Oncology

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.

Immune checkpoint inhibitors (ICIs) have become important in oncology and represent an evolving area of therapeutics. Since their approval by the US Food and Drug Administration (FDA) in 2011, ICIs have been increasingly used as modalities in neoadjuvant and adjuvant treatment for resectable solid malignancies and in unresectable disease, such as advanced melanoma, and are associated with improved survival.¹

Immune checkpoints are present on the cell surface of activated T cells as well as other immune cells like B cells and natural killer cells. By regulating the length and amplitude of the body’s innate immune response, they maintain immune homeostasis and prevent its overactivation. Immune checkpoints are often thought of as the brakes on the immune system.²

Two glycoproteins that act as immune checkpoints and are targeted by ICIs are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is upregulated on activated T cells. PD-1 is also expressed on activated T cells, as well as macrophages, B cells, and dendritic cells. Cancer cells can evade immune surveillance by exploiting immune checkpoint pathways. Inhibition of these checkpoints with ICIs reactivates T cells and enables the immune system to recognize and attack cancer cells more effectively. Ipilimumab blocks the activity of CTLA-4 on T cells. Nivolumab and pembrolizumab block the interaction between PD-1 on T cells and its ligand PD-L1 on cancer cells.^3,4

Inhibition of these checkpoints is often effective in cancer treatment but can result in the loss of immunologic tolerance with resultant immune-related adverse events (irAEs) and potentially permanent autoimmune disorders. Autoreactive T cells can damage host cell tissues including the colon, lungs, liver, pituitary gland, thyroid, and skin. Severe irAEs include type 1 diabetes mellitus, myositis, nephritis, colitis, pneumonitis, hepatitis, uveitis, hypophysitis, and adrenalitis.⁴

Hypophysitis is inflammation of the pituitary gland, often with thickening of the pituitary stalk, resulting in dysfunction and hormone deficiencies. While primary hypophysitis is idiopathic, secondary hypophysitis is the result of an underlying condition such as exposure to an ICI. Immune-mediated inflammation of the pituitary gland in hypophysitis may disrupt corticotroph function, leading to adrenocorticotropic hormone (ACTH) deficiency. Early warning features are often vague and nonspecific, such as headache, fatigue, and weakness, which makes diagnosis challenging.^3,5

CASE PRESENTATION

A 73-year-old male veteran with a history of metastatic melanoma on ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks (a standard combination regimen for advanced melanoma) presented to the emergency department (ED) with 2 weeks of cough, nausea, and severe headache 3 weeks after cycle 2 of combination ICI therapy. The patient had undergone excision of multiple sites of melanoma in situ with recurrence and disease progression after 5 cycles of pembrolizumab. He was subsequently started on combination ICI therapy.

On ED arrival, the patient was afebrile and saturating well on room air. He was normotensive but found to have orthostatic blood pressure. Physical examination was remarkable for dry oral mucosa and decreased skin turgor. Initial laboratory results were significant for hyponatremia of 123 mmol/L (reference range, 136-145 mmol/L), low-normal free thyroxine (T4) level of 0.5 ng/dL (reference range, 0.6-1.2 ng/dL), a low total triiodothyronine level of 32.14 ng/dL (reference range, 85-178 ng/dL), and a low thyrotropin level of 0.19 mIU/L (reference range, 0.35-5.50 mIU/L). Serum osmolarity was low at 259 mOsm/kg (reference range, 285-315 mOsm/kg), urine sodium was high at 168 mEq/L (reference, 20 mEq/L), and urine osmolarity was inappropriately concentrated at 726 mOsm/kg (reference range, 250-1000 mOsm/kg). The patient was admitted for additional testing. His morning cortisol level was within normal limits at 15 mcg/dL (reference range, 6.7-22.5 mcg/dL).

Computed tomography (CT) of the patient’s head revealed no acute findings. Chest CT revealed posterior right lower lobe mild ground-glass opacities, with possible ICI-induced pneumonitis. The patient received fluid resuscitation. Given concern for syndrome of inappropriate antidiuretic hormone secretion, the patient was started on 3 g salt tablets 3 times a day and urea 30 g powder daily. The etiology of the abnormal thyroid levels was unclear to endocrinology at that time. The differential diagnosis included a nonthyroidal illness or central hypothyroidism.

The patient started levothyroxine 75 mcg due to abnormal thyroid levels and persistent fatigue and fludrocortisone 0.1 mg daily to manage orthostatic hypotension. His sodium levels improved to 132 mmol/L over 6 days and he was discharged with levothyroxine 75 mcg daily, fludrocortisone 0.1 mg daily, 3 g salt tabs 3 times a day, urea 30 g powder daily, as well as oral cefpodoxime 500 mg twice daily for 3 days and azithromycin 500 mg once daily for 2 days (for a total of 10 days of antibiotic therapy) to treat potential occult pneumonia.

The patient returned to the ED 3 days after discharge following an outpatient oncology appointment with ongoing severe headaches and persistent nausea. There was concern for recurrent hyponatremia. His sodium level was within normal limits at 133 mmol/L. Repeat morning cortisol was low-normal at 9 mcg/dL. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease, but showed a slight interval increase in size of the pituitary gland compared with an MRI from 6 months prior, with mild fullness and a slightly convex superior margin near homogeneous enhancement, raising concern for infection or hypophysitis (Figure 1).

The patient was readmitted to the general medicine service and was given intravenous hydrocortisone 100 mg every 8 hours because of concern for central adrenal insufficiency due to grade 3 hypophysitis in the setting of MRI imaging and severe headaches (Table 1). He was not hypotensive at the time of hydrocortisone initiation and other vital signs were stable. A cosyntropin stimulation test—a standard diagnostic test for central adrenal insufficiency—was not performed because the patient had already started high-dose hydrocortisone. The patient’s free T4 on this admission remained low at 0.6 ng/dL.

No adjustments were made to his levothyroxine dose given that he recently began the medication and levels may lag after initiation. After a 4-day hospitalization, the decision was made to continue with the steroid taper and follow up with outpatient endocrinology to obtain a cosyntropin stimulation test to complete a full assessment of his pituitary axis (Figure 2). Repeat thyroid function testing for levothyroxine titration was arranged. The levothyroxine dosage was later increased to 88 mcg daily, but the patient discontinued the medication and remained euthyroid. Endocrinology attributed a nonthyroidal illness as the etiology of his hypothyroidism, likely euthyroid sick syndrome in the setting of illness. His hydrocortisone was tapered during outpatient care and fludrocortisone was discontinued due to hypertension.

One month after his second discharge, the patient presented to the ED with 2 weeks of dizziness, associated lightheadedness, and blurred vision when standing from a sitting position. Upon assessment, symptoms were attributed to poor oral intake. The patient’s vital signs were again positive for orthostatic hypotension, though refractory to adequate fluid replacement. Laboratory testing was significant for a low ACTH level of 3.0 pg/mL (reference range, 7.2-63.3 pg/mL). Given that the patient had not received steroids for 1 week, he underwent a cosyntropin stimulation test, which revealed a blunted response supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis (Table 2).

The patient was again readmitted to the general medicine service. A brain MRI showed interval shrinkage of the pituitary gland compared to imaging one month prior, which was attributed to hydrocortisone treatment during this month. CT of the patient’s abdomen demonstrated normal-sized adrenal glands. Positron emission tomography (PET)/CT showed no evidence of pituitary or adrenal metastases. Endocrinology recommended reinitiating oral hydrocortisone 50 mg in the morning and 50 mg around 3 pm daily with fludrocortisone 0.2 mg once daily, which resulted in near resolution of the patient’s symptoms. He was discharged after a 14-day hospitalization with home physical therapy services and endocrinology, nephrology, and oncology follow-up appointments.

The patient was readmitted twice to the general medicine service over the next 6 months for complications from hydrocortisone and fludrocortisone treatment including hypokalemia. He followed up with outpatient clinicians until his death 14 months later. He did not restart ICI therapy, and eventually joined a clinical trial for other advanced melanoma treatments at another institution. The patient’s family consented to the publication of this case report with the accompanying images.

DISCUSSION

The combination of ipilimumab (anti-CTLA-4 monoclonal antibody) and nivolumab (anti-PD-1 monoclonal antibody) is FDA-approved for treatment of advanced melanoma with the goal of harnessing complementary and synergistic mechanisms of dual therapy.^6-8 Combination therapy, however, can increase the incidence of irAEs, which are often endocrine-related and more common in patients treated with dual immunotherapy than with monotherapy.⁹ Hypophysitis has the lowest reported fatality rate among ICI-related irAEs (< 1%), compared with higher mortality rates seen in myocarditis (25%-50%) and pneumonitis (10%-20%).^4,10

The patient initially presented with ICI-related hypothyroidism, later identified as secondary (central) hypothyroidism. He was treated with levothyroxine until central hypothyroidism was confirmed. Subsequently, the patient developed headache, poor appetite, and lightheadedness, with MRI findings suggestive of hypophysitis, for which he was started on hydrocortisone. A component of primary adrenal insufficiency was initially considered, given the low ACTH level and blunted response to cosyntropin stimulation following prior high-dose steroid therapy. However, CT imaging demonstrated normal adrenal morphology without atrophy, supporting a diagnosis of central adrenal insufficiency secondary to ICI-induced hypophysitis.

The estimated incidence of ICI-induced hypophysitis is 1.5% to 13.3% with anti-CTLA-4 agents, 0.3% to 3.0% with anti-PD-1 agents, and can be as high as 12.8% with combination therapy.¹ ICI-induced hypophysitis is believed to arise from the direct binding of ICI antibodies to their targets on anterior pituitary cells, such as corticotrophs, thyrotrophs, and gonadotrophs, triggering an immune response. One theory for targeting these cells is high CTLA-4 expression in the anterior pituitary gland.¹¹ PD-1 therapies tend to manifest as either hypothyroidism, hyperthyroidism, Graves’ disease, diabetes, or adrenal insufficiency.¹⁰

A concern in patients with advanced melanoma is metastasis. Melanoma has a high propensity for brain metastasis.¹² There was moderate suspicion for pituitary gland metastasis in this case, though pituitary metastasis more often manifests with symptoms of posterior pituitary gland deficiency, such as polyuria and polydipsia.¹³ The adrenal gland is the fourth-most common site for melanoma metastases, after the lung, liver, and bone.¹⁴ This patient had no evidence of pituitary or adrenal metastases on PET/CT. Therefore, his symptoms were most likely due to ICI therapy. Cases of ≥ 1 endocrine dysfunction have been reported as an ICI therapy irAE.¹⁵ In these situations, diagnosing primary and central adrenal insufficiency in the same patient is complex because hormone profiles are intertwined.

Many patients who develop hypophysitis from ICI therapy will require permanent replacement therapy. It is unclear whether low-dose replacement steroids have a significant effect on the efficacy of ICIs. Given that ICI treatment works by enhancing the immune system, medications that suppress the body’s immune system, such as steroids, could interfere with treatment efficacy. However, there are speculations that the development of irAEs is an indicator of effective treatment. In a phase 1 trial of a CTLA-4 blocker in patients with metastatic melanoma, there was a correlation between reduced CTLA-4 expression as well as low rates of melanoma recurrence and a higher incidence of irAEs.¹⁶

When assessing patients on ICI treatment, clinicians must remain vigilant for all potential irAEs, especially in patients receiving combination therapy. ICI-induced irAEs can present with vague and nonspecific symptoms. Concurrent endocrine irAEs, such as hypophysitis with thyroiditis or adrenalitis, are not uncommon in combination therapy and can complicate interpretation of hormone profiles. It is prudent for clinicians to review known risk factors. Hypophysitis is typically associated with older adult male patients.^17,18

The irAEs of ICI therapy deeply affected the quality of life of the patient in this case, as he was often experiencing many of the clinical symptoms of his hormone insufficiencies as well as the treatment modalities, thus requiring repeated hospital admissions. The risks and benefits of continuing ICI therapy should be an ongoing discussion between the physician and patient and should take into account the acuity and severity of irAEs and oncological disease burden, among other variables. Given the severity of his AEs, the patient stopped ICI therapy and instead opted to enroll in a clinical trial at another institution for continued alternative treatments.

CONCLUSIONS

This case offers a lesson in the diagnostic challenges of vague symptoms in patients with cancer who are receiving ICI therapy. ICI therapy is widely used in the treatment of solid malignancies, and as its use increases, it is expected that clinicians will likely see more cases of irAEs in hospitalized patients. The vague presentation of irAEs can often lead to treatment delays, especially when > 1 irAE presents concurrently. There are ongoing studies researching potential ways to predict the likelihood of developing these irAEs. It is imperative that clinicians are aware of these ICI-related complications and that more research be conducted to understand patient quality of life and treatment guidance based on irAE severity and disease burden.

Precision oncology (PO) is cancer treatment individualized to the special characteristics of a patient’s tumor. It has become standard care for most patients with advanced cancer. Advances in molecular cell biology and immunology have identified numerous targets and many therapies have been developed as a result. Molecular testing and targeted therapy are typically covered by insurance, even when inflation-adjusted price growth is considered.¹ Barriers remain, however, and pathologists are uniquely qualified to address some of the challenges.²

Most US laboratories do not perform molecular diagnostic tests for PO, particularly comprehensive evaluation of multiple targets by next-generation sequencing, or other techniques. Instead, these tests are sent to reference laboratories. The workload associated with referral testing is an obstacle to increased use of such tests. Despite guideline recommendations, a minority of indicated tests are performed.³ This is true even when testing costs are covered by clinical trials or grants, such as those in the Veterans Health Administration (VHA).

The main characteristic of successful PO programs is a multidisciplinary commitment, including pathology involvement in molecular tumor boards and assistance with test selection, tissue collection, and result interpretation.² This, however, adds to the workload for the pathology department, an underappreciated phenomenon in the context of pathology workforce shortages.⁴

Workforce shortages impact all occupations in the laboratory setting. Though the shortage of medical technologists in clinical pathology laboratories has repeatedly been identified as critical at the VHA as well as in the private sector, the same cannot be said for staff shortages in anatomic pathology laboratories. Thus, the hospital laboratory divisions are concerned with biopsy or resection tissue specimens as opposed to the bodily fluid specimens that predominate in clinical laboratories.⁵ The lack of accurate data on histopathology technicians and technologists has precluded the degree of recognition seen for medical technologists. In labor statistics, these occupations are often obscured by inclusion with other jobs in broad categories such as medical and clinical laboratory technologists and technicians.⁶ Vacancy—the principal metric used to assess medical laboratory workforce shortage—fails to account for positions that are eventually eliminated after remaining vacant for prolonged periods, positions not replaced as a result of ambitious efficiency measures, or positions that were never created due to insufficient funding, reasons for administrative disapproval, or coverage by laboratory professionals working extra shifts or second jobs.⁷

Increased demand for pathologists is suggested by a 42% increase in workload per pathologist over the last decade, while a shortage is suggested by decreases in absolute and population-adjusted numbers of pathologists.^8,9 An influx of pathologists is not an expected remedy due to the global decline in medical graduates pursuing careers in the field.⁸

Approximations for required labor and potential revenue generation are necessary to justify creation of pathology positions. This work mostly has gone uncaptured due to the limitations of Current Procedural Terminology (CPT) codes. Few laboratories have consistently used the 88363, 88325, and G0452 CPT codes. The pathology clinical consultation CPT codes (80503-80506) released in 2022 enhance acquisition of this work. The new codes replace 80500 and 80502 and allow for more precise identification of any work requiring medical judgment that a pathologist does at the request of another qualified health care professional (HCP) or as required by federal or state regulation.

