focus on “The Road to Leadership in GI.”

Come join us!

The success of the AGA depends on the 16,000 members who volunteer their time for committees, councils, and the governing board. Since its inception, the Trainee and Early Career Committee has allowed young GIs to have a role in the AGA as well as benefit from all of the resources that the AGA has to offer in leadership training, networking, and career preparation. In the past three years, participation of young GIs in the Trainee and Early Career Committee events has been on the rise, which we hope is a reflection of our efforts to address the educational needs of early GIs and the transition from fellowship to practice. We would love to see more fellows and early-career GIs involved!

For more information about the Trainee and Early Career committee, becoming a committee member, and our programs, please visit http://www.gastro.org/trainees. If you have any ideas that you think the committee should consider, please let us know at trainees@gastro.org.
 

Dr. Liang is an instructor in the division of gastroenterology, New York University School of Medicine, New York, and an attending physician in the VA New York Harbor Healthcare System, New York. Dr. Kushner is a transplant hepatology fellow in the division of gastroenterology, University of California, San Francisco. Dr. May is assistant professor in the division of digestive diseases, David Geffen School of Medicine, University of California, Los Angeles, and an attending physician in the department of gastroenterology in the VA Greater Los Angeles Healthcare System, Los Angeles.

AGA’s focus on young GIs

The AGA Trainee and Early Career Committee (formerly Trainee and Young GI Committee) is composed of 12 trainee and early-career AGA members and meets twice a year to develop programs and events specifically targeted to trainees and gastroenterologists (GIs) in their first five years out of fellowship training. The committee was formed by the AGA in February 2013 to address the specific needs of early-career GI professionals and to develop programs to expose younger members to all that the AGA has to offer. The new committee also became a creative space to organize efforts to increase membership among early-career GIs. Trainee and Early Career Committee members are selected for 2-year terms and represent fellowship training programs, universities, and practices from around the nation. Each committee member serves simultaneously on one other AGA committee, which gives young GIs additional opportunities for leadership roles. The committee meets regularly with AGA staff and a governing board liaison to discuss committee goals and the issues most relevant to physicians during and directly after GI fellowship training. The committee also provides feedback to other committees about how programs and initiatives might involve or impact GI fellows and recent graduates. The result is a unique focus group where young GIs from all over the country work collectively to improve the young GI experience through flagship programs like the Regional Practice Skills Workshop, the Young Delegates Program, and Trainee and Early Career events at Digestive Disease Week (DDW)®.

AGA Regional Practice Skills Workshops

The workshop agenda is similar across locations and includes sessions on career options in research and clinical practice, how to evaluate a job, contract negotiation, health care reform, financial planning, and work-life balance. The program is geared toward second- and third-year fellows, recent fellowship graduates, and those considering a job or career change. All workshops include catered meals and are free to both AGA members and non-members. Those interested in attending one of the workshops can find more information at http://www.gastro.org/trainees. The Trainee and Early Career committee is also looking to expand to additional cities in future years so that more trainees and early-career GIs can participate in these workshops.
 

The AGA Young Delegates program

The AGA highly values the efforts of our Young Delegates, and the Trainee and Early Career Committee considers them a talent pool from which we can elicit input, select committee members, and find future leaders. More importantly, we hope that the program allows young AGA members to increasingly engage with the AGA to refresh, improve, and strengthen the society. To become a Young Delegate, please visit www.gastro.org/youngdelegates to provide us with your information.
 

Trainee and early career GIs at DDW

The Trainee and Early Career Committee sponsors several events at DDW to bring together fellows and early-career GIs from all over the country. Each year, our committee hosts a DDW Trainee and Early Career symposium to provide practical advice for early-career GIs from all practice settings. Our DDW 2016 symposium was entitled “Surviving The First Years in Clinical Practice – Roundtable with the Experts,” and featured prominent leaders who shared career perspectives with attendees through formal presentations and more casual discussion. Attendees gained insider tips on how to design and run a fiscally prosperous practice, coding and documentation, and building and maintaining a clinical practice referral base from expert AGA leaders. We are now in the process of planning the DDW 2017 Trainee and Early Career symposium that will focus on “The Road to Leadership in GI.”

Come join us!

The success of the AGA depends on the 16,000 members who volunteer their time for committees, councils, and the governing board. Since its inception, the Trainee and Early Career Committee has allowed young GIs to have a role in the AGA as well as benefit from all of the resources that the AGA has to offer in leadership training, networking, and career preparation. In the past three years, participation of young GIs in the Trainee and Early Career Committee events has been on the rise, which we hope is a reflection of our efforts to address the educational needs of early GIs and the transition from fellowship to practice. We would love to see more fellows and early-career GIs involved!

For more information about the Trainee and Early Career committee, becoming a committee member, and our programs, please visit http://www.gastro.org/trainees. If you have any ideas that you think the committee should consider, please let us know at trainees@gastro.org.
 

Dr. Liang is an instructor in the division of gastroenterology, New York University School of Medicine, New York, and an attending physician in the VA New York Harbor Healthcare System, New York. Dr. Kushner is a transplant hepatology fellow in the division of gastroenterology, University of California, San Francisco. Dr. May is assistant professor in the division of digestive diseases, David Geffen School of Medicine, University of California, Los Angeles, and an attending physician in the department of gastroenterology in the VA Greater Los Angeles Healthcare System, Los Angeles.

The correct answer is B: endoscopic suture removal. As the prevalence of bariatric surgery increases to address the obesity epidemic, endoscopists are increasingly called upon to evaluate postbariatric patients.1 In one case series of patients undergoing EGD for upper GI symptoms post-RYGB, normal postsurgical anatomy was found in 31.6%, anastomotic stricture in 52.6%, marginal ulcer in 15.8%, unraveled suture material causing functional obstruction in 4% and gastro-gastric fistula in 2.6% of cases.2 Another series reported unraveled suture material thought to be contributing to upper GI symptoms in up to 10% of cases.3 Suture material is found by a mean of 34 weeks after RYGB, and presenting symptoms include abdominal pain in 65%, nausea 52%, dysphagia 22%, and melena in 13%. Unraveled suture material may be associated with marginal ulceration, or may cause obstruction as it presents a mechanical obstruction to foodstuff as it passes through the gastrojejunal anastomosis. A series of 29 therapeutic endoscopic suture removal cases reported resolution or improvement of symptoms in 83% of patients and no complications or anastomotic leaks.3

AGA Institute

References

1. ASGE Standards of Practice Committee, Evans J.A., Muthusamy V.R., et al. The role of endoscopy in the bariatric surgery patient. Gastrointest Endosc. 2015;8:1063-72.
2. Lee J.K., Van Dam J., Morton J.M., et al. Endoscopy is accurate, safe, and effective in the assessment and management of complications following gastric bypass surgery. Am J Gastroenterol. 2009;104:575-82.
3. Yu S., Jastrow K., Clapp B., et al. Foreign material erosion after laparoscopic Roux-en-Y gastric bypass: findings and treatment. Surg Endosc. 2007;21:1216-20.

The correct answer is B: endoscopic suture removal. As the prevalence of bariatric surgery increases to address the obesity epidemic, endoscopists are increasingly called upon to evaluate postbariatric patients.1 In one case series of patients undergoing EGD for upper GI symptoms post-RYGB, normal postsurgical anatomy was found in 31.6%, anastomotic stricture in 52.6%, marginal ulcer in 15.8%, unraveled suture material causing functional obstruction in 4% and gastro-gastric fistula in 2.6% of cases.2 Another series reported unraveled suture material thought to be contributing to upper GI symptoms in up to 10% of cases.3 Suture material is found by a mean of 34 weeks after RYGB, and presenting symptoms include abdominal pain in 65%, nausea 52%, dysphagia 22%, and melena in 13%. Unraveled suture material may be associated with marginal ulceration, or may cause obstruction as it presents a mechanical obstruction to foodstuff as it passes through the gastrojejunal anastomosis. A series of 29 therapeutic endoscopic suture removal cases reported resolution or improvement of symptoms in 83% of patients and no complications or anastomotic leaks.3

AGA Institute

References

1. ASGE Standards of Practice Committee, Evans J.A., Muthusamy V.R., et al. The role of endoscopy in the bariatric surgery patient. Gastrointest Endosc. 2015;8:1063-72.
2. Lee J.K., Van Dam J., Morton J.M., et al. Endoscopy is accurate, safe, and effective in the assessment and management of complications following gastric bypass surgery. Am J Gastroenterol. 2009;104:575-82.
3. Yu S., Jastrow K., Clapp B., et al. Foreign material erosion after laparoscopic Roux-en-Y gastric bypass: findings and treatment. Surg Endosc. 2007;21:1216-20.

The correct answer is B: endoscopic suture removal. As the prevalence of bariatric surgery increases to address the obesity epidemic, endoscopists are increasingly called upon to evaluate postbariatric patients.1 In one case series of patients undergoing EGD for upper GI symptoms post-RYGB, normal postsurgical anatomy was found in 31.6%, anastomotic stricture in 52.6%, marginal ulcer in 15.8%, unraveled suture material causing functional obstruction in 4% and gastro-gastric fistula in 2.6% of cases.2 Another series reported unraveled suture material thought to be contributing to upper GI symptoms in up to 10% of cases.3 Suture material is found by a mean of 34 weeks after RYGB, and presenting symptoms include abdominal pain in 65%, nausea 52%, dysphagia 22%, and melena in 13%. Unraveled suture material may be associated with marginal ulceration, or may cause obstruction as it presents a mechanical obstruction to foodstuff as it passes through the gastrojejunal anastomosis. A series of 29 therapeutic endoscopic suture removal cases reported resolution or improvement of symptoms in 83% of patients and no complications or anastomotic leaks.3

AGA Institute

References

1. ASGE Standards of Practice Committee, Evans J.A., Muthusamy V.R., et al. The role of endoscopy in the bariatric surgery patient. Gastrointest Endosc. 2015;8:1063-72.
2. Lee J.K., Van Dam J., Morton J.M., et al. Endoscopy is accurate, safe, and effective in the assessment and management of complications following gastric bypass surgery. Am J Gastroenterol. 2009;104:575-82.
3. Yu S., Jastrow K., Clapp B., et al. Foreign material erosion after laparoscopic Roux-en-Y gastric bypass: findings and treatment. Surg Endosc. 2007;21:1216-20.

In a recent video interview, Richard Peek Jr., MD, AGAF, Editor in Chief, and Douglas Corley, MD, PhD, Deputy Editor in Chief, of Gastroenterology explained how trainees and young GIs fit into their plans for the journal. Good news: this constituency is among the editors’ top priorities.

The editors have plans to implement a year-long editorial fellowship later in their term, which will allow an individual to get hands-on experience in the editorial process.

The editors also appreciate the fresh take young investigators have on research. To encourage continued high-quality submissions from young investigators, the editors will decrease submission fees for young investigators and work to increase the visibility of young investigator research.

The editors also plan to develop new features within the Gastroenterology Mentor, Education and Training Corner that will be of interest to trainees and early career GIs.

Watch the full video interview on AGA’s YouTube Channel: https://www.youtube.com/user/AmerGastroAssn.

The discussion on young investigators begins at minute 5:24.

In a recent video interview, Richard Peek Jr., MD, AGAF, Editor in Chief, and Douglas Corley, MD, PhD, Deputy Editor in Chief, of Gastroenterology explained how trainees and young GIs fit into their plans for the journal. Good news: this constituency is among the editors’ top priorities.

The editors have plans to implement a year-long editorial fellowship later in their term, which will allow an individual to get hands-on experience in the editorial process.

The editors also appreciate the fresh take young investigators have on research. To encourage continued high-quality submissions from young investigators, the editors will decrease submission fees for young investigators and work to increase the visibility of young investigator research.

The editors also plan to develop new features within the Gastroenterology Mentor, Education and Training Corner that will be of interest to trainees and early career GIs.

Watch the full video interview on AGA’s YouTube Channel: https://www.youtube.com/user/AmerGastroAssn.

The discussion on young investigators begins at minute 5:24.

In a recent video interview, Richard Peek Jr., MD, AGAF, Editor in Chief, and Douglas Corley, MD, PhD, Deputy Editor in Chief, of Gastroenterology explained how trainees and young GIs fit into their plans for the journal. Good news: this constituency is among the editors’ top priorities.

The editors have plans to implement a year-long editorial fellowship later in their term, which will allow an individual to get hands-on experience in the editorial process.

The editors also appreciate the fresh take young investigators have on research. To encourage continued high-quality submissions from young investigators, the editors will decrease submission fees for young investigators and work to increase the visibility of young investigator research.

The editors also plan to develop new features within the Gastroenterology Mentor, Education and Training Corner that will be of interest to trainees and early career GIs.

Watch the full video interview on AGA’s YouTube Channel: https://www.youtube.com/user/AmerGastroAssn.

The discussion on young investigators begins at minute 5:24.

Dear Colleagues,

Acute pancreatitis has long been one of the “bread and butter” conditions in gastroenterology and having up-to-date knowledge on its management will serve our community well. In this issue of The New Gastroenterologist, Abhishek Gulati and Georgios Papachristou (University of Pittsburgh) provide a comprehensive review of the latest advances in the treatment of acute pancreatitis and its complications, which has direct application to GI clinical practice.

Bryson W. Katona is a instructor of medicine in the division of gasteroenterology at the University of Pennsylvania.

Dear Colleagues,

Acute pancreatitis has long been one of the “bread and butter” conditions in gastroenterology and having up-to-date knowledge on its management will serve our community well. In this issue of The New Gastroenterologist, Abhishek Gulati and Georgios Papachristou (University of Pittsburgh) provide a comprehensive review of the latest advances in the treatment of acute pancreatitis and its complications, which has direct application to GI clinical practice.

