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Is cancer immunotherapy more effective in men than women?
Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.
In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.
They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).
Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.
“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.
This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.
However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.
The authors also looked at whether the studies that compared immunotherapies with nonimmunological therapies might show a different effect, but they still found a significantly higher benefit in men, compared with women.
The overall study population was two-thirds male and one-third female. The checkpoint inhibitors used were ipilimumab, tremelimumab, nivolumab, and pembrolizumab, and the trials were conducted in patients with melanoma, non–small cell lung cancer, head and neck cancer, renal cell carcinoma, urothelial tumors, gastric tumors, and mesothelioma.
Men have almost double the risk of mortality from cancer than do women, the authors said, with the greatest differences seen in melanoma, lung cancer, larynx cancer, esophagus cancer, and bladder cancer.
“This male-biased mortality is hypothesized to reflect differences not only in behavioral and biological factors, including causes of cancer and hormonal regulation, but also in the immune system.”
Despite this, sex is rarely taken into account when new therapeutic approaches are tested, the authors said.
They also commented on the fact that there was a relatively low number of women included in each trial, an issue that was recognized as far back as the 1990s as a major problem in medical trials.
“Our results further highlight this problem, showing clinically relevant differences in the efficacy of two important classes of immunological drugs, namely anti–CTLA-4 and anti–PD-1 antibodies, when compared with controls in male and female patients with advanced solid tumors,” they wrote.
They noted that they couldn’t exclude the possibility that the effect may be the result of other variables that were distributed differently between the sexes. However, they also qualified this by saying that variables known to affect the efficacy of immune checkpoint inhibitors, such as PD-L1 expression and mutation status, were not likely to explain the results.
Given their findings, the authors said a patient’s sex should be taken into account when weighing the risks and benefits of checkpoint inhibitors given the magnitude of benefit was sex-dependent. They also called for future immunotherapy studies to include more women.
No funding or conflicts of interest were declared.
SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.
While cancer immunotherapy represents one of the most significant clinical advances in cancer treatment in the past decade, the basic but important clinical question about different effects between men and woman has not been addressed until now. The authors of this study are to be congratulated on such a comprehensive and well-conducted analysis, but the data does not completely support their final conclusion that checkpoint inhibitors benefit men more than women.
There are a large number of baseline characteristics of solid tumors that might differ between men and women and that have also been reported to impact the outcomes of patients treated with checkpoint inhibitors. Some of these may be lifestyle or behavioral characteristics – such as different smoking habits between men and women with non–small cell lung cancer – or differences in the distribution of oncogenic driver mutations between men and women.
We should therefore be cautious in jumping to conclusions and changing the current standard of care with respect to checkpoint inhibitors. In particular, we should not be denying treatment to women who are otherwise indicated for checkpoint inhibitors, based on these findings.
Omar Abdel-Rahman, MD, is from the clinical oncology department of the faculty of medicine at Ain Shams University in Cairo and from the Tom Baker Cancer Centre in Calgary. These comments are taken from an accompanying editorial (Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045[18]30270-5.) No conflicts of interest were declared.
While cancer immunotherapy represents one of the most significant clinical advances in cancer treatment in the past decade, the basic but important clinical question about different effects between men and woman has not been addressed until now. The authors of this study are to be congratulated on such a comprehensive and well-conducted analysis, but the data does not completely support their final conclusion that checkpoint inhibitors benefit men more than women.
There are a large number of baseline characteristics of solid tumors that might differ between men and women and that have also been reported to impact the outcomes of patients treated with checkpoint inhibitors. Some of these may be lifestyle or behavioral characteristics – such as different smoking habits between men and women with non–small cell lung cancer – or differences in the distribution of oncogenic driver mutations between men and women.
We should therefore be cautious in jumping to conclusions and changing the current standard of care with respect to checkpoint inhibitors. In particular, we should not be denying treatment to women who are otherwise indicated for checkpoint inhibitors, based on these findings.
Omar Abdel-Rahman, MD, is from the clinical oncology department of the faculty of medicine at Ain Shams University in Cairo and from the Tom Baker Cancer Centre in Calgary. These comments are taken from an accompanying editorial (Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045[18]30270-5.) No conflicts of interest were declared.
While cancer immunotherapy represents one of the most significant clinical advances in cancer treatment in the past decade, the basic but important clinical question about different effects between men and woman has not been addressed until now. The authors of this study are to be congratulated on such a comprehensive and well-conducted analysis, but the data does not completely support their final conclusion that checkpoint inhibitors benefit men more than women.
There are a large number of baseline characteristics of solid tumors that might differ between men and women and that have also been reported to impact the outcomes of patients treated with checkpoint inhibitors. Some of these may be lifestyle or behavioral characteristics – such as different smoking habits between men and women with non–small cell lung cancer – or differences in the distribution of oncogenic driver mutations between men and women.
We should therefore be cautious in jumping to conclusions and changing the current standard of care with respect to checkpoint inhibitors. In particular, we should not be denying treatment to women who are otherwise indicated for checkpoint inhibitors, based on these findings.
Omar Abdel-Rahman, MD, is from the clinical oncology department of the faculty of medicine at Ain Shams University in Cairo and from the Tom Baker Cancer Centre in Calgary. These comments are taken from an accompanying editorial (Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045[18]30270-5.) No conflicts of interest were declared.
Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.
In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.
They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).
Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.
“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.
This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.
However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.
The authors also looked at whether the studies that compared immunotherapies with nonimmunological therapies might show a different effect, but they still found a significantly higher benefit in men, compared with women.
The overall study population was two-thirds male and one-third female. The checkpoint inhibitors used were ipilimumab, tremelimumab, nivolumab, and pembrolizumab, and the trials were conducted in patients with melanoma, non–small cell lung cancer, head and neck cancer, renal cell carcinoma, urothelial tumors, gastric tumors, and mesothelioma.
Men have almost double the risk of mortality from cancer than do women, the authors said, with the greatest differences seen in melanoma, lung cancer, larynx cancer, esophagus cancer, and bladder cancer.
“This male-biased mortality is hypothesized to reflect differences not only in behavioral and biological factors, including causes of cancer and hormonal regulation, but also in the immune system.”
Despite this, sex is rarely taken into account when new therapeutic approaches are tested, the authors said.
They also commented on the fact that there was a relatively low number of women included in each trial, an issue that was recognized as far back as the 1990s as a major problem in medical trials.
“Our results further highlight this problem, showing clinically relevant differences in the efficacy of two important classes of immunological drugs, namely anti–CTLA-4 and anti–PD-1 antibodies, when compared with controls in male and female patients with advanced solid tumors,” they wrote.
They noted that they couldn’t exclude the possibility that the effect may be the result of other variables that were distributed differently between the sexes. However, they also qualified this by saying that variables known to affect the efficacy of immune checkpoint inhibitors, such as PD-L1 expression and mutation status, were not likely to explain the results.
Given their findings, the authors said a patient’s sex should be taken into account when weighing the risks and benefits of checkpoint inhibitors given the magnitude of benefit was sex-dependent. They also called for future immunotherapy studies to include more women.
No funding or conflicts of interest were declared.
SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.
Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.
In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.
They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).
Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.
“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.
This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.
However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.
The authors also looked at whether the studies that compared immunotherapies with nonimmunological therapies might show a different effect, but they still found a significantly higher benefit in men, compared with women.
The overall study population was two-thirds male and one-third female. The checkpoint inhibitors used were ipilimumab, tremelimumab, nivolumab, and pembrolizumab, and the trials were conducted in patients with melanoma, non–small cell lung cancer, head and neck cancer, renal cell carcinoma, urothelial tumors, gastric tumors, and mesothelioma.
Men have almost double the risk of mortality from cancer than do women, the authors said, with the greatest differences seen in melanoma, lung cancer, larynx cancer, esophagus cancer, and bladder cancer.
“This male-biased mortality is hypothesized to reflect differences not only in behavioral and biological factors, including causes of cancer and hormonal regulation, but also in the immune system.”
Despite this, sex is rarely taken into account when new therapeutic approaches are tested, the authors said.
They also commented on the fact that there was a relatively low number of women included in each trial, an issue that was recognized as far back as the 1990s as a major problem in medical trials.
“Our results further highlight this problem, showing clinically relevant differences in the efficacy of two important classes of immunological drugs, namely anti–CTLA-4 and anti–PD-1 antibodies, when compared with controls in male and female patients with advanced solid tumors,” they wrote.
They noted that they couldn’t exclude the possibility that the effect may be the result of other variables that were distributed differently between the sexes. However, they also qualified this by saying that variables known to affect the efficacy of immune checkpoint inhibitors, such as PD-L1 expression and mutation status, were not likely to explain the results.
Given their findings, the authors said a patient’s sex should be taken into account when weighing the risks and benefits of checkpoint inhibitors given the magnitude of benefit was sex-dependent. They also called for future immunotherapy studies to include more women.
No funding or conflicts of interest were declared.
SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.
FROM LANCET ONCOLOGY
Key clinical point: Checkpoint inhibitors are linked with greater mortality reductions in men than in women.
Major finding: Checkpoint inhibitors are associated with a 28% reduction in cancer mortality in men and 14% in women.
Study details: Systematic review and meta-analysis of 20 randomized, controlled trials involving 11,351 patients.
Disclosures: No funding or conflicts of interest were declared.
Source: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.
Mask provides effective, cheap protection from hazardous electrocautery plumes
CHICAGO – Routine use of an N95 mask during electrocautery is an effective and inexpensive way for dermatologic surgeons to protect themselves from toxic, airborne particulate matter in the smoke generated during the procedure, Emily de Golian, MD, said at the annual meeting of the American College of Mohs Surgery.
“Our data suggest clear as well as superiority to the laser masks that are used in hair removal procedures and ablative procedures in cosmetic clinics,” commented Dr. de Golian, a Mohs micrographic surgery fellow at the University of California, San Diego.
This matter of self-protection from the effects of electrocautery smoke plumes deserves greater attention from the dermatologic community, according to Dr. de Golian. There is solid evidence that these plumes contain high concentrations of known carcinogens, including benzene, acetonitrile, and butadiene – indeed, concentrations far in excess of what’s found in second-hand cigarette smoke. Moreover, many of these airborne carcinogens and other toxins have been linked to leukemia, neurologic disorders, lung cancer, thrombotic disorders, lung disease, and infectious disease transmission, albeit not convincingly so to date in dermatologic surgeons. But why wait for definitive evidence to accrue?
“In light of these hazards – and according to governmental guidelines – dermatologic surgeons would be wise to adopt protective measures during surgical procedures,” Dr. de Golian said.
But they haven’t. She cited a national survey conducted several years ago by a colleague in which 79% of the 316 responding dermatologic surgeons indicated they use no smoke management whatsoever, neither masks nor a local exhaust evacuation system. Only 10% employed smoke management 25%-50% of the time during electrocautery, and a scant 11% of dermatologic surgeons did so at least 75% of the time (Dermatol Surg. 2014 Dec;40[12]:1373-7).
Given the far more substantial expense of installing an office smoke evacuation system, mask filtration becomes an attractive alternative. But the relative efficacy of the various types of masks in blocking fine and ultrafine particulate matter contained in electrocautery plumes hadn’t previously been systematically studied. This created the impetus for Dr. de Golian’s study.
The N95 masks were the clear winner, particularly when it came to filtering the ultrafine particles, which are of greatest concern because they remain suspended in air longer and penetrate deeper into the respiratory tract than larger particles. The N95 masks proved superior to procedural masks, which in turn were significantly more effective than the laser masks. The differences between mask performance for larger particle filtration were smaller, although the N95 remained number one. She noted that the study results probably underestimate the true filtration efficacy of N95 masks, since they form a tighter seal with the face in clinical practice than with the other two mask types.
Mask self-protection “is easily applicable in your own practice, and it meets NIOSH-recommended [National Institute for Occupational Safety and Health] standards for safety in the workplace,” the dermatologist noted.
In the next phase of her research, she plans to evaluate the optimal technology and techniques of smoke evacuation in the surgical suite. That’s an attractive method because it protects everyone in the room, not just the surgeon. And while the practitioner survey indicates this technology isn’t widely used by dermatologic surgeons on a routine basis at present, that could change, particularly in the current era in which patient-reported outcomes and satisfaction surveys have taken on added weight.
“Patients prefer not smelling their own tissue burning,” Dr. de Golian said.
She reported no financial conflicts regarding her study, which was conducted free of commercial support.
CHICAGO – Routine use of an N95 mask during electrocautery is an effective and inexpensive way for dermatologic surgeons to protect themselves from toxic, airborne particulate matter in the smoke generated during the procedure, Emily de Golian, MD, said at the annual meeting of the American College of Mohs Surgery.
“Our data suggest clear as well as superiority to the laser masks that are used in hair removal procedures and ablative procedures in cosmetic clinics,” commented Dr. de Golian, a Mohs micrographic surgery fellow at the University of California, San Diego.
This matter of self-protection from the effects of electrocautery smoke plumes deserves greater attention from the dermatologic community, according to Dr. de Golian. There is solid evidence that these plumes contain high concentrations of known carcinogens, including benzene, acetonitrile, and butadiene – indeed, concentrations far in excess of what’s found in second-hand cigarette smoke. Moreover, many of these airborne carcinogens and other toxins have been linked to leukemia, neurologic disorders, lung cancer, thrombotic disorders, lung disease, and infectious disease transmission, albeit not convincingly so to date in dermatologic surgeons. But why wait for definitive evidence to accrue?
“In light of these hazards – and according to governmental guidelines – dermatologic surgeons would be wise to adopt protective measures during surgical procedures,” Dr. de Golian said.
But they haven’t. She cited a national survey conducted several years ago by a colleague in which 79% of the 316 responding dermatologic surgeons indicated they use no smoke management whatsoever, neither masks nor a local exhaust evacuation system. Only 10% employed smoke management 25%-50% of the time during electrocautery, and a scant 11% of dermatologic surgeons did so at least 75% of the time (Dermatol Surg. 2014 Dec;40[12]:1373-7).
Given the far more substantial expense of installing an office smoke evacuation system, mask filtration becomes an attractive alternative. But the relative efficacy of the various types of masks in blocking fine and ultrafine particulate matter contained in electrocautery plumes hadn’t previously been systematically studied. This created the impetus for Dr. de Golian’s study.
The N95 masks were the clear winner, particularly when it came to filtering the ultrafine particles, which are of greatest concern because they remain suspended in air longer and penetrate deeper into the respiratory tract than larger particles. The N95 masks proved superior to procedural masks, which in turn were significantly more effective than the laser masks. The differences between mask performance for larger particle filtration were smaller, although the N95 remained number one. She noted that the study results probably underestimate the true filtration efficacy of N95 masks, since they form a tighter seal with the face in clinical practice than with the other two mask types.
Mask self-protection “is easily applicable in your own practice, and it meets NIOSH-recommended [National Institute for Occupational Safety and Health] standards for safety in the workplace,” the dermatologist noted.
In the next phase of her research, she plans to evaluate the optimal technology and techniques of smoke evacuation in the surgical suite. That’s an attractive method because it protects everyone in the room, not just the surgeon. And while the practitioner survey indicates this technology isn’t widely used by dermatologic surgeons on a routine basis at present, that could change, particularly in the current era in which patient-reported outcomes and satisfaction surveys have taken on added weight.
“Patients prefer not smelling their own tissue burning,” Dr. de Golian said.
She reported no financial conflicts regarding her study, which was conducted free of commercial support.