The codes can be used to bill for associated time spent reviewing health records, communicating with other HCPs, placing orders, and documentation. An HCP can bill according to level of medical decision-making (MDM) or time spent by the consulting pathologist. Code 80503 can be billed for 5 to 20 minutes of a pathologist's time, 80504 for 21 to 40 minutes, 80505 for 41 to 60 minutes, and 80506 for each additional 30 minutes after the first hour. Levels of MDM (low, moderate, and high) are defined as for other evaluation and management services. A consultation report must be generated and contain documentation of the consultation request, pathologist interpretation, and justification for the level of service associated with the chosen code. Relative value units (RVUs) and reimbursement associated with each as well as other consultation-related codes are available in Table 1.

This article outlines how the pathology time investment associated with anatomic pathology molecular testing at the Kansas City Veterans Affairs Medical Center (KCVAMC) can be captured using the consultation process and new CPT codes. Staff included 4 pathologists, 3 histotechnologists, 1 histology supervisor, 1 grossing room technician, and 1 cytotechnologist, 1 cytology technician.

METHODS

The AP molecular testing consultation process at the KCVAMC was mapped, with the average time measured for each step (Figure). AP records for 2021 were reviewed to determine the number of AP molecular send out tests. Cumulative time investment was calculated in hours and a theoretical number of RVUs was calculated using the new pathology clinical consultation CPT codes (80503-80506). This theoretical number of RVUs was compared with the total AP RVUs generated in 2021 to determine a potential increase in RVUs with use of the new CPT codes to capture pathology work associated with AP molecular testing consultations.

RESULTS

From 2021 to 2023, there were 21,021 AP cases at the KCVAMC. Basal cell carcinomas and squamous cell carcinomas of the skin were excluded because they comprise most cancer cases but almost never necessitate AP molecular test consultations. A total of 2118 cancer cases were included, representing 10.1% of all cases. Ancillary AP molecular send-out tests were performed on 1338 (6.4%) cases. Since ancillary tissue tests are requested by consultation at the KCVAMC, this resulted in 1338 consultations (Table 2).

The time to complete a consultation was measured by calculating the mean time required to complete each step (Table 3). With in-house specimen consultations requiring 90 minutes each and outside specimen consultations requiring 100 minutes each, a total of 2040 hours of pathology staff time was necessary to complete associated consultations. Billing for this time with the new pathology clinical consultation CPT codes would generate 3847 RVUs, which would have equated to 14.8% (3847/25,920) of the anatomic pathology RVUs.

DISCUSSION

When considering the lengths of time for tasks associated with each consultation, it is important to remember that the volume (2-3 daily), was insufficient to meaningfully benefit from batching. Thus, waiting to perform a particular task until it was needed for multiple cases reduced the inefficiency associated with starting and switching between tasks. Both the Computerized Patient Record System and VistA had to be reopened, reauthenticated, and reloaded for each step that required use of the health record, printer, or fax machine. Faxes also required waiting for transmission and printed confirmation of successful transmission. As a result, the time values denoted for each step are likely underestimated, as the effect of interruptions is significant and not reflected in the estimates recorded.¹⁰

This analysis has demonstrated that PO entails a significant amount of work for pathology departments. To determine and maintain appropriate staffing models, this work must be captured and reimbursed. Unlike other pathology work, which is performed in-house and reimbursed for the associated test, a significant proportion of PO testing is sent out. Even if more reliable assays are developed, the physical processes of sending out samples and reporting test results cannot be outsourced. Independent and commensurate reimbursement methods are necessary to allow for this work and PO.

CMS included new pathology clinical consultation codes that may be used to bill for some of this work according to the 2022 physician fee schedule due to advocacy work by the College of American Pathologists and the American Medical Association CPT editorial panel.¹¹

CONCLUSIONS

This analysis found that adoption of PO may present a significant amount of additional work for pathology departments. To determine and maintain appropriate staffing models, work completed by pathologists in this manner must be recorded and reimbursed. Pathologists need to be trained and encouraged to use these CPT codes and bill for the work described in this article. The increased revenue will allow for additional positions to alleviate the burdens imposed by understaffing so that pathology can function as a facilitator of PO rather than as a barrier to it.

Precision oncology (PO) is cancer treatment individualized to the special characteristics of a patient’s tumor. It has become standard care for most patients with advanced cancer. Advances in molecular cell biology and immunology have identified numerous targets and many therapies have been developed as a result. Molecular testing and targeted therapy are typically covered by insurance, even when inflation-adjusted price growth is considered.¹ Barriers remain, however, and pathologists are uniquely qualified to address some of the challenges.²

Most US laboratories do not perform molecular diagnostic tests for PO, particularly comprehensive evaluation of multiple targets by next-generation sequencing, or other techniques. Instead, these tests are sent to reference laboratories. The workload associated with referral testing is an obstacle to increased use of such tests. Despite guideline recommendations, a minority of indicated tests are performed.³ This is true even when testing costs are covered by clinical trials or grants, such as those in the Veterans Health Administration (VHA).

The main characteristic of successful PO programs is a multidisciplinary commitment, including pathology involvement in molecular tumor boards and assistance with test selection, tissue collection, and result interpretation.² This, however, adds to the workload for the pathology department, an underappreciated phenomenon in the context of pathology workforce shortages.⁴

Workforce shortages impact all occupations in the laboratory setting. Though the shortage of medical technologists in clinical pathology laboratories has repeatedly been identified as critical at the VHA as well as in the private sector, the same cannot be said for staff shortages in anatomic pathology laboratories. Thus, the hospital laboratory divisions are concerned with biopsy or resection tissue specimens as opposed to the bodily fluid specimens that predominate in clinical laboratories.⁵ The lack of accurate data on histopathology technicians and technologists has precluded the degree of recognition seen for medical technologists. In labor statistics, these occupations are often obscured by inclusion with other jobs in broad categories such as medical and clinical laboratory technologists and technicians.⁶ Vacancy—the principal metric used to assess medical laboratory workforce shortage—fails to account for positions that are eventually eliminated after remaining vacant for prolonged periods, positions not replaced as a result of ambitious efficiency measures, or positions that were never created due to insufficient funding, reasons for administrative disapproval, or coverage by laboratory professionals working extra shifts or second jobs.⁷

Increased demand for pathologists is suggested by a 42% increase in workload per pathologist over the last decade, while a shortage is suggested by decreases in absolute and population-adjusted numbers of pathologists.^8,9 An influx of pathologists is not an expected remedy due to the global decline in medical graduates pursuing careers in the field.⁸

Approximations for required labor and potential revenue generation are necessary to justify creation of pathology positions. This work mostly has gone uncaptured due to the limitations of Current Procedural Terminology (CPT) codes. Few laboratories have consistently used the 88363, 88325, and G0452 CPT codes. The pathology clinical consultation CPT codes (80503-80506) released in 2022 enhance acquisition of this work. The new codes replace 80500 and 80502 and allow for more precise identification of any work requiring medical judgment that a pathologist does at the request of another qualified health care professional (HCP) or as required by federal or state regulation.

The codes can be used to bill for associated time spent reviewing health records, communicating with other HCPs, placing orders, and documentation. An HCP can bill according to level of medical decision-making (MDM) or time spent by the consulting pathologist. Code 80503 can be billed for 5 to 20 minutes of a pathologist's time, 80504 for 21 to 40 minutes, 80505 for 41 to 60 minutes, and 80506 for each additional 30 minutes after the first hour. Levels of MDM (low, moderate, and high) are defined as for other evaluation and management services. A consultation report must be generated and contain documentation of the consultation request, pathologist interpretation, and justification for the level of service associated with the chosen code. Relative value units (RVUs) and reimbursement associated with each as well as other consultation-related codes are available in Table 1.

This article outlines how the pathology time investment associated with anatomic pathology molecular testing at the Kansas City Veterans Affairs Medical Center (KCVAMC) can be captured using the consultation process and new CPT codes. Staff included 4 pathologists, 3 histotechnologists, 1 histology supervisor, 1 grossing room technician, and 1 cytotechnologist, 1 cytology technician.

METHODS

The AP molecular testing consultation process at the KCVAMC was mapped, with the average time measured for each step (Figure). AP records for 2021 were reviewed to determine the number of AP molecular send out tests. Cumulative time investment was calculated in hours and a theoretical number of RVUs was calculated using the new pathology clinical consultation CPT codes (80503-80506). This theoretical number of RVUs was compared with the total AP RVUs generated in 2021 to determine a potential increase in RVUs with use of the new CPT codes to capture pathology work associated with AP molecular testing consultations.

RESULTS

From 2021 to 2023, there were 21,021 AP cases at the KCVAMC. Basal cell carcinomas and squamous cell carcinomas of the skin were excluded because they comprise most cancer cases but almost never necessitate AP molecular test consultations. A total of 2118 cancer cases were included, representing 10.1% of all cases. Ancillary AP molecular send-out tests were performed on 1338 (6.4%) cases. Since ancillary tissue tests are requested by consultation at the KCVAMC, this resulted in 1338 consultations (Table 2).

The time to complete a consultation was measured by calculating the mean time required to complete each step (Table 3). With in-house specimen consultations requiring 90 minutes each and outside specimen consultations requiring 100 minutes each, a total of 2040 hours of pathology staff time was necessary to complete associated consultations. Billing for this time with the new pathology clinical consultation CPT codes would generate 3847 RVUs, which would have equated to 14.8% (3847/25,920) of the anatomic pathology RVUs.

DISCUSSION

When considering the lengths of time for tasks associated with each consultation, it is important to remember that the volume (2-3 daily), was insufficient to meaningfully benefit from batching. Thus, waiting to perform a particular task until it was needed for multiple cases reduced the inefficiency associated with starting and switching between tasks. Both the Computerized Patient Record System and VistA had to be reopened, reauthenticated, and reloaded for each step that required use of the health record, printer, or fax machine. Faxes also required waiting for transmission and printed confirmation of successful transmission. As a result, the time values denoted for each step are likely underestimated, as the effect of interruptions is significant and not reflected in the estimates recorded.¹⁰

This analysis has demonstrated that PO entails a significant amount of work for pathology departments. To determine and maintain appropriate staffing models, this work must be captured and reimbursed. Unlike other pathology work, which is performed in-house and reimbursed for the associated test, a significant proportion of PO testing is sent out. Even if more reliable assays are developed, the physical processes of sending out samples and reporting test results cannot be outsourced. Independent and commensurate reimbursement methods are necessary to allow for this work and PO.

CMS included new pathology clinical consultation codes that may be used to bill for some of this work according to the 2022 physician fee schedule due to advocacy work by the College of American Pathologists and the American Medical Association CPT editorial panel.¹¹

CONCLUSIONS

This analysis found that adoption of PO may present a significant amount of additional work for pathology departments. To determine and maintain appropriate staffing models, work completed by pathologists in this manner must be recorded and reimbursed. Pathologists need to be trained and encouraged to use these CPT codes and bill for the work described in this article. The increased revenue will allow for additional positions to alleviate the burdens imposed by understaffing so that pathology can function as a facilitator of PO rather than as a barrier to it.

Precision oncology (PO) is cancer treatment individualized to the special characteristics of a patient’s tumor. It has become standard care for most patients with advanced cancer. Advances in molecular cell biology and immunology have identified numerous targets and many therapies have been developed as a result. Molecular testing and targeted therapy are typically covered by insurance, even when inflation-adjusted price growth is considered.¹ Barriers remain, however, and pathologists are uniquely qualified to address some of the challenges.²

Most US laboratories do not perform molecular diagnostic tests for PO, particularly comprehensive evaluation of multiple targets by next-generation sequencing, or other techniques. Instead, these tests are sent to reference laboratories. The workload associated with referral testing is an obstacle to increased use of such tests. Despite guideline recommendations, a minority of indicated tests are performed.³ This is true even when testing costs are covered by clinical trials or grants, such as those in the Veterans Health Administration (VHA).

The main characteristic of successful PO programs is a multidisciplinary commitment, including pathology involvement in molecular tumor boards and assistance with test selection, tissue collection, and result interpretation.² This, however, adds to the workload for the pathology department, an underappreciated phenomenon in the context of pathology workforce shortages.⁴

Workforce shortages impact all occupations in the laboratory setting. Though the shortage of medical technologists in clinical pathology laboratories has repeatedly been identified as critical at the VHA as well as in the private sector, the same cannot be said for staff shortages in anatomic pathology laboratories. Thus, the hospital laboratory divisions are concerned with biopsy or resection tissue specimens as opposed to the bodily fluid specimens that predominate in clinical laboratories.⁵ The lack of accurate data on histopathology technicians and technologists has precluded the degree of recognition seen for medical technologists. In labor statistics, these occupations are often obscured by inclusion with other jobs in broad categories such as medical and clinical laboratory technologists and technicians.⁶ Vacancy—the principal metric used to assess medical laboratory workforce shortage—fails to account for positions that are eventually eliminated after remaining vacant for prolonged periods, positions not replaced as a result of ambitious efficiency measures, or positions that were never created due to insufficient funding, reasons for administrative disapproval, or coverage by laboratory professionals working extra shifts or second jobs.⁷

Increased demand for pathologists is suggested by a 42% increase in workload per pathologist over the last decade, while a shortage is suggested by decreases in absolute and population-adjusted numbers of pathologists.^8,9 An influx of pathologists is not an expected remedy due to the global decline in medical graduates pursuing careers in the field.⁸

Approximations for required labor and potential revenue generation are necessary to justify creation of pathology positions. This work mostly has gone uncaptured due to the limitations of Current Procedural Terminology (CPT) codes. Few laboratories have consistently used the 88363, 88325, and G0452 CPT codes. The pathology clinical consultation CPT codes (80503-80506) released in 2022 enhance acquisition of this work. The new codes replace 80500 and 80502 and allow for more precise identification of any work requiring medical judgment that a pathologist does at the request of another qualified health care professional (HCP) or as required by federal or state regulation.

The codes can be used to bill for associated time spent reviewing health records, communicating with other HCPs, placing orders, and documentation. An HCP can bill according to level of medical decision-making (MDM) or time spent by the consulting pathologist. Code 80503 can be billed for 5 to 20 minutes of a pathologist's time, 80504 for 21 to 40 minutes, 80505 for 41 to 60 minutes, and 80506 for each additional 30 minutes after the first hour. Levels of MDM (low, moderate, and high) are defined as for other evaluation and management services. A consultation report must be generated and contain documentation of the consultation request, pathologist interpretation, and justification for the level of service associated with the chosen code. Relative value units (RVUs) and reimbursement associated with each as well as other consultation-related codes are available in Table 1.

This article outlines how the pathology time investment associated with anatomic pathology molecular testing at the Kansas City Veterans Affairs Medical Center (KCVAMC) can be captured using the consultation process and new CPT codes. Staff included 4 pathologists, 3 histotechnologists, 1 histology supervisor, 1 grossing room technician, and 1 cytotechnologist, 1 cytology technician.

METHODS

The AP molecular testing consultation process at the KCVAMC was mapped, with the average time measured for each step (Figure). AP records for 2021 were reviewed to determine the number of AP molecular send out tests. Cumulative time investment was calculated in hours and a theoretical number of RVUs was calculated using the new pathology clinical consultation CPT codes (80503-80506). This theoretical number of RVUs was compared with the total AP RVUs generated in 2021 to determine a potential increase in RVUs with use of the new CPT codes to capture pathology work associated with AP molecular testing consultations.

RESULTS

From 2021 to 2023, there were 21,021 AP cases at the KCVAMC. Basal cell carcinomas and squamous cell carcinomas of the skin were excluded because they comprise most cancer cases but almost never necessitate AP molecular test consultations. A total of 2118 cancer cases were included, representing 10.1% of all cases. Ancillary AP molecular send-out tests were performed on 1338 (6.4%) cases. Since ancillary tissue tests are requested by consultation at the KCVAMC, this resulted in 1338 consultations (Table 2).