Bryson W. Katona is a instructor of medicine in the division of gasteroenterology at the University of Pennsylvania.

Dear Colleagues,

Acute pancreatitis has long been one of the “bread and butter” conditions in gastroenterology and having up-to-date knowledge on its management will serve our community well. In this issue of The New Gastroenterologist, Abhishek Gulati and Georgios Papachristou (University of Pittsburgh) provide a comprehensive review of the latest advances in the treatment of acute pancreatitis and its complications, which has direct application to GI clinical practice.

Bryson W. Katona is a instructor of medicine in the division of gasteroenterology at the University of Pennsylvania.

INTRODUCTION

Renal cell carcinoma (RCC) is the most common malignancy arising in the kidney, comprising 90% of all renal tumors.¹ Approximately 55,000 new RCC cases are diagnosed each year.² Patients with RCC are often asymptomatic, and most cases are discovered as incidental findings on abdominal imaging performed during evaluation of nonrenal complaints. Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.² Advanced RCC is resistant to conventional chemotherapy and radiotherapy, and outcomes for patients with metastatic or unresectable RCC remain poor. However, the recent development of new therapeutic modalities that target tumor molecular pathways has expanded the treatment options for these patients and changed the management of RCC.

EPIDEMIOLOGY AND CLASSIFICATION

Median age at diagnosis in the United States is 64 years. Men have a higher incidence of RCC than women, with the highest incidence seen in American Indian and Alaska Native men (30.1 per 100,000 population). Genetic syndromes account for 2% to 4% of all RCCs.² Risk factors for RCC include smoking, hypertension, obesity, and acquired cystic kidney disease that is associated with end-stage renal failure.³ Longer duration of tobacco use is associated with a more aggressive course.

The 2004 World Health Organization (WHO) classification of renal tumors summarizes the previous classification systems (including the Heidelberg and Mainz classification systems) to describe different categories of RCC based on histologic and molecular genetics characteristics.² Using the WHO classification criteria, RCC comprises 90% of all renal tumors, with clear cell being the most common type (80%).² Other types of renal tumors include papillary, chromophobe, oncocytoma, and collecting-duct or Bellini duct tumors. Approximately 3% to 5% of tumors are unclassified. Oncocytomas are generally considered benign, and chromophobe tumors typically have an indolent course and rarely metastasize. Sarcomatoid differentiation can be seen in any histologic type and is associated with a worse prognosis. While different types of tumors may be seen in the kidney (such as transitional cell or lymphomas), the focus of this review is the primary malignancies of the renal parenchyma.

FAMILIAL SYNDROMES

Several genetic syndromes have been identified by studying families with inherited RCC. Among these, von Hippel-Lindau (VHL) gene mutation is the most commonly found inherited genetic defect. Table 1 summarizes the incidence of gene mutations and the corresponding histologic appearance of the most common sporadic and hereditary RCCs.⁴

VHL disease is an autosomal dominant familial syndrome. Patients with this mutation are at higher risk for developing RCC (clear cell histology), retinal angiomas, pheochromocytomas, as well as hemangioblastomas of the central nervous system (CNS).⁴ Of all the genetic mutations seen in RCC, the somatic mutation in the VHL tumor-suppressor gene is by far the most common.⁵ VHL targets hypoxia–inducible factor-1 alpha (HIF-α) for ubiquitination and subsequent degradation, which has been shown to suppress the growth of clear-cell RCC in mouse models.^6–8 HIF expression under hypoxic conditions leads to activation of a number of genes important in blood vessel development, cell proliferation, and glucose metabolism, including vascular endothelial growth factor (VEGF), erythropoietin, platelet-derived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), and glucose transporter-1 (GLUT-1). Mutation in the VHL gene prevents degradation of the HIF-α protein, thereby leading to increased expression of these downstream proteins, including MET and Axl. The upregulation of these angiogenic factors is thought to be the underlying process for increased vascularity of CNS hemangioblastomas and clear-cell renal tumors in VHL disease.^4–8

Other less common genetic syndromes seen in hereditary RCC include hereditary papillary RCC, hereditary leiomyomatosis, and Birt-Hogg-Dubé (BHD) syndrome.⁹ In hereditary papillary RCC, the MET gene is mutated. BHD syndrome is a rare, autosomal dominant syndrome characterized by hair follicle hamartomas of the face and neck. About 15% of patients have multiple renal tumors, the majority of which are of the chromophobe or mixed chromophobe-oncocytoma histology. The BHD gene encodes the protein folliculin, which is thought to be a tumor-suppressor gene.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 74-year-old man who works as an airplane mechanic repairman presents to the emergency department with sudden worsening of chronic right upper arm and shoulder pain after lifting a jug of orange juice. He does not have a significant past medical history and initially thought that his pain was due to a work-related injury. Upon initial evaluation in the emergency department he is found to have a fracture of his right humerus. Given that the fracture appears to be pathologic, further work-up is recommended.

Most patients are asymptomatic until the disease becomes advanced. The classic triad of flank pain, hematuria, and palpable abdominal mass is seen in approximately 10% of patients with RCC, partly because of earlier detection of renal masses by imaging performed for other purposes.¹⁰ Less frequently, patients present with signs or symptoms of metastatic disease such as bone pain or fracture (as seen in the case patient), painful adenopathy, and pulmonary symptoms related to mediastinal masses. Fever, weight loss, anemia, and/or varicocele often occur in young patients (≤ 46 years) and may indicate the presence of a hereditary form of the disease. Patients may present with paraneoplastic syndromes seen as abnormalities on routine blood work. These can include polycythemia or elevated liver function tests (LFTs) without the presence of liver metastases (known as Stauffer syndrome), which can be seen in localized renal tumors. Nearly half (45%) of patients present with localized disease, 25% present with locally advanced disease, and 30% present with metastatic disease.¹¹ Bone is the second most common site of distant metastatic spread (following lung) in patients with advanced RCC.

• What is the approach to initial evaluation for a patient with suspected RCC?

Initial evaluation consists of a physical exam, laboratory tests including complete blood count (CBC) and comprehensive metabolic panel (calcium, serum creatinine, LFTs, lactate dehydrogenase [LDH], and urinalysis), and imaging. Imaging studies include computed tomography (CT) scan with contrast of the abdomen and pelvis or magnetic resonance imaging (MRI) of the abdomen and chest imaging. A chest radiograph may be obtained, although a chest CT is more sensitive for the presence of pulmonary metastases. MRI can be used in patients with renal dysfunction to evaluate the renal vein and inferior vena cava (IVC) for thrombus or to determine the presence of local invasion.¹² Although bone and brain are common sites for metastases, routine imaging is not indicated unless the patient is symptomatic. The value of positron emission tomography in RCC remains undetermined at this time.

Staging is done according to the American Joint Committee on Cancer (AJCC) staging classification for RCC; the Figure summarizes the staging and 5-year survival data based on this classification scheme.^4,13

LIMITED-STAGE DISEASE

• What are the therapeutic options for limited-stage disease?

For patients with nondistant metastases, or limited-stage disease, surgical intervention with curative intent is considered. Convention suggests considering definitive surgery for patients with stage I and II disease, select patients with stage III disease with pathologically enlarged retroperitoneal lymph nodes, patients with IVC and/or cardiac atrium involvement of tumor thrombus, and patients with direct extension of the renal tumor into the ipsilateral adrenal gland if there is no evidence of distant disease. While there may be a role for aggressive surgical intervention in patients with distant metastatic disease, this topic will not be covered in this review.

SURGICAL INTERVENTION

Once patients are determined to be appropriate candidates for surgical removal of a renal tumor, the urologist will perform either a radical nephrectomy or a nephron-sparing nephrectomy, also called a partial nephrectomy. The urologist will evaluate the patient based on his or her body habitus, the location of the tumor, whether multiple tumors in one kidney or bilateral tumors are present, whether the patient has a solitary kidney or otherwise impaired kidney function, and whether the patient has a history of a hereditary syndrome involving kidney cancer as this affects the risk of future kidney tumors.

A radical nephrectomy is surgically preferred in the presence of the following factors: tumor larger than 7 cm in diameter, a more centrally located tumor, suspicion of lymph node involvement, tumor involvement with renal vein or IVC, and/or direct extension of the tumor into the ipsilateral adrenal gland. Nephrectomy involves ligation of the vascular supply (renal artery and vein) followed by removal of the kidney and surrounding Gerota’s fascia. The ipsilateral adrenal gland is removed if there is a high-risk for or presence of invasion of the adrenal gland. Removal of the adrenal gland is not standard since the literature demonstrates there is less than a 10% chance of solitary, ipsilateral adrenal gland involvement of tumor at the time of nephrectomy in the absence of high-risk features, and a recent systematic review suggests that the chance may be as low as 1.8%.¹⁴ Preoperative factors that correlated with adrenal involvement included upper pole kidney location, renal vein thrombosis, higher T stage (T3a and greater), multifocal tumors, and evidence for distant metastases or lymph node involvement. Lymphadenectomy previously had been included in radical nephrectomy but now is performed selectively. Radical nephrectomy may be performed as

Conversely, a nephron-sparing approach is preferred for tumors less than 7 cm in diameter, for patients with a solitary kidney or impaired renal function, for patients with multiple small ipsilateral tumors or with bilateral tumors, or for radical nephrectomy candidates with comorbidities for whom a limited intervention is deemed to be a lower-risk procedure. A nephron-sparing procedure may also be performed open or laparoscopically. In nephron-sparing procedures, the tumor is removed along with a small margin of normal parenchyma.¹⁵

In summary, the goal of surgical intervention is curative intent with removal of the tumor while maintaining as much residual renal function as possible to limit long-term morbidity of chronic kidney disease and associated cardiovascular events.¹⁸ Oncologic outcomes for radical nephrectomy and partial nephrectomy are similar. In one study, overall survival was slightly lower in the partial nephrectomy cohort, but only a small number of the deaths were due to RCC.¹⁹

ADJUVANT THERAPY

Adjuvant systemic therapy currently has no role following nephrectomy for RCC because no systemic therapy has been able to reduce the likelihood of relapse. Randomized trials of cytokine therapy (eg, interferon, interleukin 2) or tyrosine kinase inhibitors (TKIs; eg, sorafenib, sunitinib) with observation alone in patients with locally advanced completely resected RCC have shown no delay in time to relapse or improvement of survival with adjuvant therapy.²⁰ Similarly, adjuvant radiation therapy has not shown benefit even in patients with nodal involvement or incomplete resection.²¹ Therefore, observation remains the standard of care after nephrectomy.

RENAL TUMOR ABLATION

For patients who are deemed not to be surgical candidates due to age, comorbidities, or patient preference and who have tumors less than 4 cm in size (stage I tumors), ablative techniques may be considered. The 2 most well-studied and effective techniques at present are cryoablation and radiofrequency ablation (RFA). Microwave ablation may be an option in some facilities, but the data in RCC are limited. An emerging ablative technique under investigation is irreversible electroporation. At present, the long-term efficacy of all ablative techniques is unknown.

Patient selection is undertaken by urologists and interventional radiologists who evaluate the patient with ultrasound, CT, and/or MRI to determine the location and size of the tumor and the presence or absence of metastatic disease. A pretreatment biopsy is recommended to document the histology of the lesion to confirm a malignancy and to guide future treatment for recurrent or metastatic disease. Contraindications to the procedure include the presence of metastatic disease, a life expectancy of less than 1 year, general medical instability, or uncorrectable coagulopathy due to increased risk of bleeding complications. Tumors in close proximity to the renal hilum or collecting system are a contraindication to the procedure because of the risk for hemorrhage or damage to the collecting system. The location of the tumor in relation to the vasculature is also important to maximize efficacy because the vasculature acts as a “heat sink,” causing dissipation of the thermal energy. Occasionally, stenting of the proximal ureter due to upper tumor location is necessary to prevent thermal injury that could lead to urine leaks.

Selection of the modality to be used primarily depends on operator comfort, which translates to good patient outcomes, such as better cancer control and fewer complications. Cryoablation and RFA have both demonstrated good clinical efficacy and cancer control of 89% and 90%, respectively, with comparable complication rates.²² There have been no studies performed directly comparing the modalities.

Cryoablation

Cryoablation is performed through the insertion of a probe into the tumor, which may be done through a surgical or percutaneous approach. Once the probe is in place, a high- pressure gas (argon, nitrogen) is passed through the probe and upon entering a low pressure region the gas cools. The gas is able to cool to temperatures as low as –185°C. The tissue is then rewarmed through the use of helium, which conversely warms when entering a low pressure area. The process of freezing followed by rewarming subsequently causes cell death/tissue destruction through direct cell injury from cellular dehydration and vascular injury. Clinically, 2 freeze-thaw cycles are used to treat a tumor.^23,24

Radiofrequency ablation, or RFA, targets tumors via an electrode placed within the mass that produces intense frictional heat from medium-frequency alternating current (approximately 500 kHz) produced by a connected generator that is grounded on the patient. The thermal energy created causes coagulative necrosis. Due to the reliance on heat for tumor destruction, central lesions are less amenable to this approach because of the “heat sink” effect from the hilum.²⁴

Microwave Ablation

Microwave ablation, like RFA, relies on the generation of frictional heat to cause cell death by coagulative necrosis. In this case, the friction is created through the activation of water molecules; because of the different thermal kinetics involved with microwave ablation, the “heat sink” effect is minimized when treatment is employed near large vessels, in comparison to RFA.²⁴ The data on this mechanism of ablation are still maturing, with varied outcomes thus far. One study demonstrated outcomes comparable to RFA and cryoablation, with cancer-specific survival of 97.8% at 3 years.²⁵ However, a study by Castle and colleagues²⁶ demonstrated higher recurrence rates. The overarching impediment to widespread adoption of microwave ablation is inconclusive data gleaned from studies with small numbers of patients with limited follow up. The role of this modality will need to be revisited.