CHICAGO – Routine use of an N95 mask during electrocautery is an effective and inexpensive way for dermatologic surgeons to protect themselves from toxic, airborne particulate matter in the smoke generated during the procedure, Emily de Golian, MD, said at the annual meeting of the American College of Mohs Surgery.
“Our data suggest clear as well as superiority to the laser masks that are used in hair removal procedures and ablative procedures in cosmetic clinics,” commented Dr. de Golian, a Mohs micrographic surgery fellow at the University of California, San Diego.
This matter of self-protection from the effects of electrocautery smoke plumes deserves greater attention from the dermatologic community, according to Dr. de Golian. There is solid evidence that these plumes contain high concentrations of known carcinogens, including benzene, acetonitrile, and butadiene – indeed, concentrations far in excess of what’s found in second-hand cigarette smoke. Moreover, many of these airborne carcinogens and other toxins have been linked to leukemia, neurologic disorders, lung cancer, thrombotic disorders, lung disease, and infectious disease transmission, albeit not convincingly so to date in dermatologic surgeons. But why wait for definitive evidence to accrue?
“In light of these hazards – and according to governmental guidelines – dermatologic surgeons would be wise to adopt protective measures during surgical procedures,” Dr. de Golian said.
But they haven’t. She cited a national survey conducted several years ago by a colleague in which 79% of the 316 responding dermatologic surgeons indicated they use no smoke management whatsoever, neither masks nor a local exhaust evacuation system. Only 10% employed smoke management 25%-50% of the time during electrocautery, and a scant 11% of dermatologic surgeons did so at least 75% of the time (Dermatol Surg. 2014 Dec;40[12]:1373-7).
Given the far more substantial expense of installing an office smoke evacuation system, mask filtration becomes an attractive alternative. But the relative efficacy of the various types of masks in blocking fine and ultrafine particulate matter contained in electrocautery plumes hadn’t previously been systematically studied. This created the impetus for Dr. de Golian’s study.
The N95 masks were the clear winner, particularly when it came to filtering the ultrafine particles, which are of greatest concern because they remain suspended in air longer and penetrate deeper into the respiratory tract than larger particles. The N95 masks proved superior to procedural masks, which in turn were significantly more effective than the laser masks. The differences between mask performance for larger particle filtration were smaller, although the N95 remained number one. She noted that the study results probably underestimate the true filtration efficacy of N95 masks, since they form a tighter seal with the face in clinical practice than with the other two mask types.
Mask self-protection “is easily applicable in your own practice, and it meets NIOSH-recommended [National Institute for Occupational Safety and Health] standards for safety in the workplace,” the dermatologist noted.
In the next phase of her research, she plans to evaluate the optimal technology and techniques of smoke evacuation in the surgical suite. That’s an attractive method because it protects everyone in the room, not just the surgeon. And while the practitioner survey indicates this technology isn’t widely used by dermatologic surgeons on a routine basis at present, that could change, particularly in the current era in which patient-reported outcomes and satisfaction surveys have taken on added weight.
“Patients prefer not smelling their own tissue burning,” Dr. de Golian said.
She reported no financial conflicts regarding her study, which was conducted free of commercial support.
REPORTING FROM THE ACMS ANNUAL MEETING
Key clinical point: Electrocautery smoke is bad news, and wearing an N95 mask affords protection.
Major finding: The N95 mask was significantly more effective than basic procedural or laser masks at filtering particulate matter less than 1 mcm in size contained in electrocautery smoke.
Study details: This study utilized highly sensitive airborne particle counting devices to assess the relative protective filtration afforded by three types of masks.
Disclosures: The presenter reported no financial conflicts regarding this study, which was conducted free of commercial support.
Checkpoint inhibitors get to patients quickly
Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.
“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”
Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.
More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.
“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.
Investigators wrote that the findings are cause for caution.
“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”
SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.
Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.
“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”
Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.
More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.
“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.
Investigators wrote that the findings are cause for caution.
“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”
SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.
Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.
“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”
Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.
More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.
“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.
Investigators wrote that the findings are cause for caution.
“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”
SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.
FROM JAMA ONCOLOGY
Key clinical point: Fast adoption but older patient age is seen in clinical use of checkpoint inhibitors.
Major finding: About 60% of patients were aged 65 years and older in clinical settings, compared with about 30%-40% in trials.
Study details: A retrospective study of data from the Flatiron Health longitudinal EHR database, which includes 233 academic and community practices.
Disclosures: The study was sponsored by the National Institutes of Health. Investigators reported receiving financial support from Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, and other companies.
Source: Gross C et al. JAMA Oncology. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.
Enhanced Melanoma Diagnosis With Multispectral Digital Skin Lesion Analysis
Early detection of melanoma, which is known to improve survival rates, remains a challenge for dermatologists. Suspicious pigmented lesions typically are evaluated via clinical examination and dermoscopy; however, new technologies are being developed to provide additional objective information for clinicians to incorporate into their biopsy decisions.
Multispectral digital skin lesion analysis (MSDSLA) uses 10 bands of visible and near-infrared light (430–950 nm) to image and analyze pigmented skin lesions (PSLs) down to 2.5 mm below the skin surface and measures the distribution of melanin using 75 unique algorithms to determine the degree of the morphologic disorder. Using a logical regression model previously validated on a set of 1632 PSLs, the probability of melanoma and probability of being a melanoma/PSL of high-risk malignant potential are then provided to the clinician.1
In this study, we analyzed aggregate data from 7 prior studies2-8 to better determine how MSDSLA impacts the biopsy decisions of dermatologists and nondermatologists following clinical examination and dermoscopic evaluation of PSLs.
Methods
Results
Overall sensitivity for the detection of melanoma or other high-grade PSLs improved from 70% on clinical and dermoscopic evaluation to 88% after MSDSLA information was provided (P<.0001), and specificity increased from 52% to 58% (P<.001). Diagnostic accuracy also improved from 59% on clinical evaluation to 69% after review of MSDSLA findings (P<.0001). The positive predictive value of biopsy decisions was 47% following clinical evaluation, which improved to 56% after evaluation of MSDSLA findings (P<.001), and the negative predictive value increased from 74% to 89% (P<.0001). The overall percentage of lesions selected for biopsy did not significantly change following MSDSLA data integration (57% vs 60%)(Figure). Given that similar numbers of lesions were biopsied with improved sensitivity and specificity, the integration of MSDSLA data into the biopsy decision led to an improved biopsy ratio (ratio of melanomas biopsied to total biopsies) and fewer unnecessary biopsies.
Comment
Our broad analysis further supported the findings of prior studies that decisions to biopsy clinically suspicious PSLs are more sensitive, specific, and accurate when practitioners are provided MSDSLA information following clinical examination.2-8
Given the evolution in health care economics, it is clear that greater emphasis will continue to be placed on superior, evidence-based, effective care. The reported diagnostic sensitivities and specificities of clinical evaluation and dermoscopy for melanoma detection vary widely throughout the literature, with sensitivities ranging from 58% to over 90% and specificities ranging from 77% to 99%.9-11
Our study had several limitations. For this analysis to be more representative of lesion biopsy selection in the clinical setting, biopsy sensitivity (correctly identifying lesions appropriate for biopsy) vs melanoma sensitivity (identifying a lesion as melanoma) was used.13 The overall sensitivity found was within the range of prior studies,2-8 but this approach may have potentially led to a lower specificity due to an increased number of lesions biopsied. Additionally, the melanomas selected for these studies were early (malignant melanoma in situ or mean thickness of invasive malignant melanoma of 0.3 mm), and the nonmelanomas (including low-grade dysplastic nevi) were not necessarily diagnostically straightforward. This may have led to the clinical and dermoscopic sensitivity and specificity noted being lower than in some prior studies.9-11
The risk of missing a melanoma with MSDSLA devices has led manufacturers to strive for a high sensitivity for their devices, leading to lower specificity as a consequence. For this reason and other ambiguous practical considerations (eg, device and patient costs, difficulty with insurance reimbursement), the adoption of this technology into routine clinical practice has remained relatively static; however, using enhanced diagnostic technologies such as MSDSLA may help with more accurate identification of high-risk PSLs, thereby leading to earlier detection and overall less expensive, more cost-effective treatment of melanoma.
- Monheit G, Cognetta AB, Ferris L, et al. The performance of MelaFind: a prospective multicenter study. Arch Dermatol. 2011;147:188-194.
- Rigel DS, Roy M, Yoo J, et al. Impact of guidance from a computer-aided multispectral digital skin lesion analysis device on decision to biopsy lesions clinically suggestive of melanoma. Arch Dermatol. 2012;148:541-543.
- Yoo J, Rigel DS, Roy M, et al. Impact of guidance from a multispectral digital skin lesion analysis device on dermatology residents decisions to biopsy lesions clinically suggestive of melanoma. J Am Acad Dermatol. 2013;68:AB152.
- Winkelmann RR, Yoo J, Tucker N, et al. Impact of guidance provided by a multispectral digital skin lesion analysis device following dermoscopy on decisions to biopsy atypical melanocytic lesions. J Clin Aesthet Dermatol. 2015;8:21-24.
- Winkelmann RR, Hauschild A, Tucker N, et al. The impact of multispectral digital skin lesion analysis on German dermatologist decisions to biopsy atypical pigmented lesions with clinical characteristics of melanoma. J Clin Aesthet Dermatol. 2015;8:27-29.
- Winkelmann RR, Tucker N, White R, et al. Pigmented skin lesion biopsies after computer-aided multispectral digital skin lesion analysis. J Am Osteopath Assoc. 2015;115:666-669.
- Winkelmann RR, Farberg AS, Tucker N, et al. Enhancement of international dermatologists’ pigmented skin lesion biopsy decisions following dermoscopy with subsequent integration of multispectral digital skin lesion analysis [published online July 1, 2016]. J Clin Aesthet Dermatol. 2016;9:53-55.
- Farberg AS, Winkelmann RR, Tucker N, et al. The impact of quantitative data provided by a multi-spectral digital skin lesion analysis device on dermatologists’ decisions to biopsy pigmented lesions [published online September 1, 2017]. J Clin Aesthet Dermatol. 2017;10:24-26.
- Wolf IH, Smolle J, Soyer HP, et al. Sensitivity in the clinical diagnosis of malignant melanoma. Melanoma Res. 1998;8:425-429.
- Kittler H, Pehamberger H, Wolff K, et al. Diagnostic accuracy of dermoscopy. Lancet Oncol. 2002;3:159-165.
- Ascierto PA, Palmieri G, Celentano E, et al. Sensitivity and specificity of epiluminescence microscopy: evaluation on a sample of 2731 excised cutaneous pigmented lesions: the Melanoma Cooperative Study. Br J Dermatol. 2000;142:893-898.
- Carli P, Nardini P, Crocetti E, et al. Frequency and characteristics of melanomas missed at a pigmented lesion clinic: a registry-based study. Melanoma Res. 2004;14:403-407.
- Friedman RJ, Gutkowicz-Krusin D, Farber MJ, et al. The diagnostic performance of expert dermoscopists vs a computer-vision system on small-diameter melanomas. Arch Dermatol. 2008;144:476-482.
Early detection of melanoma, which is known to improve survival rates, remains a challenge for dermatologists. Suspicious pigmented lesions typically are evaluated via clinical examination and dermoscopy; however, new technologies are being developed to provide additional objective information for clinicians to incorporate into their biopsy decisions.
Multispectral digital skin lesion analysis (MSDSLA) uses 10 bands of visible and near-infrared light (430–950 nm) to image and analyze pigmented skin lesions (PSLs) down to 2.5 mm below the skin surface and measures the distribution of melanin using 75 unique algorithms to determine the degree of the morphologic disorder. Using a logical regression model previously validated on a set of 1632 PSLs, the probability of melanoma and probability of being a melanoma/PSL of high-risk malignant potential are then provided to the clinician.1
In this study, we analyzed aggregate data from 7 prior studies2-8 to better determine how MSDSLA impacts the biopsy decisions of dermatologists and nondermatologists following clinical examination and dermoscopic evaluation of PSLs.
Methods
Results
Overall sensitivity for the detection of melanoma or other high-grade PSLs improved from 70% on clinical and dermoscopic evaluation to 88% after MSDSLA information was provided (P<.0001), and specificity increased from 52% to 58% (P<.001). Diagnostic accuracy also improved from 59% on clinical evaluation to 69% after review of MSDSLA findings (P<.0001). The positive predictive value of biopsy decisions was 47% following clinical evaluation, which improved to 56% after evaluation of MSDSLA findings (P<.001), and the negative predictive value increased from 74% to 89% (P<.0001). The overall percentage of lesions selected for biopsy did not significantly change following MSDSLA data integration (57% vs 60%)(Figure). Given that similar numbers of lesions were biopsied with improved sensitivity and specificity, the integration of MSDSLA data into the biopsy decision led to an improved biopsy ratio (ratio of melanomas biopsied to total biopsies) and fewer unnecessary biopsies.
Comment
Our broad analysis further supported the findings of prior studies that decisions to biopsy clinically suspicious PSLs are more sensitive, specific, and accurate when practitioners are provided MSDSLA information following clinical examination.2-8
Given the evolution in health care economics, it is clear that greater emphasis will continue to be placed on superior, evidence-based, effective care. The reported diagnostic sensitivities and specificities of clinical evaluation and dermoscopy for melanoma detection vary widely throughout the literature, with sensitivities ranging from 58% to over 90% and specificities ranging from 77% to 99%.9-11
Our study had several limitations. For this analysis to be more representative of lesion biopsy selection in the clinical setting, biopsy sensitivity (correctly identifying lesions appropriate for biopsy) vs melanoma sensitivity (identifying a lesion as melanoma) was used.13 The overall sensitivity found was within the range of prior studies,2-8 but this approach may have potentially led to a lower specificity due to an increased number of lesions biopsied. Additionally, the melanomas selected for these studies were early (malignant melanoma in situ or mean thickness of invasive malignant melanoma of 0.3 mm), and the nonmelanomas (including low-grade dysplastic nevi) were not necessarily diagnostically straightforward. This may have led to the clinical and dermoscopic sensitivity and specificity noted being lower than in some prior studies.9-11
The risk of missing a melanoma with MSDSLA devices has led manufacturers to strive for a high sensitivity for their devices, leading to lower specificity as a consequence. For this reason and other ambiguous practical considerations (eg, device and patient costs, difficulty with insurance reimbursement), the adoption of this technology into routine clinical practice has remained relatively static; however, using enhanced diagnostic technologies such as MSDSLA may help with more accurate identification of high-risk PSLs, thereby leading to earlier detection and overall less expensive, more cost-effective treatment of melanoma.
Early detection of melanoma, which is known to improve survival rates, remains a challenge for dermatologists. Suspicious pigmented lesions typically are evaluated via clinical examination and dermoscopy; however, new technologies are being developed to provide additional objective information for clinicians to incorporate into their biopsy decisions.
Multispectral digital skin lesion analysis (MSDSLA) uses 10 bands of visible and near-infrared light (430–950 nm) to image and analyze pigmented skin lesions (PSLs) down to 2.5 mm below the skin surface and measures the distribution of melanin using 75 unique algorithms to determine the degree of the morphologic disorder. Using a logical regression model previously validated on a set of 1632 PSLs, the probability of melanoma and probability of being a melanoma/PSL of high-risk malignant potential are then provided to the clinician.1
In this study, we analyzed aggregate data from 7 prior studies2-8 to better determine how MSDSLA impacts the biopsy decisions of dermatologists and nondermatologists following clinical examination and dermoscopic evaluation of PSLs.