The time to complete a consultation was measured by calculating the mean time required to complete each step (Table 3). With in-house specimen consultations requiring 90 minutes each and outside specimen consultations requiring 100 minutes each, a total of 2040 hours of pathology staff time was necessary to complete associated consultations. Billing for this time with the new pathology clinical consultation CPT codes would generate 3847 RVUs, which would have equated to 14.8% (3847/25,920) of the anatomic pathology RVUs.

DISCUSSION

When considering the lengths of time for tasks associated with each consultation, it is important to remember that the volume (2-3 daily), was insufficient to meaningfully benefit from batching. Thus, waiting to perform a particular task until it was needed for multiple cases reduced the inefficiency associated with starting and switching between tasks. Both the Computerized Patient Record System and VistA had to be reopened, reauthenticated, and reloaded for each step that required use of the health record, printer, or fax machine. Faxes also required waiting for transmission and printed confirmation of successful transmission. As a result, the time values denoted for each step are likely underestimated, as the effect of interruptions is significant and not reflected in the estimates recorded.¹⁰

This analysis has demonstrated that PO entails a significant amount of work for pathology departments. To determine and maintain appropriate staffing models, this work must be captured and reimbursed. Unlike other pathology work, which is performed in-house and reimbursed for the associated test, a significant proportion of PO testing is sent out. Even if more reliable assays are developed, the physical processes of sending out samples and reporting test results cannot be outsourced. Independent and commensurate reimbursement methods are necessary to allow for this work and PO.

CMS included new pathology clinical consultation codes that may be used to bill for some of this work according to the 2022 physician fee schedule due to advocacy work by the College of American Pathologists and the American Medical Association CPT editorial panel.¹¹

CONCLUSIONS

This analysis found that adoption of PO may present a significant amount of additional work for pathology departments. To determine and maintain appropriate staffing models, work completed by pathologists in this manner must be recorded and reimbursed. Pathologists need to be trained and encouraged to use these CPT codes and bill for the work described in this article. The increased revenue will allow for additional positions to alleviate the burdens imposed by understaffing so that pathology can function as a facilitator of PO rather than as a barrier to it.

The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.^1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.^3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.^5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.

The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.^7,8

MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.⁹ Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.¹⁰ Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.⁹

At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.

To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.

METHODS

This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.

The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.¹¹ This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.¹¹ Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.

The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.^12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.

Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.

RESULTS

Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.

The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).

Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).

DISCUSSION

The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.¹⁴ However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.^15,16

Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.¹⁷ Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.¹⁸ Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.¹⁹ The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.^17-19

This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.

Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.^12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.²¹

Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.²² This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.²³

It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.^7,8,24

Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.

Limitations

The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.

CONCLUSIONS

Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.

This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.

The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.^1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.^3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.^5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.

The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.^7,8

MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.⁹ Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.¹⁰ Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.⁹

At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.

To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.

METHODS

This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.

The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.¹¹ This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.¹¹ Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.

The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.^12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.

Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.

RESULTS

Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.

The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).

Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).

DISCUSSION

The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.¹⁴ However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.^15,16

Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.¹⁷ Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.¹⁸ Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.¹⁹ The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.^17-19

This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.

Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.^12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.²¹

Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.²² This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.²³

It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.^7,8,24

Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.

Limitations

The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.

CONCLUSIONS

Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.

This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.

The US Department of Veterans Affairs (VA) annually treats around 450,000 veterans with cancer and diagnoses an additional 56,000.^1,2 Oral multikinase inhibitors (MKIs) are widely used as targeted therapies for many different malignancies. Despite the ease of oral administration, these agents are often accompanied by significant adverse effects (AEs) and drug-drug interactions.^3,4 Common AEs include hypertension, cutaneous reactions, gastrointestinal disturbances, proteinuria, and fatigue. Some serious outcomes that may occur are myocardial infarction, thrombosis, nephrotic syndrome, hemorrhage, hepatotoxicity, and gastrointestinal events.^5,6 Due to poor tolerability of these AEs, dose reductions, frequent therapy holds, and discontinuation of therapy may occur.

The US Food and Drug Administration recognizes dosing challenges with novel therapies and has created the Oncology Center of Excellence (OCE) Project Optimus initiative to reform dose optimization in oncology drug development. The initiative aims to shift the focus from establishing dose regimens based on the maximum tolerated doses of cytotoxic chemotherapeutics to an emphasis on maximum efficacy, safety, and tolerability, which better reflect real-world dosing.^7,8

MKIs can be challenging to manage because of the frequent toxicity-related dose reductions, interruptions, and discontinuations. In a multicenter retrospective study, Schnadig et al investigated dosing characteristics of first-line sunitinib for advanced renal cell carcinoma (RCC) and found that, among 114 patients who experienced AEs while taking sunitinib, 39.5% had dose reductions, 5.3% delayed therapy, 18.4% required additional supportive medications, and 22.8% discontinued sunitinib.⁹ Overall survival and median progression-free survival of these patients were lower than reported by Motzer et al in a phase 3 clinical trial.¹⁰ Schnadig et al concluded that patients treated with sunitinib for RCC in the community setting required more frequent dose reductions and had less time on therapy compared with patients in clinical trials, which ultimately impacted clinical outcomes.⁹

At the VA North Texas Health Care System (VANTHCS), patients with cancer have difficulty tolerating MKIs and often require dose alterations and/or discontinuation because of drug intolerance rather than discontinuation due to progression. Frequent dose adjustments for toxicity management can place more strain on patients and health care resources because of additional appointments, clinician time, and emergency department visits. Escalating drug costs can also cause concern when prescription doses are unused or changed frequently.

To capture and quantify prescribing practices and dose adjustments, this study evaluated the tolerability of MKIs at VANTHCS. This analysis may also guide clinicians in the selection of starting doses as well as dose titration expectations to optimize MKI therapy.

METHODS

This single-center, retrospective chart review analyzed patients receiving oral oncology MKIs for various malignancies at VANTHCS between January 1, 2014, and October 31, 2024. Participants included adults aged ≥ 18 years with a prescription for axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sorafenib, or sunitinib initiated by the hematology/oncology service at VANTHCS. Patients were included if they had follow-up documentation with the hematology/oncology service and/or other VANTHCS clinicians outlining their course of therapy after MKI initiation. Patients were excluded if they did not have sufficient follow-up documentation (eg, transferred care to a non-VA health care practitioner [HCP], moved to another VA health care system), were enrolled in clinical trials, or were prescribed an MKI from a Care in the Community (CITC) prescriber. Electronic health record review and data collection were performed using the VA Computerized Patient Record System and Research Electronic Data Capture. Data were collected from the time of initiation to cessation of therapy and included information regarding therapy changes, progressive disease, and date of death, when available. Data collected included age, sex, race, comorbidities, date of death, type of malignancy and subtypes, cancer stage, MKI used (ie, drug, dose, frequency, schedule, and indication), dates of medication changes (ie, start, adjustment, hold, discontinuation), concurrent antineoplastic treatments, and AEs documented at times of dose change or interruption.

The primary outcome was MKI tolerance determined using relative dose intensity (RDI) and mean and median time on therapy. Two methods are used to calculate RDI that vary in how they approach time on therapy as outlined in Hawn et al.¹¹ This study used method 2, which accounts for holds in therapy by comparing the actual duration of treatment with the duration expected according to treatment protocol. Method 1 compares the prescribed dose with the administered dose and does not adjust for holds.¹¹ Using method 2, the RDI in this study was calculated by dividing the total actual dose given by the total indicated dose for the malignancy being treated, which accounts for duration of treatment.

The total actual dose was the strength, frequency, and days on therapy for each time frame of treatment multiplied together. This method accounted for all dose adjustments and time periods of treatment holds, including patient self-adjustments, prescriber-directed adjustments, and nonadherence determined by HCP documentation and/or prescription data. Similarly, the indicated total dose was calculated by multiplying the indicated strength, frequency, and all days that treatment should have occurred (time from start to finish). Indicated doses were derived from the prescribing information for each malignancy with the exception of sunitinib, for which the off-label dose of 37.5 mg daily was considered a full dose.^12,13 The total indicated dose for axitinib was calculated by considering the dose escalation schedule from the prescribing information.

Patients who required dose reductions due to renal/hepatic impairments or drug-drug interactions had their total indicated dose calculated using dose adjustments listed in the prescribing information. The mean RDI for each MKI agent was calculated by averaging the RDI for each prescription. The overall combined mean RDI included the means of all the MKIs reviewed to avoid skewing the results toward an MKI with more prescriptions. RDIs were also calculated for each cancer type for each agent. Additional descriptive secondary outcomes included rates of AEs and adjustments in doses.

RESULTS

Electronic data extraction identified 278 patients with 366 MKI prescriptions, of which 108 veterans with 158 MKI prescriptions were excluded. The top reason for exclusion was patients managed through CITC. Ultimately, 170 veterans with 208 MKI prescriptions managed by the VANTHCS hematology/oncology clinic were included (Table 1). Among patients receiving MKIs, the mean age was 72.7 years, 98% were male, and 99% had metastatic disease.

The overall combined mean MKI RDI was 67.5% using method 2 and ranged from 85.5% for sunitinib to 49.0% for sorafenib (Figure 1). Additional information regarding mean and median RDIs using method 2 is shown in Figure 1 and further subdivided by cancer type in Table 2. Median RDIs overall were similar to mean RDIs for most agents. Figure 2 indicates the mean and median time on therapy, reflecting time on therapy excluding days therapy was held. The overall combined mean and median days on therapy for all MKIs were 155 days and 95 days, respectively. Mean time on therapy depended on the agent used and ranged from 35 days (regorafenib) to 237 days (cabozantinib).

Of 208 MKI prescriptions, 127 (61.1%) were initiated at a reduced dose due to baseline concerns for tolerance such as performance status, frailty, and prior intolerance of other treatments. Eighty-one prescriptions (38.9%) were initiated at their indicated doses. Ninety prescriptions (43.3%) required dose reductions during treatment. Some MKI prescriptions had multiple dose increases and decreases, which is why RDI more accurately reflects dose adjustments. A total of 376 AEs that contributed to a dose adjustment, hold, or discontinuation occurred across all MKI prescriptions. The most common AEs were 82 failure-to-thrive events (21.8%) (fatigue, malaise, loss of appetite, reduced mobility, global decline), 79 gastrointestinal events (21.0%) (nausea, vomiting, diarrhea, abdominal pain), 62 dermatologic events (16.5%) (rash, hand-foot skin reactions, allergic response), 61 hepatic dysfunction events (16.2%) (liver enzyme elevations, hyperbilirubinemia), 40 cardiovascular events (10.6%) (hypertension, heart failure exacerbations, edema), and 33 renal dysfunction events (8.8%) (acute kidney injury, proteinuria) (Appendix 1).

DISCUSSION

The mean RDI of MKI prescriptions used in the veteran population at VANTHCS was about two-thirds of the indicated dose. These results indicate that most veterans required dose reductions and/or holds due to concerns over initial tolerance/performance status, worsening clinical condition, and/or intolerable AEs attributed to treatment. A retrospective study conducted by Denduluri et al suggested that an RDI of < 85% is a clinically meaningful reduction for traditional chemotherapy based on previous literature.¹⁴ However, it is less clear what RDI should be expected specifically for MKIs in real-world populations. The MKI phase 3 approval trials in RCC for axitinib, lenvatinib, and sunitinib found median RDIs of 89.4%, 69.6% to 70.4%, and 83.9%, respectively. Each trial cited dose reductions most commonly as the result of treatment-related AEs.^15,16

Studies on the impact of RDIs on survival outcomes found that higher RDIs may improve overall and progression-free survival. Retrospective studies inspecting lenvatinib in hepatocellular carcinoma (HCC) indicated that an RDI > 70% in the initial 4 weeks resulted in favorable survival outcomes.¹⁷ Similarly, a retrospective study investigating sunitinib in RCC found that an RDI > 60% conferred favorable survival outcomes.¹⁸ Alghamdi et al noted that patients taking sorafenib for HCC who had RDI > 50% had a favorable trend in survival characteristics. Interestingly, the study found an RDI of 50% to 75% appeared to have better survival than an RDI > 75%.¹⁹ The authors of these studies hypothesized that additional dose reductions allowed for longer total time on therapy due to improved tolerability.^17-19

This analysis found that the RDIs for most MKI agents at VANTHCS were < 85% and lower than the RDIs found in other review articles and phase 3 trials, with the exceptions of pazopanib in thyroid cancer and sunitinib in gastrointestinal stromal tumor (GIST), thyroid cancer, and neuroendocrine cancer. The reasons for the lower RDIs in this study are likely multifactorial, reflecting patient population characteristics, off-label dosing practices, and HCP experiences with these agents. Many veterans have chronic comorbidities that could contribute to reduced performance status and ability to tolerate these therapies. Despite attempts to preemptively reduce doses for patients and account for potential impaired tolerance, there were patients who required further dose reductions in our study.

Failure to thrive was the most common AE leading to dose adjustment or discontinuation, which illustrates the extensive effects these agents have on patient functioning in a real-world population. Notably though, the RDI for sunitinib was higher in this population because about half of patients were dosed using the off-label recommendation, whereas the prescribing information recommends a more intensive 6-week dosing cycle for certain cancer types.^12,13,20 Sorafenib was also often dose-adjusted based on a pharmacokinetic study of sorafenib in renal/hepatic dysfunction, and the RDI likely reflects the off-label prescribing pattern.²¹

Patients with thyroid cancer were found to have higher RDIs compared with those receiving the same agents for other cancer types. Improved tolerability of MKIs in thyroid cancer may be due to a generally more tolerable disease course. Thyroid cancer is the most common cancer in individuals aged < 40 years, a population that is often more robust with fewer comorbidities. Moreover, the 5-year relative survival rate for thyroid cancer remains > 98%.²² This rate is in contrast to those for other cancer types such as HCC, with a 5-year relative survival rate of only 15%.²³

It is challenging to compare the mean and median times on therapy found in this study with those in current literature, as this review included multiple different cancer types for each agent. However, the numbers are generally lower than durations of therapy found across the different disease states and further emphasize the difficulty in tolerating MKIs in the VANTHCS population. Regorafenib had a short duration of time on therapy, which highlights the importance of trials like ReDOS and initiatives such as OCE Project Optimus in helping improve tolerance.^7,8,24

Comparing our results with other studies proved challenging because the RDI calculation methods were not specified. Calculating RDIs in this study using method 1, which does not account for holds, resulted in higher RDIs (Appendix 2). Using method 1, all MKIs had RDIs < 85%, except for pazopanib in thyroid cancer (100%) and RCC (87.9%), and sunitinib in GIST (93.6%), thyroid cancer (100%), and neuroendocrine cancer (93.7%). Notably, using method 1 increased the RDI for pazopanib in neuroendocrine cancer from 5.4% to 50.0%. The low RDI was attributed to a single veteran with a long hold duration, which demonstrates the discrepancy that can occur between the 2 methods.

Limitations

The retrospective design, lack of survival outcomes, and difficulty comparing results with other literature were limitations of this study. Because survival outcomes were not evaluated, future research should seek to investigate how RDIs and dose adjustments made among MKIs can affect survival outcomes in real-world populations. This veteran population with cancer often had multiple chronic comorbidities, which may have contributed to difficulty tolerating MKIs and could have impacted results. Disease-related factors may have influenced the poor tolerance of the MKIs and were not specifically accounted for. Adjustment for comorbidities was not possible because of discrepancies and/or incomplete diagnosis codes and Eastern Cooperative Oncology Group performance status scores documented in patient charts. Therefore, we decided not to report these findings due to potential inaccuracies.