Irreversible Electroporation

Irreversible electroporation (IRE) is under investigation. IRE is a non-thermal ablative technique that employs rapid electrical pulses to create pores in cell membranes, leading to cell death. The postulated benefits of IRE include the lack of an effect from “heat sinks” and less collateral damage to the surrounding tissues, when compared with the thermal modalities. In a human phase 1 study of patients undergoing IRE prior to immediate surgical resection, the procedure appeared feasible and safe.²⁷ Significant concerns for this method of ablation possibly inducing cardiac arrhythmias, and the resultant need for sedation with neuromuscular blockade and associated electrocardiography monitoring, may impede its implementation in nonresearch settings.²⁴

ACTIVE SURVEILLANCE

Due to the more frequent use of imaging for various indications, there has been an increase in the discovery of small renal masses (SRM); 85% of RCC that present in an asymptomatic or incidental manner are tumors under 4 cm in diameter.^28,29 The role of active surveillance is evolving, but is primarily suggested for patients who are not candidates for more aggressive intervention based on comorbidities. A recent prospective, nonrandomized analysis of data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry evaluated outcomes for patients with SRM looking at primary intervention compared with active surveillance.³⁰ The primary intervention selected was at the discretion of the provider; treatments included partial nephrectomy, RFA, and cryoablation, and active surveillance patients were followed with imaging every 6 months. Progression of SRM, with recommendation for delayed intervention, was defined as a growth rate of mass greater than 0.5 cm/year, size greater than 4 cm, or hematuria. Thirty-six of 158 patients on active surveillance met criteria for progression; 21 underwent delayed intervention. Of note, even the patients who progressed but did not undergo delayed intervention did not develop metastatic disease during the follow-up interval. With a median follow-up of 2 years, cancer-specific survival was noted to be 99% and 100% at 5 years for primary intervention and active surveillance, respectively. Overall survival at 2 years for primary intervention was 98% and 96% for active surveillance; at 5 years, the survival rates were 92% and 75% (P = 0.06). Of note, 2 patients in the primary intervention arm died of RCC, while none in the active surveillance arm died. As would be expected, active surveillance patients were older, had a worse performance status, and had more comorbidities. Interestingly, 40% of patients enrolled selected active surveillance as their preferred management for SRM. The DISSRM results were consistent with data from the Renal Cell Consortium of Canada and other retrospective reviews.^31–33

• What is the approach to follow-up after treatment of localized RCC?

After a patient undergoes treatment for a localized RCC, the goal is to optimize oncologic outcomes, monitor for treatment sequelae, such as renal failure, and focus on survivorship. At this time, there is no consensus in the literature or across published national and international guidelines with regards to the appropriate schedule for surveillance to achieve these goals. In principle, the greatest risk for recurrence occurs within the first 3 years, so many guidelines focus on this timeframe. Likewise, the route of spread tends to be hematogenous, so patients present with pulmonary, bone, and brain metastases, in addition to local recurrence within the renal bed. Symptomatic recurrences often are seen

METASTATIC DISEASE

CASE CONTINUED

CT scan with contrast of the chest, abdomen, and pelvis as well as bone scan are done. CT of the abdomen and pelvis demonstrates a 7.8-cm left renal mass arising from the lower pole of the left kidney. Paraesophageal lymphadenopathy and mesenteric nodules are also noted. CT of the chest demonstrates bilateral pulmonary emboli. Bone scan is significant for increased activity related to the pathological fracture involving the right humerus. The patient undergoes surgery to stabilize the pathologic fracture of his humerus. He is diagnosed with metastatic RCC (clear cell histology) and undergoes palliative debulking nephrectomy.

• How is prognosis defined for metastatic RCC?

PROGNOSTIC MODELS

Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates for stage T1 and T2 disease approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.¹³ Approximately 30% of patients have metastatic disease at diagnosis, and about one-third of patients who have undergone treatment for localized disease experience relapse.^36,37 Common sites of metastases include lung, lymph nodes, bone, liver, adrenal gland, and brain.

Prognostic scoring systems have been developed to define risk groups and assist with determining appropriate therapy in the metastatic setting. The most widely used validated prognostic factor model is that from the Memorial Sloan-Kettering Cancer Center (MSKCC), which was developed using a multivariate analysis derived from data of patients enrolled in clinical trials and treated with interferon alfa.³⁸ The factors included in the MSKCC model are Karnofsky performance status less than 80, time from diagnosis to treatment with interferon alfa less than 12 months, hemoglobin level less than lower limit of laboratory’s reference range, LDH level greater than 1.5 times the upper limit of laboratory’s reference range, and corrected serum calcium level greater than 10 mg/dL. Risk groups are categorized as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors).³⁹ Median survival for favorable-, intermediate-, and poor-risk patients was 20, 10, and 4 months, respectively.⁴⁰

Another prognostic model, the International Metastatic RCC Database Consortium, or Heng, model was developed to evaluate prognosis in patients treated with VEGF-targeted therapy.⁴¹ This model was developed from a retrospective study of patients treated with sunitinib, sorafenib, and bevacizumab plus interferon alfa or prior immunotherapy. Prognostic factors in this model include 4 of the 5 MSKCC risk factors (hemoglobin level, corrected serum calcium level, Karnofsky performance status, and time to initial diagnosis). Additionally, this model includes both absolute neutrophil and platelet counts greater than the upper limit of normal. Risk groups are identified as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors). Median survival for favorable-, intermediate-, and poor-risk patients was not reached, 27 months, and 8.8 months, respectively. The University of California, Los Angeles scoring algorithm to predict survival after nephrectomy and immunotherapy (SANI) in patients with metastatic RCC is another prognostic model that can be used. This simplified scoring system incorporates lymph node status, constitutional symptoms, metastases location, histology, and thyroid stimulating hormone (TSH) level.⁴²

The role of debulking or cytoreductive nephrectomy in treatment of metastatic RCC is well established. Large randomized studies have demonstrated a statistically significant median survival benefit for patients undergoing nephrectomy plus interferon alfa therapy compared with patients treated with interferon alfa alone (13.6 months versus 7.8 months, respectively).⁴³ The role of cytoreductive nephrectomy in combination with antiangiogenic agents is less clear. While a retrospective study investigating outcomes of patients with metastatic RCC receiving anti-VEGF agents showed a prolonged survival with nephrectomy, results of large randomized trials are not yet available.^44,45 Patients with lung-only metastases, good prognostic features, and a good performance status are historically the most likely to benefit from cytoreductive surgery.

CASE CONTINUED

Based on the MSKCC prognostic factor model, the patient is considered to be in the intermediate-risk group (Karnofsky performance status of 80, calcium 9.5 mg/dL, LDH 204 U/L, hemoglobin 13.6 g/dL). He is started on treatment for his bilateral pulmonary emboli and recovers well from orthopedic surgery as well as palliative debulking nephrectomy.

Several approaches to systemic therapy for advanced RCC have been taken based on the histologic type of the tumor. Clear-cell is by far the predominant histologic type in RCC. Several options are available as first-line treatment for patients with metastatic clear-cell RCC (Table 2).^46–54 These include biologic agents such as high-dose interleukin-2 (IL-2) immune therapy, as well as targeted therapies including TKIs and anti-VEGF antibodies. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is recommended as first-line therapy in patients with poor prognosis only. Second-line therapies for clear-cell RCC following antiangiogenic therapy include TKIs, mTOR inhibitors, nivolumab (PD-1 inhibitor), and the combination of the TKI lenvatinib and mTOR inhibitor everolimus.⁵⁵ In addition, after initial cytokine therapy, TKIs, temsirolimus, and the anti-VEGF antibody bevacizumab are other treatment options available to patients. Best supportive care should always be provided along with initial and subsequent therapies. Clinical trials are also an appropriate choice as first-line or subsequent therapies. All of these therapies require periodic monitoring to prevent and quickly treat adverse effects. Table 3 lists recommended monitoring parameters for each of these agents.⁵⁶

Based on several studies, TKIs seem to be less effective in patients with non–clear-cell type histology.^57,58 In these patients, risk factors can guide therapy. In the ASPEN trial, where 108 patients were randomly assigned to everolimus or sunitinib, patients in the good- and intermediate-risk groups had longer overall and median progression-free survival (PFS) on sunitinib (8.3 months versus 5.3 months, respectively). However, those in the poor-risk group had a longer median overall survival with everolimus.⁵⁹ Given that the role of targeted therapies in non–clear-cell RCCs is less well established, enrollment in clinical trials should be considered as a first-line treatment option.²¹

Sarcomatoid features can be observed in any of the histologic types of RCC, and RCC with these features has an aggressive course and a poor prognosis. Currently, there is no standard therapy for treatment of patients with metastatic or unresectable RCC with sarcomatoid features.⁶⁰ Chemotherapeutic regimens used for soft tissue sarcomas, including a trial of ifosfamide and doxorubicin, did not show any objective response.⁶¹ A small trial of 10 patients treated with doxorubicin and gemcitabine resulted in complete response in 2 patients and partial response in 1 patient.⁶²

Enrollment in a clinical trial remains a first-line treatment option for these patients. More recently, a phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid (39 patients) and/or poor-risk (33 patients) metastatic RCC showed overall response rates (ORR) of 26% and 24%, respectively. A higher clinical benefit rate (defined as ORR plus stable disease) was seen in patients with tumors containing more than 10% sarcomatoid histology, as compared with patients whose tumors contained less than 10% sarcomatoid histology. Neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7) were the most common grade 3 toxicities seen in all the patients. Although this was a small study, the results showed a trend towards better efficacy of the combination therapy as compared with the single-agent regimen. Currently, another study is underway to further investigate this in a larger group of patients.⁶³

BIOLOGICS

Cytokine therapy, including high-dose IL-2 and interferon alfa, had long been the only first-line treatment option for patients with metastatic or unresectable RCC. Studies of high-dose IL-2 have shown an ORR of 25% and durable response in up to 11% of patients with clear-cell histology.⁶⁴ Toxicities were similar to those previously observed with high-dose IL-2 treatment; the most commonly observed grade 3 toxicities were hypotension and capillary leak syndrome. IL-2 requires strict monitoring (Table 3). It is important to note that retrospective studies evaluating the safety and efficacy of using IL-2 as second-line treatment in patients previously treated with TKIs demonstrated significant toxicity without achieving partial or complete response in any of the patients.⁶⁵

Prior to the advent of TKIs in the treatment of RCC, interferon alfa was a first-line treatment option for those who could not receive high-dose IL-2. It has been shown to produce response rates of approximately 20%, with maximum response seen with a higher dose range of 5 to 20 million units daily in 1 study.^66,67 However, with the introduction of TKIs, which produce a higher and more durable response, interferon alfa alone is no longer recommended as a treatment option.

Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo.⁶⁸ In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SC] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001).^47,48 Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.

TYROSINE KINASE INHIBITORS

TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.

Sunitinib

Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues^52,53 compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SC 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy.^69–71

Pazopanib

Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4%.⁷² This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy.⁵⁰ In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.

Sorafenib

Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy.⁷³ A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029).⁵¹ Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.

Axitinib

Axitinib is an oral inhibitor of VEGFRs 1, 2, and 3. Results of the phase 3 AXIS trial comparing axitinib (5 mg orally twice daily) with sorafenib (400 mg orally twice daily) in patients receiving 1 prior systemic therapy showed axitinib was more active than sorafenib in improving ORR (19% versus 9%; P = 0.001) and PFS (6.7 versus 4.7 months; P < 0.001), although no difference in overall survival times was noted.⁷⁴ In a subsequent phase 3 trial comparing these drugs in the first-line setting, axitinib showed a nonsignificantly higher response rate and PFS. Despite this, the National Comprehensive Cancer Network guidelines consider axitinib an acceptable first-line therapy because activity with acceptable toxicity was demonstrated (Table 2).⁴⁶ The most common adverse effects of axitinib are diarrhea, hypertension, fatigue, decreased appetite, dysphonia, hypothyroidism, and upper abdominal pain.

CABOZANTINIB

Given that resistance eventually develops in most patients treated with standard treatments, including bevacizumab and TKIs, the need to evaluate the safety and efficacy of novel agents targeting VEGFR and overcoming this resistance is of vital importance. Cabozantinib is an oral small-molecule inhibitor of VEGFR, Met, and Axl, all tyrosine kinases implicated in metastatic RCC. Overexpression of Met and Axl, which occurs as a result of inactivation of the VHL gene, is associated with a poor prognosis in patients with RCC. In a

MTOR INHIBITORS

The mTOR inhibitors, temsirolimus and everolimus, are also approved for the treatment of metastatic or advanced RCC. These drugs block mTOR’s phosphorylation and subsequent translation of mRNA to inhibit cell proliferation, cell growth, and angiogenesis.⁷⁷ Temsirolimus can be used as first-line therapy for patients with a poor prognosis, and everolimus is appropriate as a subsequent therapy.