Methods
Results
Overall sensitivity for the detection of melanoma or other high-grade PSLs improved from 70% on clinical and dermoscopic evaluation to 88% after MSDSLA information was provided (P<.0001), and specificity increased from 52% to 58% (P<.001). Diagnostic accuracy also improved from 59% on clinical evaluation to 69% after review of MSDSLA findings (P<.0001). The positive predictive value of biopsy decisions was 47% following clinical evaluation, which improved to 56% after evaluation of MSDSLA findings (P<.001), and the negative predictive value increased from 74% to 89% (P<.0001). The overall percentage of lesions selected for biopsy did not significantly change following MSDSLA data integration (57% vs 60%)(Figure). Given that similar numbers of lesions were biopsied with improved sensitivity and specificity, the integration of MSDSLA data into the biopsy decision led to an improved biopsy ratio (ratio of melanomas biopsied to total biopsies) and fewer unnecessary biopsies.
Comment
Our broad analysis further supported the findings of prior studies that decisions to biopsy clinically suspicious PSLs are more sensitive, specific, and accurate when practitioners are provided MSDSLA information following clinical examination.2-8
Given the evolution in health care economics, it is clear that greater emphasis will continue to be placed on superior, evidence-based, effective care. The reported diagnostic sensitivities and specificities of clinical evaluation and dermoscopy for melanoma detection vary widely throughout the literature, with sensitivities ranging from 58% to over 90% and specificities ranging from 77% to 99%.9-11
Our study had several limitations. For this analysis to be more representative of lesion biopsy selection in the clinical setting, biopsy sensitivity (correctly identifying lesions appropriate for biopsy) vs melanoma sensitivity (identifying a lesion as melanoma) was used.13 The overall sensitivity found was within the range of prior studies,2-8 but this approach may have potentially led to a lower specificity due to an increased number of lesions biopsied. Additionally, the melanomas selected for these studies were early (malignant melanoma in situ or mean thickness of invasive malignant melanoma of 0.3 mm), and the nonmelanomas (including low-grade dysplastic nevi) were not necessarily diagnostically straightforward. This may have led to the clinical and dermoscopic sensitivity and specificity noted being lower than in some prior studies.9-11
The risk of missing a melanoma with MSDSLA devices has led manufacturers to strive for a high sensitivity for their devices, leading to lower specificity as a consequence. For this reason and other ambiguous practical considerations (eg, device and patient costs, difficulty with insurance reimbursement), the adoption of this technology into routine clinical practice has remained relatively static; however, using enhanced diagnostic technologies such as MSDSLA may help with more accurate identification of high-risk PSLs, thereby leading to earlier detection and overall less expensive, more cost-effective treatment of melanoma.
- Monheit G, Cognetta AB, Ferris L, et al. The performance of MelaFind: a prospective multicenter study. Arch Dermatol. 2011;147:188-194.
- Rigel DS, Roy M, Yoo J, et al. Impact of guidance from a computer-aided multispectral digital skin lesion analysis device on decision to biopsy lesions clinically suggestive of melanoma. Arch Dermatol. 2012;148:541-543.
- Yoo J, Rigel DS, Roy M, et al. Impact of guidance from a multispectral digital skin lesion analysis device on dermatology residents decisions to biopsy lesions clinically suggestive of melanoma. J Am Acad Dermatol. 2013;68:AB152.
- Winkelmann RR, Yoo J, Tucker N, et al. Impact of guidance provided by a multispectral digital skin lesion analysis device following dermoscopy on decisions to biopsy atypical melanocytic lesions. J Clin Aesthet Dermatol. 2015;8:21-24.
- Winkelmann RR, Hauschild A, Tucker N, et al. The impact of multispectral digital skin lesion analysis on German dermatologist decisions to biopsy atypical pigmented lesions with clinical characteristics of melanoma. J Clin Aesthet Dermatol. 2015;8:27-29.
- Winkelmann RR, Tucker N, White R, et al. Pigmented skin lesion biopsies after computer-aided multispectral digital skin lesion analysis. J Am Osteopath Assoc. 2015;115:666-669.
- Winkelmann RR, Farberg AS, Tucker N, et al. Enhancement of international dermatologists’ pigmented skin lesion biopsy decisions following dermoscopy with subsequent integration of multispectral digital skin lesion analysis [published online July 1, 2016]. J Clin Aesthet Dermatol. 2016;9:53-55.
- Farberg AS, Winkelmann RR, Tucker N, et al. The impact of quantitative data provided by a multi-spectral digital skin lesion analysis device on dermatologists’ decisions to biopsy pigmented lesions [published online September 1, 2017]. J Clin Aesthet Dermatol. 2017;10:24-26.
- Wolf IH, Smolle J, Soyer HP, et al. Sensitivity in the clinical diagnosis of malignant melanoma. Melanoma Res. 1998;8:425-429.
- Kittler H, Pehamberger H, Wolff K, et al. Diagnostic accuracy of dermoscopy. Lancet Oncol. 2002;3:159-165.
- Ascierto PA, Palmieri G, Celentano E, et al. Sensitivity and specificity of epiluminescence microscopy: evaluation on a sample of 2731 excised cutaneous pigmented lesions: the Melanoma Cooperative Study. Br J Dermatol. 2000;142:893-898.
- Carli P, Nardini P, Crocetti E, et al. Frequency and characteristics of melanomas missed at a pigmented lesion clinic: a registry-based study. Melanoma Res. 2004;14:403-407.
- Friedman RJ, Gutkowicz-Krusin D, Farber MJ, et al. The diagnostic performance of expert dermoscopists vs a computer-vision system on small-diameter melanomas. Arch Dermatol. 2008;144:476-482.
- Monheit G, Cognetta AB, Ferris L, et al. The performance of MelaFind: a prospective multicenter study. Arch Dermatol. 2011;147:188-194.
- Rigel DS, Roy M, Yoo J, et al. Impact of guidance from a computer-aided multispectral digital skin lesion analysis device on decision to biopsy lesions clinically suggestive of melanoma. Arch Dermatol. 2012;148:541-543.
- Yoo J, Rigel DS, Roy M, et al. Impact of guidance from a multispectral digital skin lesion analysis device on dermatology residents decisions to biopsy lesions clinically suggestive of melanoma. J Am Acad Dermatol. 2013;68:AB152.
- Winkelmann RR, Yoo J, Tucker N, et al. Impact of guidance provided by a multispectral digital skin lesion analysis device following dermoscopy on decisions to biopsy atypical melanocytic lesions. J Clin Aesthet Dermatol. 2015;8:21-24.
- Winkelmann RR, Hauschild A, Tucker N, et al. The impact of multispectral digital skin lesion analysis on German dermatologist decisions to biopsy atypical pigmented lesions with clinical characteristics of melanoma. J Clin Aesthet Dermatol. 2015;8:27-29.
- Winkelmann RR, Tucker N, White R, et al. Pigmented skin lesion biopsies after computer-aided multispectral digital skin lesion analysis. J Am Osteopath Assoc. 2015;115:666-669.
- Winkelmann RR, Farberg AS, Tucker N, et al. Enhancement of international dermatologists’ pigmented skin lesion biopsy decisions following dermoscopy with subsequent integration of multispectral digital skin lesion analysis [published online July 1, 2016]. J Clin Aesthet Dermatol. 2016;9:53-55.
- Farberg AS, Winkelmann RR, Tucker N, et al. The impact of quantitative data provided by a multi-spectral digital skin lesion analysis device on dermatologists’ decisions to biopsy pigmented lesions [published online September 1, 2017]. J Clin Aesthet Dermatol. 2017;10:24-26.
- Wolf IH, Smolle J, Soyer HP, et al. Sensitivity in the clinical diagnosis of malignant melanoma. Melanoma Res. 1998;8:425-429.
- Kittler H, Pehamberger H, Wolff K, et al. Diagnostic accuracy of dermoscopy. Lancet Oncol. 2002;3:159-165.
- Ascierto PA, Palmieri G, Celentano E, et al. Sensitivity and specificity of epiluminescence microscopy: evaluation on a sample of 2731 excised cutaneous pigmented lesions: the Melanoma Cooperative Study. Br J Dermatol. 2000;142:893-898.
- Carli P, Nardini P, Crocetti E, et al. Frequency and characteristics of melanomas missed at a pigmented lesion clinic: a registry-based study. Melanoma Res. 2004;14:403-407.
- Friedman RJ, Gutkowicz-Krusin D, Farber MJ, et al. The diagnostic performance of expert dermoscopists vs a computer-vision system on small-diameter melanomas. Arch Dermatol. 2008;144:476-482.
Practice Points
- Multispectral digital skin lesion analysis (MSDSLA) can be a valuable tool in the evaluation of pigmented skin lesions (PSLs).
- MSDSLA may help to better identify high-risk PSLs and improve cost of care.
Mohs Micrographic Surgery for Digital Melanoma and Nonmelanoma Skin Cancers
Mohs micrographic surgery (MMS) is a specialized surgical technique for the treatment of melanoma and nonmelanoma skin cancers (NMSCs).1-3 The procedure involves surgical excision, histopathologic examination, precise mapping of malignant tissue, and wound management. Indications for MMS in skin cancer patients include recurring lesions, lesions in high-risk anatomic locations, aggressive histologic subtypes (ie, morpheaform, micronodular, infiltrative, high-grade, poorly differentiated), perineural invasion, large lesion size (>2 cm in diameter), poorly defined lateral or vertical clinical borders, rapid growth of the lesion, immunocompromised status, and sites of positive margins on prior excision. The therapeutic advantages of MMS include tissue conservation and optimal margin control in cosmetically or functionally sensitive areas, such as acral sites (eg, hands, feet, digits).1,3
The intricacies of the nail apparatus complicate diagnostic biopsy and precise delineation of peripheral margins in digital skin cancers; thus, early diagnosis and intraoperative histologic examination of the margins are essential. Traditionally, the surgical approach to subungual cutaneous tumors such as melanoma has included digital amputation4; however, a study of the treatment of subungual melanoma revealed no difference in survival based on the level of amputation, therefore advocating for less radical treatment.4
Interestingly, MMS for cutaneous tumors localized to the digits is not frequently reviewed in the dermatologic literature. We present a retrospective case series evaluating the clinical outcomes of digital melanoma and NMSCs treated with MMS.
Methods
A retrospective chart review was performed at a private dermatology practice to identify patients who underwent MMS for melanoma or NMSC localized to the digits from January 2009 to December 2014. All patients were treated in the office by 1 Mohs surgeon (A.H.) and were evaluated before and after MMS. Data were collected from the electronic medical record of the practice, including patient demographics, histopathologic diagnosis, tumor status (primary or recurrent lesion), anatomic site of the tumor, preoperative and postoperative size of the lesion, number of MMS stages, surgical repair technique, postoperative complications, and follow-up period.
Results
Twenty-seven patients (13 male, 14 female) with a total of 28 lesions (malignant melanoma or NMSC) localized to the digits were identified (Table). The mean age at the time of MMS was 64.07 years.
Surgical techniques used for repair following MMS included xenograft (10/28 [35.71%]); split-thickness skin graft (7/28 [25.0%]); secondary intention (4/28 [14.29%]); flap (4/28 [14.29%]); full-thickness skin graft (2/28 [7.14%]); and complex closure (1/28 [3.57%]). Clinical preoperative, operative, and postoperative photos from Patient 21 in this series are shown here (Figure). Two patients required bony phalanx resection due to invasion of the tumor into the periosteum: 1 had a malignant melanoma (Breslow depth, 2.52 mm); the other had an SCC. In addition, following removal of a severely dysplastic nevus, debulked tissue revealed melanoma in 1 patient.
Postoperative complications were noted in 4 (14.29%) of 28 MMS procedures, including bacterial wound infection (3.57%), excess granulation tissue that required wound debridement (7.14%), and delay in wound healing (3.57%). Follow-up data were available for 25 of the 28 MMS procedures (mean follow-up, 35.4 months), during which no recurrences were observed.
Comment
Mohs micrographic surgery is a specialized technique used in the treatment of cutaneous tumors, including basal cell carcinoma, SCC, melanoma in situ, atypical fibroxanthoma, dermatofibrosarcoma protuberans, sebaceous carcinoma, microcystic adnexal carcinoma, and Merkel cell carcinoma, among other cutaneous tumors.1-3 Mohs micrographic surgery provides the advantage of tissue conservation as well as optimal margin control in cosmetically or functionally sensitive areas while providing a higher cure rate than surgical excision. During the procedure, the surgical margin is examined histologically, thus ensuring definitive removal of the tumor but minimal loss of surrounding normal tissue.1-3 Mohs micrographic surgery is particularly useful for treating lesions on acral sites (eg, hands, feet, and digits).3-5
The treatment of digital skin cancers has evolved over the past 50 years with advancements resulting in more precise, tissue-sparing methods, in contrast to previous treatments such as amputation and wide local excision.6 More specifically, traditional digital amputation for the treatment of subungual melanoma has been reevaluated in multiple studies, which did not demonstrate a statistically significant difference in survival based on the level of amputation, thereby favoring less radical treatment.4,6 Moehrle et al7 found no statistical difference in recurrence rate when comparing patients with digital melanomas treated with partial amputation and those treated with digit-sparing surgery with limited excision and histologic evaluation of margins. Additionally, in a study conducted by Lazar et al,8 no recurrence of 13 subungual malignancies treated with MMS that utilized a full-thickness graft was reported at 4-year follow-up. In a large retrospective series of digital melanomas treated with MMS, Terushkin et al5 reported that 96.5% (55/57) of patients with primary melanomas that were treated with MMS avoided amputation, and the 5- and 10-year melanoma-specific survival rates for all patients treated with MMS were 95.0% and 82.6%, respectively.
In our study, cutaneous malignancies were located most often on the fingers, and the most common skin cancer identified was SCC in situ. The literature has shown that SCC in situ and SCC are the most common cutaneous neoplasms of the digits and nail unit.9 The most common specific anatomic site of cutaneous malignancy in our study was the great toe, followed by the fourth finger. A study conducted by Tan et al9 revealed that the great toe was the most common location of melanoma of the nail bed and subungual region, followed by the thumb. In contrast, primary subungual SCCs occur most frequently on the finger, with rare cases involving the toes.10
The etiology of digital SCC may involve extensive sun exposure, chronic trauma and wounds, and viral infection.9,11 More specifically, the dermatologic literature provides evidence of human papillomavirus (HPV) type 16 involvement in the pathogenesis of digital and periungual SCC. A genital-digital mechanism of spread has been implicated.11,12 An increased recurrence rate of HPV-associated digital SCCs has been reported following MMS, likely secondary to residual postsurgical HPV infection.11,12
Maintaining function and cosmesis of the hands, feet, and digits following MMS can be challenging, sometimes requiring skin grafts and flaps to close the defect. In the 28 MMS procedures evaluated in our study, 19 (67.9%) surgical defects were repaired with a graft (ie, split-thickness skin graft, full-thickness skin graft, xenograft), 4 (14.3%) with a flap (advancement and rotation), 4 (14.3%) by secondary intention, and 1 (3.6%) with primary complex closure.