CONCLUSIONS

Results of this study demonstrate that oncology MKI agents used at VANTHCS were difficult for patients to tolerate, leading to suboptimal dosing compared with indicated doses established in clinical trials and prescribing information. Clinicians may use these data to help guide clinical decision-making whenever initiating and managing MKI agents in this population. These findings reinforce that MKI agents are often difficult to tolerate in real-world practice, and indicated doses are often not achieved. Further studies should aim to investigate the effect that various RDIs have on overall survival. Further investigation into different dosing schemes for MKIs to improve tolerability and longer-term use may also prove beneficial.

This analysis may help guide clinicians to carefully approach dosing MKI agents in the veteran population. Given the RDI and AEs, more clinicians may consider starting at lower than indicated doses with the goal to titrate up as tolerated. Additionally, the results highlight the importance of considering palliative care consults and ensuring appropriate supportive care agents are preemptively engaged and adjusted as needed. Approaching dosing and titrations cautiously may help reduce the burden of management on the health care system.

Chronic myeloid leukemia (CML) is a hematologic malignancy resulting from an acquired mutation. The mutation results in a reciprocal translocation between the long arms of chromosomes 9 and 22 and is known as the Philadelphia chromosome (Ph), or Ph-positive (Ph+) when present. The translocation results in the formation of a BCR-ABL fusion oncogene, which leads to continuous cell cycling and proliferation, altered differentiation, and a loss of apoptosis.^1,2

Until the 1980s, CML was considered fatal.³ The mainstay of treatment consisted of 2 oral chemotherapeutic agents, busulfan and hydroxyurea. These medications did not prevent blast crisis, a fatal form of leukemia.^4,5 The introduction of tyrosine kinase inhibitors (TKIs) transformed CML management and improved 10-year overall survival from about 20% to > 80% by delaying the transition to blast crisis. Now, the risk of death from general health conditions or comorbidities is higher than that of CML.⁶

TKIs target the root cause of CML through inhibition of the BCR-ABL oncoprotein.^1,2 For CML, the goals of treatment include maintaining hematologic, cytogenetic, and molecular remission; preventing progression to accelerated phase or blast crisis; minimizing toxicity; and enabling potential cessation of therapy in carefully selected patients.^7,8

Small cohort studies suggest that dose reduction of TKIs in patients who achieve optimal responses may reduce the risk of long-term adverse effects (AEs). However, optimal dose-reduction and minimum effective dose of each agent are unknown.⁷ The ability to maintain undetectable minimal residual disease or disease detectable at a stable low level after TKI discontinuation has been called treatment-free remission. Studies suggest that about 40% to 50% of patients who have achieved a stable deep molecular response remain in treatment-free remission after stopping first-line treatment.^9,10 Of the patients who relapse following TKI discontinuation, 80% relapse within the first 6 months of treatment cessation. Molecular response is regained in almost all patients when treatment is resumed with the same TKI.¹¹

The National Comprehensive Cancer Network (NCCN) recommends considering discontinuation of TKI therapy only outside the setting of a clinical trial and only in patients who consent to discontinuation after a thorough discussion of the potential risks and benefits. The NCCN criteria for patients who may be eligible for discontinuation are listed in Table 1. The Life After Stopping TKIs study reported that 80% of patients with well-controlled chronic phase CML who discontinued TKIs had a clinically meaningful improvement in fatigue. Patients also reported clinically meaningful improvements in depression, diarrhea, sleep disturbance, and pain interference. These symptoms worsened after restarting TKI therapy.¹²

TKI DISCONTINUATION

Electronic health record data were extracted using structured query language from the US Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW). To be eligible for discontinuation, veterans had to be aged > 18 years, receive oncology care within a Veterans Integrated Services Network (VISN) 21 health care system (HCS) (VA Sierra Nevada HCS, VA Southern Nevada HCS, VA Central California HCS, VA Palo Alto HCS, VA Northern California HCS, and VA San Francisco HCS) or be a veteran referred to a community-based oncology practitioner. Patients had to have a documented diagnosis of chronic phase CML, have an active order for a TKI, be on TKI therapy for ≥ 3 years, and have a stable molecular response (BCR-ABL1 ≤ 0.01% on the International Scale for ≥ 2 years with ≥ 4 tests done ≥ 3 months apart) as of October 1, 2024. Veterans were excluded if they had a history of advanced accelerated phase CML, previous TKI discontinuation trials, nonadherence to the TKI, or if they did not want to consider TKI discontinuation.

This analysis evaluated the potential cost avoidance associated with TKI discontinuation. Cost avoidance was calculated using the average wholesale price of each TKI. Secondary objectives evaluated health outcomes of TKI discontinuation including CML relapse, reported AEs, long-term remission, and TKI withdrawal syndrome. Health outcomes were determined through chart review of AEs and clinic notes documented in the electronic health record during the study time frame.

Baseline information for eligible patients was collected, including age, sex, and race, and chart reviews were completed to evaluate reported AEs associated with therapy. Oncology clinical pharmacy practitioners (CPPs) at each VISN 21 facility were notified of eligible patients to facilitate discussion with oncologists and establish monitoring if therapy was discontinued. Following TKI discontinuation, health outcomes were evaluated, including CML relapse, changes in reported AEs, long-term remission, and TKI withdrawal syndrome. Descriptive statistics were used to analyze the baseline characteristics. Cost avoidance was calculated using the average wholesale price for each TKI. The number of tablets required to reach each patient’s individual dose was taken into consideration when determining the cost avoidance. A dashboard was created using the query from the CDW and was developed in Microsoft Power BI.

Preliminary Results

In FY 2024, VISN 21 had 3819 oncology patients. Twenty-four patients had taken a TKI for ≥ 3 years, 20 had a stable molecular response, and 15 had not previously attempted to discontinue their TKI (Figure 1). Fifteen veterans were eligible for therapy discontinuation for a total potential annual cost avoidance of $1.2 million (Figure 2). Most of the cost avoidance, $935,057 (78%), was attributed to 3 patients on nilotinib. The mean age of the population was 74 years. All patients were male, and 12 (80%) were White. (Table 2). At baseline, 11 patients (73%) were taking imatinib. One patient received oncology care from a community care clinician. All 15 patients decided to remain on therapy.

DISCUSSION

As a multisite quality improvement initiative, this project raised awareness of TKI therapy discontinuation in select patients with CML. It also sparked collaboration among oncology CPPs and clinicians and stimulated conversations about CML treatment. The development of the TKI discontinuation dashboard provides a population health management tool for CPPs and clinicians to identify eligible patients in the future.

Adherence to TKIs is crucial for disease control and survival in patients with CML. Patients are counseled that poor adherence to therapy may contribute to worsening disease or suboptimal response, the development of resistance, and greater health care costs.¹³ Therefore, it was a challenge for patients to understand and accept that they could stop TKI therapy after achieving a stable deep molecular response. Discussions with patients about the goal of therapy—suppressing the BCR-ABL oncogene, which they have achieved—could encourage patients to trial therapy discontinuation.

Only small cohort studies have been completed to evaluate the outcomes of therapy discontinuation. Much remains unknown regarding the optimal dose-reduction strategy and the minimum effective dose of each agent. Additionally, understanding the qualities of a good candidate for TKI discontinuation remains a barrier. A similar project was conducted in VISN 17. Five patients were counseled on TKI discontinuation; however, only 1 discontinued TKI therapy. Unfortunately, soon after discontinuing treatment, the patient had to restart therapy. Additional literature will enhance understanding of therapy discontinuation.

An unexpected finding of TKI discontinuation trials has been a reversible phenomenon known as TKI withdrawal syndrome.⁹ It can occur regardless of the TKI used and results in pruritus and new or worsening musculoskeletal pain within several weeks of TKI discontinuation in about 30% of patients. Symptoms may last several months and may require acetaminophen or nonsteroidal anti-inflammatory drugs for pain control.^9,10,14

The potential cost avoidance of $1.2 million is an underestimation because VA contracts allow for greater cost savings. However, that information is confidential and therefore average wholesale price had to be used for this project. Most of the cost avoidance was due to 4 patients who could not tolerate imatinib and used nilotinib, which is more expensive.

Limitations

The small sample size presented some limitations. Of the 3819 oncology patients within VISN 21 in FY 2024, 186 received a TKI and only 15 were eligible for discontinuation. Additionally, challenges emerged when discussing discontinuation with community care clinicians and patients. Community care clinicians were difficult to contact, making it challenging to discuss the project with them. CPPs noted hesitancy among VA clinicians and patients to discontinue a medication for which adherence was continually emphasized.

Conclusions

Discussions about CML TKI discontinuation led to collaboration with the oncology care team and could lead to significant cost avoidance. Barriers to TKI discontinuation included patients’ concern for relapse, risk of discontinuation syndrome, the requirement for close monitoring, and clinician buy-in. Outcome studies are needed to gain a greater understanding of the benefits and risks of therapy discontinuation. In the future, evaluation of possible clinical and biological predictors of successful TKI discontinuation may be beneficial.

Chronic myeloid leukemia (CML) is a hematologic malignancy resulting from an acquired mutation. The mutation results in a reciprocal translocation between the long arms of chromosomes 9 and 22 and is known as the Philadelphia chromosome (Ph), or Ph-positive (Ph+) when present. The translocation results in the formation of a BCR-ABL fusion oncogene, which leads to continuous cell cycling and proliferation, altered differentiation, and a loss of apoptosis.^1,2

Until the 1980s, CML was considered fatal.³ The mainstay of treatment consisted of 2 oral chemotherapeutic agents, busulfan and hydroxyurea. These medications did not prevent blast crisis, a fatal form of leukemia.^4,5 The introduction of tyrosine kinase inhibitors (TKIs) transformed CML management and improved 10-year overall survival from about 20% to > 80% by delaying the transition to blast crisis. Now, the risk of death from general health conditions or comorbidities is higher than that of CML.⁶

TKIs target the root cause of CML through inhibition of the BCR-ABL oncoprotein.^1,2 For CML, the goals of treatment include maintaining hematologic, cytogenetic, and molecular remission; preventing progression to accelerated phase or blast crisis; minimizing toxicity; and enabling potential cessation of therapy in carefully selected patients.^7,8

Small cohort studies suggest that dose reduction of TKIs in patients who achieve optimal responses may reduce the risk of long-term adverse effects (AEs). However, optimal dose-reduction and minimum effective dose of each agent are unknown.⁷ The ability to maintain undetectable minimal residual disease or disease detectable at a stable low level after TKI discontinuation has been called treatment-free remission. Studies suggest that about 40% to 50% of patients who have achieved a stable deep molecular response remain in treatment-free remission after stopping first-line treatment.^9,10 Of the patients who relapse following TKI discontinuation, 80% relapse within the first 6 months of treatment cessation. Molecular response is regained in almost all patients when treatment is resumed with the same TKI.¹¹

The National Comprehensive Cancer Network (NCCN) recommends considering discontinuation of TKI therapy only outside the setting of a clinical trial and only in patients who consent to discontinuation after a thorough discussion of the potential risks and benefits. The NCCN criteria for patients who may be eligible for discontinuation are listed in Table 1. The Life After Stopping TKIs study reported that 80% of patients with well-controlled chronic phase CML who discontinued TKIs had a clinically meaningful improvement in fatigue. Patients also reported clinically meaningful improvements in depression, diarrhea, sleep disturbance, and pain interference. These symptoms worsened after restarting TKI therapy.¹²

TKI DISCONTINUATION

Electronic health record data were extracted using structured query language from the US Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW). To be eligible for discontinuation, veterans had to be aged > 18 years, receive oncology care within a Veterans Integrated Services Network (VISN) 21 health care system (HCS) (VA Sierra Nevada HCS, VA Southern Nevada HCS, VA Central California HCS, VA Palo Alto HCS, VA Northern California HCS, and VA San Francisco HCS) or be a veteran referred to a community-based oncology practitioner. Patients had to have a documented diagnosis of chronic phase CML, have an active order for a TKI, be on TKI therapy for ≥ 3 years, and have a stable molecular response (BCR-ABL1 ≤ 0.01% on the International Scale for ≥ 2 years with ≥ 4 tests done ≥ 3 months apart) as of October 1, 2024. Veterans were excluded if they had a history of advanced accelerated phase CML, previous TKI discontinuation trials, nonadherence to the TKI, or if they did not want to consider TKI discontinuation.

This analysis evaluated the potential cost avoidance associated with TKI discontinuation. Cost avoidance was calculated using the average wholesale price of each TKI. Secondary objectives evaluated health outcomes of TKI discontinuation including CML relapse, reported AEs, long-term remission, and TKI withdrawal syndrome. Health outcomes were determined through chart review of AEs and clinic notes documented in the electronic health record during the study time frame.

Baseline information for eligible patients was collected, including age, sex, and race, and chart reviews were completed to evaluate reported AEs associated with therapy. Oncology clinical pharmacy practitioners (CPPs) at each VISN 21 facility were notified of eligible patients to facilitate discussion with oncologists and establish monitoring if therapy was discontinued. Following TKI discontinuation, health outcomes were evaluated, including CML relapse, changes in reported AEs, long-term remission, and TKI withdrawal syndrome. Descriptive statistics were used to analyze the baseline characteristics. Cost avoidance was calculated using the average wholesale price for each TKI. The number of tablets required to reach each patient’s individual dose was taken into consideration when determining the cost avoidance. A dashboard was created using the query from the CDW and was developed in Microsoft Power BI.

Preliminary Results

In FY 2024, VISN 21 had 3819 oncology patients. Twenty-four patients had taken a TKI for ≥ 3 years, 20 had a stable molecular response, and 15 had not previously attempted to discontinue their TKI (Figure 1). Fifteen veterans were eligible for therapy discontinuation for a total potential annual cost avoidance of $1.2 million (Figure 2). Most of the cost avoidance, $935,057 (78%), was attributed to 3 patients on nilotinib. The mean age of the population was 74 years. All patients were male, and 12 (80%) were White. (Table 2). At baseline, 11 patients (73%) were taking imatinib. One patient received oncology care from a community care clinician. All 15 patients decided to remain on therapy.

DISCUSSION

As a multisite quality improvement initiative, this project raised awareness of TKI therapy discontinuation in select patients with CML. It also sparked collaboration among oncology CPPs and clinicians and stimulated conversations about CML treatment. The development of the TKI discontinuation dashboard provides a population health management tool for CPPs and clinicians to identify eligible patients in the future.

Adherence to TKIs is crucial for disease control and survival in patients with CML. Patients are counseled that poor adherence to therapy may contribute to worsening disease or suboptimal response, the development of resistance, and greater health care costs.¹³ Therefore, it was a challenge for patients to understand and accept that they could stop TKI therapy after achieving a stable deep molecular response. Discussions with patients about the goal of therapy—suppressing the BCR-ABL oncogene, which they have achieved—could encourage patients to trial therapy discontinuation.

Only small cohort studies have been completed to evaluate the outcomes of therapy discontinuation. Much remains unknown regarding the optimal dose-reduction strategy and the minimum effective dose of each agent. Additionally, understanding the qualities of a good candidate for TKI discontinuation remains a barrier. A similar project was conducted in VISN 17. Five patients were counseled on TKI discontinuation; however, only 1 discontinued TKI therapy. Unfortunately, soon after discontinuing treatment, the patient had to restart therapy. Additional literature will enhance understanding of therapy discontinuation.

An unexpected finding of TKI discontinuation trials has been a reversible phenomenon known as TKI withdrawal syndrome.⁹ It can occur regardless of the TKI used and results in pruritus and new or worsening musculoskeletal pain within several weeks of TKI discontinuation in about 30% of patients. Symptoms may last several months and may require acetaminophen or nonsteroidal anti-inflammatory drugs for pain control.^9,10,14

The potential cost avoidance of $1.2 million is an underestimation because VA contracts allow for greater cost savings. However, that information is confidential and therefore average wholesale price had to be used for this project. Most of the cost avoidance was due to 4 patients who could not tolerate imatinib and used nilotinib, which is more expensive.

