Melanoma

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Response rates were high without dose-limiting toxicities in a small phase 1 study that evaluated the addition of propranolol to pembrolizumab in treatment-naive patients with metastatic melanoma.

“To our knowledge, this effort is the first prospective clinical trial to show that the combination of propranolol with pembrolizumab is safe, and additionally suggests preliminary synergistic antitumor activity in treatment-naive metastatic melanoma,” wrote the two co-first authors, Shipra Gandhi, MD, and Manu Pandey, MBBS, from the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and coauthors.

The need for combinations built on anti-PD1 checkpoint inhibitor therapy strategies in metastatic melanoma that safely improve outcomes is underscored by the high (59%) grade 3 or 4 treatment-related adverse event (TRAE) rates when an anti-CTLA4 agent (ipilimumab) was added to an anti-PD-1 agent (nivolumab), they noted. In contrast, a TRAE rate of only 17% has been reported with pembrolizumab monotherapy.

The phase 1b study was stimulated by preclinical, retrospective observations of improved overall survival (OS) in cancer patients treated with beta-blockers. These were preceded by murine melanoma studies showing decreased tumor growth and metastasis with the nonselective beta-blocker propranolol. “Propranolol exerts an antitumor effect,” the authors stated, “by favorably modulating the tumor microenvironment (TME) by decreasing myeloid-derived suppressor cells and increasing CD8+ T-cell and natural killer cells in the TME.” Other research in a melanoma model in chronically-stressed mice has demonstrated synergy between an anti-PD1 antibody and propranolol.

“We know that stress can have a significant negative effect on health, but the extent to which stress may impact the outcome of cancer therapy is not well understood at all,” Dr. Ghandi said in a statement provided by Roswell Park. “We set out to better understand this relationship and to explore its implications for cancer treatment.”

The investigators recruited nine White adults (median age 65 years) with treatment-naive, histologically confirmed unresectable stage III or IV melanoma and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 to the open-label, single arm, nonrandomized, single-center, dose-finding study. Patients received standard of care intravenous pembrolizumab 200 mg every 3 weeks and, in three groups, propranolol doses of 10 mg, 20 mg, or 30 mg twice a day until 2 years on study or disease progression or the development of dose-limiting toxicities (DLTs). Assessing the safety and efficacy (overall response rate [ORR] within 6 months of starting therapy) of pembrolizumab with the increasing doses of propranolol and selecting the recommended phase 2 dose were the study’s primary objectives.

Objective responses (complete or partial responses) were reported in seven of the nine patients, with partial tumor responses in two patients in the propranolol 10-mg group, two partial responses in the 20-mg group, and three partial responses in the 30-mg group.

While all patients experienced TRAEs, only one was above grade 2. The most commonly reported TRAEs were fatigue, rash and vitiligo, reported in four of the nine patients. Two patients in the 20-mg twice-a-day group discontinued therapy because of TRAEs (hemophagocytic lymphohistiocytosis and labyrinthitis). No DLTs were observed at any of the three dose levels, and no deaths occurred on study treatment.

The authors said that propranolol 30 mg twice a day was chosen as the recommended phase 2 dose, because in combination with pembrolizumab, there were no DLTs, and preliminary antitumor efficacy was observed in all three patients. Also, in all three patients, the investigators observed a trend toward higher CD8+T-cell percentage, higher ratios of CD8+T-cell/ Treg and CD8+T-cell/ polymorphonuclear myeloid-derived suppressor cells. They underscored, however, that the small size and significant heterogeneity in biomarkers made a statistically sound and meaningful interpretation of biomarkers for deciding the phase 2 dose difficult.

“In repurposing propranolol,” Dr. Pandey said in the Roswell statement, “we’ve gained important insights on how to manage stress in people with cancer – who can face dangerously elevated levels of mental and physical stress related to their diagnosis and treatment.”