Surgical grafts can be categorized based on the origin of the graft.2,13 Autografts, derived from the patient’s skin, are the most frequently used dermatologic graft and can be further categorized as full-thickness skin grafts, which include the epidermis and the entire dermis, thus preserving adnexal structures, and split-thickness skin grafts, which include the epidermis and partial dermis.2,13
A cross-sectional survey of fellowship-trained Mohs surgeons revealed that more than two-thirds of repairs for cutaneous acral cancers were performed using a primary closure technique, and one-fourth of closures were performed using secondary intention.15 Of the less frequently utilized skin-graft repairs, more were for acral lesions on the legs than on the arms.14 The type of procedure and graft used is dependent on multiple variables, including the anatomic location of the lesion and final size of the defect following MMS.2 Similarly, the use of specific types of sutures depends on the anatomic location of the lesion, relative thickness of the skin, degree of tension, and desired cosmetic result.15 The expertise of a hand surgeon may be required, particularly in cases in which the extensor tendon of the distal interphalangeal joint is compromised, manifested by a droopy fingertip when the hand is held horizontally. Additionally, special attention should be paid to removing the entire nail matrix before skin grafting for subungual tumors to avoid nail growth under the skin graft.
Evaluation of debulked tissue from digital skin cancers proved to be important in our study. In Patient 21, debulked tissue revealed melanoma following removal of a severely dysplastic nevus. This finding emphasizes the importance of complete excision of such lesions, as remaining underlying portions of the lesion can reveal residual tumor of the same or different histopathology.
In a prospective study, MMS was shown to have a low rate (0.91%; 95% confidence interval, 0.38%-1.45%) of surgical site infection in the absence of prophylactic antibiotics.16 The highest rates of surgical site infection were closely associated with flap closure. In our study, most patients had an uncomplicated and successful postoperative recovery. Only 1 (3.57%) of the 28 MMS procedures (Patient 22) was complicated by a bacterial wound infection postoperatively. The lesion removed in this case was a severely dysplastic melanocytic nevus on the toe. Infection resolved after a course of oral antibiotics, but the underlying cause of the wound infection in the patient was unclear. Other postoperative complications in our study included delayed wound healing and excess granulation tissue requiring wound debridement.
There are limited data in the dermatologic literature regarding outcomes following MMS for the treatment of cutaneous malignancies localized to the digits.
Additional limitations of this case review include its single-center and retrospective design, the small sample size, and 1 Mohs surgeon having performed all surgeries.
Conclusion
This study provides further evidence of the benefit of MMS for the treatment of malignant melanoma and NMSCs of the digits. This procedure provides margin-controlled excision of these malignant neoplasms while preserving maximal normal tissue, thereby providing patients with improved postoperative function and cosmesis. Long-term follow-up data demonstrating a lack of tumor recurrence underscores the assertion that MMS is safe and effective for the treatment of skin cancer of the digits.
- Dim-Jamora KC, Perone JB. Management of cutaneous tumors with mohs micrographic surgery. Semin Plast Surg. 2008;22:247-256.
- McLeod MP, Choudhary S, Alqubaisy YA, et al. Indications for Mohs micrographic surgery. In: Nouri K, ed. Mohs Micrographic Surgery. New York, NY: Springer; 2012:5-13.
- Loosemore MP, Morales-Burgos A, Goldberg LH. Acral lentiginous melanoma of the toe treated using Mohs surgery with sparing of the digit and subsequent reconstruction using split-thickness skin graft. Dermatol Surg. 2013;39:136-138.
- Rayatt SS, Dancey AL, Davison PM. Thumb subungual melanoma: is amputation necessary? J Plast Reconstr Aesthet Surg. 2007;60:635-638.
- Terushkin V, Brodland DG, Sharon DJ, et al. Digit-sparing Mohs surgery for melanoma. Dermatol Surg. 2016;42:83-93.
- Viola KV, Jhaveri MB, Soulos PR, et al. Mohs micrographic surgery and surgical excision for nonmelanoma skin cancer treatment in the Medicare population. Arch Dermatol. 2012;148:473-477.
- Moehrle M, Metzger S, Schippert W. “Functional” surgery in subungual melanoma. Dermatol Surg. 2003;29:366-374.
- Lazar A, Abimelec P, Dumontier C, et al. Full thickness skin graft from nail unit reconstruction. J Hand Surg Br. 2005;30:194-198.
- Tan KB, Moncrieff M, Thompson JF, et al. Subungual melanoma: a study of 124 cases highlighting features of early lesions, potential for histologic reports. Am J Surg Pathol. 2007;31:1902-1912.
- Nasca MR, Innocenzi D, Micali G. Subungual squamous cell carcinoma of the toe: report on three cases. Dermatol Surg. 2004;30:345-348.
- Dika E, Piraccini BM, Balestri RR, et al. Mohs surgery for squamous cell carcinoma of the nail: report of 15 cases. our experience and a long-term follow-up. Br J Dermatol. 2012;167:1310-1314.
- Alam M, Caldwell JB, Eliezri YD. Human papillomavirus-associated digital squamous cell carcinoma: literature review and report of 21 new cases. J Am Acad Dermatol. 2003;48:385-393.
- Filho L, Anselmo J, Dadalti P, et al. Skin grafts in cutaneous oncology. Braz Ann Dermatol. 2006;81:465-472.
- Raimer DW, Group AR, Petitt MS, et al. Porcine xenograft biosynthetic wound dressings for the management of postoperative Mohs wounds. Dermatol Online J. 2011;17:1.
- Alam M, Helenowksi IB, Cohen JL, et al. Association between type of reconstruction after Mohs micrographic surgery and surgeon-, patient-, and tumor-specific features: a cross-sectional study. Dermatol Surg. 2013;39:51-55.
- Rogers HD, Desciak EB, Marcus RP, et al. Prospective study of wound infections in Mohs micrographic surgery using clean surgical technique in the absence of prophylactic antibiotics. J Am Acad Dermatol. 2010;63:842-851.
Mohs micrographic surgery (MMS) is a specialized surgical technique for the treatment of melanoma and nonmelanoma skin cancers (NMSCs).1-3 The procedure involves surgical excision, histopathologic examination, precise mapping of malignant tissue, and wound management. Indications for MMS in skin cancer patients include recurring lesions, lesions in high-risk anatomic locations, aggressive histologic subtypes (ie, morpheaform, micronodular, infiltrative, high-grade, poorly differentiated), perineural invasion, large lesion size (>2 cm in diameter), poorly defined lateral or vertical clinical borders, rapid growth of the lesion, immunocompromised status, and sites of positive margins on prior excision. The therapeutic advantages of MMS include tissue conservation and optimal margin control in cosmetically or functionally sensitive areas, such as acral sites (eg, hands, feet, digits).1,3
The intricacies of the nail apparatus complicate diagnostic biopsy and precise delineation of peripheral margins in digital skin cancers; thus, early diagnosis and intraoperative histologic examination of the margins are essential. Traditionally, the surgical approach to subungual cutaneous tumors such as melanoma has included digital amputation4; however, a study of the treatment of subungual melanoma revealed no difference in survival based on the level of amputation, therefore advocating for less radical treatment.4
Interestingly, MMS for cutaneous tumors localized to the digits is not frequently reviewed in the dermatologic literature. We present a retrospective case series evaluating the clinical outcomes of digital melanoma and NMSCs treated with MMS.
Methods
A retrospective chart review was performed at a private dermatology practice to identify patients who underwent MMS for melanoma or NMSC localized to the digits from January 2009 to December 2014. All patients were treated in the office by 1 Mohs surgeon (A.H.) and were evaluated before and after MMS. Data were collected from the electronic medical record of the practice, including patient demographics, histopathologic diagnosis, tumor status (primary or recurrent lesion), anatomic site of the tumor, preoperative and postoperative size of the lesion, number of MMS stages, surgical repair technique, postoperative complications, and follow-up period.
Results
Twenty-seven patients (13 male, 14 female) with a total of 28 lesions (malignant melanoma or NMSC) localized to the digits were identified (Table). The mean age at the time of MMS was 64.07 years.
Surgical techniques used for repair following MMS included xenograft (10/28 [35.71%]); split-thickness skin graft (7/28 [25.0%]); secondary intention (4/28 [14.29%]); flap (4/28 [14.29%]); full-thickness skin graft (2/28 [7.14%]); and complex closure (1/28 [3.57%]). Clinical preoperative, operative, and postoperative photos from Patient 21 in this series are shown here (Figure). Two patients required bony phalanx resection due to invasion of the tumor into the periosteum: 1 had a malignant melanoma (Breslow depth, 2.52 mm); the other had an SCC. In addition, following removal of a severely dysplastic nevus, debulked tissue revealed melanoma in 1 patient.
Postoperative complications were noted in 4 (14.29%) of 28 MMS procedures, including bacterial wound infection (3.57%), excess granulation tissue that required wound debridement (7.14%), and delay in wound healing (3.57%). Follow-up data were available for 25 of the 28 MMS procedures (mean follow-up, 35.4 months), during which no recurrences were observed.
Comment
Mohs micrographic surgery is a specialized technique used in the treatment of cutaneous tumors, including basal cell carcinoma, SCC, melanoma in situ, atypical fibroxanthoma, dermatofibrosarcoma protuberans, sebaceous carcinoma, microcystic adnexal carcinoma, and Merkel cell carcinoma, among other cutaneous tumors.1-3 Mohs micrographic surgery provides the advantage of tissue conservation as well as optimal margin control in cosmetically or functionally sensitive areas while providing a higher cure rate than surgical excision. During the procedure, the surgical margin is examined histologically, thus ensuring definitive removal of the tumor but minimal loss of surrounding normal tissue.1-3 Mohs micrographic surgery is particularly useful for treating lesions on acral sites (eg, hands, feet, and digits).3-5
The treatment of digital skin cancers has evolved over the past 50 years with advancements resulting in more precise, tissue-sparing methods, in contrast to previous treatments such as amputation and wide local excision.6 More specifically, traditional digital amputation for the treatment of subungual melanoma has been reevaluated in multiple studies, which did not demonstrate a statistically significant difference in survival based on the level of amputation, thereby favoring less radical treatment.4,6 Moehrle et al7 found no statistical difference in recurrence rate when comparing patients with digital melanomas treated with partial amputation and those treated with digit-sparing surgery with limited excision and histologic evaluation of margins. Additionally, in a study conducted by Lazar et al,8 no recurrence of 13 subungual malignancies treated with MMS that utilized a full-thickness graft was reported at 4-year follow-up. In a large retrospective series of digital melanomas treated with MMS, Terushkin et al5 reported that 96.5% (55/57) of patients with primary melanomas that were treated with MMS avoided amputation, and the 5- and 10-year melanoma-specific survival rates for all patients treated with MMS were 95.0% and 82.6%, respectively.
In our study, cutaneous malignancies were located most often on the fingers, and the most common skin cancer identified was SCC in situ. The literature has shown that SCC in situ and SCC are the most common cutaneous neoplasms of the digits and nail unit.9 The most common specific anatomic site of cutaneous malignancy in our study was the great toe, followed by the fourth finger. A study conducted by Tan et al9 revealed that the great toe was the most common location of melanoma of the nail bed and subungual region, followed by the thumb. In contrast, primary subungual SCCs occur most frequently on the finger, with rare cases involving the toes.10
The etiology of digital SCC may involve extensive sun exposure, chronic trauma and wounds, and viral infection.9,11 More specifically, the dermatologic literature provides evidence of human papillomavirus (HPV) type 16 involvement in the pathogenesis of digital and periungual SCC. A genital-digital mechanism of spread has been implicated.11,12 An increased recurrence rate of HPV-associated digital SCCs has been reported following MMS, likely secondary to residual postsurgical HPV infection.11,12
Maintaining function and cosmesis of the hands, feet, and digits following MMS can be challenging, sometimes requiring skin grafts and flaps to close the defect. In the 28 MMS procedures evaluated in our study, 19 (67.9%) surgical defects were repaired with a graft (ie, split-thickness skin graft, full-thickness skin graft, xenograft), 4 (14.3%) with a flap (advancement and rotation), 4 (14.3%) by secondary intention, and 1 (3.6%) with primary complex closure.
Surgical grafts can be categorized based on the origin of the graft.2,13 Autografts, derived from the patient’s skin, are the most frequently used dermatologic graft and can be further categorized as full-thickness skin grafts, which include the epidermis and the entire dermis, thus preserving adnexal structures, and split-thickness skin grafts, which include the epidermis and partial dermis.2,13
A cross-sectional survey of fellowship-trained Mohs surgeons revealed that more than two-thirds of repairs for cutaneous acral cancers were performed using a primary closure technique, and one-fourth of closures were performed using secondary intention.15 Of the less frequently utilized skin-graft repairs, more were for acral lesions on the legs than on the arms.14 The type of procedure and graft used is dependent on multiple variables, including the anatomic location of the lesion and final size of the defect following MMS.2 Similarly, the use of specific types of sutures depends on the anatomic location of the lesion, relative thickness of the skin, degree of tension, and desired cosmetic result.15 The expertise of a hand surgeon may be required, particularly in cases in which the extensor tendon of the distal interphalangeal joint is compromised, manifested by a droopy fingertip when the hand is held horizontally. Additionally, special attention should be paid to removing the entire nail matrix before skin grafting for subungual tumors to avoid nail growth under the skin graft.
Evaluation of debulked tissue from digital skin cancers proved to be important in our study. In Patient 21, debulked tissue revealed melanoma following removal of a severely dysplastic nevus. This finding emphasizes the importance of complete excision of such lesions, as remaining underlying portions of the lesion can reveal residual tumor of the same or different histopathology.
In a prospective study, MMS was shown to have a low rate (0.91%; 95% confidence interval, 0.38%-1.45%) of surgical site infection in the absence of prophylactic antibiotics.16 The highest rates of surgical site infection were closely associated with flap closure. In our study, most patients had an uncomplicated and successful postoperative recovery. Only 1 (3.57%) of the 28 MMS procedures (Patient 22) was complicated by a bacterial wound infection postoperatively. The lesion removed in this case was a severely dysplastic melanocytic nevus on the toe. Infection resolved after a course of oral antibiotics, but the underlying cause of the wound infection in the patient was unclear. Other postoperative complications in our study included delayed wound healing and excess granulation tissue requiring wound debridement.
There are limited data in the dermatologic literature regarding outcomes following MMS for the treatment of cutaneous malignancies localized to the digits.
Additional limitations of this case review include its single-center and retrospective design, the small sample size, and 1 Mohs surgeon having performed all surgeries.
Conclusion
This study provides further evidence of the benefit of MMS for the treatment of malignant melanoma and NMSCs of the digits. This procedure provides margin-controlled excision of these malignant neoplasms while preserving maximal normal tissue, thereby providing patients with improved postoperative function and cosmesis. Long-term follow-up data demonstrating a lack of tumor recurrence underscores the assertion that MMS is safe and effective for the treatment of skin cancer of the digits.