Limitations

The small sample size presented some limitations. Of the 3819 oncology patients within VISN 21 in FY 2024, 186 received a TKI and only 15 were eligible for discontinuation. Additionally, challenges emerged when discussing discontinuation with community care clinicians and patients. Community care clinicians were difficult to contact, making it challenging to discuss the project with them. CPPs noted hesitancy among VA clinicians and patients to discontinue a medication for which adherence was continually emphasized.

Conclusions

Discussions about CML TKI discontinuation led to collaboration with the oncology care team and could lead to significant cost avoidance. Barriers to TKI discontinuation included patients’ concern for relapse, risk of discontinuation syndrome, the requirement for close monitoring, and clinician buy-in. Outcome studies are needed to gain a greater understanding of the benefits and risks of therapy discontinuation. In the future, evaluation of possible clinical and biological predictors of successful TKI discontinuation may be beneficial.

Chronic myeloid leukemia (CML) is a hematologic malignancy resulting from an acquired mutation. The mutation results in a reciprocal translocation between the long arms of chromosomes 9 and 22 and is known as the Philadelphia chromosome (Ph), or Ph-positive (Ph+) when present. The translocation results in the formation of a BCR-ABL fusion oncogene, which leads to continuous cell cycling and proliferation, altered differentiation, and a loss of apoptosis.^1,2

Until the 1980s, CML was considered fatal.³ The mainstay of treatment consisted of 2 oral chemotherapeutic agents, busulfan and hydroxyurea. These medications did not prevent blast crisis, a fatal form of leukemia.^4,5 The introduction of tyrosine kinase inhibitors (TKIs) transformed CML management and improved 10-year overall survival from about 20% to > 80% by delaying the transition to blast crisis. Now, the risk of death from general health conditions or comorbidities is higher than that of CML.⁶

TKIs target the root cause of CML through inhibition of the BCR-ABL oncoprotein.^1,2 For CML, the goals of treatment include maintaining hematologic, cytogenetic, and molecular remission; preventing progression to accelerated phase or blast crisis; minimizing toxicity; and enabling potential cessation of therapy in carefully selected patients.^7,8

Small cohort studies suggest that dose reduction of TKIs in patients who achieve optimal responses may reduce the risk of long-term adverse effects (AEs). However, optimal dose-reduction and minimum effective dose of each agent are unknown.⁷ The ability to maintain undetectable minimal residual disease or disease detectable at a stable low level after TKI discontinuation has been called treatment-free remission. Studies suggest that about 40% to 50% of patients who have achieved a stable deep molecular response remain in treatment-free remission after stopping first-line treatment.^9,10 Of the patients who relapse following TKI discontinuation, 80% relapse within the first 6 months of treatment cessation. Molecular response is regained in almost all patients when treatment is resumed with the same TKI.¹¹

The National Comprehensive Cancer Network (NCCN) recommends considering discontinuation of TKI therapy only outside the setting of a clinical trial and only in patients who consent to discontinuation after a thorough discussion of the potential risks and benefits. The NCCN criteria for patients who may be eligible for discontinuation are listed in Table 1. The Life After Stopping TKIs study reported that 80% of patients with well-controlled chronic phase CML who discontinued TKIs had a clinically meaningful improvement in fatigue. Patients also reported clinically meaningful improvements in depression, diarrhea, sleep disturbance, and pain interference. These symptoms worsened after restarting TKI therapy.¹²

TKI DISCONTINUATION

Electronic health record data were extracted using structured query language from the US Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW). To be eligible for discontinuation, veterans had to be aged > 18 years, receive oncology care within a Veterans Integrated Services Network (VISN) 21 health care system (HCS) (VA Sierra Nevada HCS, VA Southern Nevada HCS, VA Central California HCS, VA Palo Alto HCS, VA Northern California HCS, and VA San Francisco HCS) or be a veteran referred to a community-based oncology practitioner. Patients had to have a documented diagnosis of chronic phase CML, have an active order for a TKI, be on TKI therapy for ≥ 3 years, and have a stable molecular response (BCR-ABL1 ≤ 0.01% on the International Scale for ≥ 2 years with ≥ 4 tests done ≥ 3 months apart) as of October 1, 2024. Veterans were excluded if they had a history of advanced accelerated phase CML, previous TKI discontinuation trials, nonadherence to the TKI, or if they did not want to consider TKI discontinuation.

This analysis evaluated the potential cost avoidance associated with TKI discontinuation. Cost avoidance was calculated using the average wholesale price of each TKI. Secondary objectives evaluated health outcomes of TKI discontinuation including CML relapse, reported AEs, long-term remission, and TKI withdrawal syndrome. Health outcomes were determined through chart review of AEs and clinic notes documented in the electronic health record during the study time frame.

Baseline information for eligible patients was collected, including age, sex, and race, and chart reviews were completed to evaluate reported AEs associated with therapy. Oncology clinical pharmacy practitioners (CPPs) at each VISN 21 facility were notified of eligible patients to facilitate discussion with oncologists and establish monitoring if therapy was discontinued. Following TKI discontinuation, health outcomes were evaluated, including CML relapse, changes in reported AEs, long-term remission, and TKI withdrawal syndrome. Descriptive statistics were used to analyze the baseline characteristics. Cost avoidance was calculated using the average wholesale price for each TKI. The number of tablets required to reach each patient’s individual dose was taken into consideration when determining the cost avoidance. A dashboard was created using the query from the CDW and was developed in Microsoft Power BI.

Preliminary Results

In FY 2024, VISN 21 had 3819 oncology patients. Twenty-four patients had taken a TKI for ≥ 3 years, 20 had a stable molecular response, and 15 had not previously attempted to discontinue their TKI (Figure 1). Fifteen veterans were eligible for therapy discontinuation for a total potential annual cost avoidance of $1.2 million (Figure 2). Most of the cost avoidance, $935,057 (78%), was attributed to 3 patients on nilotinib. The mean age of the population was 74 years. All patients were male, and 12 (80%) were White. (Table 2). At baseline, 11 patients (73%) were taking imatinib. One patient received oncology care from a community care clinician. All 15 patients decided to remain on therapy.

DISCUSSION

As a multisite quality improvement initiative, this project raised awareness of TKI therapy discontinuation in select patients with CML. It also sparked collaboration among oncology CPPs and clinicians and stimulated conversations about CML treatment. The development of the TKI discontinuation dashboard provides a population health management tool for CPPs and clinicians to identify eligible patients in the future.

Adherence to TKIs is crucial for disease control and survival in patients with CML. Patients are counseled that poor adherence to therapy may contribute to worsening disease or suboptimal response, the development of resistance, and greater health care costs.¹³ Therefore, it was a challenge for patients to understand and accept that they could stop TKI therapy after achieving a stable deep molecular response. Discussions with patients about the goal of therapy—suppressing the BCR-ABL oncogene, which they have achieved—could encourage patients to trial therapy discontinuation.

Only small cohort studies have been completed to evaluate the outcomes of therapy discontinuation. Much remains unknown regarding the optimal dose-reduction strategy and the minimum effective dose of each agent. Additionally, understanding the qualities of a good candidate for TKI discontinuation remains a barrier. A similar project was conducted in VISN 17. Five patients were counseled on TKI discontinuation; however, only 1 discontinued TKI therapy. Unfortunately, soon after discontinuing treatment, the patient had to restart therapy. Additional literature will enhance understanding of therapy discontinuation.

An unexpected finding of TKI discontinuation trials has been a reversible phenomenon known as TKI withdrawal syndrome.⁹ It can occur regardless of the TKI used and results in pruritus and new or worsening musculoskeletal pain within several weeks of TKI discontinuation in about 30% of patients. Symptoms may last several months and may require acetaminophen or nonsteroidal anti-inflammatory drugs for pain control.^9,10,14

The potential cost avoidance of $1.2 million is an underestimation because VA contracts allow for greater cost savings. However, that information is confidential and therefore average wholesale price had to be used for this project. Most of the cost avoidance was due to 4 patients who could not tolerate imatinib and used nilotinib, which is more expensive.

Limitations

The small sample size presented some limitations. Of the 3819 oncology patients within VISN 21 in FY 2024, 186 received a TKI and only 15 were eligible for discontinuation. Additionally, challenges emerged when discussing discontinuation with community care clinicians and patients. Community care clinicians were difficult to contact, making it challenging to discuss the project with them. CPPs noted hesitancy among VA clinicians and patients to discontinue a medication for which adherence was continually emphasized.

Conclusions

Discussions about CML TKI discontinuation led to collaboration with the oncology care team and could lead to significant cost avoidance. Barriers to TKI discontinuation included patients’ concern for relapse, risk of discontinuation syndrome, the requirement for close monitoring, and clinician buy-in. Outcome studies are needed to gain a greater understanding of the benefits and risks of therapy discontinuation. In the future, evaluation of possible clinical and biological predictors of successful TKI discontinuation may be beneficial.

Women with epithelial ovarian cancer treated in the US Department of Defense (DoD) universal health care system demonstrate better 5-year survival compared with similar patients from the national population. The survival advantage persists across multiple age groups and disease stages, with particularly notable improvements in patients aged 35-49 years and those with stage III disease.

METHODOLOGY:

• Researchers compared 1504 patients with invasive stage I-IV epithelial ovarian carcinoma from the Automated Center Tumor Registry (ACTUR) for the DoD with 6016 matched patients from the 18-region Surveillance, Epidemiology, and End Results (SEER) program between 1987 and 2013.
• Patients from ACTUR were matched in a 1:4 ratio with SEER patients stratified for age, race, year of diagnosis, and histology, including serous carcinoma, clear cell carcinoma, mucinous carcinoma, and endometrioid carcinoma with adenocarcinoma subtypes.
• Five-year overall survival was evaluated using the Kaplan-Meier method and compared using log-rank test, with median follow-up time of 46 months in ACTUR and 44 months in SEER.
• Adjusted hazard ratio (AHR) and 95% CI for all-cause mortality were estimated from multivariable Cox proportional regression modeling controlling for age, race, year of diagnosis, region of diagnosis, stage, histology, and grade.

TAKEAWAY:

• Overall survival differs between registries: 5-year survival of 53.2% in ACTUR vs 47.7% in matched SEER cohort (log-rank P = .001).
• In the primary adjusted model, ACTUR is associated with a lower risk for all-cause mortality vs SEER (AHR, 0.83; 95% CI, 0.76-0.91; P < .0001).
• Subset results retain lower adjusted risk for death for ACTUR vs SEER among ages 35-49 years (AHR, 0.66; 95% CI, 0.52-0.83; P = .0005), ages ≥ 65 years (AHR, 0.82; 95% CI, 0.70-0.96; P = .016), and stage III cancer (AHR, 0.79; 95% CI, 0.69-0.91; P = .0015).
• Histology-stratified findings show lower adjusted risk for death in ACTUR vs SEER for clear cell carcinoma (AHR, 0.63; 95% CI, 0.43-0.93; P =.02) and for endometrioid and other adenocarcinomas (AHR, 0.68; 95% CI, 0.56-0.81; P < .0001).

IN PRACTICE:

"This study is envisioned to be a stepping stone to further investigations of survival and other cancer health outcomes starting with patients diagnosed between 2014 and 2024 with epithelial carcinoma of the ovary, fallopian tube, or primary peritoneum in the DoD Healthcare System versus the national population or other Healthcare Systems,” wrote the authors of the study. “Dedicated funding and support in the [Military Health System] are needed to invest in infrastructure, technology, security, education, and research.”

SOURCE:

The study was led by Kathleen M. Darcy, PhD, and Christopher M. Tarney, MD, from the Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery & Obstetrics, Uniformed Services University, Walter Reed National Military Medical Center in Bethesda, Maryland. It was published online in Military Medicine.

LIMITATIONS:

The retrospective cohort study design limits causal inference. Although groups were balanced by age, race, year, and region of diagnosis, other demographic factors and socioeconomic variables such as patient comorbidities, educational attainment, household income, and health insurance status were not available and may have affected results. The databases fundamentally differ in how data are acquired, with ACTUR following hospital-based Facility Oncology Registry Data Standards and SEER being a national population-based registry, potentially affecting data quality, consistency, and reliability of survival outcome comparisons. The inclusion of patients diagnosed only through 2013 represents a limitation as it does not allow for contemporary evaluation of survival outcomes, particularly given advances over the past decade including maximal cytoreductive effort to no residual disease, increased adoption of neoadjuvant chemotherapy, and introduction of targeted maintenance agents. The study could not incorporate details regarding residual disease status or control for specifics regarding surgical and medical management, including primary vs interval debulking surgery or the type and timing of agents utilized in first-line, maintenance, and recurrent disease settings. Data regarding circulating biomarkers including CA125, molecular subtypes or alterations, and stratification by homologous recombination deficiency vs proficiency status were not available. Epithelial carcinomas of the fallopian tube and primary peritoneum were excluded from this study, which now are commonly incorporated with ovarian carcinomas. Results may not be generalizable to other populations given the unique characteristics of the Military Health System beneficiary population.

DISCLOSURES:

This research received funding from the Uniformed Services University from the Defense Health Program to the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., including award HU0001-18-2-0032 to the Murtha Cancer Center Research Program and awards HU0001-19-2-0031 and HU0001-24-2-0047 to the Gynecologic Cancer Center of Excellence Program. All coauthors disclosed no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Women with epithelial ovarian cancer treated in the US Department of Defense (DoD) universal health care system demonstrate better 5-year survival compared with similar patients from the national population. The survival advantage persists across multiple age groups and disease stages, with particularly notable improvements in patients aged 35-49 years and those with stage III disease.

METHODOLOGY:

• Researchers compared 1504 patients with invasive stage I-IV epithelial ovarian carcinoma from the Automated Center Tumor Registry (ACTUR) for the DoD with 6016 matched patients from the 18-region Surveillance, Epidemiology, and End Results (SEER) program between 1987 and 2013.
• Patients from ACTUR were matched in a 1:4 ratio with SEER patients stratified for age, race, year of diagnosis, and histology, including serous carcinoma, clear cell carcinoma, mucinous carcinoma, and endometrioid carcinoma with adenocarcinoma subtypes.
• Five-year overall survival was evaluated using the Kaplan-Meier method and compared using log-rank test, with median follow-up time of 46 months in ACTUR and 44 months in SEER.
• Adjusted hazard ratio (AHR) and 95% CI for all-cause mortality were estimated from multivariable Cox proportional regression modeling controlling for age, race, year of diagnosis, region of diagnosis, stage, histology, and grade.

TAKEAWAY:

• Overall survival differs between registries: 5-year survival of 53.2% in ACTUR vs 47.7% in matched SEER cohort (log-rank P = .001).
• In the primary adjusted model, ACTUR is associated with a lower risk for all-cause mortality vs SEER (AHR, 0.83; 95% CI, 0.76-0.91; P < .0001).
• Subset results retain lower adjusted risk for death for ACTUR vs SEER among ages 35-49 years (AHR, 0.66; 95% CI, 0.52-0.83; P = .0005), ages ≥ 65 years (AHR, 0.82; 95% CI, 0.70-0.96; P = .016), and stage III cancer (AHR, 0.79; 95% CI, 0.69-0.91; P = .0015).
• Histology-stratified findings show lower adjusted risk for death in ACTUR vs SEER for clear cell carcinoma (AHR, 0.63; 95% CI, 0.43-0.93; P =.02) and for endometrioid and other adenocarcinomas (AHR, 0.68; 95% CI, 0.56-0.81; P < .0001).