Temsirolimus is an intravenous prodrug of rapamycin. It was the first of the class to be approved for metastatic RCC for treatment-naïve patients with a poor prognosis (ie, at least 3 of 6 predictors of poor survival based on MSKCC model).⁵⁴ The pivotal ARCC trial compared temsirolimus (25 mg IV weekly) alone, interferon alfa (3 million units SC 3 times weekly) alone, or the combination (temsirolimus 15 mg IV weekly plus interferon alfa 6 million units SC 3 times weekly). In this trial, temsirolimus monotherapy produced a significantly longer overall survival time than interferon alfa alone (10.9 versus 7.3 months; P = 0.008) and improved PFS time when administered alone or in combination with interferon alfa (3.8 and 3.7 months, respectively, versus 1.9 months). Because no real efficacy advantage of the combination was demonstrated, temsirolimus is administered alone. The most common adverse effects of temsirolimus are asthenia, rash, anemia, nausea, anorexia, pain, and dyspnea. Additionally, hyperglycemia, hyper-cholesterolemia, and hyperlipidemia occur with these agents. Noninfectious pneumonitis is a rare but often fatal complication.

Everolimus is also an orally administered derivative of rapamycin that is approved for use after failure of VEGF-targeted therapies. The results of the landmark trial RECORD-1 demonstrated that everolimus (10 mg orally daily) is effective at prolonging PFS (4 versus 1.9 months; P < 0.001) when compared with best supportive care, a viable treatment option at the time of approval.⁷⁸ The most common adverse effects of everolimus are stomatitis, rash, fatigue, asthenia, and diarrhea. As with temsirolimus, elevations in glucose, lipids, and triglycerides and noninfectious pneumonitis can occur.

TKI + MTOR INHIBITOR

Lenvatinib is also a small molecule targeting multiple tyrosine kinases, primarily VEGF2. Combined with the mTOR inhibitor everolimus, it has been shown to be an effective regimen in patients with metastatic RCC who have failed other therapies. In a randomized phase 2 study involving patients with advanced or metastatic clear-cell RCC, patients were randomly assigned to receive either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively). Patients received the treatment continuously on a 28-day cycle until progression or inability to tolerate toxicity. Patients in the lenvatinib plus everolimus arm had median PFS of 14.6 months (95% CI 5.9 to 20.1) versus 5.5 months (95% CI 3.5 to 7.1) with everlolimus alone (HR 0.40 [95% CI 0.24 to 0.68]; P = 0.0005). PFS with levantinib alone was 7.4 months (95% CI 5.6 to 10.20; HR 0.66 [95% CI 0.30 to 1.10]; P = 0.12). In addition, PFS with levantinib alone was significantly prolonged in comparison with everolimus alone (HR 0.61 [95% CI 0.38 to 0.98]; P = 0.048). Grade 3 or 4 toxicity were less frequent in the everolimus only arm and the most common grade 3 or 4 toxicity in the lenvatinib plus everolimus arm was diarrhea. The results of this study show that the combination of lenvatinib plus everolimus is an acceptable second-line option for treatment of patients with advanced or metastatic RCC.⁵⁵

 

 

CASE CONTINUED

The patient is initially started on pazopanib and tolerates the medication well, with partial response to the treatment. However, on restaging scans he is noted to have small bowel perforation. Pazopanib is discontinued until the patient has a full recovery. He is then started on everolimus. Restaging scans done 3 months after starting everolimus demonstrate disease progression.

• What is the appropriate next step in treatment?

PD1 BLOCKADE

Programmed death 1 (PD-1) protein is a T-cell inhibitory receptor with 2 ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors. Blocking the interaction between PD-1 and PD-L1 by anti-PD-1 humanized antibodies potentiates a robust immune response and has been a breakthrough in the field of cancer immunotherapy.⁷⁹ Previous studies have demonstrated that overexpression of PD-L1 leads to worse outcomes and poor prognosis in patients with RCC.⁸⁰ Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. In a randomized, open-label, phase 3 study comparing nivolumab with everolimus in patients with RCC who had previously undergone treatment with other standard therapies, Motzer and colleagues⁸¹ demonstrated a longer overall survival time and fewer adverse effects with nivolumab. In this study, 821 patients with clear-cell RCC were randomly assigned to receive nivolumab (3 mg/kg of body weight IV every 2 weeks) or everolimus (10 mg orally once daily). The median overall survival time with nivolumab was 25 months versus 19.6 months with everolimus (P < 0.0148). Nineteen percent of patients receiving nivolumab experienced grade 3 or 4 toxicities, with fatigue being the most common adverse effect. Grade 3 or 4 toxicities were observed in 37% of patients treated with everolimus, with anemia being the most common. Based on the results of this trial, on November 23, 2015, the U.S. Food and Drug Administration approved nivolumab to treat patients with metastatic RCC who have received a prior antiangiogenic therapy.

CASE CONCLUSION

Both TKI and mTOR inhibitor therapy fail, and the patient is eligible for third-line therapy. Because of his previous GI perforation, other TKIs are not an option. The patient opts for enrollment in hospice due to declining performance status. For other patients in this situation with a good performance status, nivolumab would be a reasonable option.

FUTURE DIRECTIONS

With the approval of nivolumab, multiple treatment options are now available for patients with metastatic or unresectable RCC. Development of other PD-1 inhibitors and immunotherapies as well as multi-targeted TKIs will only serve to expand treatment options for these patients. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.

INTRODUCTION

Renal cell carcinoma (RCC) is the most common malignancy arising in the kidney, comprising 90% of all renal tumors.¹ Approximately 55,000 new RCC cases are diagnosed each year.² Patients with RCC are often asymptomatic, and most cases are discovered as incidental findings on abdominal imaging performed during evaluation of nonrenal complaints. Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.² Advanced RCC is resistant to conventional chemotherapy and radiotherapy, and outcomes for patients with metastatic or unresectable RCC remain poor. However, the recent development of new therapeutic modalities that target tumor molecular pathways has expanded the treatment options for these patients and changed the management of RCC.

EPIDEMIOLOGY AND CLASSIFICATION

Median age at diagnosis in the United States is 64 years. Men have a higher incidence of RCC than women, with the highest incidence seen in American Indian and Alaska Native men (30.1 per 100,000 population). Genetic syndromes account for 2% to 4% of all RCCs.² Risk factors for RCC include smoking, hypertension, obesity, and acquired cystic kidney disease that is associated with end-stage renal failure.³ Longer duration of tobacco use is associated with a more aggressive course.

The 2004 World Health Organization (WHO) classification of renal tumors summarizes the previous classification systems (including the Heidelberg and Mainz classification systems) to describe different categories of RCC based on histologic and molecular genetics characteristics.² Using the WHO classification criteria, RCC comprises 90% of all renal tumors, with clear cell being the most common type (80%).² Other types of renal tumors include papillary, chromophobe, oncocytoma, and collecting-duct or Bellini duct tumors. Approximately 3% to 5% of tumors are unclassified. Oncocytomas are generally considered benign, and chromophobe tumors typically have an indolent course and rarely metastasize. Sarcomatoid differentiation can be seen in any histologic type and is associated with a worse prognosis. While different types of tumors may be seen in the kidney (such as transitional cell or lymphomas), the focus of this review is the primary malignancies of the renal parenchyma.

FAMILIAL SYNDROMES

Several genetic syndromes have been identified by studying families with inherited RCC. Among these, von Hippel-Lindau (VHL) gene mutation is the most commonly found inherited genetic defect. Table 1 summarizes the incidence of gene mutations and the corresponding histologic appearance of the most common sporadic and hereditary RCCs.⁴

VHL disease is an autosomal dominant familial syndrome. Patients with this mutation are at higher risk for developing RCC (clear cell histology), retinal angiomas, pheochromocytomas, as well as hemangioblastomas of the central nervous system (CNS).⁴ Of all the genetic mutations seen in RCC, the somatic mutation in the VHL tumor-suppressor gene is by far the most common.⁵ VHL targets hypoxia–inducible factor-1 alpha (HIF-α) for ubiquitination and subsequent degradation, which has been shown to suppress the growth of clear-cell RCC in mouse models.^6–8 HIF expression under hypoxic conditions leads to activation of a number of genes important in blood vessel development, cell proliferation, and glucose metabolism, including vascular endothelial growth factor (VEGF), erythropoietin, platelet-derived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), and glucose transporter-1 (GLUT-1). Mutation in the VHL gene prevents degradation of the HIF-α protein, thereby leading to increased expression of these downstream proteins, including MET and Axl. The upregulation of these angiogenic factors is thought to be the underlying process for increased vascularity of CNS hemangioblastomas and clear-cell renal tumors in VHL disease.^4–8

Other less common genetic syndromes seen in hereditary RCC include hereditary papillary RCC, hereditary leiomyomatosis, and Birt-Hogg-Dubé (BHD) syndrome.⁹ In hereditary papillary RCC, the MET gene is mutated. BHD syndrome is a rare, autosomal dominant syndrome characterized by hair follicle hamartomas of the face and neck. About 15% of patients have multiple renal tumors, the majority of which are of the chromophobe or mixed chromophobe-oncocytoma histology. The BHD gene encodes the protein folliculin, which is thought to be a tumor-suppressor gene.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 74-year-old man who works as an airplane mechanic repairman presents to the emergency department with sudden worsening of chronic right upper arm and shoulder pain after lifting a jug of orange juice. He does not have a significant past medical history and initially thought that his pain was due to a work-related injury. Upon initial evaluation in the emergency department he is found to have a fracture of his right humerus. Given that the fracture appears to be pathologic, further work-up is recommended.

Most patients are asymptomatic until the disease becomes advanced. The classic triad of flank pain, hematuria, and palpable abdominal mass is seen in approximately 10% of patients with RCC, partly because of earlier detection of renal masses by imaging performed for other purposes.¹⁰ Less frequently, patients present with signs or symptoms of metastatic disease such as bone pain or fracture (as seen in the case patient), painful adenopathy, and pulmonary symptoms related to mediastinal masses. Fever, weight loss, anemia, and/or varicocele often occur in young patients (≤ 46 years) and may indicate the presence of a hereditary form of the disease. Patients may present with paraneoplastic syndromes seen as abnormalities on routine blood work. These can include polycythemia or elevated liver function tests (LFTs) without the presence of liver metastases (known as Stauffer syndrome), which can be seen in localized renal tumors. Nearly half (45%) of patients present with localized disease, 25% present with locally advanced disease, and 30% present with metastatic disease.¹¹ Bone is the second most common site of distant metastatic spread (following lung) in patients with advanced RCC.

• What is the approach to initial evaluation for a patient with suspected RCC?

Initial evaluation consists of a physical exam, laboratory tests including complete blood count (CBC) and comprehensive metabolic panel (calcium, serum creatinine, LFTs, lactate dehydrogenase [LDH], and urinalysis), and imaging. Imaging studies include computed tomography (CT) scan with contrast of the abdomen and pelvis or magnetic resonance imaging (MRI) of the abdomen and chest imaging. A chest radiograph may be obtained, although a chest CT is more sensitive for the presence of pulmonary metastases. MRI can be used in patients with renal dysfunction to evaluate the renal vein and inferior vena cava (IVC) for thrombus or to determine the presence of local invasion.¹² Although bone and brain are common sites for metastases, routine imaging is not indicated unless the patient is symptomatic. The value of positron emission tomography in RCC remains undetermined at this time.

Staging is done according to the American Joint Committee on Cancer (AJCC) staging classification for RCC; the Figure summarizes the staging and 5-year survival data based on this classification scheme.^4,13

LIMITED-STAGE DISEASE

• What are the therapeutic options for limited-stage disease?

For patients with nondistant metastases, or limited-stage disease, surgical intervention with curative intent is considered. Convention suggests considering definitive surgery for patients with stage I and II disease, select patients with stage III disease with pathologically enlarged retroperitoneal lymph nodes, patients with IVC and/or cardiac atrium involvement of tumor thrombus, and patients with direct extension of the renal tumor into the ipsilateral adrenal gland if there is no evidence of distant disease. While there may be a role for aggressive surgical intervention in patients with distant metastatic disease, this topic will not be covered in this review.

SURGICAL INTERVENTION

Once patients are determined to be appropriate candidates for surgical removal of a renal tumor, the urologist will perform either a radical nephrectomy or a nephron-sparing nephrectomy, also called a partial nephrectomy. The urologist will evaluate the patient based on his or her body habitus, the location of the tumor, whether multiple tumors in one kidney or bilateral tumors are present, whether the patient has a solitary kidney or otherwise impaired kidney function, and whether the patient has a history of a hereditary syndrome involving kidney cancer as this affects the risk of future kidney tumors.