Mohs micrographic surgery (MMS) is a specialized surgical technique for the treatment of melanoma and nonmelanoma skin cancers (NMSCs).1-3 The procedure involves surgical excision, histopathologic examination, precise mapping of malignant tissue, and wound management. Indications for MMS in skin cancer patients include recurring lesions, lesions in high-risk anatomic locations, aggressive histologic subtypes (ie, morpheaform, micronodular, infiltrative, high-grade, poorly differentiated), perineural invasion, large lesion size (>2 cm in diameter), poorly defined lateral or vertical clinical borders, rapid growth of the lesion, immunocompromised status, and sites of positive margins on prior excision. The therapeutic advantages of MMS include tissue conservation and optimal margin control in cosmetically or functionally sensitive areas, such as acral sites (eg, hands, feet, digits).1,3
The intricacies of the nail apparatus complicate diagnostic biopsy and precise delineation of peripheral margins in digital skin cancers; thus, early diagnosis and intraoperative histologic examination of the margins are essential. Traditionally, the surgical approach to subungual cutaneous tumors such as melanoma has included digital amputation4; however, a study of the treatment of subungual melanoma revealed no difference in survival based on the level of amputation, therefore advocating for less radical treatment.4
Interestingly, MMS for cutaneous tumors localized to the digits is not frequently reviewed in the dermatologic literature. We present a retrospective case series evaluating the clinical outcomes of digital melanoma and NMSCs treated with MMS.
Methods
A retrospective chart review was performed at a private dermatology practice to identify patients who underwent MMS for melanoma or NMSC localized to the digits from January 2009 to December 2014. All patients were treated in the office by 1 Mohs surgeon (A.H.) and were evaluated before and after MMS. Data were collected from the electronic medical record of the practice, including patient demographics, histopathologic diagnosis, tumor status (primary or recurrent lesion), anatomic site of the tumor, preoperative and postoperative size of the lesion, number of MMS stages, surgical repair technique, postoperative complications, and follow-up period.
Results
Twenty-seven patients (13 male, 14 female) with a total of 28 lesions (malignant melanoma or NMSC) localized to the digits were identified (Table). The mean age at the time of MMS was 64.07 years.
Surgical techniques used for repair following MMS included xenograft (10/28 [35.71%]); split-thickness skin graft (7/28 [25.0%]); secondary intention (4/28 [14.29%]); flap (4/28 [14.29%]); full-thickness skin graft (2/28 [7.14%]); and complex closure (1/28 [3.57%]). Clinical preoperative, operative, and postoperative photos from Patient 21 in this series are shown here (Figure). Two patients required bony phalanx resection due to invasion of the tumor into the periosteum: 1 had a malignant melanoma (Breslow depth, 2.52 mm); the other had an SCC. In addition, following removal of a severely dysplastic nevus, debulked tissue revealed melanoma in 1 patient.
Postoperative complications were noted in 4 (14.29%) of 28 MMS procedures, including bacterial wound infection (3.57%), excess granulation tissue that required wound debridement (7.14%), and delay in wound healing (3.57%). Follow-up data were available for 25 of the 28 MMS procedures (mean follow-up, 35.4 months), during which no recurrences were observed.
Comment
Mohs micrographic surgery is a specialized technique used in the treatment of cutaneous tumors, including basal cell carcinoma, SCC, melanoma in situ, atypical fibroxanthoma, dermatofibrosarcoma protuberans, sebaceous carcinoma, microcystic adnexal carcinoma, and Merkel cell carcinoma, among other cutaneous tumors.1-3 Mohs micrographic surgery provides the advantage of tissue conservation as well as optimal margin control in cosmetically or functionally sensitive areas while providing a higher cure rate than surgical excision. During the procedure, the surgical margin is examined histologically, thus ensuring definitive removal of the tumor but minimal loss of surrounding normal tissue.1-3 Mohs micrographic surgery is particularly useful for treating lesions on acral sites (eg, hands, feet, and digits).3-5
The treatment of digital skin cancers has evolved over the past 50 years with advancements resulting in more precise, tissue-sparing methods, in contrast to previous treatments such as amputation and wide local excision.6 More specifically, traditional digital amputation for the treatment of subungual melanoma has been reevaluated in multiple studies, which did not demonstrate a statistically significant difference in survival based on the level of amputation, thereby favoring less radical treatment.4,6 Moehrle et al7 found no statistical difference in recurrence rate when comparing patients with digital melanomas treated with partial amputation and those treated with digit-sparing surgery with limited excision and histologic evaluation of margins. Additionally, in a study conducted by Lazar et al,8 no recurrence of 13 subungual malignancies treated with MMS that utilized a full-thickness graft was reported at 4-year follow-up. In a large retrospective series of digital melanomas treated with MMS, Terushkin et al5 reported that 96.5% (55/57) of patients with primary melanomas that were treated with MMS avoided amputation, and the 5- and 10-year melanoma-specific survival rates for all patients treated with MMS were 95.0% and 82.6%, respectively.
In our study, cutaneous malignancies were located most often on the fingers, and the most common skin cancer identified was SCC in situ. The literature has shown that SCC in situ and SCC are the most common cutaneous neoplasms of the digits and nail unit.9 The most common specific anatomic site of cutaneous malignancy in our study was the great toe, followed by the fourth finger. A study conducted by Tan et al9 revealed that the great toe was the most common location of melanoma of the nail bed and subungual region, followed by the thumb. In contrast, primary subungual SCCs occur most frequently on the finger, with rare cases involving the toes.10
The etiology of digital SCC may involve extensive sun exposure, chronic trauma and wounds, and viral infection.9,11 More specifically, the dermatologic literature provides evidence of human papillomavirus (HPV) type 16 involvement in the pathogenesis of digital and periungual SCC. A genital-digital mechanism of spread has been implicated.11,12 An increased recurrence rate of HPV-associated digital SCCs has been reported following MMS, likely secondary to residual postsurgical HPV infection.11,12
Maintaining function and cosmesis of the hands, feet, and digits following MMS can be challenging, sometimes requiring skin grafts and flaps to close the defect. In the 28 MMS procedures evaluated in our study, 19 (67.9%) surgical defects were repaired with a graft (ie, split-thickness skin graft, full-thickness skin graft, xenograft), 4 (14.3%) with a flap (advancement and rotation), 4 (14.3%) by secondary intention, and 1 (3.6%) with primary complex closure.
Surgical grafts can be categorized based on the origin of the graft.2,13 Autografts, derived from the patient’s skin, are the most frequently used dermatologic graft and can be further categorized as full-thickness skin grafts, which include the epidermis and the entire dermis, thus preserving adnexal structures, and split-thickness skin grafts, which include the epidermis and partial dermis.2,13
A cross-sectional survey of fellowship-trained Mohs surgeons revealed that more than two-thirds of repairs for cutaneous acral cancers were performed using a primary closure technique, and one-fourth of closures were performed using secondary intention.15 Of the less frequently utilized skin-graft repairs, more were for acral lesions on the legs than on the arms.14 The type of procedure and graft used is dependent on multiple variables, including the anatomic location of the lesion and final size of the defect following MMS.2 Similarly, the use of specific types of sutures depends on the anatomic location of the lesion, relative thickness of the skin, degree of tension, and desired cosmetic result.15 The expertise of a hand surgeon may be required, particularly in cases in which the extensor tendon of the distal interphalangeal joint is compromised, manifested by a droopy fingertip when the hand is held horizontally. Additionally, special attention should be paid to removing the entire nail matrix before skin grafting for subungual tumors to avoid nail growth under the skin graft.
Evaluation of debulked tissue from digital skin cancers proved to be important in our study. In Patient 21, debulked tissue revealed melanoma following removal of a severely dysplastic nevus. This finding emphasizes the importance of complete excision of such lesions, as remaining underlying portions of the lesion can reveal residual tumor of the same or different histopathology.
In a prospective study, MMS was shown to have a low rate (0.91%; 95% confidence interval, 0.38%-1.45%) of surgical site infection in the absence of prophylactic antibiotics.16 The highest rates of surgical site infection were closely associated with flap closure. In our study, most patients had an uncomplicated and successful postoperative recovery. Only 1 (3.57%) of the 28 MMS procedures (Patient 22) was complicated by a bacterial wound infection postoperatively. The lesion removed in this case was a severely dysplastic melanocytic nevus on the toe. Infection resolved after a course of oral antibiotics, but the underlying cause of the wound infection in the patient was unclear. Other postoperative complications in our study included delayed wound healing and excess granulation tissue requiring wound debridement.
There are limited data in the dermatologic literature regarding outcomes following MMS for the treatment of cutaneous malignancies localized to the digits.
Additional limitations of this case review include its single-center and retrospective design, the small sample size, and 1 Mohs surgeon having performed all surgeries.
Conclusion
This study provides further evidence of the benefit of MMS for the treatment of malignant melanoma and NMSCs of the digits. This procedure provides margin-controlled excision of these malignant neoplasms while preserving maximal normal tissue, thereby providing patients with improved postoperative function and cosmesis. Long-term follow-up data demonstrating a lack of tumor recurrence underscores the assertion that MMS is safe and effective for the treatment of skin cancer of the digits.
- Dim-Jamora KC, Perone JB. Management of cutaneous tumors with mohs micrographic surgery. Semin Plast Surg. 2008;22:247-256.
- McLeod MP, Choudhary S, Alqubaisy YA, et al. Indications for Mohs micrographic surgery. In: Nouri K, ed. Mohs Micrographic Surgery. New York, NY: Springer; 2012:5-13.
- Loosemore MP, Morales-Burgos A, Goldberg LH. Acral lentiginous melanoma of the toe treated using Mohs surgery with sparing of the digit and subsequent reconstruction using split-thickness skin graft. Dermatol Surg. 2013;39:136-138.
- Rayatt SS, Dancey AL, Davison PM. Thumb subungual melanoma: is amputation necessary? J Plast Reconstr Aesthet Surg. 2007;60:635-638.
- Terushkin V, Brodland DG, Sharon DJ, et al. Digit-sparing Mohs surgery for melanoma. Dermatol Surg. 2016;42:83-93.
- Viola KV, Jhaveri MB, Soulos PR, et al. Mohs micrographic surgery and surgical excision for nonmelanoma skin cancer treatment in the Medicare population. Arch Dermatol. 2012;148:473-477.
- Moehrle M, Metzger S, Schippert W. “Functional” surgery in subungual melanoma. Dermatol Surg. 2003;29:366-374.
- Lazar A, Abimelec P, Dumontier C, et al. Full thickness skin graft from nail unit reconstruction. J Hand Surg Br. 2005;30:194-198.
- Tan KB, Moncrieff M, Thompson JF, et al. Subungual melanoma: a study of 124 cases highlighting features of early lesions, potential for histologic reports. Am J Surg Pathol. 2007;31:1902-1912.
- Nasca MR, Innocenzi D, Micali G. Subungual squamous cell carcinoma of the toe: report on three cases. Dermatol Surg. 2004;30:345-348.
- Dika E, Piraccini BM, Balestri RR, et al. Mohs surgery for squamous cell carcinoma of the nail: report of 15 cases. our experience and a long-term follow-up. Br J Dermatol. 2012;167:1310-1314.
- Alam M, Caldwell JB, Eliezri YD. Human papillomavirus-associated digital squamous cell carcinoma: literature review and report of 21 new cases. J Am Acad Dermatol. 2003;48:385-393.
- Filho L, Anselmo J, Dadalti P, et al. Skin grafts in cutaneous oncology. Braz Ann Dermatol. 2006;81:465-472.
- Raimer DW, Group AR, Petitt MS, et al. Porcine xenograft biosynthetic wound dressings for the management of postoperative Mohs wounds. Dermatol Online J. 2011;17:1.
- Alam M, Helenowksi IB, Cohen JL, et al. Association between type of reconstruction after Mohs micrographic surgery and surgeon-, patient-, and tumor-specific features: a cross-sectional study. Dermatol Surg. 2013;39:51-55.
- Rogers HD, Desciak EB, Marcus RP, et al. Prospective study of wound infections in Mohs micrographic surgery using clean surgical technique in the absence of prophylactic antibiotics. J Am Acad Dermatol. 2010;63:842-851.
- Dim-Jamora KC, Perone JB. Management of cutaneous tumors with mohs micrographic surgery. Semin Plast Surg. 2008;22:247-256.
- McLeod MP, Choudhary S, Alqubaisy YA, et al. Indications for Mohs micrographic surgery. In: Nouri K, ed. Mohs Micrographic Surgery. New York, NY: Springer; 2012:5-13.
- Loosemore MP, Morales-Burgos A, Goldberg LH. Acral lentiginous melanoma of the toe treated using Mohs surgery with sparing of the digit and subsequent reconstruction using split-thickness skin graft. Dermatol Surg. 2013;39:136-138.
- Rayatt SS, Dancey AL, Davison PM. Thumb subungual melanoma: is amputation necessary? J Plast Reconstr Aesthet Surg. 2007;60:635-638.
- Terushkin V, Brodland DG, Sharon DJ, et al. Digit-sparing Mohs surgery for melanoma. Dermatol Surg. 2016;42:83-93.
- Viola KV, Jhaveri MB, Soulos PR, et al. Mohs micrographic surgery and surgical excision for nonmelanoma skin cancer treatment in the Medicare population. Arch Dermatol. 2012;148:473-477.
- Moehrle M, Metzger S, Schippert W. “Functional” surgery in subungual melanoma. Dermatol Surg. 2003;29:366-374.
- Lazar A, Abimelec P, Dumontier C, et al. Full thickness skin graft from nail unit reconstruction. J Hand Surg Br. 2005;30:194-198.
- Tan KB, Moncrieff M, Thompson JF, et al. Subungual melanoma: a study of 124 cases highlighting features of early lesions, potential for histologic reports. Am J Surg Pathol. 2007;31:1902-1912.
- Nasca MR, Innocenzi D, Micali G. Subungual squamous cell carcinoma of the toe: report on three cases. Dermatol Surg. 2004;30:345-348.
- Dika E, Piraccini BM, Balestri RR, et al. Mohs surgery for squamous cell carcinoma of the nail: report of 15 cases. our experience and a long-term follow-up. Br J Dermatol. 2012;167:1310-1314.
- Alam M, Caldwell JB, Eliezri YD. Human papillomavirus-associated digital squamous cell carcinoma: literature review and report of 21 new cases. J Am Acad Dermatol. 2003;48:385-393.
- Filho L, Anselmo J, Dadalti P, et al. Skin grafts in cutaneous oncology. Braz Ann Dermatol. 2006;81:465-472.
- Raimer DW, Group AR, Petitt MS, et al. Porcine xenograft biosynthetic wound dressings for the management of postoperative Mohs wounds. Dermatol Online J. 2011;17:1.
- Alam M, Helenowksi IB, Cohen JL, et al. Association between type of reconstruction after Mohs micrographic surgery and surgeon-, patient-, and tumor-specific features: a cross-sectional study. Dermatol Surg. 2013;39:51-55.
- Rogers HD, Desciak EB, Marcus RP, et al. Prospective study of wound infections in Mohs micrographic surgery using clean surgical technique in the absence of prophylactic antibiotics. J Am Acad Dermatol. 2010;63:842-851.
Practice Points
- Melanoma and nonmelanoma skin cancers of the digits traditionally have been treated with wide local surgical excision and even amputation.
- Conservative tissue sparing techniques such as Mohs micrographic surgery can be used to treat digital skin cancers with high cure rates and improved functional and cosmetic results.
Penile Squamous Cell Carcinoma With Urethral Extension Treated With Mohs Micrographic Surgery
Penile squamous cell carcinoma (SCC) with considerable urethral extension is uncommon and difficult to manage. It often is resistant to less invasive and nonsurgical treatments and frequently results in partial or total penectomy, which can lead to cosmetic disfigurement, functional issues, and psychological distress. We report a case of penile SCC in situ with considerable urethral extension with a focus of cells suspicious for moderately well-differentiated and invasive SCC that was treated with
Mohs micrographic surgery with distal urethrectomy and reconstruction is a valuable treatment technique for cases of SCC involving the glans penis and distal urethra. It offers equivalent or better overall cure rates compared to more radical interventions. Additionally, preservation of the penis with MMS spares patients from considerable physical and psychosocial morbidity. Our case, along with growing body of literature,1-4 calls on dermatologists and urologists to consider MMS as a treatment for penile SCC with or without urethral involvement.