IN PRACTICE:

"This study is envisioned to be a stepping stone to further investigations of survival and other cancer health outcomes starting with patients diagnosed between 2014 and 2024 with epithelial carcinoma of the ovary, fallopian tube, or primary peritoneum in the DoD Healthcare System versus the national population or other Healthcare Systems,” wrote the authors of the study. “Dedicated funding and support in the [Military Health System] are needed to invest in infrastructure, technology, security, education, and research.”

SOURCE:

The study was led by Kathleen M. Darcy, PhD, and Christopher M. Tarney, MD, from the Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery & Obstetrics, Uniformed Services University, Walter Reed National Military Medical Center in Bethesda, Maryland. It was published online in Military Medicine.

LIMITATIONS:

The retrospective cohort study design limits causal inference. Although groups were balanced by age, race, year, and region of diagnosis, other demographic factors and socioeconomic variables such as patient comorbidities, educational attainment, household income, and health insurance status were not available and may have affected results. The databases fundamentally differ in how data are acquired, with ACTUR following hospital-based Facility Oncology Registry Data Standards and SEER being a national population-based registry, potentially affecting data quality, consistency, and reliability of survival outcome comparisons. The inclusion of patients diagnosed only through 2013 represents a limitation as it does not allow for contemporary evaluation of survival outcomes, particularly given advances over the past decade including maximal cytoreductive effort to no residual disease, increased adoption of neoadjuvant chemotherapy, and introduction of targeted maintenance agents. The study could not incorporate details regarding residual disease status or control for specifics regarding surgical and medical management, including primary vs interval debulking surgery or the type and timing of agents utilized in first-line, maintenance, and recurrent disease settings. Data regarding circulating biomarkers including CA125, molecular subtypes or alterations, and stratification by homologous recombination deficiency vs proficiency status were not available. Epithelial carcinomas of the fallopian tube and primary peritoneum were excluded from this study, which now are commonly incorporated with ovarian carcinomas. Results may not be generalizable to other populations given the unique characteristics of the Military Health System beneficiary population.

DISCLOSURES:

This research received funding from the Uniformed Services University from the Defense Health Program to the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., including award HU0001-18-2-0032 to the Murtha Cancer Center Research Program and awards HU0001-19-2-0031 and HU0001-24-2-0047 to the Gynecologic Cancer Center of Excellence Program. All coauthors disclosed no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Women with epithelial ovarian cancer treated in the US Department of Defense (DoD) universal health care system demonstrate better 5-year survival compared with similar patients from the national population. The survival advantage persists across multiple age groups and disease stages, with particularly notable improvements in patients aged 35-49 years and those with stage III disease.

METHODOLOGY:

• Researchers compared 1504 patients with invasive stage I-IV epithelial ovarian carcinoma from the Automated Center Tumor Registry (ACTUR) for the DoD with 6016 matched patients from the 18-region Surveillance, Epidemiology, and End Results (SEER) program between 1987 and 2013.
• Patients from ACTUR were matched in a 1:4 ratio with SEER patients stratified for age, race, year of diagnosis, and histology, including serous carcinoma, clear cell carcinoma, mucinous carcinoma, and endometrioid carcinoma with adenocarcinoma subtypes.
• Five-year overall survival was evaluated using the Kaplan-Meier method and compared using log-rank test, with median follow-up time of 46 months in ACTUR and 44 months in SEER.
• Adjusted hazard ratio (AHR) and 95% CI for all-cause mortality were estimated from multivariable Cox proportional regression modeling controlling for age, race, year of diagnosis, region of diagnosis, stage, histology, and grade.

TAKEAWAY:

• Overall survival differs between registries: 5-year survival of 53.2% in ACTUR vs 47.7% in matched SEER cohort (log-rank P = .001).
• In the primary adjusted model, ACTUR is associated with a lower risk for all-cause mortality vs SEER (AHR, 0.83; 95% CI, 0.76-0.91; P < .0001).
• Subset results retain lower adjusted risk for death for ACTUR vs SEER among ages 35-49 years (AHR, 0.66; 95% CI, 0.52-0.83; P = .0005), ages ≥ 65 years (AHR, 0.82; 95% CI, 0.70-0.96; P = .016), and stage III cancer (AHR, 0.79; 95% CI, 0.69-0.91; P = .0015).
• Histology-stratified findings show lower adjusted risk for death in ACTUR vs SEER for clear cell carcinoma (AHR, 0.63; 95% CI, 0.43-0.93; P =.02) and for endometrioid and other adenocarcinomas (AHR, 0.68; 95% CI, 0.56-0.81; P < .0001).

IN PRACTICE:

"This study is envisioned to be a stepping stone to further investigations of survival and other cancer health outcomes starting with patients diagnosed between 2014 and 2024 with epithelial carcinoma of the ovary, fallopian tube, or primary peritoneum in the DoD Healthcare System versus the national population or other Healthcare Systems,” wrote the authors of the study. “Dedicated funding and support in the [Military Health System] are needed to invest in infrastructure, technology, security, education, and research.”

SOURCE:

The study was led by Kathleen M. Darcy, PhD, and Christopher M. Tarney, MD, from the Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery & Obstetrics, Uniformed Services University, Walter Reed National Military Medical Center in Bethesda, Maryland. It was published online in Military Medicine.

LIMITATIONS:

The retrospective cohort study design limits causal inference. Although groups were balanced by age, race, year, and region of diagnosis, other demographic factors and socioeconomic variables such as patient comorbidities, educational attainment, household income, and health insurance status were not available and may have affected results. The databases fundamentally differ in how data are acquired, with ACTUR following hospital-based Facility Oncology Registry Data Standards and SEER being a national population-based registry, potentially affecting data quality, consistency, and reliability of survival outcome comparisons. The inclusion of patients diagnosed only through 2013 represents a limitation as it does not allow for contemporary evaluation of survival outcomes, particularly given advances over the past decade including maximal cytoreductive effort to no residual disease, increased adoption of neoadjuvant chemotherapy, and introduction of targeted maintenance agents. The study could not incorporate details regarding residual disease status or control for specifics regarding surgical and medical management, including primary vs interval debulking surgery or the type and timing of agents utilized in first-line, maintenance, and recurrent disease settings. Data regarding circulating biomarkers including CA125, molecular subtypes or alterations, and stratification by homologous recombination deficiency vs proficiency status were not available. Epithelial carcinomas of the fallopian tube and primary peritoneum were excluded from this study, which now are commonly incorporated with ovarian carcinomas. Results may not be generalizable to other populations given the unique characteristics of the Military Health System beneficiary population.

DISCLOSURES:

This research received funding from the Uniformed Services University from the Defense Health Program to the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., including award HU0001-18-2-0032 to the Murtha Cancer Center Research Program and awards HU0001-19-2-0031 and HU0001-24-2-0047 to the Gynecologic Cancer Center of Excellence Program. All coauthors disclosed no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Offering adjuvant therapy to patients with stage III melanoma offers no melanoma-specific or overall survival benefit, reveals extended follow-up from the first population-based national study to estimate the impact of the treatment.

Hildur Helgadottir, MD, PhD, presented the new findings at the 22nd European Association of Dermato-Oncology (EADO) Congress 2026 on April 24 and described the lead-up to the latest update on the study.

To investigate the impact of adjuvant treatment in patients with stage III melanoma, researchers initially conducted a study in which they used the Swedish Melanoma Registry (SweMR) to identify a precohort of those treated before the introduction of adjuvant therapy in 2018 and a postcohort of those treated subsequently, following both groups out to 2023, she explained.

The analysis revealed no significant difference in melanoma-specific survival between the two groups, at a hazard ratio of 0.92, nor in overall survival, at a hazard ratio of 0.93 (P = .60 for both). However, median follow-up differed between the groups, at 69 months vs 39 months for the precohort vs the postcohort.

Helgadottir, who is a senior research specialist at the Karolinska Comprehensive Cancer Center in Stockholm, Sweden, said that when the earlier results were presented at the European Society for Medical Oncology 2024, there was some criticism that the follow-up was not long enough and that there was no information on the actual adjuvant treatment received in the postcohort patients.

The researchers therefore extended their study out to 2024 to increase the median follow-up to 60 months vs 92 months in the postcohort group vs the precohort group.

They also focused patient selection on patients aged less than 75 years because exposure to adjuvant therapy in older patients was low and restricted the analysis to sentinel lymph node-positive stage IIIB-D cutaneous melanoma diagnosed between 2016 and 2020. This was because adjuvant exposure in stage IIIA disease was low, and patients with clinically detected stage III melanoma started to receive neoadjuvant therapy from 2022 onward.

The current analysis, which was recently published in the European Journal of Cancer, involved 287 patients in the precohort and 349 in the postcohort, who had a median age of 60.0 years and 61.0 years, respectively, and of whom 62.0% and 60.5%, respectively, were male. The groups were well balanced in terms of baseline disease characteristics.

Helgadottir explained that 73% of patients in the postcohort received some form of adjuvant treatment, with the majority treated with PD-1 inhibitors, and a smaller proportion given B-Raf serine-threonine kinase inhibitors. The main reasons for not giving adjuvant therapy were favorable tumor characteristics and the presence of comorbidities.

Five-year melanoma-specific survival rates in the precohorts and postcohorts were 71.4% vs 73.2%, at a hazard ratio adjusted for age, sex, and American Joint Committee on Cancer stage of 1.01 (P = .931). Five-year overall survival rates were 67.3% vs 70.1%, at an adjusted hazard ratio of 0.96 (P = .791).

Helgadottir showed that there were also no significant survival differences in any of the prespecified subgroups for neither melanoma-specific nor overall survival.

There were, again, no significant differences in survival outcomes between the two patient groups, she reported.

The latest results are similar to those from another study conducted in Netherlands and a Danish analysis, Helgadottir said.

Taken together, and “considering the side effects and the costs, it is possible that we will go back to closely following up our patients and treating only at relapse,” she said, “and optimally, of course, that will be already in the neoadjuvant setting.”

“And of course we will need biomarkers because there could be some patients that really need adjuvant treatment, but we need to identify these patients,” continued Helgadottir. Overall survival results from KEYNOTE-054, which compares pembrolizumab with placebo after resection of high-risk stage III melanoma, are awaited, she continued.

Helgadottir explained that adjuvant treatment for stage III melanoma was approved in Sweden in 2018, with treatments freely available to all Swedish residents.

The SweMR is a population-based national register that has near-complete and detailed data on primary cutaneous melanomas, including nodal status and satellite and in-transit disease, and is linked to the national Cause of Death Registry. Helgadottir noted, however, that the SweMR does not contain any information on relapses or the nature of the oncologic treatment received by patients with melanoma.

Following her presentation, she was challenged by an audience member as to whether, on the basis of her findings, she would go back to following up with patients and treating at relapses.

“Maybe we should do that and believe in our own data, and we do. But still, the gold standard must always be the randomized clinical trial,” Helgadottir responded. “So I think, although that we believe in this data, we also want to see the results of the randomized studies.”

The audience member commented that she can see in the data from her own institution that they treat fewer and fewer patients with melanoma with adjuvant therapy by discussing it more thoroughly and being stricter on who should receive it.

Helgadottir agreed, adding that “based on this experience, we did not introduce it to stage II patients because it’s always harder to go back” once a group of patients has started to receive a treatment.

The research was supported by Regional Cancer Centres in Sweden and with grants from the Swedish Cancer Society, Region Stockholm, and the Cancer Research Funds of Radiumhemmet. Helgadottir declared having relationships with Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Novartis.

The trial was supported by SkinVision. The researchers declared having no relevant financial relationships.

This article was previously published by Medscape.

Offering adjuvant therapy to patients with stage III melanoma offers no melanoma-specific or overall survival benefit, reveals extended follow-up from the first population-based national study to estimate the impact of the treatment.

Hildur Helgadottir, MD, PhD, presented the new findings at the 22nd European Association of Dermato-Oncology (EADO) Congress 2026 on April 24 and described the lead-up to the latest update on the study.

To investigate the impact of adjuvant treatment in patients with stage III melanoma, researchers initially conducted a study in which they used the Swedish Melanoma Registry (SweMR) to identify a precohort of those treated before the introduction of adjuvant therapy in 2018 and a postcohort of those treated subsequently, following both groups out to 2023, she explained.

The analysis revealed no significant difference in melanoma-specific survival between the two groups, at a hazard ratio of 0.92, nor in overall survival, at a hazard ratio of 0.93 (P = .60 for both). However, median follow-up differed between the groups, at 69 months vs 39 months for the precohort vs the postcohort.

Helgadottir, who is a senior research specialist at the Karolinska Comprehensive Cancer Center in Stockholm, Sweden, said that when the earlier results were presented at the European Society for Medical Oncology 2024, there was some criticism that the follow-up was not long enough and that there was no information on the actual adjuvant treatment received in the postcohort patients.

The researchers therefore extended their study out to 2024 to increase the median follow-up to 60 months vs 92 months in the postcohort group vs the precohort group.

They also focused patient selection on patients aged less than 75 years because exposure to adjuvant therapy in older patients was low and restricted the analysis to sentinel lymph node-positive stage IIIB-D cutaneous melanoma diagnosed between 2016 and 2020. This was because adjuvant exposure in stage IIIA disease was low, and patients with clinically detected stage III melanoma started to receive neoadjuvant therapy from 2022 onward.

The current analysis, which was recently published in the European Journal of Cancer, involved 287 patients in the precohort and 349 in the postcohort, who had a median age of 60.0 years and 61.0 years, respectively, and of whom 62.0% and 60.5%, respectively, were male. The groups were well balanced in terms of baseline disease characteristics.

Helgadottir explained that 73% of patients in the postcohort received some form of adjuvant treatment, with the majority treated with PD-1 inhibitors, and a smaller proportion given B-Raf serine-threonine kinase inhibitors. The main reasons for not giving adjuvant therapy were favorable tumor characteristics and the presence of comorbidities.

Five-year melanoma-specific survival rates in the precohorts and postcohorts were 71.4% vs 73.2%, at a hazard ratio adjusted for age, sex, and American Joint Committee on Cancer stage of 1.01 (P = .931). Five-year overall survival rates were 67.3% vs 70.1%, at an adjusted hazard ratio of 0.96 (P = .791).

Helgadottir showed that there were also no significant survival differences in any of the prespecified subgroups for neither melanoma-specific nor overall survival.

There were, again, no significant differences in survival outcomes between the two patient groups, she reported.

The latest results are similar to those from another study conducted in Netherlands and a Danish analysis, Helgadottir said.

Taken together, and “considering the side effects and the costs, it is possible that we will go back to closely following up our patients and treating only at relapse,” she said, “and optimally, of course, that will be already in the neoadjuvant setting.”

“And of course we will need biomarkers because there could be some patients that really need adjuvant treatment, but we need to identify these patients,” continued Helgadottir. Overall survival results from KEYNOTE-054, which compares pembrolizumab with placebo after resection of high-risk stage III melanoma, are awaited, she continued.

Helgadottir explained that adjuvant treatment for stage III melanoma was approved in Sweden in 2018, with treatments freely available to all Swedish residents.

The SweMR is a population-based national register that has near-complete and detailed data on primary cutaneous melanomas, including nodal status and satellite and in-transit disease, and is linked to the national Cause of Death Registry. Helgadottir noted, however, that the SweMR does not contain any information on relapses or the nature of the oncologic treatment received by patients with melanoma.

Following her presentation, she was challenged by an audience member as to whether, on the basis of her findings, she would go back to following up with patients and treating at relapses.

“Maybe we should do that and believe in our own data, and we do. But still, the gold standard must always be the randomized clinical trial,” Helgadottir responded. “So I think, although that we believe in this data, we also want to see the results of the randomized studies.”