In an interview, one of the two senior authors, Elizabeth Repasky, PhD, professor of oncology and immunology at Roswell Park, said, “it’s exciting that an extremely inexpensive drug like propranolol that could be used in every country around the world could have an impact on cancer by blocking stress, especially chronic stress.” Her murine research showing that adding propranolol to immunotherapy or radiotherapy or chemotherapy improved tumor growth control provided rationale for the current study.

“The breakthrough in this study is that it reveals the immune system as the best target to look at, and shows that what stress reduction is doing is improving a patient’s immune response to his or her own tumor,” Dr. Repasky said. “The mind/body connection is so important, but we have not had a handle on how to study it,” she added.

Further research funded by Herd of Hope grants at Roswell will look at tumor effects of propranolol and nonpharmacological reducers of chronic stress such as exercise, meditation, yoga, and Tai Chi, with first studies in breast cancer.

The study was funded by Roswell Park, private, and NIH grants. The authors had no disclosures.
 

SOURCE: Gandhi S et al. Clin Cancer Res. 2020 Oct 30. doi: 10.1158/1078-0432.CCR-20-2381

Response rates were high without dose-limiting toxicities in a small phase 1 study that evaluated the addition of propranolol to pembrolizumab in treatment-naive patients with metastatic melanoma.

“To our knowledge, this effort is the first prospective clinical trial to show that the combination of propranolol with pembrolizumab is safe, and additionally suggests preliminary synergistic antitumor activity in treatment-naive metastatic melanoma,” wrote the two co-first authors, Shipra Gandhi, MD, and Manu Pandey, MBBS, from the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and coauthors.

The need for combinations built on anti-PD1 checkpoint inhibitor therapy strategies in metastatic melanoma that safely improve outcomes is underscored by the high (59%) grade 3 or 4 treatment-related adverse event (TRAE) rates when an anti-CTLA4 agent (ipilimumab) was added to an anti-PD-1 agent (nivolumab), they noted. In contrast, a TRAE rate of only 17% has been reported with pembrolizumab monotherapy.

The phase 1b study was stimulated by preclinical, retrospective observations of improved overall survival (OS) in cancer patients treated with beta-blockers. These were preceded by murine melanoma studies showing decreased tumor growth and metastasis with the nonselective beta-blocker propranolol. “Propranolol exerts an antitumor effect,” the authors stated, “by favorably modulating the tumor microenvironment (TME) by decreasing myeloid-derived suppressor cells and increasing CD8+ T-cell and natural killer cells in the TME.” Other research in a melanoma model in chronically-stressed mice has demonstrated synergy between an anti-PD1 antibody and propranolol.

“We know that stress can have a significant negative effect on health, but the extent to which stress may impact the outcome of cancer therapy is not well understood at all,” Dr. Ghandi said in a statement provided by Roswell Park. “We set out to better understand this relationship and to explore its implications for cancer treatment.”

The investigators recruited nine White adults (median age 65 years) with treatment-naive, histologically confirmed unresectable stage III or IV melanoma and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 to the open-label, single arm, nonrandomized, single-center, dose-finding study. Patients received standard of care intravenous pembrolizumab 200 mg every 3 weeks and, in three groups, propranolol doses of 10 mg, 20 mg, or 30 mg twice a day until 2 years on study or disease progression or the development of dose-limiting toxicities (DLTs). Assessing the safety and efficacy (overall response rate [ORR] within 6 months of starting therapy) of pembrolizumab with the increasing doses of propranolol and selecting the recommended phase 2 dose were the study’s primary objectives.

Objective responses (complete or partial responses) were reported in seven of the nine patients, with partial tumor responses in two patients in the propranolol 10-mg group, two partial responses in the 20-mg group, and three partial responses in the 30-mg group.

While all patients experienced TRAEs, only one was above grade 2. The most commonly reported TRAEs were fatigue, rash and vitiligo, reported in four of the nine patients. Two patients in the 20-mg twice-a-day group discontinued therapy because of TRAEs (hemophagocytic lymphohistiocytosis and labyrinthitis). No DLTs were observed at any of the three dose levels, and no deaths occurred on study treatment.