Case Report
A 61-year-old man presented to the dermatology department with a pruritic lesion on the penis that had been present for 6 years. Shave biopsy demonstrated SCC in situ with a focus of cells suspicious for moderately well-differentiated and invasive SCC. Physical examination revealed an ill-defined, 2.2×1.9-cm, pink, eroded plaque involving the tip of the penis and surrounding the external urinary meatus (Figure 1). There was no palpable inguinal lymphadenopathy.
Distal penectomy and lymph node biopsy was recommended following evaluation by the urologic oncology department, but the patient declined these interventions and presented to our dermatology department (A.H.) for a second opinion. The tumor, including the invasive perineural portion, was removed using MMS several weeks after initially presenting to urologic oncology. Ventral meatotomy allowed access to the SCC in situ portion extending proximally up the pendulous urethra (Figure 2). Clear margins were obtained after the eighth stage of MMS, which required removal of 4 to 5 cm of the distal urethra (Figure 3). Reconstruction of the wound required urethral advancement, urethrostomy, and meatoplasty. A positive outcome was achieved with preservation of the length and shape of the penis as well as the cosmetic appearance of the glans penis (Figure 4). The patient was satisfied with the outcome. At 49 months’ follow-up, no evidence of local recurrence or disease progression was noted, and the distal urethrostomy remained intact and functional.
Comment
Penile SCC is a rare malignancy that represents between 0.4% and 0.6% of all malignant tumors in the United States and occurs most commonly in men aged 50 to 70 years.4 The incidence is higher in developing countries, approaching 10% of malignancies in men. It occurs most commonly on the glans penis, prepuce, and coronal sulcus, and has multiple possible appearances, including erythematous and indurated, warty and exophytic, or flat and ulcerated lesions.5 Some reports indicate that more than 40% of penile SCCs are attributable to human papilloma virus,6 while lack of circumcision, chronic inflammation, poor hygiene, balanitis xerotica obliterans, penile trauma, human immunodeficiency virus, UVA treatment of penile psoriasis, and tobacco use are known risk factors.5
Invasive penile SCC generally is treated with penectomy (partial or total), radiation therapy, or MMS; SCC in situ can be treated with topical chemotherapy, laser therapy, and wide local excision (2-cm margins) including circumcision, complete glansectomy, or MMS.5 Squamous cell carcinoma in situ with urethral involvement treated with nonsurgical therapies is associated with higher recurrence rates, ultimately necessitating more aggressive treatments, most commonly partial penectomy.7 The high local recurrence rate of SCC in situ with urethral involvement treated with nonsurgical therapies reflects the fact that determining the presence of urethral extension is difficult and, if present, is inherently inaccessible to these local therapies because the urethra is not an outward-facing tissue surface; MMS represents one possible solution to these issues.
Across all treatment modalities, the most prognostic factor of cancer-specific survival in patients with penile SCC is pelvic lymph node involvement. Some reports cite 5-year survival rates as low as 0% in the setting of pelvic lymph node involvement,5 whereas others had cited rates of 29% to 40%4; 5-year survival rates of higher than 85% have been reported in node-negative patients.4 Recurrence rates vary widely by treatment modality, ranging from less than 10% with partial penectomy and long-term follow-up8 and up to 50% within 2 years with penile-preserving approaches (eg, topical chemotherapy, laser therapy, radiotherapy).5 Multiple case series of penile cancer (the most common of which was SCC/SCC in situ) treated with MMS report comparable and at times superior survival and recurrence data (Table).1-4 Slightly higher recurrences of penile SCC treated with MMS compared to penectomy have been reported, along with considerably higher recurrence rates compared to nonpenile cutaneous SCC treated with MMS (reported to be less than 3%).4 The elastic and expansile nature of penile tissue may lead to distortion from swelling/local anesthesia when taking individual Mohs layers. Additionally, as a large percentage of penile SCCs are attributable to human papillomavirus, difficulty in detecting human papilloma virus–infected cells (which may have oncogenic potential) with the naked eye or histologically with typical staining techniques may help explain the higher recurrence rate of penile SCC treated with MMS compared to penectomy. Despite the higher recurrence rates, survival is comparable or higher in cases treated with MMS (Table).
Partial penectomy also has a negative impact on health-related quality of life. Kieffer et al9 compared the impact of penile-sparing surgery (PSS)(including MMS) versus partial or total penectomy on sexual function and health-related quality of life in 90 patients with penile cancer. Although the association between the extent of surgery (partial penectomy/total penectomy/PSS) surgery type and extent and most outcome measures was not statistically significant, partial penectomy was associated with significantly more problems with orgasm (P=.031), concerns about appearance (P=.008), interference in daily life (P=.032), and urinary function (P<.0001) when compared to patients treated with PSS.9 Although this study included only laser/local excision with or without circumcision or glans penis amputation with or without reconstruction as PSSs and did not explicitly include MMS, MMS is clearly a tissue-sparing technique and the study results are generaliz
Conclusion
Penile SCC with considerable urethral extension is uncommon, difficult to manage, and often is resistant to less invasive and nonsurgical treatments. As a result, partial or total penectomy is sometimes necessary. Such cases benefit from MMS with distal urethrectomy and reconstruction because MMS provides equivalent or better overall cure rates compared to more radical interventions.1-4 Importantly, preservation of the penis with MMS can spare patients considerable physical and psychosocial morbidity. Partial penectomy is associated with more health-related quality-of-life problems with orgasm, concerns about appearance, interference in daily life, and urinary function compared to PSSs such as MMS.9 This case, and a growing body of literature, are a call to dermatologists and urologists to consider MMS as a treatment for penile SCC, even with involvement of the urethra.
- Brown MD, Zachary CB, Grekin RC, et al. Penile tumors: their management by Mohs micrographic surgery. J Dermatol Surg Oncol. 1987;13:1163-1167.
- Mohs FE, Snow SN, Larson PO. Mohs micrographic surgery for penile tumors. Urol Clin North Am. 1992;19:291-304.
- Shindel AW, Mann MW, Lev RY, et al. Mohs micrographic surgery for penile cancer: management and long-term followup. J Urol. 2007;178:1980-1985.
- Machan M, Brodland D, Zitelli J. Penile squamous cell carcinoma: penis-preserving treatment with Mohs micrographic surgery. Dermatol Surg. 2016;42:936-944.
- Spiess PE, Horenblas S, Pagliaro LC, et al. Current concepts in penile cancer. J Natl Compr Canc Netw. 2013;11:617-624.
- Hernandez BY, Barnholtz-Sloan J, German RR, et al. Burden of invasive squamous cell carcinoma of the penis in the United States, 1998-2003. Cancer. 2008;113(10 suppl):2883-2891.
- Nash PA, Bihrle R, Gleason PE, et al. Mohs micrographic surgery and distal urethrectomy with immediate urethral reconstruction for glanular carcinoma in situ with significant urethral extension. Urology. 1996;47:108-110.
- Djordjevic ML, Palminteri E, Martins F. Male genital reconstruction for the penile cancer survivor. Curr Opin Urol. 2014;24:427-433.
- Kieffer JM, Djajadiningrat RS, van Muilekom EA, et al. Quality of life for patients treated for penile cancer. J Urol. 2014;192:1105-1110.
Penile squamous cell carcinoma (SCC) with considerable urethral extension is uncommon and difficult to manage. It often is resistant to less invasive and nonsurgical treatments and frequently results in partial or total penectomy, which can lead to cosmetic disfigurement, functional issues, and psychological distress. We report a case of penile SCC in situ with considerable urethral extension with a focus of cells suspicious for moderately well-differentiated and invasive SCC that was treated with
Mohs micrographic surgery with distal urethrectomy and reconstruction is a valuable treatment technique for cases of SCC involving the glans penis and distal urethra. It offers equivalent or better overall cure rates compared to more radical interventions. Additionally, preservation of the penis with MMS spares patients from considerable physical and psychosocial morbidity. Our case, along with growing body of literature,1-4 calls on dermatologists and urologists to consider MMS as a treatment for penile SCC with or without urethral involvement.
Case Report
A 61-year-old man presented to the dermatology department with a pruritic lesion on the penis that had been present for 6 years. Shave biopsy demonstrated SCC in situ with a focus of cells suspicious for moderately well-differentiated and invasive SCC. Physical examination revealed an ill-defined, 2.2×1.9-cm, pink, eroded plaque involving the tip of the penis and surrounding the external urinary meatus (Figure 1). There was no palpable inguinal lymphadenopathy.
Distal penectomy and lymph node biopsy was recommended following evaluation by the urologic oncology department, but the patient declined these interventions and presented to our dermatology department (A.H.) for a second opinion. The tumor, including the invasive perineural portion, was removed using MMS several weeks after initially presenting to urologic oncology. Ventral meatotomy allowed access to the SCC in situ portion extending proximally up the pendulous urethra (Figure 2). Clear margins were obtained after the eighth stage of MMS, which required removal of 4 to 5 cm of the distal urethra (Figure 3). Reconstruction of the wound required urethral advancement, urethrostomy, and meatoplasty. A positive outcome was achieved with preservation of the length and shape of the penis as well as the cosmetic appearance of the glans penis (Figure 4). The patient was satisfied with the outcome. At 49 months’ follow-up, no evidence of local recurrence or disease progression was noted, and the distal urethrostomy remained intact and functional.
Comment
Penile SCC is a rare malignancy that represents between 0.4% and 0.6% of all malignant tumors in the United States and occurs most commonly in men aged 50 to 70 years.4 The incidence is higher in developing countries, approaching 10% of malignancies in men. It occurs most commonly on the glans penis, prepuce, and coronal sulcus, and has multiple possible appearances, including erythematous and indurated, warty and exophytic, or flat and ulcerated lesions.5 Some reports indicate that more than 40% of penile SCCs are attributable to human papilloma virus,6 while lack of circumcision, chronic inflammation, poor hygiene, balanitis xerotica obliterans, penile trauma, human immunodeficiency virus, UVA treatment of penile psoriasis, and tobacco use are known risk factors.5
Invasive penile SCC generally is treated with penectomy (partial or total), radiation therapy, or MMS; SCC in situ can be treated with topical chemotherapy, laser therapy, and wide local excision (2-cm margins) including circumcision, complete glansectomy, or MMS.5 Squamous cell carcinoma in situ with urethral involvement treated with nonsurgical therapies is associated with higher recurrence rates, ultimately necessitating more aggressive treatments, most commonly partial penectomy.7 The high local recurrence rate of SCC in situ with urethral involvement treated with nonsurgical therapies reflects the fact that determining the presence of urethral extension is difficult and, if present, is inherently inaccessible to these local therapies because the urethra is not an outward-facing tissue surface; MMS represents one possible solution to these issues.
Across all treatment modalities, the most prognostic factor of cancer-specific survival in patients with penile SCC is pelvic lymph node involvement. Some reports cite 5-year survival rates as low as 0% in the setting of pelvic lymph node involvement,5 whereas others had cited rates of 29% to 40%4; 5-year survival rates of higher than 85% have been reported in node-negative patients.4 Recurrence rates vary widely by treatment modality, ranging from less than 10% with partial penectomy and long-term follow-up8 and up to 50% within 2 years with penile-preserving approaches (eg, topical chemotherapy, laser therapy, radiotherapy).5 Multiple case series of penile cancer (the most common of which was SCC/SCC in situ) treated with MMS report comparable and at times superior survival and recurrence data (Table).1-4 Slightly higher recurrences of penile SCC treated with MMS compared to penectomy have been reported, along with considerably higher recurrence rates compared to nonpenile cutaneous SCC treated with MMS (reported to be less than 3%).4 The elastic and expansile nature of penile tissue may lead to distortion from swelling/local anesthesia when taking individual Mohs layers. Additionally, as a large percentage of penile SCCs are attributable to human papillomavirus, difficulty in detecting human papilloma virus–infected cells (which may have oncogenic potential) with the naked eye or histologically with typical staining techniques may help explain the higher recurrence rate of penile SCC treated with MMS compared to penectomy. Despite the higher recurrence rates, survival is comparable or higher in cases treated with MMS (Table).
Partial penectomy also has a negative impact on health-related quality of life. Kieffer et al9 compared the impact of penile-sparing surgery (PSS)(including MMS) versus partial or total penectomy on sexual function and health-related quality of life in 90 patients with penile cancer. Although the association between the extent of surgery (partial penectomy/total penectomy/PSS) surgery type and extent and most outcome measures was not statistically significant, partial penectomy was associated with significantly more problems with orgasm (P=.031), concerns about appearance (P=.008), interference in daily life (P=.032), and urinary function (P<.0001) when compared to patients treated with PSS.9 Although this study included only laser/local excision with or without circumcision or glans penis amputation with or without reconstruction as PSSs and did not explicitly include MMS, MMS is clearly a tissue-sparing technique and the study results are generaliz
Conclusion
Penile SCC with considerable urethral extension is uncommon, difficult to manage, and often is resistant to less invasive and nonsurgical treatments. As a result, partial or total penectomy is sometimes necessary. Such cases benefit from MMS with distal urethrectomy and reconstruction because MMS provides equivalent or better overall cure rates compared to more radical interventions.1-4 Importantly, preservation of the penis with MMS can spare patients considerable physical and psychosocial morbidity. Partial penectomy is associated with more health-related quality-of-life problems with orgasm, concerns about appearance, interference in daily life, and urinary function compared to PSSs such as MMS.9 This case, and a growing body of literature, are a call to dermatologists and urologists to consider MMS as a treatment for penile SCC, even with involvement of the urethra.
Penile squamous cell carcinoma (SCC) with considerable urethral extension is uncommon and difficult to manage. It often is resistant to less invasive and nonsurgical treatments and frequently results in partial or total penectomy, which can lead to cosmetic disfigurement, functional issues, and psychological distress. We report a case of penile SCC in situ with considerable urethral extension with a focus of cells suspicious for moderately well-differentiated and invasive SCC that was treated with
Mohs micrographic surgery with distal urethrectomy and reconstruction is a valuable treatment technique for cases of SCC involving the glans penis and distal urethra. It offers equivalent or better overall cure rates compared to more radical interventions. Additionally, preservation of the penis with MMS spares patients from considerable physical and psychosocial morbidity. Our case, along with growing body of literature,1-4 calls on dermatologists and urologists to consider MMS as a treatment for penile SCC with or without urethral involvement.
Case Report
A 61-year-old man presented to the dermatology department with a pruritic lesion on the penis that had been present for 6 years. Shave biopsy demonstrated SCC in situ with a focus of cells suspicious for moderately well-differentiated and invasive SCC. Physical examination revealed an ill-defined, 2.2×1.9-cm, pink, eroded plaque involving the tip of the penis and surrounding the external urinary meatus (Figure 1). There was no palpable inguinal lymphadenopathy.