A radical nephrectomy is surgically preferred in the presence of the following factors: tumor larger than 7 cm in diameter, a more centrally located tumor, suspicion of lymph node involvement, tumor involvement with renal vein or IVC, and/or direct extension of the tumor into the ipsilateral adrenal gland. Nephrectomy involves ligation of the vascular supply (renal artery and vein) followed by removal of the kidney and surrounding Gerota’s fascia. The ipsilateral adrenal gland is removed if there is a high-risk for or presence of invasion of the adrenal gland. Removal of the adrenal gland is not standard since the literature demonstrates there is less than a 10% chance of solitary, ipsilateral adrenal gland involvement of tumor at the time of nephrectomy in the absence of high-risk features, and a recent systematic review suggests that the chance may be as low as 1.8%.¹⁴ Preoperative factors that correlated with adrenal involvement included upper pole kidney location, renal vein thrombosis, higher T stage (T3a and greater), multifocal tumors, and evidence for distant metastases or lymph node involvement. Lymphadenectomy previously had been included in radical nephrectomy but now is performed selectively. Radical nephrectomy may be performed as

Conversely, a nephron-sparing approach is preferred for tumors less than 7 cm in diameter, for patients with a solitary kidney or impaired renal function, for patients with multiple small ipsilateral tumors or with bilateral tumors, or for radical nephrectomy candidates with comorbidities for whom a limited intervention is deemed to be a lower-risk procedure. A nephron-sparing procedure may also be performed open or laparoscopically. In nephron-sparing procedures, the tumor is removed along with a small margin of normal parenchyma.¹⁵

In summary, the goal of surgical intervention is curative intent with removal of the tumor while maintaining as much residual renal function as possible to limit long-term morbidity of chronic kidney disease and associated cardiovascular events.¹⁸ Oncologic outcomes for radical nephrectomy and partial nephrectomy are similar. In one study, overall survival was slightly lower in the partial nephrectomy cohort, but only a small number of the deaths were due to RCC.¹⁹

ADJUVANT THERAPY

Adjuvant systemic therapy currently has no role following nephrectomy for RCC because no systemic therapy has been able to reduce the likelihood of relapse. Randomized trials of cytokine therapy (eg, interferon, interleukin 2) or tyrosine kinase inhibitors (TKIs; eg, sorafenib, sunitinib) with observation alone in patients with locally advanced completely resected RCC have shown no delay in time to relapse or improvement of survival with adjuvant therapy.²⁰ Similarly, adjuvant radiation therapy has not shown benefit even in patients with nodal involvement or incomplete resection.²¹ Therefore, observation remains the standard of care after nephrectomy.

RENAL TUMOR ABLATION

For patients who are deemed not to be surgical candidates due to age, comorbidities, or patient preference and who have tumors less than 4 cm in size (stage I tumors), ablative techniques may be considered. The 2 most well-studied and effective techniques at present are cryoablation and radiofrequency ablation (RFA). Microwave ablation may be an option in some facilities, but the data in RCC are limited. An emerging ablative technique under investigation is irreversible electroporation. At present, the long-term efficacy of all ablative techniques is unknown.

Patient selection is undertaken by urologists and interventional radiologists who evaluate the patient with ultrasound, CT, and/or MRI to determine the location and size of the tumor and the presence or absence of metastatic disease. A pretreatment biopsy is recommended to document the histology of the lesion to confirm a malignancy and to guide future treatment for recurrent or metastatic disease. Contraindications to the procedure include the presence of metastatic disease, a life expectancy of less than 1 year, general medical instability, or uncorrectable coagulopathy due to increased risk of bleeding complications. Tumors in close proximity to the renal hilum or collecting system are a contraindication to the procedure because of the risk for hemorrhage or damage to the collecting system. The location of the tumor in relation to the vasculature is also important to maximize efficacy because the vasculature acts as a “heat sink,” causing dissipation of the thermal energy. Occasionally, stenting of the proximal ureter due to upper tumor location is necessary to prevent thermal injury that could lead to urine leaks.

Selection of the modality to be used primarily depends on operator comfort, which translates to good patient outcomes, such as better cancer control and fewer complications. Cryoablation and RFA have both demonstrated good clinical efficacy and cancer control of 89% and 90%, respectively, with comparable complication rates.²² There have been no studies performed directly comparing the modalities.

Cryoablation

Cryoablation is performed through the insertion of a probe into the tumor, which may be done through a surgical or percutaneous approach. Once the probe is in place, a high- pressure gas (argon, nitrogen) is passed through the probe and upon entering a low pressure region the gas cools. The gas is able to cool to temperatures as low as –185°C. The tissue is then rewarmed through the use of helium, which conversely warms when entering a low pressure area. The process of freezing followed by rewarming subsequently causes cell death/tissue destruction through direct cell injury from cellular dehydration and vascular injury. Clinically, 2 freeze-thaw cycles are used to treat a tumor.^23,24

Radiofrequency ablation, or RFA, targets tumors via an electrode placed within the mass that produces intense frictional heat from medium-frequency alternating current (approximately 500 kHz) produced by a connected generator that is grounded on the patient. The thermal energy created causes coagulative necrosis. Due to the reliance on heat for tumor destruction, central lesions are less amenable to this approach because of the “heat sink” effect from the hilum.²⁴

Microwave Ablation

Microwave ablation, like RFA, relies on the generation of frictional heat to cause cell death by coagulative necrosis. In this case, the friction is created through the activation of water molecules; because of the different thermal kinetics involved with microwave ablation, the “heat sink” effect is minimized when treatment is employed near large vessels, in comparison to RFA.²⁴ The data on this mechanism of ablation are still maturing, with varied outcomes thus far. One study demonstrated outcomes comparable to RFA and cryoablation, with cancer-specific survival of 97.8% at 3 years.²⁵ However, a study by Castle and colleagues²⁶ demonstrated higher recurrence rates. The overarching impediment to widespread adoption of microwave ablation is inconclusive data gleaned from studies with small numbers of patients with limited follow up. The role of this modality will need to be revisited.

Irreversible Electroporation

Irreversible electroporation (IRE) is under investigation. IRE is a non-thermal ablative technique that employs rapid electrical pulses to create pores in cell membranes, leading to cell death. The postulated benefits of IRE include the lack of an effect from “heat sinks” and less collateral damage to the surrounding tissues, when compared with the thermal modalities. In a human phase 1 study of patients undergoing IRE prior to immediate surgical resection, the procedure appeared feasible and safe.²⁷ Significant concerns for this method of ablation possibly inducing cardiac arrhythmias, and the resultant need for sedation with neuromuscular blockade and associated electrocardiography monitoring, may impede its implementation in nonresearch settings.²⁴

ACTIVE SURVEILLANCE

Due to the more frequent use of imaging for various indications, there has been an increase in the discovery of small renal masses (SRM); 85% of RCC that present in an asymptomatic or incidental manner are tumors under 4 cm in diameter.^28,29 The role of active surveillance is evolving, but is primarily suggested for patients who are not candidates for more aggressive intervention based on comorbidities. A recent prospective, nonrandomized analysis of data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry evaluated outcomes for patients with SRM looking at primary intervention compared with active surveillance.³⁰ The primary intervention selected was at the discretion of the provider; treatments included partial nephrectomy, RFA, and cryoablation, and active surveillance patients were followed with imaging every 6 months. Progression of SRM, with recommendation for delayed intervention, was defined as a growth rate of mass greater than 0.5 cm/year, size greater than 4 cm, or hematuria. Thirty-six of 158 patients on active surveillance met criteria for progression; 21 underwent delayed intervention. Of note, even the patients who progressed but did not undergo delayed intervention did not develop metastatic disease during the follow-up interval. With a median follow-up of 2 years, cancer-specific survival was noted to be 99% and 100% at 5 years for primary intervention and active surveillance, respectively. Overall survival at 2 years for primary intervention was 98% and 96% for active surveillance; at 5 years, the survival rates were 92% and 75% (P = 0.06). Of note, 2 patients in the primary intervention arm died of RCC, while none in the active surveillance arm died. As would be expected, active surveillance patients were older, had a worse performance status, and had more comorbidities. Interestingly, 40% of patients enrolled selected active surveillance as their preferred management for SRM. The DISSRM results were consistent with data from the Renal Cell Consortium of Canada and other retrospective reviews.^31–33

• What is the approach to follow-up after treatment of localized RCC?

After a patient undergoes treatment for a localized RCC, the goal is to optimize oncologic outcomes, monitor for treatment sequelae, such as renal failure, and focus on survivorship. At this time, there is no consensus in the literature or across published national and international guidelines with regards to the appropriate schedule for surveillance to achieve these goals. In principle, the greatest risk for recurrence occurs within the first 3 years, so many guidelines focus on this timeframe. Likewise, the route of spread tends to be hematogenous, so patients present with pulmonary, bone, and brain metastases, in addition to local recurrence within the renal bed. Symptomatic recurrences often are seen

METASTATIC DISEASE

CASE CONTINUED

CT scan with contrast of the chest, abdomen, and pelvis as well as bone scan are done. CT of the abdomen and pelvis demonstrates a 7.8-cm left renal mass arising from the lower pole of the left kidney. Paraesophageal lymphadenopathy and mesenteric nodules are also noted. CT of the chest demonstrates bilateral pulmonary emboli. Bone scan is significant for increased activity related to the pathological fracture involving the right humerus. The patient undergoes surgery to stabilize the pathologic fracture of his humerus. He is diagnosed with metastatic RCC (clear cell histology) and undergoes palliative debulking nephrectomy.

• How is prognosis defined for metastatic RCC?

PROGNOSTIC MODELS

Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates for stage T1 and T2 disease approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.¹³ Approximately 30% of patients have metastatic disease at diagnosis, and about one-third of patients who have undergone treatment for localized disease experience relapse.^36,37 Common sites of metastases include lung, lymph nodes, bone, liver, adrenal gland, and brain.

Prognostic scoring systems have been developed to define risk groups and assist with determining appropriate therapy in the metastatic setting. The most widely used validated prognostic factor model is that from the Memorial Sloan-Kettering Cancer Center (MSKCC), which was developed using a multivariate analysis derived from data of patients enrolled in clinical trials and treated with interferon alfa.³⁸ The factors included in the MSKCC model are Karnofsky performance status less than 80, time from diagnosis to treatment with interferon alfa less than 12 months, hemoglobin level less than lower limit of laboratory’s reference range, LDH level greater than 1.5 times the upper limit of laboratory’s reference range, and corrected serum calcium level greater than 10 mg/dL. Risk groups are categorized as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors).³⁹ Median survival for favorable-, intermediate-, and poor-risk patients was 20, 10, and 4 months, respectively.⁴⁰

Another prognostic model, the International Metastatic RCC Database Consortium, or Heng, model was developed to evaluate prognosis in patients treated with VEGF-targeted therapy.⁴¹ This model was developed from a retrospective study of patients treated with sunitinib, sorafenib, and bevacizumab plus interferon alfa or prior immunotherapy. Prognostic factors in this model include 4 of the 5 MSKCC risk factors (hemoglobin level, corrected serum calcium level, Karnofsky performance status, and time to initial diagnosis). Additionally, this model includes both absolute neutrophil and platelet counts greater than the upper limit of normal. Risk groups are identified as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors). Median survival for favorable-, intermediate-, and poor-risk patients was not reached, 27 months, and 8.8 months, respectively. The University of California, Los Angeles scoring algorithm to predict survival after nephrectomy and immunotherapy (SANI) in patients with metastatic RCC is another prognostic model that can be used. This simplified scoring system incorporates lymph node status, constitutional symptoms, metastases location, histology, and thyroid stimulating hormone (TSH) level.⁴²

The role of debulking or cytoreductive nephrectomy in treatment of metastatic RCC is well established. Large randomized studies have demonstrated a statistically significant median survival benefit for patients undergoing nephrectomy plus interferon alfa therapy compared with patients treated with interferon alfa alone (13.6 months versus 7.8 months, respectively).⁴³ The role of cytoreductive nephrectomy in combination with antiangiogenic agents is less clear. While a retrospective study investigating outcomes of patients with metastatic RCC receiving anti-VEGF agents showed a prolonged survival with nephrectomy, results of large randomized trials are not yet available.^44,45 Patients with lung-only metastases, good prognostic features, and a good performance status are historically the most likely to benefit from cytoreductive surgery.

CASE CONTINUED

Based on the MSKCC prognostic factor model, the patient is considered to be in the intermediate-risk group (Karnofsky performance status of 80, calcium 9.5 mg/dL, LDH 204 U/L, hemoglobin 13.6 g/dL). He is started on treatment for his bilateral pulmonary emboli and recovers well from orthopedic surgery as well as palliative debulking nephrectomy.

Several approaches to systemic therapy for advanced RCC have been taken based on the histologic type of the tumor. Clear-cell is by far the predominant histologic type in RCC. Several options are available as first-line treatment for patients with metastatic clear-cell RCC (Table 2).^46–54 These include biologic agents such as high-dose interleukin-2 (IL-2) immune therapy, as well as targeted therapies including TKIs and anti-VEGF antibodies. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is recommended as first-line therapy in patients with poor prognosis only. Second-line therapies for clear-cell RCC following antiangiogenic therapy include TKIs, mTOR inhibitors, nivolumab (PD-1 inhibitor), and the combination of the TKI lenvatinib and mTOR inhibitor everolimus.⁵⁵ In addition, after initial cytokine therapy, TKIs, temsirolimus, and the anti-VEGF antibody bevacizumab are other treatment options available to patients. Best supportive care should always be provided along with initial and subsequent therapies. Clinical trials are also an appropriate choice as first-line or subsequent therapies. All of these therapies require periodic monitoring to prevent and quickly treat adverse effects. Table 3 lists recommended monitoring parameters for each of these agents.⁵⁶

Based on several studies, TKIs seem to be less effective in patients with non–clear-cell type histology.^57,58 In these patients, risk factors can guide therapy. In the ASPEN trial, where 108 patients were randomly assigned to everolimus or sunitinib, patients in the good- and intermediate-risk groups had longer overall and median progression-free survival (PFS) on sunitinib (8.3 months versus 5.3 months, respectively). However, those in the poor-risk group had a longer median overall survival with everolimus.⁵⁹ Given that the role of targeted therapies in non–clear-cell RCCs is less well established, enrollment in clinical trials should be considered as a first-line treatment option.²¹

Sarcomatoid features can be observed in any of the histologic types of RCC, and RCC with these features has an aggressive course and a poor prognosis. Currently, there is no standard therapy for treatment of patients with metastatic or unresectable RCC with sarcomatoid features.⁶⁰ Chemotherapeutic regimens used for soft tissue sarcomas, including a trial of ifosfamide and doxorubicin, did not show any objective response.⁶¹ A small trial of 10 patients treated with doxorubicin and gemcitabine resulted in complete response in 2 patients and partial response in 1 patient.⁶²

Enrollment in a clinical trial remains a first-line treatment option for these patients. More recently, a phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid (39 patients) and/or poor-risk (33 patients) metastatic RCC showed overall response rates (ORR) of 26% and 24%, respectively. A higher clinical benefit rate (defined as ORR plus stable disease) was seen in patients with tumors containing more than 10% sarcomatoid histology, as compared with patients whose tumors contained less than 10% sarcomatoid histology. Neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7) were the most common grade 3 toxicities seen in all the patients. Although this was a small study, the results showed a trend towards better efficacy of the combination therapy as compared with the single-agent regimen. Currently, another study is underway to further investigate this in a larger group of patients.⁶³

BIOLOGICS

Cytokine therapy, including high-dose IL-2 and interferon alfa, had long been the only first-line treatment option for patients with metastatic or unresectable RCC. Studies of high-dose IL-2 have shown an ORR of 25% and durable response in up to 11% of patients with clear-cell histology.⁶⁴ Toxicities were similar to those previously observed with high-dose IL-2 treatment; the most commonly observed grade 3 toxicities were hypotension and capillary leak syndrome. IL-2 requires strict monitoring (Table 3). It is important to note that retrospective studies evaluating the safety and efficacy of using IL-2 as second-line treatment in patients previously treated with TKIs demonstrated significant toxicity without achieving partial or complete response in any of the patients.⁶⁵

Prior to the advent of TKIs in the treatment of RCC, interferon alfa was a first-line treatment option for those who could not receive high-dose IL-2. It has been shown to produce response rates of approximately 20%, with maximum response seen with a higher dose range of 5 to 20 million units daily in 1 study.^66,67 However, with the introduction of TKIs, which produce a higher and more durable response, interferon alfa alone is no longer recommended as a treatment option.

Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo.⁶⁸ In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SC] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001).^47,48 Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.

TYROSINE KINASE INHIBITORS

TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.

Sunitinib

Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues^52,53 compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SC 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy.^69–71

Pazopanib

Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4%.⁷² This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy.⁵⁰ In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.

Sorafenib

Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy.⁷³ A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029).⁵¹ Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.

Axitinib

Axitinib is an oral inhibitor of VEGFRs 1, 2, and 3. Results of the phase 3 AXIS trial comparing axitinib (5 mg orally twice daily) with sorafenib (400 mg orally twice daily) in patients receiving 1 prior systemic therapy showed axitinib was more active than sorafenib in improving ORR (19% versus 9%; P = 0.001) and PFS (6.7 versus 4.7 months; P < 0.001), although no difference in overall survival times was noted.⁷⁴ In a subsequent phase 3 trial comparing these drugs in the first-line setting, axitinib showed a nonsignificantly higher response rate and PFS. Despite this, the National Comprehensive Cancer Network guidelines consider axitinib an acceptable first-line therapy because activity with acceptable toxicity was demonstrated (Table 2).⁴⁶ The most common adverse effects of axitinib are diarrhea, hypertension, fatigue, decreased appetite, dysphonia, hypothyroidism, and upper abdominal pain.

CABOZANTINIB

Given that resistance eventually develops in most patients treated with standard treatments, including bevacizumab and TKIs, the need to evaluate the safety and efficacy of novel agents targeting VEGFR and overcoming this resistance is of vital importance. Cabozantinib is an oral small-molecule inhibitor of VEGFR, Met, and Axl, all tyrosine kinases implicated in metastatic RCC. Overexpression of Met and Axl, which occurs as a result of inactivation of the VHL gene, is associated with a poor prognosis in patients with RCC. In a

MTOR INHIBITORS

The mTOR inhibitors, temsirolimus and everolimus, are also approved for the treatment of metastatic or advanced RCC. These drugs block mTOR’s phosphorylation and subsequent translation of mRNA to inhibit cell proliferation, cell growth, and angiogenesis.⁷⁷ Temsirolimus can be used as first-line therapy for patients with a poor prognosis, and everolimus is appropriate as a subsequent therapy.

Temsirolimus is an intravenous prodrug of rapamycin. It was the first of the class to be approved for metastatic RCC for treatment-naïve patients with a poor prognosis (ie, at least 3 of 6 predictors of poor survival based on MSKCC model).⁵⁴ The pivotal ARCC trial compared temsirolimus (25 mg IV weekly) alone, interferon alfa (3 million units SC 3 times weekly) alone, or the combination (temsirolimus 15 mg IV weekly plus interferon alfa 6 million units SC 3 times weekly). In this trial, temsirolimus monotherapy produced a significantly longer overall survival time than interferon alfa alone (10.9 versus 7.3 months; P = 0.008) and improved PFS time when administered alone or in combination with interferon alfa (3.8 and 3.7 months, respectively, versus 1.9 months). Because no real efficacy advantage of the combination was demonstrated, temsirolimus is administered alone. The most common adverse effects of temsirolimus are asthenia, rash, anemia, nausea, anorexia, pain, and dyspnea. Additionally, hyperglycemia, hyper-cholesterolemia, and hyperlipidemia occur with these agents. Noninfectious pneumonitis is a rare but often fatal complication.

Everolimus is also an orally administered derivative of rapamycin that is approved for use after failure of VEGF-targeted therapies. The results of the landmark trial RECORD-1 demonstrated that everolimus (10 mg orally daily) is effective at prolonging PFS (4 versus 1.9 months; P < 0.001) when compared with best supportive care, a viable treatment option at the time of approval.⁷⁸ The most common adverse effects of everolimus are stomatitis, rash, fatigue, asthenia, and diarrhea. As with temsirolimus, elevations in glucose, lipids, and triglycerides and noninfectious pneumonitis can occur.

TKI + MTOR INHIBITOR

Lenvatinib is also a small molecule targeting multiple tyrosine kinases, primarily VEGF2. Combined with the mTOR inhibitor everolimus, it has been shown to be an effective regimen in patients with metastatic RCC who have failed other therapies. In a randomized phase 2 study involving patients with advanced or metastatic clear-cell RCC, patients were randomly assigned to receive either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively). Patients received the treatment continuously on a 28-day cycle until progression or inability to tolerate toxicity. Patients in the lenvatinib plus everolimus arm had median PFS of 14.6 months (95% CI 5.9 to 20.1) versus 5.5 months (95% CI 3.5 to 7.1) with everlolimus alone (HR 0.40 [95% CI 0.24 to 0.68]; P = 0.0005). PFS with levantinib alone was 7.4 months (95% CI 5.6 to 10.20; HR 0.66 [95% CI 0.30 to 1.10]; P = 0.12). In addition, PFS with levantinib alone was significantly prolonged in comparison with everolimus alone (HR 0.61 [95% CI 0.38 to 0.98]; P = 0.048). Grade 3 or 4 toxicity were less frequent in the everolimus only arm and the most common grade 3 or 4 toxicity in the lenvatinib plus everolimus arm was diarrhea. The results of this study show that the combination of lenvatinib plus everolimus is an acceptable second-line option for treatment of patients with advanced or metastatic RCC.⁵⁵

 

 

CASE CONTINUED

The patient is initially started on pazopanib and tolerates the medication well, with partial response to the treatment. However, on restaging scans he is noted to have small bowel perforation. Pazopanib is discontinued until the patient has a full recovery. He is then started on everolimus. Restaging scans done 3 months after starting everolimus demonstrate disease progression.

• What is the appropriate next step in treatment?

PD1 BLOCKADE

Programmed death 1 (PD-1) protein is a T-cell inhibitory receptor with 2 ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors. Blocking the interaction between PD-1 and PD-L1 by anti-PD-1 humanized antibodies potentiates a robust immune response and has been a breakthrough in the field of cancer immunotherapy.⁷⁹ Previous studies have demonstrated that overexpression of PD-L1 leads to worse outcomes and poor prognosis in patients with RCC.⁸⁰ Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. In a randomized, open-label, phase 3 study comparing nivolumab with everolimus in patients with RCC who had previously undergone treatment with other standard therapies, Motzer and colleagues⁸¹ demonstrated a longer overall survival time and fewer adverse effects with nivolumab. In this study, 821 patients with clear-cell RCC were randomly assigned to receive nivolumab (3 mg/kg of body weight IV every 2 weeks) or everolimus (10 mg orally once daily). The median overall survival time with nivolumab was 25 months versus 19.6 months with everolimus (P < 0.0148). Nineteen percent of patients receiving nivolumab experienced grade 3 or 4 toxicities, with fatigue being the most common adverse effect. Grade 3 or 4 toxicities were observed in 37% of patients treated with everolimus, with anemia being the most common. Based on the results of this trial, on November 23, 2015, the U.S. Food and Drug Administration approved nivolumab to treat patients with metastatic RCC who have received a prior antiangiogenic therapy.

CASE CONCLUSION

Both TKI and mTOR inhibitor therapy fail, and the patient is eligible for third-line therapy. Because of his previous GI perforation, other TKIs are not an option. The patient opts for enrollment in hospice due to declining performance status. For other patients in this situation with a good performance status, nivolumab would be a reasonable option.

FUTURE DIRECTIONS

With the approval of nivolumab, multiple treatment options are now available for patients with metastatic or unresectable RCC. Development of other PD-1 inhibitors and immunotherapies as well as multi-targeted TKIs will only serve to expand treatment options for these patients. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.

INTRODUCTION

Renal cell carcinoma (RCC) is the most common malignancy arising in the kidney, comprising 90% of all renal tumors.¹ Approximately 55,000 new RCC cases are diagnosed each year.² Patients with RCC are often asymptomatic, and most cases are discovered as incidental findings on abdominal imaging performed during evaluation of nonrenal complaints. Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.² Advanced RCC is resistant to conventional chemotherapy and radiotherapy, and outcomes for patients with metastatic or unresectable RCC remain poor. However, the recent development of new therapeutic modalities that target tumor molecular pathways has expanded the treatment options for these patients and changed the management of RCC.

EPIDEMIOLOGY AND CLASSIFICATION

Median age at diagnosis in the United States is 64 years. Men have a higher incidence of RCC than women, with the highest incidence seen in American Indian and Alaska Native men (30.1 per 100,000 population). Genetic syndromes account for 2% to 4% of all RCCs.² Risk factors for RCC include smoking, hypertension, obesity, and acquired cystic kidney disease that is associated with end-stage renal failure.³ Longer duration of tobacco use is associated with a more aggressive course.

The 2004 World Health Organization (WHO) classification of renal tumors summarizes the previous classification systems (including the Heidelberg and Mainz classification systems) to describe different categories of RCC based on histologic and molecular genetics characteristics.² Using the WHO classification criteria, RCC comprises 90% of all renal tumors, with clear cell being the most common type (80%).² Other types of renal tumors include papillary, chromophobe, oncocytoma, and collecting-duct or Bellini duct tumors. Approximately 3% to 5% of tumors are unclassified. Oncocytomas are generally considered benign, and chromophobe tumors typically have an indolent course and rarely metastasize. Sarcomatoid differentiation can be seen in any histologic type and is associated with a worse prognosis. While different types of tumors may be seen in the kidney (such as transitional cell or lymphomas), the focus of this review is the primary malignancies of the renal parenchyma.

FAMILIAL SYNDROMES

Several genetic syndromes have been identified by studying families with inherited RCC. Among these, von Hippel-Lindau (VHL) gene mutation is the most commonly found inherited genetic defect. Table 1 summarizes the incidence of gene mutations and the corresponding histologic appearance of the most common sporadic and hereditary RCCs.⁴

VHL disease is an autosomal dominant familial syndrome. Patients with this mutation are at higher risk for developing RCC (clear cell histology), retinal angiomas, pheochromocytomas, as well as hemangioblastomas of the central nervous system (CNS).⁴ Of all the genetic mutations seen in RCC, the somatic mutation in the VHL tumor-suppressor gene is by far the most common.⁵ VHL targets hypoxia–inducible factor-1 alpha (HIF-α) for ubiquitination and subsequent degradation, which has been shown to suppress the growth of clear-cell RCC in mouse models.^6–8 HIF expression under hypoxic conditions leads to activation of a number of genes important in blood vessel development, cell proliferation, and glucose metabolism, including vascular endothelial growth factor (VEGF), erythropoietin, platelet-derived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), and glucose transporter-1 (GLUT-1). Mutation in the VHL gene prevents degradation of the HIF-α protein, thereby leading to increased expression of these downstream proteins, including MET and Axl. The upregulation of these angiogenic factors is thought to be the underlying process for increased vascularity of CNS hemangioblastomas and clear-cell renal tumors in VHL disease.^4–8

Other less common genetic syndromes seen in hereditary RCC include hereditary papillary RCC, hereditary leiomyomatosis, and Birt-Hogg-Dubé (BHD) syndrome.⁹ In hereditary papillary RCC, the MET gene is mutated. BHD syndrome is a rare, autosomal dominant syndrome characterized by hair follicle hamartomas of the face and neck. About 15% of patients have multiple renal tumors, the majority of which are of the chromophobe or mixed chromophobe-oncocytoma histology. The BHD gene encodes the protein folliculin, which is thought to be a tumor-suppressor gene.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 74-year-old man who works as an airplane mechanic repairman presents to the emergency department with sudden worsening of chronic right upper arm and shoulder pain after lifting a jug of orange juice. He does not have a significant past medical history and initially thought that his pain was due to a work-related injury. Upon initial evaluation in the emergency department he is found to have a fracture of his right humerus. Given that the fracture appears to be pathologic, further work-up is recommended.