The authors said that propranolol 30 mg twice a day was chosen as the recommended phase 2 dose, because in combination with pembrolizumab, there were no DLTs, and preliminary antitumor efficacy was observed in all three patients. Also, in all three patients, the investigators observed a trend toward higher CD8+T-cell percentage, higher ratios of CD8+T-cell/ Treg and CD8+T-cell/ polymorphonuclear myeloid-derived suppressor cells. They underscored, however, that the small size and significant heterogeneity in biomarkers made a statistically sound and meaningful interpretation of biomarkers for deciding the phase 2 dose difficult.

“In repurposing propranolol,” Dr. Pandey said in the Roswell statement, “we’ve gained important insights on how to manage stress in people with cancer – who can face dangerously elevated levels of mental and physical stress related to their diagnosis and treatment.”

In an interview, one of the two senior authors, Elizabeth Repasky, PhD, professor of oncology and immunology at Roswell Park, said, “it’s exciting that an extremely inexpensive drug like propranolol that could be used in every country around the world could have an impact on cancer by blocking stress, especially chronic stress.” Her murine research showing that adding propranolol to immunotherapy or radiotherapy or chemotherapy improved tumor growth control provided rationale for the current study.

“The breakthrough in this study is that it reveals the immune system as the best target to look at, and shows that what stress reduction is doing is improving a patient’s immune response to his or her own tumor,” Dr. Repasky said. “The mind/body connection is so important, but we have not had a handle on how to study it,” she added.

Further research funded by Herd of Hope grants at Roswell will look at tumor effects of propranolol and nonpharmacological reducers of chronic stress such as exercise, meditation, yoga, and Tai Chi, with first studies in breast cancer.

The study was funded by Roswell Park, private, and NIH grants. The authors had no disclosures.
 

SOURCE: Gandhi S et al. Clin Cancer Res. 2020 Oct 30. doi: 10.1158/1078-0432.CCR-20-2381

Response rates were high without dose-limiting toxicities in a small phase 1 study that evaluated the addition of propranolol to pembrolizumab in treatment-naive patients with metastatic melanoma.

“To our knowledge, this effort is the first prospective clinical trial to show that the combination of propranolol with pembrolizumab is safe, and additionally suggests preliminary synergistic antitumor activity in treatment-naive metastatic melanoma,” wrote the two co-first authors, Shipra Gandhi, MD, and Manu Pandey, MBBS, from the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and coauthors.

The need for combinations built on anti-PD1 checkpoint inhibitor therapy strategies in metastatic melanoma that safely improve outcomes is underscored by the high (59%) grade 3 or 4 treatment-related adverse event (TRAE) rates when an anti-CTLA4 agent (ipilimumab) was added to an anti-PD-1 agent (nivolumab), they noted. In contrast, a TRAE rate of only 17% has been reported with pembrolizumab monotherapy.

The phase 1b study was stimulated by preclinical, retrospective observations of improved overall survival (OS) in cancer patients treated with beta-blockers. These were preceded by murine melanoma studies showing decreased tumor growth and metastasis with the nonselective beta-blocker propranolol. “Propranolol exerts an antitumor effect,” the authors stated, “by favorably modulating the tumor microenvironment (TME) by decreasing myeloid-derived suppressor cells and increasing CD8+ T-cell and natural killer cells in the TME.” Other research in a melanoma model in chronically-stressed mice has demonstrated synergy between an anti-PD1 antibody and propranolol.

“We know that stress can have a significant negative effect on health, but the extent to which stress may impact the outcome of cancer therapy is not well understood at all,” Dr. Ghandi said in a statement provided by Roswell Park. “We set out to better understand this relationship and to explore its implications for cancer treatment.”