Distal penectomy and lymph node biopsy was recommended following evaluation by the urologic oncology department, but the patient declined these interventions and presented to our dermatology department (A.H.) for a second opinion. The tumor, including the invasive perineural portion, was removed using MMS several weeks after initially presenting to urologic oncology. Ventral meatotomy allowed access to the SCC in situ portion extending proximally up the pendulous urethra (Figure 2). Clear margins were obtained after the eighth stage of MMS, which required removal of 4 to 5 cm of the distal urethra (Figure 3). Reconstruction of the wound required urethral advancement, urethrostomy, and meatoplasty. A positive outcome was achieved with preservation of the length and shape of the penis as well as the cosmetic appearance of the glans penis (Figure 4). The patient was satisfied with the outcome. At 49 months’ follow-up, no evidence of local recurrence or disease progression was noted, and the distal urethrostomy remained intact and functional.
Comment
Penile SCC is a rare malignancy that represents between 0.4% and 0.6% of all malignant tumors in the United States and occurs most commonly in men aged 50 to 70 years.4 The incidence is higher in developing countries, approaching 10% of malignancies in men. It occurs most commonly on the glans penis, prepuce, and coronal sulcus, and has multiple possible appearances, including erythematous and indurated, warty and exophytic, or flat and ulcerated lesions.5 Some reports indicate that more than 40% of penile SCCs are attributable to human papilloma virus,6 while lack of circumcision, chronic inflammation, poor hygiene, balanitis xerotica obliterans, penile trauma, human immunodeficiency virus, UVA treatment of penile psoriasis, and tobacco use are known risk factors.5
Invasive penile SCC generally is treated with penectomy (partial or total), radiation therapy, or MMS; SCC in situ can be treated with topical chemotherapy, laser therapy, and wide local excision (2-cm margins) including circumcision, complete glansectomy, or MMS.5 Squamous cell carcinoma in situ with urethral involvement treated with nonsurgical therapies is associated with higher recurrence rates, ultimately necessitating more aggressive treatments, most commonly partial penectomy.7 The high local recurrence rate of SCC in situ with urethral involvement treated with nonsurgical therapies reflects the fact that determining the presence of urethral extension is difficult and, if present, is inherently inaccessible to these local therapies because the urethra is not an outward-facing tissue surface; MMS represents one possible solution to these issues.
Across all treatment modalities, the most prognostic factor of cancer-specific survival in patients with penile SCC is pelvic lymph node involvement. Some reports cite 5-year survival rates as low as 0% in the setting of pelvic lymph node involvement,5 whereas others had cited rates of 29% to 40%4; 5-year survival rates of higher than 85% have been reported in node-negative patients.4 Recurrence rates vary widely by treatment modality, ranging from less than 10% with partial penectomy and long-term follow-up8 and up to 50% within 2 years with penile-preserving approaches (eg, topical chemotherapy, laser therapy, radiotherapy).5 Multiple case series of penile cancer (the most common of which was SCC/SCC in situ) treated with MMS report comparable and at times superior survival and recurrence data (Table).1-4 Slightly higher recurrences of penile SCC treated with MMS compared to penectomy have been reported, along with considerably higher recurrence rates compared to nonpenile cutaneous SCC treated with MMS (reported to be less than 3%).4 The elastic and expansile nature of penile tissue may lead to distortion from swelling/local anesthesia when taking individual Mohs layers. Additionally, as a large percentage of penile SCCs are attributable to human papillomavirus, difficulty in detecting human papilloma virus–infected cells (which may have oncogenic potential) with the naked eye or histologically with typical staining techniques may help explain the higher recurrence rate of penile SCC treated with MMS compared to penectomy. Despite the higher recurrence rates, survival is comparable or higher in cases treated with MMS (Table).
Partial penectomy also has a negative impact on health-related quality of life. Kieffer et al9 compared the impact of penile-sparing surgery (PSS)(including MMS) versus partial or total penectomy on sexual function and health-related quality of life in 90 patients with penile cancer. Although the association between the extent of surgery (partial penectomy/total penectomy/PSS) surgery type and extent and most outcome measures was not statistically significant, partial penectomy was associated with significantly more problems with orgasm (P=.031), concerns about appearance (P=.008), interference in daily life (P=.032), and urinary function (P<.0001) when compared to patients treated with PSS.9 Although this study included only laser/local excision with or without circumcision or glans penis amputation with or without reconstruction as PSSs and did not explicitly include MMS, MMS is clearly a tissue-sparing technique and the study results are generaliz
Conclusion
Penile SCC with considerable urethral extension is uncommon, difficult to manage, and often is resistant to less invasive and nonsurgical treatments. As a result, partial or total penectomy is sometimes necessary. Such cases benefit from MMS with distal urethrectomy and reconstruction because MMS provides equivalent or better overall cure rates compared to more radical interventions.1-4 Importantly, preservation of the penis with MMS can spare patients considerable physical and psychosocial morbidity. Partial penectomy is associated with more health-related quality-of-life problems with orgasm, concerns about appearance, interference in daily life, and urinary function compared to PSSs such as MMS.9 This case, and a growing body of literature, are a call to dermatologists and urologists to consider MMS as a treatment for penile SCC, even with involvement of the urethra.
- Brown MD, Zachary CB, Grekin RC, et al. Penile tumors: their management by Mohs micrographic surgery. J Dermatol Surg Oncol. 1987;13:1163-1167.
- Mohs FE, Snow SN, Larson PO. Mohs micrographic surgery for penile tumors. Urol Clin North Am. 1992;19:291-304.
- Shindel AW, Mann MW, Lev RY, et al. Mohs micrographic surgery for penile cancer: management and long-term followup. J Urol. 2007;178:1980-1985.
- Machan M, Brodland D, Zitelli J. Penile squamous cell carcinoma: penis-preserving treatment with Mohs micrographic surgery. Dermatol Surg. 2016;42:936-944.
- Spiess PE, Horenblas S, Pagliaro LC, et al. Current concepts in penile cancer. J Natl Compr Canc Netw. 2013;11:617-624.
- Hernandez BY, Barnholtz-Sloan J, German RR, et al. Burden of invasive squamous cell carcinoma of the penis in the United States, 1998-2003. Cancer. 2008;113(10 suppl):2883-2891.
- Nash PA, Bihrle R, Gleason PE, et al. Mohs micrographic surgery and distal urethrectomy with immediate urethral reconstruction for glanular carcinoma in situ with significant urethral extension. Urology. 1996;47:108-110.
- Djordjevic ML, Palminteri E, Martins F. Male genital reconstruction for the penile cancer survivor. Curr Opin Urol. 2014;24:427-433.
- Kieffer JM, Djajadiningrat RS, van Muilekom EA, et al. Quality of life for patients treated for penile cancer. J Urol. 2014;192:1105-1110.
- Brown MD, Zachary CB, Grekin RC, et al. Penile tumors: their management by Mohs micrographic surgery. J Dermatol Surg Oncol. 1987;13:1163-1167.
- Mohs FE, Snow SN, Larson PO. Mohs micrographic surgery for penile tumors. Urol Clin North Am. 1992;19:291-304.
- Shindel AW, Mann MW, Lev RY, et al. Mohs micrographic surgery for penile cancer: management and long-term followup. J Urol. 2007;178:1980-1985.
- Machan M, Brodland D, Zitelli J. Penile squamous cell carcinoma: penis-preserving treatment with Mohs micrographic surgery. Dermatol Surg. 2016;42:936-944.
- Spiess PE, Horenblas S, Pagliaro LC, et al. Current concepts in penile cancer. J Natl Compr Canc Netw. 2013;11:617-624.
- Hernandez BY, Barnholtz-Sloan J, German RR, et al. Burden of invasive squamous cell carcinoma of the penis in the United States, 1998-2003. Cancer. 2008;113(10 suppl):2883-2891.
- Nash PA, Bihrle R, Gleason PE, et al. Mohs micrographic surgery and distal urethrectomy with immediate urethral reconstruction for glanular carcinoma in situ with significant urethral extension. Urology. 1996;47:108-110.
- Djordjevic ML, Palminteri E, Martins F. Male genital reconstruction for the penile cancer survivor. Curr Opin Urol. 2014;24:427-433.
- Kieffer JM, Djajadiningrat RS, van Muilekom EA, et al. Quality of life for patients treated for penile cancer. J Urol. 2014;192:1105-1110.
Resident Pearl
- Penile squamous cell carcinoma (SCC) often is treated with partial or total penectomy, especially when there is urethral extension. Mohs micrographic surgery for penile SCC results in equivalent or better overall cure rates and decreases morbidity.
Circulating biomarkers predicted melanoma survival
Among patients with metastatic melanoma, detectable circulating levels of BRAFV600 mutated circulating tumor DNA and elevated levels of circulating hepatocyte growth factor separately predicted significantly worse survival, regardless of treatment.
After adjusting for lactate dehydrogenase, ECOG (Eastern Cooperative Oncology Group) status, disease stage, and treatment, hazard ratios for overall survival were 1.75 (95% confidence interval, 1.35-2.28) for detectable versus undetectable circulating tumor DNA (ctDNA) and 1.24 (95% CI, 1.00-1.53) for high versus low circulating hepatocyte growth factor (cHGF), reported William Lu, PhD, of Genentech in South San Francisco, with his associates. Their retrospective, exploratory analysis of the phase 3 BRIM-3 trial was published in JCO Precision Oncology.
BRIM-3 was a multicenter, open-label trial of 675 patients with previously untreated unresectable stage IIIC or stage IV melanoma that tested positive for the BRAFV600 mutation. Patients received either vemurafenib or dacarbazine therapy.
Baseline ctDNA, baseline cHGF, and ECOG performance status most strongly predicted overall survival, said the investigators. Patients whose mutant ctDNA fraction exceeded 0.039 had an 11.5-month shorter median overall survival on vemurafenib (P less than .001) and a 13.9-month shorter median overall survival on dacarbazine (P less than .001) than patients whose mutant ctDNA fraction was less than 0.039, they explained. Similarly, median overall survival times were 5.4 months shorter for vemurafenib (P = .002) and 12.3 months shorter for dacarbazine (P less than .001) when patients had high (more than 438 pg/mL) versus low circulating cHGF.
Median overall survival for vemurafenib was shortest (7.3 months) in the subgroup of 64 patients with detectable BRAFV600 ctDNA and elevated cHGF, according to the researchers. In contrast, median overall survival for vemurafenib was longest (22.0 months) when patients had undetectable ctDNA and an ECOG status of 0.
“Although similar studies have been performed, to our knowledge, our study is unique in its size and in its design as a randomized trial,” Dr. Lu and associates concluded. “The biomarkers in this study can be readily acquired and measured, and require only small volumes of plasma.” They suggested validating the findings in a separate dataset.
F. Hoffman-La Roche provided funding. Roche Molecular Systems makes the Cobas 4800 BRAFV600 Mutation Test used in the study. Dr. Lu disclosed employment and research funding from Genentech/Roche.
SOURCE: Lu W et al. JCO Precis Oncol. 2018 Apr 25. doi: 10.1200/PO.17.00168.
Among patients with metastatic melanoma, detectable circulating levels of BRAFV600 mutated circulating tumor DNA and elevated levels of circulating hepatocyte growth factor separately predicted significantly worse survival, regardless of treatment.
After adjusting for lactate dehydrogenase, ECOG (Eastern Cooperative Oncology Group) status, disease stage, and treatment, hazard ratios for overall survival were 1.75 (95% confidence interval, 1.35-2.28) for detectable versus undetectable circulating tumor DNA (ctDNA) and 1.24 (95% CI, 1.00-1.53) for high versus low circulating hepatocyte growth factor (cHGF), reported William Lu, PhD, of Genentech in South San Francisco, with his associates. Their retrospective, exploratory analysis of the phase 3 BRIM-3 trial was published in JCO Precision Oncology.
BRIM-3 was a multicenter, open-label trial of 675 patients with previously untreated unresectable stage IIIC or stage IV melanoma that tested positive for the BRAFV600 mutation. Patients received either vemurafenib or dacarbazine therapy.
Baseline ctDNA, baseline cHGF, and ECOG performance status most strongly predicted overall survival, said the investigators. Patients whose mutant ctDNA fraction exceeded 0.039 had an 11.5-month shorter median overall survival on vemurafenib (P less than .001) and a 13.9-month shorter median overall survival on dacarbazine (P less than .001) than patients whose mutant ctDNA fraction was less than 0.039, they explained. Similarly, median overall survival times were 5.4 months shorter for vemurafenib (P = .002) and 12.3 months shorter for dacarbazine (P less than .001) when patients had high (more than 438 pg/mL) versus low circulating cHGF.
Median overall survival for vemurafenib was shortest (7.3 months) in the subgroup of 64 patients with detectable BRAFV600 ctDNA and elevated cHGF, according to the researchers. In contrast, median overall survival for vemurafenib was longest (22.0 months) when patients had undetectable ctDNA and an ECOG status of 0.
“Although similar studies have been performed, to our knowledge, our study is unique in its size and in its design as a randomized trial,” Dr. Lu and associates concluded. “The biomarkers in this study can be readily acquired and measured, and require only small volumes of plasma.” They suggested validating the findings in a separate dataset.
F. Hoffman-La Roche provided funding. Roche Molecular Systems makes the Cobas 4800 BRAFV600 Mutation Test used in the study. Dr. Lu disclosed employment and research funding from Genentech/Roche.
SOURCE: Lu W et al. JCO Precis Oncol. 2018 Apr 25. doi: 10.1200/PO.17.00168.
Among patients with metastatic melanoma, detectable circulating levels of BRAFV600 mutated circulating tumor DNA and elevated levels of circulating hepatocyte growth factor separately predicted significantly worse survival, regardless of treatment.
After adjusting for lactate dehydrogenase, ECOG (Eastern Cooperative Oncology Group) status, disease stage, and treatment, hazard ratios for overall survival were 1.75 (95% confidence interval, 1.35-2.28) for detectable versus undetectable circulating tumor DNA (ctDNA) and 1.24 (95% CI, 1.00-1.53) for high versus low circulating hepatocyte growth factor (cHGF), reported William Lu, PhD, of Genentech in South San Francisco, with his associates. Their retrospective, exploratory analysis of the phase 3 BRIM-3 trial was published in JCO Precision Oncology.
BRIM-3 was a multicenter, open-label trial of 675 patients with previously untreated unresectable stage IIIC or stage IV melanoma that tested positive for the BRAFV600 mutation. Patients received either vemurafenib or dacarbazine therapy.
Baseline ctDNA, baseline cHGF, and ECOG performance status most strongly predicted overall survival, said the investigators. Patients whose mutant ctDNA fraction exceeded 0.039 had an 11.5-month shorter median overall survival on vemurafenib (P less than .001) and a 13.9-month shorter median overall survival on dacarbazine (P less than .001) than patients whose mutant ctDNA fraction was less than 0.039, they explained. Similarly, median overall survival times were 5.4 months shorter for vemurafenib (P = .002) and 12.3 months shorter for dacarbazine (P less than .001) when patients had high (more than 438 pg/mL) versus low circulating cHGF.
Median overall survival for vemurafenib was shortest (7.3 months) in the subgroup of 64 patients with detectable BRAFV600 ctDNA and elevated cHGF, according to the researchers. In contrast, median overall survival for vemurafenib was longest (22.0 months) when patients had undetectable ctDNA and an ECOG status of 0.
“Although similar studies have been performed, to our knowledge, our study is unique in its size and in its design as a randomized trial,” Dr. Lu and associates concluded. “The biomarkers in this study can be readily acquired and measured, and require only small volumes of plasma.” They suggested validating the findings in a separate dataset.
F. Hoffman-La Roche provided funding. Roche Molecular Systems makes the Cobas 4800 BRAFV600 Mutation Test used in the study. Dr. Lu disclosed employment and research funding from Genentech/Roche.