Most patients are asymptomatic until the disease becomes advanced. The classic triad of flank pain, hematuria, and palpable abdominal mass is seen in approximately 10% of patients with RCC, partly because of earlier detection of renal masses by imaging performed for other purposes.¹⁰ Less frequently, patients present with signs or symptoms of metastatic disease such as bone pain or fracture (as seen in the case patient), painful adenopathy, and pulmonary symptoms related to mediastinal masses. Fever, weight loss, anemia, and/or varicocele often occur in young patients (≤ 46 years) and may indicate the presence of a hereditary form of the disease. Patients may present with paraneoplastic syndromes seen as abnormalities on routine blood work. These can include polycythemia or elevated liver function tests (LFTs) without the presence of liver metastases (known as Stauffer syndrome), which can be seen in localized renal tumors. Nearly half (45%) of patients present with localized disease, 25% present with locally advanced disease, and 30% present with metastatic disease.¹¹ Bone is the second most common site of distant metastatic spread (following lung) in patients with advanced RCC.

• What is the approach to initial evaluation for a patient with suspected RCC?

Initial evaluation consists of a physical exam, laboratory tests including complete blood count (CBC) and comprehensive metabolic panel (calcium, serum creatinine, LFTs, lactate dehydrogenase [LDH], and urinalysis), and imaging. Imaging studies include computed tomography (CT) scan with contrast of the abdomen and pelvis or magnetic resonance imaging (MRI) of the abdomen and chest imaging. A chest radiograph may be obtained, although a chest CT is more sensitive for the presence of pulmonary metastases. MRI can be used in patients with renal dysfunction to evaluate the renal vein and inferior vena cava (IVC) for thrombus or to determine the presence of local invasion.¹² Although bone and brain are common sites for metastases, routine imaging is not indicated unless the patient is symptomatic. The value of positron emission tomography in RCC remains undetermined at this time.

Staging is done according to the American Joint Committee on Cancer (AJCC) staging classification for RCC; the Figure summarizes the staging and 5-year survival data based on this classification scheme.^4,13

LIMITED-STAGE DISEASE

• What are the therapeutic options for limited-stage disease?

For patients with nondistant metastases, or limited-stage disease, surgical intervention with curative intent is considered. Convention suggests considering definitive surgery for patients with stage I and II disease, select patients with stage III disease with pathologically enlarged retroperitoneal lymph nodes, patients with IVC and/or cardiac atrium involvement of tumor thrombus, and patients with direct extension of the renal tumor into the ipsilateral adrenal gland if there is no evidence of distant disease. While there may be a role for aggressive surgical intervention in patients with distant metastatic disease, this topic will not be covered in this review.

SURGICAL INTERVENTION

Once patients are determined to be appropriate candidates for surgical removal of a renal tumor, the urologist will perform either a radical nephrectomy or a nephron-sparing nephrectomy, also called a partial nephrectomy. The urologist will evaluate the patient based on his or her body habitus, the location of the tumor, whether multiple tumors in one kidney or bilateral tumors are present, whether the patient has a solitary kidney or otherwise impaired kidney function, and whether the patient has a history of a hereditary syndrome involving kidney cancer as this affects the risk of future kidney tumors.

A radical nephrectomy is surgically preferred in the presence of the following factors: tumor larger than 7 cm in diameter, a more centrally located tumor, suspicion of lymph node involvement, tumor involvement with renal vein or IVC, and/or direct extension of the tumor into the ipsilateral adrenal gland. Nephrectomy involves ligation of the vascular supply (renal artery and vein) followed by removal of the kidney and surrounding Gerota’s fascia. The ipsilateral adrenal gland is removed if there is a high-risk for or presence of invasion of the adrenal gland. Removal of the adrenal gland is not standard since the literature demonstrates there is less than a 10% chance of solitary, ipsilateral adrenal gland involvement of tumor at the time of nephrectomy in the absence of high-risk features, and a recent systematic review suggests that the chance may be as low as 1.8%.¹⁴ Preoperative factors that correlated with adrenal involvement included upper pole kidney location, renal vein thrombosis, higher T stage (T3a and greater), multifocal tumors, and evidence for distant metastases or lymph node involvement. Lymphadenectomy previously had been included in radical nephrectomy but now is performed selectively. Radical nephrectomy may be performed as

Conversely, a nephron-sparing approach is preferred for tumors less than 7 cm in diameter, for patients with a solitary kidney or impaired renal function, for patients with multiple small ipsilateral tumors or with bilateral tumors, or for radical nephrectomy candidates with comorbidities for whom a limited intervention is deemed to be a lower-risk procedure. A nephron-sparing procedure may also be performed open or laparoscopically. In nephron-sparing procedures, the tumor is removed along with a small margin of normal parenchyma.¹⁵

In summary, the goal of surgical intervention is curative intent with removal of the tumor while maintaining as much residual renal function as possible to limit long-term morbidity of chronic kidney disease and associated cardiovascular events.¹⁸ Oncologic outcomes for radical nephrectomy and partial nephrectomy are similar. In one study, overall survival was slightly lower in the partial nephrectomy cohort, but only a small number of the deaths were due to RCC.¹⁹

ADJUVANT THERAPY

Adjuvant systemic therapy currently has no role following nephrectomy for RCC because no systemic therapy has been able to reduce the likelihood of relapse. Randomized trials of cytokine therapy (eg, interferon, interleukin 2) or tyrosine kinase inhibitors (TKIs; eg, sorafenib, sunitinib) with observation alone in patients with locally advanced completely resected RCC have shown no delay in time to relapse or improvement of survival with adjuvant therapy.²⁰ Similarly, adjuvant radiation therapy has not shown benefit even in patients with nodal involvement or incomplete resection.²¹ Therefore, observation remains the standard of care after nephrectomy.

RENAL TUMOR ABLATION

For patients who are deemed not to be surgical candidates due to age, comorbidities, or patient preference and who have tumors less than 4 cm in size (stage I tumors), ablative techniques may be considered. The 2 most well-studied and effective techniques at present are cryoablation and radiofrequency ablation (RFA). Microwave ablation may be an option in some facilities, but the data in RCC are limited. An emerging ablative technique under investigation is irreversible electroporation. At present, the long-term efficacy of all ablative techniques is unknown.

Patient selection is undertaken by urologists and interventional radiologists who evaluate the patient with ultrasound, CT, and/or MRI to determine the location and size of the tumor and the presence or absence of metastatic disease. A pretreatment biopsy is recommended to document the histology of the lesion to confirm a malignancy and to guide future treatment for recurrent or metastatic disease. Contraindications to the procedure include the presence of metastatic disease, a life expectancy of less than 1 year, general medical instability, or uncorrectable coagulopathy due to increased risk of bleeding complications. Tumors in close proximity to the renal hilum or collecting system are a contraindication to the procedure because of the risk for hemorrhage or damage to the collecting system. The location of the tumor in relation to the vasculature is also important to maximize efficacy because the vasculature acts as a “heat sink,” causing dissipation of the thermal energy. Occasionally, stenting of the proximal ureter due to upper tumor location is necessary to prevent thermal injury that could lead to urine leaks.

Selection of the modality to be used primarily depends on operator comfort, which translates to good patient outcomes, such as better cancer control and fewer complications. Cryoablation and RFA have both demonstrated good clinical efficacy and cancer control of 89% and 90%, respectively, with comparable complication rates.²² There have been no studies performed directly comparing the modalities.

Cryoablation

Cryoablation is performed through the insertion of a probe into the tumor, which may be done through a surgical or percutaneous approach. Once the probe is in place, a high- pressure gas (argon, nitrogen) is passed through the probe and upon entering a low pressure region the gas cools. The gas is able to cool to temperatures as low as –185°C. The tissue is then rewarmed through the use of helium, which conversely warms when entering a low pressure area. The process of freezing followed by rewarming subsequently causes cell death/tissue destruction through direct cell injury from cellular dehydration and vascular injury. Clinically, 2 freeze-thaw cycles are used to treat a tumor.^23,24

Radiofrequency ablation, or RFA, targets tumors via an electrode placed within the mass that produces intense frictional heat from medium-frequency alternating current (approximately 500 kHz) produced by a connected generator that is grounded on the patient. The thermal energy created causes coagulative necrosis. Due to the reliance on heat for tumor destruction, central lesions are less amenable to this approach because of the “heat sink” effect from the hilum.²⁴

Microwave Ablation

Microwave ablation, like RFA, relies on the generation of frictional heat to cause cell death by coagulative necrosis. In this case, the friction is created through the activation of water molecules; because of the different thermal kinetics involved with microwave ablation, the “heat sink” effect is minimized when treatment is employed near large vessels, in comparison to RFA.²⁴ The data on this mechanism of ablation are still maturing, with varied outcomes thus far. One study demonstrated outcomes comparable to RFA and cryoablation, with cancer-specific survival of 97.8% at 3 years.²⁵ However, a study by Castle and colleagues²⁶ demonstrated higher recurrence rates. The overarching impediment to widespread adoption of microwave ablation is inconclusive data gleaned from studies with small numbers of patients with limited follow up. The role of this modality will need to be revisited.

Irreversible Electroporation

Irreversible electroporation (IRE) is under investigation. IRE is a non-thermal ablative technique that employs rapid electrical pulses to create pores in cell membranes, leading to cell death. The postulated benefits of IRE include the lack of an effect from “heat sinks” and less collateral damage to the surrounding tissues, when compared with the thermal modalities. In a human phase 1 study of patients undergoing IRE prior to immediate surgical resection, the procedure appeared feasible and safe.²⁷ Significant concerns for this method of ablation possibly inducing cardiac arrhythmias, and the resultant need for sedation with neuromuscular blockade and associated electrocardiography monitoring, may impede its implementation in nonresearch settings.²⁴

ACTIVE SURVEILLANCE

Due to the more frequent use of imaging for various indications, there has been an increase in the discovery of small renal masses (SRM); 85% of RCC that present in an asymptomatic or incidental manner are tumors under 4 cm in diameter.^28,29 The role of active surveillance is evolving, but is primarily suggested for patients who are not candidates for more aggressive intervention based on comorbidities. A recent prospective, nonrandomized analysis of data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry evaluated outcomes for patients with SRM looking at primary intervention compared with active surveillance.³⁰ The primary intervention selected was at the discretion of the provider; treatments included partial nephrectomy, RFA, and cryoablation, and active surveillance patients were followed with imaging every 6 months. Progression of SRM, with recommendation for delayed intervention, was defined as a growth rate of mass greater than 0.5 cm/year, size greater than 4 cm, or hematuria. Thirty-six of 158 patients on active surveillance met criteria for progression; 21 underwent delayed intervention. Of note, even the patients who progressed but did not undergo delayed intervention did not develop metastatic disease during the follow-up interval. With a median follow-up of 2 years, cancer-specific survival was noted to be 99% and 100% at 5 years for primary intervention and active surveillance, respectively. Overall survival at 2 years for primary intervention was 98% and 96% for active surveillance; at 5 years, the survival rates were 92% and 75% (P = 0.06). Of note, 2 patients in the primary intervention arm died of RCC, while none in the active surveillance arm died. As would be expected, active surveillance patients were older, had a worse performance status, and had more comorbidities. Interestingly, 40% of patients enrolled selected active surveillance as their preferred management for SRM. The DISSRM results were consistent with data from the Renal Cell Consortium of Canada and other retrospective reviews.^31–33

• What is the approach to follow-up after treatment of localized RCC?

After a patient undergoes treatment for a localized RCC, the goal is to optimize oncologic outcomes, monitor for treatment sequelae, such as renal failure, and focus on survivorship. At this time, there is no consensus in the literature or across published national and international guidelines with regards to the appropriate schedule for surveillance to achieve these goals. In principle, the greatest risk for recurrence occurs within the first 3 years, so many guidelines focus on this timeframe. Likewise, the route of spread tends to be hematogenous, so patients present with pulmonary, bone, and brain metastases, in addition to local recurrence within the renal bed. Symptomatic recurrences often are seen

METASTATIC DISEASE

CASE CONTINUED

CT scan with contrast of the chest, abdomen, and pelvis as well as bone scan are done. CT of the abdomen and pelvis demonstrates a 7.8-cm left renal mass arising from the lower pole of the left kidney. Paraesophageal lymphadenopathy and mesenteric nodules are also noted. CT of the chest demonstrates bilateral pulmonary emboli. Bone scan is significant for increased activity related to the pathological fracture involving the right humerus. The patient undergoes surgery to stabilize the pathologic fracture of his humerus. He is diagnosed with metastatic RCC (clear cell histology) and undergoes palliative debulking nephrectomy.

• How is prognosis defined for metastatic RCC?

PROGNOSTIC MODELS

Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates for stage T1 and T2 disease approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.¹³ Approximately 30% of patients have metastatic disease at diagnosis, and about one-third of patients who have undergone treatment for localized disease experience relapse.^36,37 Common sites of metastases include lung, lymph nodes, bone, liver, adrenal gland, and brain.