The audience member commented that she can see in the data from her own institution that they treat fewer and fewer patients with melanoma with adjuvant therapy by discussing it more thoroughly and being stricter on who should receive it.

Helgadottir agreed, adding that “based on this experience, we did not introduce it to stage II patients because it’s always harder to go back” once a group of patients has started to receive a treatment.

The research was supported by Regional Cancer Centres in Sweden and with grants from the Swedish Cancer Society, Region Stockholm, and the Cancer Research Funds of Radiumhemmet. Helgadottir declared having relationships with Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Novartis.

The trial was supported by SkinVision. The researchers declared having no relevant financial relationships.

This article was previously published by Medscape.

Offering adjuvant therapy to patients with stage III melanoma offers no melanoma-specific or overall survival benefit, reveals extended follow-up from the first population-based national study to estimate the impact of the treatment.

Hildur Helgadottir, MD, PhD, presented the new findings at the 22nd European Association of Dermato-Oncology (EADO) Congress 2026 on April 24 and described the lead-up to the latest update on the study.

To investigate the impact of adjuvant treatment in patients with stage III melanoma, researchers initially conducted a study in which they used the Swedish Melanoma Registry (SweMR) to identify a precohort of those treated before the introduction of adjuvant therapy in 2018 and a postcohort of those treated subsequently, following both groups out to 2023, she explained.

The analysis revealed no significant difference in melanoma-specific survival between the two groups, at a hazard ratio of 0.92, nor in overall survival, at a hazard ratio of 0.93 (P = .60 for both). However, median follow-up differed between the groups, at 69 months vs 39 months for the precohort vs the postcohort.

Helgadottir, who is a senior research specialist at the Karolinska Comprehensive Cancer Center in Stockholm, Sweden, said that when the earlier results were presented at the European Society for Medical Oncology 2024, there was some criticism that the follow-up was not long enough and that there was no information on the actual adjuvant treatment received in the postcohort patients.

The researchers therefore extended their study out to 2024 to increase the median follow-up to 60 months vs 92 months in the postcohort group vs the precohort group.

They also focused patient selection on patients aged less than 75 years because exposure to adjuvant therapy in older patients was low and restricted the analysis to sentinel lymph node-positive stage IIIB-D cutaneous melanoma diagnosed between 2016 and 2020. This was because adjuvant exposure in stage IIIA disease was low, and patients with clinically detected stage III melanoma started to receive neoadjuvant therapy from 2022 onward.

The current analysis, which was recently published in the European Journal of Cancer, involved 287 patients in the precohort and 349 in the postcohort, who had a median age of 60.0 years and 61.0 years, respectively, and of whom 62.0% and 60.5%, respectively, were male. The groups were well balanced in terms of baseline disease characteristics.

Helgadottir explained that 73% of patients in the postcohort received some form of adjuvant treatment, with the majority treated with PD-1 inhibitors, and a smaller proportion given B-Raf serine-threonine kinase inhibitors. The main reasons for not giving adjuvant therapy were favorable tumor characteristics and the presence of comorbidities.

Five-year melanoma-specific survival rates in the precohorts and postcohorts were 71.4% vs 73.2%, at a hazard ratio adjusted for age, sex, and American Joint Committee on Cancer stage of 1.01 (P = .931). Five-year overall survival rates were 67.3% vs 70.1%, at an adjusted hazard ratio of 0.96 (P = .791).

Helgadottir showed that there were also no significant survival differences in any of the prespecified subgroups for neither melanoma-specific nor overall survival.

There were, again, no significant differences in survival outcomes between the two patient groups, she reported.

The latest results are similar to those from another study conducted in Netherlands and a Danish analysis, Helgadottir said.

Taken together, and “considering the side effects and the costs, it is possible that we will go back to closely following up our patients and treating only at relapse,” she said, “and optimally, of course, that will be already in the neoadjuvant setting.”

“And of course we will need biomarkers because there could be some patients that really need adjuvant treatment, but we need to identify these patients,” continued Helgadottir. Overall survival results from KEYNOTE-054, which compares pembrolizumab with placebo after resection of high-risk stage III melanoma, are awaited, she continued.

Helgadottir explained that adjuvant treatment for stage III melanoma was approved in Sweden in 2018, with treatments freely available to all Swedish residents.

The SweMR is a population-based national register that has near-complete and detailed data on primary cutaneous melanomas, including nodal status and satellite and in-transit disease, and is linked to the national Cause of Death Registry. Helgadottir noted, however, that the SweMR does not contain any information on relapses or the nature of the oncologic treatment received by patients with melanoma.

Following her presentation, she was challenged by an audience member as to whether, on the basis of her findings, she would go back to following up with patients and treating at relapses.

“Maybe we should do that and believe in our own data, and we do. But still, the gold standard must always be the randomized clinical trial,” Helgadottir responded. “So I think, although that we believe in this data, we also want to see the results of the randomized studies.”

The audience member commented that she can see in the data from her own institution that they treat fewer and fewer patients with melanoma with adjuvant therapy by discussing it more thoroughly and being stricter on who should receive it.

Helgadottir agreed, adding that “based on this experience, we did not introduce it to stage II patients because it’s always harder to go back” once a group of patients has started to receive a treatment.

The research was supported by Regional Cancer Centres in Sweden and with grants from the Swedish Cancer Society, Region Stockholm, and the Cancer Research Funds of Radiumhemmet. Helgadottir declared having relationships with Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Novartis.

The trial was supported by SkinVision. The researchers declared having no relevant financial relationships.

This article was previously published by Medscape.

Wildfire smoke exposure may be associated with increased risks for multiple types of cancer, suggests an analysis of prospective cohort data from over 90,000 individuals.

To determine how this widespread pollution might be affecting cancer risk, senior author Shuguang Leng, MBBS, PhD, and colleagues analyzed data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. That prospective national study enrolled approximately 154,000 participants between 1993 and 2001 and tracked cancer incidence through 2018. Of these, 91,460 participants had wildfire smoke exposure data and were included in the analysis.

During the 2006-2018 exposure period, the investigators identified incident cases of 242 ovarian, 800 colorectal, 896 bladder, 1696 hematopoietic, 1739 breast, and 1758 lung cancers, as well as 1127 melanoma cases. The median 36-month moving average for wildfire smoke PM_2.5 (fine particulate matter) across the cohort was 0.37 µg/m³.

Wildfire smoke exposure was significantly associated with increased risks for lung, colorectal, breast, bladder, and hematopoietic cancer, according to the results of the study presented by Leng at American Association for Cancer Research (AACR) Annual Meeting 2026.

Each 1 µg/m³ increase in the 36-month moving average of wildfire smoke PM_2.5 was associated with a 63% higher risk for hematopoietic cancer (HR, 1.63; 95% CI, 1.02-2.60), a nearly twofold higher risk for lung cancer (hazard ratio [HR], 1.92; 95% CI, 1.18-3.15), more than twofold higher risks for breast cancer (HR, 2.09; 95% CI, 1.34-3.26) and colorectal cancer (HR, 2.31; 95% CI, 1.11-4.81), and a more than threefold higher risk for bladder cancer (HR, 3.49; 95% CI, 1.66-7.34). No significant associations were observed for ovarian cancer or melanoma.

The investigators quantified wildfire smoke exposure at each participant’s residence on a monthly basis using three measures: near-ground wildfire smoke PM_2.5, wildfire smoke black carbon, and satellite-derived wildfire smoke plume-day counts, with measurements available from 2006 until first cancer diagnosis or last contact.

Given evidence that 3 years of air pollution exposure can influence the development of epidermal growth factor receptor-positive lung adenocarcinoma, the team modeled exposure as a time-varying variable using 36-month moving averages preceding each month. HRs were estimated using Cox proportional hazards models stratified by study center, with restricted cubic splines applied to evaluate dose-response relationships. Models were adjusted for age, sex, race and ethnicity, education, smoking history, BMI, and trial arm.

All five cancer types linked with wildfire smoke exposure showed linear dose-response relationships, Leng noted, “which means the higher the exposure, the higher the cancer risk.”

Results based on wildfire smoke plume-day counts were generally consistent with those for PM_2.5, while associations for black carbon exposure were observed only for breast and bladder cancers.

With wildfires on the rise, these findings suggest that the resulting smoke may become a “major driver for cancer burden in the US in the coming decades,” said Leng, of the University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico.

“Wildfire smoke has become a major source of air pollution in the United States,” he continued. Large fires in the US are three times more common than they were 50 years ago, and the “tons of toxicants and particles” released by these fires “can travel hundreds of miles to affect communities far away.”

The investigators also conducted histology-specific analyses, finding that adenocarcinoma showed the strongest association with wildfire smoke among lung cancer subtypes. Among colorectal cancers, proximal tumors appeared more sensitive to wildfire smoke exposure, while among bladder cancers, the association was strongest for muscle-invasive disease.

Wildfire Smoke Exposure Expected to Rise

Under even the most conservative climate projections, wildfire smoke exposure in the US is expected to rise over the next 20-30 years, Leng said.

Annual average wildfire smoke PM_2.5 levels, currently estimated at around 0.5 µg/m³, could rise to 1 µg/m³. Based on the study’s dose-response data, this would correspond to substantially greater cancer risk.

There will be “a much larger area” of the US exposed “at a much higher dose,” Leng predicted.

Mitigating the Risks of Wildfire Smoke

This is a “strong hypothesis-generating study,” Jun Wu, PhD, professor of environmental and occupational health at the UC Irvine Program in Public Health, Irvine, California, told Medscape Medical News.

“This is one of the first large, prospective US cohort studies to examine wildfire smoke specifically in relation to cancer risk, especially cancer sites beyond the lung,” Wu said. “A major strength is that the PLCO platform has around 91,000 participants with longitudinal follow-up and detailed covariate data, including smoking history, which is often a weak point in previous air pollution-cancer studies.”

According to Wu, who was not involved in the analysis but recently published data linking wildfire smoke exposure to preterm birth, the reported risks for colorectal, breast, bladder, and hematopoietic cancers represent novel contributions to the literature. However, she cautioned against viewing the specific HRs as a precise estimates of risk due to wide confidence intervals.

The findings should encourage individuals, public health officials, and clinicians to mitigate the risks of wildfire smoke, Wu said.

Specifically, she suggested that public health assessments expand beyond acute outcomes like emergency department visits to include long-term endpoints such as cancer, while community clean-air shelters need to be made more widely available.

She advised clinicians to incorporate wildfire exposure into routine patient histories and to provide vulnerable patients — such as those with asthma, chronic obstructive pulmonary disease, heart failure, or pregnancy — with smoke-season action plans.

Risk mitigation begins with awareness, according to Wu, who advised individuals check their local air quality index on AirNow.gov or PurpleAir.

On smoky days, she suggested prioritizing indoor air quality by keeping windows closed and running air purifiers. If going outside on such days is necessary, she suggested an N95 or KN95 mask, as these offer “meaningful protection,” while cloth and surgical masks do not.

These preventive steps may have once been out of the ordinary, Wu said, but the risk for wildfire smoke exposure is becoming a part of everyday life.

“The common thread is a shift in framing,” Wu said. “Wildfire smoke has traditionally been treated as an acute event, but the emerging evidence points to a chronic environmental exposure. Both our clinical and public health systems have room to grow into that reality.”

The analysis was funded by the National Institutes of Health. The investigators and Wu reported having no conflicts of interest.

This article was previously published on Medscape.

Wildfire smoke exposure may be associated with increased risks for multiple types of cancer, suggests an analysis of prospective cohort data from over 90,000 individuals.

To determine how this widespread pollution might be affecting cancer risk, senior author Shuguang Leng, MBBS, PhD, and colleagues analyzed data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. That prospective national study enrolled approximately 154,000 participants between 1993 and 2001 and tracked cancer incidence through 2018. Of these, 91,460 participants had wildfire smoke exposure data and were included in the analysis.

During the 2006-2018 exposure period, the investigators identified incident cases of 242 ovarian, 800 colorectal, 896 bladder, 1696 hematopoietic, 1739 breast, and 1758 lung cancers, as well as 1127 melanoma cases. The median 36-month moving average for wildfire smoke PM_2.5 (fine particulate matter) across the cohort was 0.37 µg/m³.

Wildfire smoke exposure was significantly associated with increased risks for lung, colorectal, breast, bladder, and hematopoietic cancer, according to the results of the study presented by Leng at American Association for Cancer Research (AACR) Annual Meeting 2026.

Each 1 µg/m³ increase in the 36-month moving average of wildfire smoke PM_2.5 was associated with a 63% higher risk for hematopoietic cancer (HR, 1.63; 95% CI, 1.02-2.60), a nearly twofold higher risk for lung cancer (hazard ratio [HR], 1.92; 95% CI, 1.18-3.15), more than twofold higher risks for breast cancer (HR, 2.09; 95% CI, 1.34-3.26) and colorectal cancer (HR, 2.31; 95% CI, 1.11-4.81), and a more than threefold higher risk for bladder cancer (HR, 3.49; 95% CI, 1.66-7.34). No significant associations were observed for ovarian cancer or melanoma.

The investigators quantified wildfire smoke exposure at each participant’s residence on a monthly basis using three measures: near-ground wildfire smoke PM_2.5, wildfire smoke black carbon, and satellite-derived wildfire smoke plume-day counts, with measurements available from 2006 until first cancer diagnosis or last contact.

Given evidence that 3 years of air pollution exposure can influence the development of epidermal growth factor receptor-positive lung adenocarcinoma, the team modeled exposure as a time-varying variable using 36-month moving averages preceding each month. HRs were estimated using Cox proportional hazards models stratified by study center, with restricted cubic splines applied to evaluate dose-response relationships. Models were adjusted for age, sex, race and ethnicity, education, smoking history, BMI, and trial arm.

All five cancer types linked with wildfire smoke exposure showed linear dose-response relationships, Leng noted, “which means the higher the exposure, the higher the cancer risk.”

Results based on wildfire smoke plume-day counts were generally consistent with those for PM_2.5, while associations for black carbon exposure were observed only for breast and bladder cancers.

With wildfires on the rise, these findings suggest that the resulting smoke may become a “major driver for cancer burden in the US in the coming decades,” said Leng, of the University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico.

“Wildfire smoke has become a major source of air pollution in the United States,” he continued. Large fires in the US are three times more common than they were 50 years ago, and the “tons of toxicants and particles” released by these fires “can travel hundreds of miles to affect communities far away.”

The investigators also conducted histology-specific analyses, finding that adenocarcinoma showed the strongest association with wildfire smoke among lung cancer subtypes. Among colorectal cancers, proximal tumors appeared more sensitive to wildfire smoke exposure, while among bladder cancers, the association was strongest for muscle-invasive disease.

Wildfire Smoke Exposure Expected to Rise

Under even the most conservative climate projections, wildfire smoke exposure in the US is expected to rise over the next 20-30 years, Leng said.

Annual average wildfire smoke PM_2.5 levels, currently estimated at around 0.5 µg/m³, could rise to 1 µg/m³. Based on the study’s dose-response data, this would correspond to substantially greater cancer risk.

There will be “a much larger area” of the US exposed “at a much higher dose,” Leng predicted.

Mitigating the Risks of Wildfire Smoke

This is a “strong hypothesis-generating study,” Jun Wu, PhD, professor of environmental and occupational health at the UC Irvine Program in Public Health, Irvine, California, told Medscape Medical News.

“This is one of the first large, prospective US cohort studies to examine wildfire smoke specifically in relation to cancer risk, especially cancer sites beyond the lung,” Wu said. “A major strength is that the PLCO platform has around 91,000 participants with longitudinal follow-up and detailed covariate data, including smoking history, which is often a weak point in previous air pollution-cancer studies.”