SOURCE: Lu W et al. JCO Precis Oncol. 2018 Apr 25. doi: 10.1200/PO.17.00168.
FROM JCO PRECISION ONCOLOGY
Key clinical point: Among patients with metastatic melanoma, high circulating levels of BRAFV600 mutated circulating tumor DNA and circulating hepatocyte growth factor predicted significantly worse overall survival, irrespective of treatment.
Major finding: Adjusted hazard ratios for overall survival were 1.75 for high versus undetectable circulating tumor DNA and 1.24 for high versus low circulating hepatocyte growth factor.
Study details: A retrospective, exploratory analysis of 675 patients with metastatic BRAFV600 mutated advanced melanoma.
Disclosures: F. Hoffman-La Roche provided funding. Roche Molecular Systems makes the Cobas 4800 BRAFV600 Mutation Test used in the study. Dr. Lu disclosed employment and research funding from Genentech/Roche.
Source: Lu W et al. JCO Precis Oncol. 2018 Apr 25. doi: 10.1200/PO.17.00168.
World Trade Center responders face greater cancer burden, including greater risk of multiple myeloma
Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.
In particular, they may be at risk of developing multiple myeloma at an earlier age.
The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.
The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).
“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.
However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.
“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.
A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.
The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.
In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.
Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.
“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.
Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.
The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.
“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.
The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.
The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.
SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.
When the heroes of the World Trade Center are diagnosed with even a common cancer, there is a natural tendency to assume that the diagnosis is the result of their service during the disaster. However, it is important to appreciate that the firefighting profession is known to be associated with higher risks of monoclonal gammopathy of undetermined significance and multiple myelomas, compared with the general population.
Given that, it would have been preferable to compare the World Trade Center–exposed populations with an equally intensively screened, age-matched cohort of firefighters from another major city.
If we apply Sir Richard Doll’s rule that a single epidemiologic study cannot be persuasive until the lower bound of the 95% confidence interval is greater than three, the relative risks in the study by Landgren and colleagues are too small to be persuasive.
The predicted increases in cancers of the prostate, thyroid, and myeloma are interesting, but these have also been previously reported in firefighters from other cities.
Despite this, we owe it to these men and women to find the truth and determine the illnesses that are associated with their service.
Otis W. Brawley, MD, is chief medical and scientific officer and executive vice president of the American Cancer Society and a professor at Emory University, Atlanta. These comments are taken from an accompanying editorial (JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0498.) No conflicts of interest were declared.
When the heroes of the World Trade Center are diagnosed with even a common cancer, there is a natural tendency to assume that the diagnosis is the result of their service during the disaster. However, it is important to appreciate that the firefighting profession is known to be associated with higher risks of monoclonal gammopathy of undetermined significance and multiple myelomas, compared with the general population.
Given that, it would have been preferable to compare the World Trade Center–exposed populations with an equally intensively screened, age-matched cohort of firefighters from another major city.
If we apply Sir Richard Doll’s rule that a single epidemiologic study cannot be persuasive until the lower bound of the 95% confidence interval is greater than three, the relative risks in the study by Landgren and colleagues are too small to be persuasive.
The predicted increases in cancers of the prostate, thyroid, and myeloma are interesting, but these have also been previously reported in firefighters from other cities.
Despite this, we owe it to these men and women to find the truth and determine the illnesses that are associated with their service.
Otis W. Brawley, MD, is chief medical and scientific officer and executive vice president of the American Cancer Society and a professor at Emory University, Atlanta. These comments are taken from an accompanying editorial (JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0498.) No conflicts of interest were declared.
When the heroes of the World Trade Center are diagnosed with even a common cancer, there is a natural tendency to assume that the diagnosis is the result of their service during the disaster. However, it is important to appreciate that the firefighting profession is known to be associated with higher risks of monoclonal gammopathy of undetermined significance and multiple myelomas, compared with the general population.
Given that, it would have been preferable to compare the World Trade Center–exposed populations with an equally intensively screened, age-matched cohort of firefighters from another major city.
If we apply Sir Richard Doll’s rule that a single epidemiologic study cannot be persuasive until the lower bound of the 95% confidence interval is greater than three, the relative risks in the study by Landgren and colleagues are too small to be persuasive.
The predicted increases in cancers of the prostate, thyroid, and myeloma are interesting, but these have also been previously reported in firefighters from other cities.
Despite this, we owe it to these men and women to find the truth and determine the illnesses that are associated with their service.
Otis W. Brawley, MD, is chief medical and scientific officer and executive vice president of the American Cancer Society and a professor at Emory University, Atlanta. These comments are taken from an accompanying editorial (JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0498.) No conflicts of interest were declared.
Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.
In particular, they may be at risk of developing multiple myeloma at an earlier age.
The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.
The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).
“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.
However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.
“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.
A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.
The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.
In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.
Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.
“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.
Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.
The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.
“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.
The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.
The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.
SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.
Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.
In particular, they may be at risk of developing multiple myeloma at an earlier age.
The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.
The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).
“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.
However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.
“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.
A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.
The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.
In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.
Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.
“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.
Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.
The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.
“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.
The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.
The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.
SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.
FROM JAMA ONCOLOGY
Key clinical point: Monoclonal gammopathies and multiple myeloma may occur more often and earlier in World Trade Center rescue workers.
Major finding: Prevalence of light-chain monoclonal gammopathies is threefold higher in exposed firefighters than in a reference population of white males.
Study details: A cohort study in 14,474 employees of the Fire Department of the City of New York exposed to the Sept. 11, 2001, World Trade Center disaster, a case series of 16 exposed white male firefighters diagnosed with multiple myeloma, and a seroprevalence study of monoclonal gammopathies of undetermined significance in 781 exposed firefighters.
Disclosures: The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared. The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.
Source: Zeig-Owens R et al. JAMA Oncology 2018, Apr 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology 2018, Apr 26. doi: 10.1001/jamaoncol.2018.0509.
Ideal sun protection practices by parents low in Toronto
according to Marcus G. Tan, MD, of the University of Toronto, and his associates.
Too much sun exposure as a child is a known risk factor for skin cancer, and “it has been estimated that approximately half of cumulative ultraviolet exposure by age 60 occurs before age 20.” So it is important that children be protected from excessive sun exposure, the investigators wrote, underscoring the reason for their study of parental sun protection by Canadian parents in Toronto, which has a multiracial population.
Parental sun protection efforts were considered ideal if they used sun protection every day; on sunny days all year round; or during the summer, using at least SPF 30, and reapplying sunscreen at least every 2 hours. Parental efforts would be considered nonideal if they did not meet any of these three criteria.
Of 183 parents, 17% used ideal sun protection for their children; 28% were in the lighter-skinned group (Fitzpatrick phototype I-III) and 5% in the darker-skinned group (Fitzpatrick phototype IV-V), The greater likelihood of using ideal sun protection among those in the lighter-skinned group was statistically significant (odds ratio, 7.4; P less than .001). As each child grew 1 year older, parents were 31% less likely to use ideal sun protection (OR, 0.69; P = .007).
Parents whose children were in the lighter-skinned group were “more likely to believe that sun exposure was harmful” for their children (OR, 17.2), and “to perceive value in sun protection,” (OR, 11.4) the researchers said. The parents whose children were in the darker-skinned group were more likely to consider sun protection as having drawbacks (OR, 9.2), and to believe that darker skin tone provides more sun protection (OR, 12.4). Neither of the two groups was more likely to consider that sun exposure provided health benefits or that it improved appearance.
Parents whose children were in the lighter-skinned group reported significantly more frequent use of sunscreen (OR, 3.6), sunglasses (OR, 2.3), and sun suits (OR, 2.7). The parents of the children in this group reported similar or higher rates of use of hats, long-sleeved clothing, and umbrellas; seeking shade; and staying indoors between 12 pm and 2 pm, but these rates were not statistically significantly different from those reported by the parents of children in the darker-skinned group, the investigators said.
“Our study suggests that more targeted education guidelines are necessary to ensure sun safety for all children, especially in a multiracial population,” said Dr. Tan and his colleagues. “Dermatologists and primary care physicians are in ideal positions to initiate personalized efforts to improve overall rates of sun protection.”
Dr. Tan reported no relevant financial disclosures. Dr. Miriam Weinstein has worked as an advisory board member for Johnson & Johnson, which manufactures sunscreen; and Dr. Shudeshna Nag consults for Valeant, which manufactures sunscreen.
SOURCE: Tan MG et al. Pediatr Dermatol. 2018 Feb 13. doi: 10.1111/pde.13433.
according to Marcus G. Tan, MD, of the University of Toronto, and his associates.
Too much sun exposure as a child is a known risk factor for skin cancer, and “it has been estimated that approximately half of cumulative ultraviolet exposure by age 60 occurs before age 20.” So it is important that children be protected from excessive sun exposure, the investigators wrote, underscoring the reason for their study of parental sun protection by Canadian parents in Toronto, which has a multiracial population.
Parental sun protection efforts were considered ideal if they used sun protection every day; on sunny days all year round; or during the summer, using at least SPF 30, and reapplying sunscreen at least every 2 hours. Parental efforts would be considered nonideal if they did not meet any of these three criteria.
Of 183 parents, 17% used ideal sun protection for their children; 28% were in the lighter-skinned group (Fitzpatrick phototype I-III) and 5% in the darker-skinned group (Fitzpatrick phototype IV-V), The greater likelihood of using ideal sun protection among those in the lighter-skinned group was statistically significant (odds ratio, 7.4; P less than .001). As each child grew 1 year older, parents were 31% less likely to use ideal sun protection (OR, 0.69; P = .007).
Parents whose children were in the lighter-skinned group were “more likely to believe that sun exposure was harmful” for their children (OR, 17.2), and “to perceive value in sun protection,” (OR, 11.4) the researchers said. The parents whose children were in the darker-skinned group were more likely to consider sun protection as having drawbacks (OR, 9.2), and to believe that darker skin tone provides more sun protection (OR, 12.4). Neither of the two groups was more likely to consider that sun exposure provided health benefits or that it improved appearance.
Parents whose children were in the lighter-skinned group reported significantly more frequent use of sunscreen (OR, 3.6), sunglasses (OR, 2.3), and sun suits (OR, 2.7). The parents of the children in this group reported similar or higher rates of use of hats, long-sleeved clothing, and umbrellas; seeking shade; and staying indoors between 12 pm and 2 pm, but these rates were not statistically significantly different from those reported by the parents of children in the darker-skinned group, the investigators said.
“Our study suggests that more targeted education guidelines are necessary to ensure sun safety for all children, especially in a multiracial population,” said Dr. Tan and his colleagues. “Dermatologists and primary care physicians are in ideal positions to initiate personalized efforts to improve overall rates of sun protection.”
Dr. Tan reported no relevant financial disclosures. Dr. Miriam Weinstein has worked as an advisory board member for Johnson & Johnson, which manufactures sunscreen; and Dr. Shudeshna Nag consults for Valeant, which manufactures sunscreen.
SOURCE: Tan MG et al. Pediatr Dermatol. 2018 Feb 13. doi: 10.1111/pde.13433.
according to Marcus G. Tan, MD, of the University of Toronto, and his associates.
Too much sun exposure as a child is a known risk factor for skin cancer, and “it has been estimated that approximately half of cumulative ultraviolet exposure by age 60 occurs before age 20.” So it is important that children be protected from excessive sun exposure, the investigators wrote, underscoring the reason for their study of parental sun protection by Canadian parents in Toronto, which has a multiracial population.
Parental sun protection efforts were considered ideal if they used sun protection every day; on sunny days all year round; or during the summer, using at least SPF 30, and reapplying sunscreen at least every 2 hours. Parental efforts would be considered nonideal if they did not meet any of these three criteria.
Of 183 parents, 17% used ideal sun protection for their children; 28% were in the lighter-skinned group (Fitzpatrick phototype I-III) and 5% in the darker-skinned group (Fitzpatrick phototype IV-V), The greater likelihood of using ideal sun protection among those in the lighter-skinned group was statistically significant (odds ratio, 7.4; P less than .001). As each child grew 1 year older, parents were 31% less likely to use ideal sun protection (OR, 0.69; P = .007).
Parents whose children were in the lighter-skinned group were “more likely to believe that sun exposure was harmful” for their children (OR, 17.2), and “to perceive value in sun protection,” (OR, 11.4) the researchers said. The parents whose children were in the darker-skinned group were more likely to consider sun protection as having drawbacks (OR, 9.2), and to believe that darker skin tone provides more sun protection (OR, 12.4). Neither of the two groups was more likely to consider that sun exposure provided health benefits or that it improved appearance.
Parents whose children were in the lighter-skinned group reported significantly more frequent use of sunscreen (OR, 3.6), sunglasses (OR, 2.3), and sun suits (OR, 2.7). The parents of the children in this group reported similar or higher rates of use of hats, long-sleeved clothing, and umbrellas; seeking shade; and staying indoors between 12 pm and 2 pm, but these rates were not statistically significantly different from those reported by the parents of children in the darker-skinned group, the investigators said.
“Our study suggests that more targeted education guidelines are necessary to ensure sun safety for all children, especially in a multiracial population,” said Dr. Tan and his colleagues. “Dermatologists and primary care physicians are in ideal positions to initiate personalized efforts to improve overall rates of sun protection.”
Dr. Tan reported no relevant financial disclosures. Dr. Miriam Weinstein has worked as an advisory board member for Johnson & Johnson, which manufactures sunscreen; and Dr. Shudeshna Nag consults for Valeant, which manufactures sunscreen.
SOURCE: Tan MG et al. Pediatr Dermatol. 2018 Feb 13. doi: 10.1111/pde.13433.
FROM PEDIATRIC DERMATOLOGY
Key clinical point: More targeted education of parents regarding sun protection practices may be needed.
Major finding: Of 183 parents, 17% used ideal sun protection; 28% were in the lighter-skinned group and 5% in the darker-skinned group (odds ratio, 7.4; P less than .001).
Study details: The parents of 183 children aged from 6 months to 6 years in Toronto completed a questionnaire about their sun protection practices.
Disclosures: Dr. Marcus G. Tan reported no relevant financial disclosures. Dr.Miriam Weinstein has worked as an advisory board member for Johnson & Johnson, which manufactures sunscreen; and Dr. Shudeshna Nag consults for Valeant, which manufactures sunscreen.
Source: Tan MG et al. Pediatr Dermatol. 2018 Feb 13. doi: 10.1111/pde.13433.
Early results favorable for combo TLR9 agonist + pembro in advanced melanoma
CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.
Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.
For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.
In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.
The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.
“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.
The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.
A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.
Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.
“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.
Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.
It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.
Dr. Milhem had no financial relationships to disclose.
SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.
CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.
Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.
For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.
In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.
The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.
“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.
The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.
A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.
Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.
“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.
Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.
It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.
Dr. Milhem had no financial relationships to disclose.
SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.
CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.
Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.
For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.
In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.
The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.
“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.
The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.
A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.
Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.
“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.
Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.
It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.
Dr. Milhem had no financial relationships to disclose.
SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.
REPORTING FROM THE AACR ANNUAL MEETING
Key clinical point: The combination demonstrated a manageable toxicity profile with ORR of 22%.
Major finding: Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively.
Study details: This phase 1b study comprised 69 patients (44 in escalation and 25 in expansion).
Disclosures: Dr. Milhem had no financial relationships to disclose.
Source: Milhem MD et al. AACR Annual Meeting. Abstract CT144.