Prognostic scoring systems have been developed to define risk groups and assist with determining appropriate therapy in the metastatic setting. The most widely used validated prognostic factor model is that from the Memorial Sloan-Kettering Cancer Center (MSKCC), which was developed using a multivariate analysis derived from data of patients enrolled in clinical trials and treated with interferon alfa.³⁸ The factors included in the MSKCC model are Karnofsky performance status less than 80, time from diagnosis to treatment with interferon alfa less than 12 months, hemoglobin level less than lower limit of laboratory’s reference range, LDH level greater than 1.5 times the upper limit of laboratory’s reference range, and corrected serum calcium level greater than 10 mg/dL. Risk groups are categorized as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors).³⁹ Median survival for favorable-, intermediate-, and poor-risk patients was 20, 10, and 4 months, respectively.⁴⁰

Another prognostic model, the International Metastatic RCC Database Consortium, or Heng, model was developed to evaluate prognosis in patients treated with VEGF-targeted therapy.⁴¹ This model was developed from a retrospective study of patients treated with sunitinib, sorafenib, and bevacizumab plus interferon alfa or prior immunotherapy. Prognostic factors in this model include 4 of the 5 MSKCC risk factors (hemoglobin level, corrected serum calcium level, Karnofsky performance status, and time to initial diagnosis). Additionally, this model includes both absolute neutrophil and platelet counts greater than the upper limit of normal. Risk groups are identified as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors). Median survival for favorable-, intermediate-, and poor-risk patients was not reached, 27 months, and 8.8 months, respectively. The University of California, Los Angeles scoring algorithm to predict survival after nephrectomy and immunotherapy (SANI) in patients with metastatic RCC is another prognostic model that can be used. This simplified scoring system incorporates lymph node status, constitutional symptoms, metastases location, histology, and thyroid stimulating hormone (TSH) level.⁴²

The role of debulking or cytoreductive nephrectomy in treatment of metastatic RCC is well established. Large randomized studies have demonstrated a statistically significant median survival benefit for patients undergoing nephrectomy plus interferon alfa therapy compared with patients treated with interferon alfa alone (13.6 months versus 7.8 months, respectively).⁴³ The role of cytoreductive nephrectomy in combination with antiangiogenic agents is less clear. While a retrospective study investigating outcomes of patients with metastatic RCC receiving anti-VEGF agents showed a prolonged survival with nephrectomy, results of large randomized trials are not yet available.^44,45 Patients with lung-only metastases, good prognostic features, and a good performance status are historically the most likely to benefit from cytoreductive surgery.

CASE CONTINUED

Based on the MSKCC prognostic factor model, the patient is considered to be in the intermediate-risk group (Karnofsky performance status of 80, calcium 9.5 mg/dL, LDH 204 U/L, hemoglobin 13.6 g/dL). He is started on treatment for his bilateral pulmonary emboli and recovers well from orthopedic surgery as well as palliative debulking nephrectomy.

Several approaches to systemic therapy for advanced RCC have been taken based on the histologic type of the tumor. Clear-cell is by far the predominant histologic type in RCC. Several options are available as first-line treatment for patients with metastatic clear-cell RCC (Table 2).^46–54 These include biologic agents such as high-dose interleukin-2 (IL-2) immune therapy, as well as targeted therapies including TKIs and anti-VEGF antibodies. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is recommended as first-line therapy in patients with poor prognosis only. Second-line therapies for clear-cell RCC following antiangiogenic therapy include TKIs, mTOR inhibitors, nivolumab (PD-1 inhibitor), and the combination of the TKI lenvatinib and mTOR inhibitor everolimus.⁵⁵ In addition, after initial cytokine therapy, TKIs, temsirolimus, and the anti-VEGF antibody bevacizumab are other treatment options available to patients. Best supportive care should always be provided along with initial and subsequent therapies. Clinical trials are also an appropriate choice as first-line or subsequent therapies. All of these therapies require periodic monitoring to prevent and quickly treat adverse effects. Table 3 lists recommended monitoring parameters for each of these agents.⁵⁶

Based on several studies, TKIs seem to be less effective in patients with non–clear-cell type histology.^57,58 In these patients, risk factors can guide therapy. In the ASPEN trial, where 108 patients were randomly assigned to everolimus or sunitinib, patients in the good- and intermediate-risk groups had longer overall and median progression-free survival (PFS) on sunitinib (8.3 months versus 5.3 months, respectively). However, those in the poor-risk group had a longer median overall survival with everolimus.⁵⁹ Given that the role of targeted therapies in non–clear-cell RCCs is less well established, enrollment in clinical trials should be considered as a first-line treatment option.²¹

Sarcomatoid features can be observed in any of the histologic types of RCC, and RCC with these features has an aggressive course and a poor prognosis. Currently, there is no standard therapy for treatment of patients with metastatic or unresectable RCC with sarcomatoid features.⁶⁰ Chemotherapeutic regimens used for soft tissue sarcomas, including a trial of ifosfamide and doxorubicin, did not show any objective response.⁶¹ A small trial of 10 patients treated with doxorubicin and gemcitabine resulted in complete response in 2 patients and partial response in 1 patient.⁶²

Enrollment in a clinical trial remains a first-line treatment option for these patients. More recently, a phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid (39 patients) and/or poor-risk (33 patients) metastatic RCC showed overall response rates (ORR) of 26% and 24%, respectively. A higher clinical benefit rate (defined as ORR plus stable disease) was seen in patients with tumors containing more than 10% sarcomatoid histology, as compared with patients whose tumors contained less than 10% sarcomatoid histology. Neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7) were the most common grade 3 toxicities seen in all the patients. Although this was a small study, the results showed a trend towards better efficacy of the combination therapy as compared with the single-agent regimen. Currently, another study is underway to further investigate this in a larger group of patients.⁶³

BIOLOGICS

Cytokine therapy, including high-dose IL-2 and interferon alfa, had long been the only first-line treatment option for patients with metastatic or unresectable RCC. Studies of high-dose IL-2 have shown an ORR of 25% and durable response in up to 11% of patients with clear-cell histology.⁶⁴ Toxicities were similar to those previously observed with high-dose IL-2 treatment; the most commonly observed grade 3 toxicities were hypotension and capillary leak syndrome. IL-2 requires strict monitoring (Table 3). It is important to note that retrospective studies evaluating the safety and efficacy of using IL-2 as second-line treatment in patients previously treated with TKIs demonstrated significant toxicity without achieving partial or complete response in any of the patients.⁶⁵

Prior to the advent of TKIs in the treatment of RCC, interferon alfa was a first-line treatment option for those who could not receive high-dose IL-2. It has been shown to produce response rates of approximately 20%, with maximum response seen with a higher dose range of 5 to 20 million units daily in 1 study.^66,67 However, with the introduction of TKIs, which produce a higher and more durable response, interferon alfa alone is no longer recommended as a treatment option.

Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo.⁶⁸ In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SC] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001).^47,48 Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.

TYROSINE KINASE INHIBITORS

TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.

Sunitinib

Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues^52,53 compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SC 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy.^69–71

Pazopanib

Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4%.⁷² This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy.⁵⁰ In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.

Sorafenib

Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy.⁷³ A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029).⁵¹ Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.

Axitinib

Axitinib is an oral inhibitor of VEGFRs 1, 2, and 3. Results of the phase 3 AXIS trial comparing axitinib (5 mg orally twice daily) with sorafenib (400 mg orally twice daily) in patients receiving 1 prior systemic therapy showed axitinib was more active than sorafenib in improving ORR (19% versus 9%; P = 0.001) and PFS (6.7 versus 4.7 months; P < 0.001), although no difference in overall survival times was noted.⁷⁴ In a subsequent phase 3 trial comparing these drugs in the first-line setting, axitinib showed a nonsignificantly higher response rate and PFS. Despite this, the National Comprehensive Cancer Network guidelines consider axitinib an acceptable first-line therapy because activity with acceptable toxicity was demonstrated (Table 2).⁴⁶ The most common adverse effects of axitinib are diarrhea, hypertension, fatigue, decreased appetite, dysphonia, hypothyroidism, and upper abdominal pain.

CABOZANTINIB

Given that resistance eventually develops in most patients treated with standard treatments, including bevacizumab and TKIs, the need to evaluate the safety and efficacy of novel agents targeting VEGFR and overcoming this resistance is of vital importance. Cabozantinib is an oral small-molecule inhibitor of VEGFR, Met, and Axl, all tyrosine kinases implicated in metastatic RCC. Overexpression of Met and Axl, which occurs as a result of inactivation of the VHL gene, is associated with a poor prognosis in patients with RCC. In a

MTOR INHIBITORS

The mTOR inhibitors, temsirolimus and everolimus, are also approved for the treatment of metastatic or advanced RCC. These drugs block mTOR’s phosphorylation and subsequent translation of mRNA to inhibit cell proliferation, cell growth, and angiogenesis.⁷⁷ Temsirolimus can be used as first-line therapy for patients with a poor prognosis, and everolimus is appropriate as a subsequent therapy.

Temsirolimus is an intravenous prodrug of rapamycin. It was the first of the class to be approved for metastatic RCC for treatment-naïve patients with a poor prognosis (ie, at least 3 of 6 predictors of poor survival based on MSKCC model).⁵⁴ The pivotal ARCC trial compared temsirolimus (25 mg IV weekly) alone, interferon alfa (3 million units SC 3 times weekly) alone, or the combination (temsirolimus 15 mg IV weekly plus interferon alfa 6 million units SC 3 times weekly). In this trial, temsirolimus monotherapy produced a significantly longer overall survival time than interferon alfa alone (10.9 versus 7.3 months; P = 0.008) and improved PFS time when administered alone or in combination with interferon alfa (3.8 and 3.7 months, respectively, versus 1.9 months). Because no real efficacy advantage of the combination was demonstrated, temsirolimus is administered alone. The most common adverse effects of temsirolimus are asthenia, rash, anemia, nausea, anorexia, pain, and dyspnea. Additionally, hyperglycemia, hyper-cholesterolemia, and hyperlipidemia occur with these agents. Noninfectious pneumonitis is a rare but often fatal complication.

Everolimus is also an orally administered derivative of rapamycin that is approved for use after failure of VEGF-targeted therapies. The results of the landmark trial RECORD-1 demonstrated that everolimus (10 mg orally daily) is effective at prolonging PFS (4 versus 1.9 months; P < 0.001) when compared with best supportive care, a viable treatment option at the time of approval.⁷⁸ The most common adverse effects of everolimus are stomatitis, rash, fatigue, asthenia, and diarrhea. As with temsirolimus, elevations in glucose, lipids, and triglycerides and noninfectious pneumonitis can occur.

TKI + MTOR INHIBITOR

Lenvatinib is also a small molecule targeting multiple tyrosine kinases, primarily VEGF2. Combined with the mTOR inhibitor everolimus, it has been shown to be an effective regimen in patients with metastatic RCC who have failed other therapies. In a randomized phase 2 study involving patients with advanced or metastatic clear-cell RCC, patients were randomly assigned to receive either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively). Patients received the treatment continuously on a 28-day cycle until progression or inability to tolerate toxicity. Patients in the lenvatinib plus everolimus arm had median PFS of 14.6 months (95% CI 5.9 to 20.1) versus 5.5 months (95% CI 3.5 to 7.1) with everlolimus alone (HR 0.40 [95% CI 0.24 to 0.68]; P = 0.0005). PFS with levantinib alone was 7.4 months (95% CI 5.6 to 10.20; HR 0.66 [95% CI 0.30 to 1.10]; P = 0.12). In addition, PFS with levantinib alone was significantly prolonged in comparison with everolimus alone (HR 0.61 [95% CI 0.38 to 0.98]; P = 0.048). Grade 3 or 4 toxicity were less frequent in the everolimus only arm and the most common grade 3 or 4 toxicity in the lenvatinib plus everolimus arm was diarrhea. The results of this study show that the combination of lenvatinib plus everolimus is an acceptable second-line option for treatment of patients with advanced or metastatic RCC.⁵⁵

 

 

CASE CONTINUED

The patient is initially started on pazopanib and tolerates the medication well, with partial response to the treatment. However, on restaging scans he is noted to have small bowel perforation. Pazopanib is discontinued until the patient has a full recovery. He is then started on everolimus. Restaging scans done 3 months after starting everolimus demonstrate disease progression.

• What is the appropriate next step in treatment?

PD1 BLOCKADE

Programmed death 1 (PD-1) protein is a T-cell inhibitory receptor with 2 ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors. Blocking the interaction between PD-1 and PD-L1 by anti-PD-1 humanized antibodies potentiates a robust immune response and has been a breakthrough in the field of cancer immunotherapy.⁷⁹ Previous studies have demonstrated that overexpression of PD-L1 leads to worse outcomes and poor prognosis in patients with RCC.⁸⁰ Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. In a randomized, open-label, phase 3 study comparing nivolumab with everolimus in patients with RCC who had previously undergone treatment with other standard therapies, Motzer and colleagues⁸¹ demonstrated a longer overall survival time and fewer adverse effects with nivolumab. In this study, 821 patients with clear-cell RCC were randomly assigned to receive nivolumab (3 mg/kg of body weight IV every 2 weeks) or everolimus (10 mg orally once daily). The median overall survival time with nivolumab was 25 months versus 19.6 months with everolimus (P < 0.0148). Nineteen percent of patients receiving nivolumab experienced grade 3 or 4 toxicities, with fatigue being the most common adverse effect. Grade 3 or 4 toxicities were observed in 37% of patients treated with everolimus, with anemia being the most common. Based on the results of this trial, on November 23, 2015, the U.S. Food and Drug Administration approved nivolumab to treat patients with metastatic RCC who have received a prior antiangiogenic therapy.

CASE CONCLUSION

Both TKI and mTOR inhibitor therapy fail, and the patient is eligible for third-line therapy. Because of his previous GI perforation, other TKIs are not an option. The patient opts for enrollment in hospice due to declining performance status. For other patients in this situation with a good performance status, nivolumab would be a reasonable option.

FUTURE DIRECTIONS

With the approval of nivolumab, multiple treatment options are now available for patients with metastatic or unresectable RCC. Development of other PD-1 inhibitors and immunotherapies as well as multi-targeted TKIs will only serve to expand treatment options for these patients. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.