The investigators recruited nine White adults (median age 65 years) with treatment-naive, histologically confirmed unresectable stage III or IV melanoma and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 to the open-label, single arm, nonrandomized, single-center, dose-finding study. Patients received standard of care intravenous pembrolizumab 200 mg every 3 weeks and, in three groups, propranolol doses of 10 mg, 20 mg, or 30 mg twice a day until 2 years on study or disease progression or the development of dose-limiting toxicities (DLTs). Assessing the safety and efficacy (overall response rate [ORR] within 6 months of starting therapy) of pembrolizumab with the increasing doses of propranolol and selecting the recommended phase 2 dose were the study’s primary objectives.

Objective responses (complete or partial responses) were reported in seven of the nine patients, with partial tumor responses in two patients in the propranolol 10-mg group, two partial responses in the 20-mg group, and three partial responses in the 30-mg group.

While all patients experienced TRAEs, only one was above grade 2. The most commonly reported TRAEs were fatigue, rash and vitiligo, reported in four of the nine patients. Two patients in the 20-mg twice-a-day group discontinued therapy because of TRAEs (hemophagocytic lymphohistiocytosis and labyrinthitis). No DLTs were observed at any of the three dose levels, and no deaths occurred on study treatment.

The authors said that propranolol 30 mg twice a day was chosen as the recommended phase 2 dose, because in combination with pembrolizumab, there were no DLTs, and preliminary antitumor efficacy was observed in all three patients. Also, in all three patients, the investigators observed a trend toward higher CD8+T-cell percentage, higher ratios of CD8+T-cell/ Treg and CD8+T-cell/ polymorphonuclear myeloid-derived suppressor cells. They underscored, however, that the small size and significant heterogeneity in biomarkers made a statistically sound and meaningful interpretation of biomarkers for deciding the phase 2 dose difficult.

“In repurposing propranolol,” Dr. Pandey said in the Roswell statement, “we’ve gained important insights on how to manage stress in people with cancer – who can face dangerously elevated levels of mental and physical stress related to their diagnosis and treatment.”

In an interview, one of the two senior authors, Elizabeth Repasky, PhD, professor of oncology and immunology at Roswell Park, said, “it’s exciting that an extremely inexpensive drug like propranolol that could be used in every country around the world could have an impact on cancer by blocking stress, especially chronic stress.” Her murine research showing that adding propranolol to immunotherapy or radiotherapy or chemotherapy improved tumor growth control provided rationale for the current study.

“The breakthrough in this study is that it reveals the immune system as the best target to look at, and shows that what stress reduction is doing is improving a patient’s immune response to his or her own tumor,” Dr. Repasky said. “The mind/body connection is so important, but we have not had a handle on how to study it,” she added.

Further research funded by Herd of Hope grants at Roswell will look at tumor effects of propranolol and nonpharmacological reducers of chronic stress such as exercise, meditation, yoga, and Tai Chi, with first studies in breast cancer.

The study was funded by Roswell Park, private, and NIH grants. The authors had no disclosures.
 

SOURCE: Gandhi S et al. Clin Cancer Res. 2020 Oct 30. doi: 10.1158/1078-0432.CCR-20-2381

With today’s technology, it is easier than ever to access web-based tools that enrich traditional dermatology education. The literature supports the use of these innovative platforms to enhance learning at the student and trainee levels. A controlled study of pediatric residents showed that online modules effectively supplemented clinical experience with atopic dermatitis.¹ In a randomized diagnostic study of medical students, practice with an image-based web application (app) that teaches rapid recognition of melanoma proved more effective than learning a rule-based algorithm.² Given the visual nature of dermatology, pattern recognition is an essential skill that is fostered through experience and is only made more accessible with technology.

With the added benefit of convenience and accessibility, mobile apps can supplement experiential learning. Mirroring the overall growth of mobile apps, the number of available dermatology apps has increased.³ Dermatology mobile apps serve purposes ranging from quick reference tools to comprehensive modules, journals, and question banks. At an academic hospital in Taiwan, both nondermatology and dermatology trainees’ examination performance improved after 3 weeks of using a smartphone-based wallpaper learning module displaying morphologic characteristics of fungi.⁴ With the expansion of virtual microscopy, mobile apps also have been created as a learning tool for dermatopathology, giving trainees the flexibility and autonomy to view slides on their own time.⁵ Nevertheless, the literature on dermatology mobile apps designed for the education of medical students and trainees is limited, demonstrating a need for further investigation.