According to Wu, who was not involved in the analysis but recently published data linking wildfire smoke exposure to preterm birth, the reported risks for colorectal, breast, bladder, and hematopoietic cancers represent novel contributions to the literature. However, she cautioned against viewing the specific HRs as a precise estimates of risk due to wide confidence intervals.

The findings should encourage individuals, public health officials, and clinicians to mitigate the risks of wildfire smoke, Wu said.

Specifically, she suggested that public health assessments expand beyond acute outcomes like emergency department visits to include long-term endpoints such as cancer, while community clean-air shelters need to be made more widely available.

She advised clinicians to incorporate wildfire exposure into routine patient histories and to provide vulnerable patients — such as those with asthma, chronic obstructive pulmonary disease, heart failure, or pregnancy — with smoke-season action plans.

Risk mitigation begins with awareness, according to Wu, who advised individuals check their local air quality index on AirNow.gov or PurpleAir.

On smoky days, she suggested prioritizing indoor air quality by keeping windows closed and running air purifiers. If going outside on such days is necessary, she suggested an N95 or KN95 mask, as these offer “meaningful protection,” while cloth and surgical masks do not.

These preventive steps may have once been out of the ordinary, Wu said, but the risk for wildfire smoke exposure is becoming a part of everyday life.

“The common thread is a shift in framing,” Wu said. “Wildfire smoke has traditionally been treated as an acute event, but the emerging evidence points to a chronic environmental exposure. Both our clinical and public health systems have room to grow into that reality.”

The analysis was funded by the National Institutes of Health. The investigators and Wu reported having no conflicts of interest.

This article was previously published on Medscape.

Wildfire smoke exposure may be associated with increased risks for multiple types of cancer, suggests an analysis of prospective cohort data from over 90,000 individuals.

To determine how this widespread pollution might be affecting cancer risk, senior author Shuguang Leng, MBBS, PhD, and colleagues analyzed data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. That prospective national study enrolled approximately 154,000 participants between 1993 and 2001 and tracked cancer incidence through 2018. Of these, 91,460 participants had wildfire smoke exposure data and were included in the analysis.

During the 2006-2018 exposure period, the investigators identified incident cases of 242 ovarian, 800 colorectal, 896 bladder, 1696 hematopoietic, 1739 breast, and 1758 lung cancers, as well as 1127 melanoma cases. The median 36-month moving average for wildfire smoke PM_2.5 (fine particulate matter) across the cohort was 0.37 µg/m³.

Wildfire smoke exposure was significantly associated with increased risks for lung, colorectal, breast, bladder, and hematopoietic cancer, according to the results of the study presented by Leng at American Association for Cancer Research (AACR) Annual Meeting 2026.

Each 1 µg/m³ increase in the 36-month moving average of wildfire smoke PM_2.5 was associated with a 63% higher risk for hematopoietic cancer (HR, 1.63; 95% CI, 1.02-2.60), a nearly twofold higher risk for lung cancer (hazard ratio [HR], 1.92; 95% CI, 1.18-3.15), more than twofold higher risks for breast cancer (HR, 2.09; 95% CI, 1.34-3.26) and colorectal cancer (HR, 2.31; 95% CI, 1.11-4.81), and a more than threefold higher risk for bladder cancer (HR, 3.49; 95% CI, 1.66-7.34). No significant associations were observed for ovarian cancer or melanoma.

The investigators quantified wildfire smoke exposure at each participant’s residence on a monthly basis using three measures: near-ground wildfire smoke PM_2.5, wildfire smoke black carbon, and satellite-derived wildfire smoke plume-day counts, with measurements available from 2006 until first cancer diagnosis or last contact.

Given evidence that 3 years of air pollution exposure can influence the development of epidermal growth factor receptor-positive lung adenocarcinoma, the team modeled exposure as a time-varying variable using 36-month moving averages preceding each month. HRs were estimated using Cox proportional hazards models stratified by study center, with restricted cubic splines applied to evaluate dose-response relationships. Models were adjusted for age, sex, race and ethnicity, education, smoking history, BMI, and trial arm.

All five cancer types linked with wildfire smoke exposure showed linear dose-response relationships, Leng noted, “which means the higher the exposure, the higher the cancer risk.”

Results based on wildfire smoke plume-day counts were generally consistent with those for PM_2.5, while associations for black carbon exposure were observed only for breast and bladder cancers.

With wildfires on the rise, these findings suggest that the resulting smoke may become a “major driver for cancer burden in the US in the coming decades,” said Leng, of the University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico.

“Wildfire smoke has become a major source of air pollution in the United States,” he continued. Large fires in the US are three times more common than they were 50 years ago, and the “tons of toxicants and particles” released by these fires “can travel hundreds of miles to affect communities far away.”

The investigators also conducted histology-specific analyses, finding that adenocarcinoma showed the strongest association with wildfire smoke among lung cancer subtypes. Among colorectal cancers, proximal tumors appeared more sensitive to wildfire smoke exposure, while among bladder cancers, the association was strongest for muscle-invasive disease.

Wildfire Smoke Exposure Expected to Rise

Under even the most conservative climate projections, wildfire smoke exposure in the US is expected to rise over the next 20-30 years, Leng said.

Annual average wildfire smoke PM_2.5 levels, currently estimated at around 0.5 µg/m³, could rise to 1 µg/m³. Based on the study’s dose-response data, this would correspond to substantially greater cancer risk.

There will be “a much larger area” of the US exposed “at a much higher dose,” Leng predicted.

Mitigating the Risks of Wildfire Smoke

This is a “strong hypothesis-generating study,” Jun Wu, PhD, professor of environmental and occupational health at the UC Irvine Program in Public Health, Irvine, California, told Medscape Medical News.

“This is one of the first large, prospective US cohort studies to examine wildfire smoke specifically in relation to cancer risk, especially cancer sites beyond the lung,” Wu said. “A major strength is that the PLCO platform has around 91,000 participants with longitudinal follow-up and detailed covariate data, including smoking history, which is often a weak point in previous air pollution-cancer studies.”

According to Wu, who was not involved in the analysis but recently published data linking wildfire smoke exposure to preterm birth, the reported risks for colorectal, breast, bladder, and hematopoietic cancers represent novel contributions to the literature. However, she cautioned against viewing the specific HRs as a precise estimates of risk due to wide confidence intervals.

The findings should encourage individuals, public health officials, and clinicians to mitigate the risks of wildfire smoke, Wu said.

Specifically, she suggested that public health assessments expand beyond acute outcomes like emergency department visits to include long-term endpoints such as cancer, while community clean-air shelters need to be made more widely available.

She advised clinicians to incorporate wildfire exposure into routine patient histories and to provide vulnerable patients — such as those with asthma, chronic obstructive pulmonary disease, heart failure, or pregnancy — with smoke-season action plans.

Risk mitigation begins with awareness, according to Wu, who advised individuals check their local air quality index on AirNow.gov or PurpleAir.

On smoky days, she suggested prioritizing indoor air quality by keeping windows closed and running air purifiers. If going outside on such days is necessary, she suggested an N95 or KN95 mask, as these offer “meaningful protection,” while cloth and surgical masks do not.

These preventive steps may have once been out of the ordinary, Wu said, but the risk for wildfire smoke exposure is becoming a part of everyday life.

“The common thread is a shift in framing,” Wu said. “Wildfire smoke has traditionally been treated as an acute event, but the emerging evidence points to a chronic environmental exposure. Both our clinical and public health systems have room to grow into that reality.”

The analysis was funded by the National Institutes of Health. The investigators and Wu reported having no conflicts of interest.

This article was previously published on Medscape.

TOPLINE: In 75,453 veterans with head and neck squamous cell carcinoma (HNSCC), 36.4% live in rural or highly rural areas and 32.0% have a national area deprivation index (ADI) ≥ 75. The average drive time to the nearest tertiary or complex US Department of Veterans Affairs (VA) facility is 94 minutes, highlighting potential access and equity barriers related to rurality, deprivation, and distance.

METHODOLOGY:

• A retrospective descriptive study using nationwide VA data from fiscal years 2012 to 2022 identified 75,453 veterans with head and neck squamous cell carcinoma (HNSCC) by International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes.

• Patients were grouped into 5 primary tumor subsites: oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx.

• Rurality was classified using Rural-Urban Commuting Area-derived urban, rural, and highly rural scores; socioeconomic disadvantage was measured with national ADI scores.

• Travel burden was assessed using time and distance to the nearest primary, secondary, and tertiary VA facilities.

TAKEAWAY:

• Oropharyngeal cancer (OPC) cases among veterans increased from 26.3% in 2012 to 46.0% in 2022, while laryngeal cancers decreased from 41.2% to 29.3%.

• HNSCCs locations included 35.6% in the larynx, 34.4% in the oropharynx, 22.6% in the oral cavity 3.7% in the hypopharynx, and 3.7% in the nasopharynx.

• Veterans with OPC were younger than non-OPC patients and more likely to be White; > 70% were current or former smokers.

IN PRACTICE: “Understanding the geographic and socioeconomic landscape of veterans with HNSCC will allow us to tease out the factors associated with poor outcomes and ultimately design interventions that target high-risk veteran populations to improve overall health outcomes,” the authors argued.

SOURCE: The study was led by researchers at the Veterans Affairs Pittsburgh Healthcare System. It was published online in Head & Neck.

LIMITATIONS: The inability to extract accurate data from a large dataset, challenges in obtaining tumor stage information due to varying documentation practices across physicians and treatment courses, and the inability to assess HPV or p16 data for the cohort represents significant limitations that may have impacted interpretation of results. Clinical outcome measures and cause of death assessment were limited in this national database, affecting the ability to draw conclusions regarding the impact of rurality, area deprivation, and travel time on outcomes.

DISCLOSURES: Chad Brenner reported holding several patents related to the development and use of circulating tumor DNA tests in patients with HNSCC. Jose P. Zevallos disclosed being the founder, equity shareholder, and board member of Droplet Biosciences and Echogenesis Therapeutics, serving as chief scientific advisor and shareholder of Vine Medical, and acting as a consultant for Merck and Johnson & Johnson. Matthew E. Spector reported serving as a consultant for Hologic. Kristen L. Zayan, Jennifer L. McCoy, Monique Y. Boudreaux-Kelly, Zachary Hahn, John Hotchkiss, and Jessica H. Maxwell declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: In 75,453 veterans with head and neck squamous cell carcinoma (HNSCC), 36.4% live in rural or highly rural areas and 32.0% have a national area deprivation index (ADI) ≥ 75. The average drive time to the nearest tertiary or complex US Department of Veterans Affairs (VA) facility is 94 minutes, highlighting potential access and equity barriers related to rurality, deprivation, and distance.

METHODOLOGY:

• A retrospective descriptive study using nationwide VA data from fiscal years 2012 to 2022 identified 75,453 veterans with head and neck squamous cell carcinoma (HNSCC) by International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes.

• Patients were grouped into 5 primary tumor subsites: oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx.

• Rurality was classified using Rural-Urban Commuting Area-derived urban, rural, and highly rural scores; socioeconomic disadvantage was measured with national ADI scores.

• Travel burden was assessed using time and distance to the nearest primary, secondary, and tertiary VA facilities.

TAKEAWAY:

• Oropharyngeal cancer (OPC) cases among veterans increased from 26.3% in 2012 to 46.0% in 2022, while laryngeal cancers decreased from 41.2% to 29.3%.

• HNSCCs locations included 35.6% in the larynx, 34.4% in the oropharynx, 22.6% in the oral cavity 3.7% in the hypopharynx, and 3.7% in the nasopharynx.

• Veterans with OPC were younger than non-OPC patients and more likely to be White; > 70% were current or former smokers.

IN PRACTICE: “Understanding the geographic and socioeconomic landscape of veterans with HNSCC will allow us to tease out the factors associated with poor outcomes and ultimately design interventions that target high-risk veteran populations to improve overall health outcomes,” the authors argued.

SOURCE: The study was led by researchers at the Veterans Affairs Pittsburgh Healthcare System. It was published online in Head & Neck.

LIMITATIONS: The inability to extract accurate data from a large dataset, challenges in obtaining tumor stage information due to varying documentation practices across physicians and treatment courses, and the inability to assess HPV or p16 data for the cohort represents significant limitations that may have impacted interpretation of results. Clinical outcome measures and cause of death assessment were limited in this national database, affecting the ability to draw conclusions regarding the impact of rurality, area deprivation, and travel time on outcomes.

DISCLOSURES: Chad Brenner reported holding several patents related to the development and use of circulating tumor DNA tests in patients with HNSCC. Jose P. Zevallos disclosed being the founder, equity shareholder, and board member of Droplet Biosciences and Echogenesis Therapeutics, serving as chief scientific advisor and shareholder of Vine Medical, and acting as a consultant for Merck and Johnson & Johnson. Matthew E. Spector reported serving as a consultant for Hologic. Kristen L. Zayan, Jennifer L. McCoy, Monique Y. Boudreaux-Kelly, Zachary Hahn, John Hotchkiss, and Jessica H. Maxwell declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: In 75,453 veterans with head and neck squamous cell carcinoma (HNSCC), 36.4% live in rural or highly rural areas and 32.0% have a national area deprivation index (ADI) ≥ 75. The average drive time to the nearest tertiary or complex US Department of Veterans Affairs (VA) facility is 94 minutes, highlighting potential access and equity barriers related to rurality, deprivation, and distance.

METHODOLOGY:

• A retrospective descriptive study using nationwide VA data from fiscal years 2012 to 2022 identified 75,453 veterans with head and neck squamous cell carcinoma (HNSCC) by International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes.

• Patients were grouped into 5 primary tumor subsites: oral cavity, oropharynx, hypopharynx, larynx, and nasopharynx.

• Rurality was classified using Rural-Urban Commuting Area-derived urban, rural, and highly rural scores; socioeconomic disadvantage was measured with national ADI scores.

• Travel burden was assessed using time and distance to the nearest primary, secondary, and tertiary VA facilities.

TAKEAWAY:

• Oropharyngeal cancer (OPC) cases among veterans increased from 26.3% in 2012 to 46.0% in 2022, while laryngeal cancers decreased from 41.2% to 29.3%.

• HNSCCs locations included 35.6% in the larynx, 34.4% in the oropharynx, 22.6% in the oral cavity 3.7% in the hypopharynx, and 3.7% in the nasopharynx.

• Veterans with OPC were younger than non-OPC patients and more likely to be White; > 70% were current or former smokers.

IN PRACTICE: “Understanding the geographic and socioeconomic landscape of veterans with HNSCC will allow us to tease out the factors associated with poor outcomes and ultimately design interventions that target high-risk veteran populations to improve overall health outcomes,” the authors argued.

SOURCE: The study was led by researchers at the Veterans Affairs Pittsburgh Healthcare System. It was published online in Head & Neck.

LIMITATIONS: The inability to extract accurate data from a large dataset, challenges in obtaining tumor stage information due to varying documentation practices across physicians and treatment courses, and the inability to assess HPV or p16 data for the cohort represents significant limitations that may have impacted interpretation of results. Clinical outcome measures and cause of death assessment were limited in this national database, affecting the ability to draw conclusions regarding the impact of rurality, area deprivation, and travel time on outcomes.

DISCLOSURES: Chad Brenner reported holding several patents related to the development and use of circulating tumor DNA tests in patients with HNSCC. Jose P. Zevallos disclosed being the founder, equity shareholder, and board member of Droplet Biosciences and Echogenesis Therapeutics, serving as chief scientific advisor and shareholder of Vine Medical, and acting as a consultant for Merck and Johnson & Johnson. Matthew E. Spector reported serving as a consultant for Hologic. Kristen L. Zayan, Jennifer L. McCoy, Monique Y. Boudreaux-Kelly, Zachary Hahn, John Hotchkiss, and Jessica H. Maxwell declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.