Prior studies have reviewed dermatology apps for patients and practicing dermatologists.^6-8 Herein, we focus on mobile apps targeting students and residents learning dermatology. General dermatology reference apps and educational aid apps have grown by 33% and 32%, respectively, from 2014 to 2017.³ As with any resource meant to educate future and current medical providers, there must be an objective review process in place to ensure accurate, unbiased, evidence-based teaching.

Well-organized, comprehensive information and a user-friendly interface are additional factors of importance when selecting an educational mobile app. When discussing supplemental resources, accessibility and affordability also are priorities given the high cost of a medical education at baseline. Overall, there is a need for a standardized method to evaluate the key factors of an educational mobile app that make it appropriate for this demographic. We conducted a search of mobile apps relating to dermatology education for students and residents.

Methods

We searched for publicly available mobile apps relating to dermatology education in the App Store (Apple Inc) from September to November 2019 using the search terms dermatology education, dermoscopy education, melanoma education, skin cancer education, psoriasis education, rosacea education, acne education, eczema education, dermal fillers education, and Mohs surgery education. We excluded apps that were not in English, were created for a conference, cost more than $5 to download, or did not include a specific dermatology education section. In this way, we hoped to evaluate apps that were relevant, accessible, and affordable.

We modeled our study after a review of patient education apps performed by Masud et al⁶ and utilized their quantified grading rubric (scale of 1 to 4). We found their established criteria—educational objectives, content, accuracy, design, and conflict of interest—to be equally applicable for evaluating apps designed for professional education.⁶ Each app earned a minimum of 1 point and a maximum of 4 points per criterion. One point was given if the app did not fulfill the criterion, 2 points for minimally fulfilling the criterion, 3 points for mostly fulfilling the criterion, and 4 points if the criterion was completely fulfilled. Two medical students (E.H. and N.C.)—one at the preclinical stage and the other at the clinical stage of medical education—reviewed the apps using the given rubric, then discussed and resolved any discrepancies in points assigned. A dermatology resident (M.A.) independently reviewed the apps using the given rubric.

The mean of the student score and the resident score was calculated for each category. The sum of the averages for each category was considered the final score for an app, determining its overall quality. Apps with a total score of 5 to 10 were considered poor and inadequate for education. A total score of 10.5 to 15 indicated that an app was somewhat adequate (ie, useful for education in some aspects but falling short in others). Apps that were considered adequate for education, across all or most criteria, received a total score ranging from 15.5 to 20.

Results

Our search generated 130 apps. After applying exclusion criteria, 42 apps were eligible for review. At the time of publication, 36 of these apps were still available. The possible range of scores based on the rubric was 5 to 20. The actual range of scores was 7 to 20. Of the 36 apps, 2 (5.6%) were poor, 16 (44.4%) were somewhat adequate, and 18 (50%) were adequate. Formats included primary resources, such as clinical decision support tools, journals, references, and a podcast (Table 1). Additionally, interactive learning tools included games, learning modules, and apps for self-evaluation (Table 2). Thirty apps covered general dermatology; others focused on skin cancer (n=5) and cosmetic dermatology (n=1). Regarding cost, 29 apps were free to download, whereas 7 charged a fee (mean price, $2.56).

Comment

In addition to the convenience of having an educational tool in their white-coat pocket, learners of dermatology have been shown to benefit from supplementing their curriculum with mobile apps, which sets the stage for formal integration of mobile apps into dermatology teaching in the future.⁸ Prior to widespread adoption, mobile apps must be evaluated for content and utility, starting with an objective rubric.

Without official scientific standards in place, it was unsurprising that only half of the dermatology education applications were classified as adequate in this study. Among the types of apps offered—clinical decision support tools, journals, references, podcast, games, learning modules, and self-evaluation—certain categories scored higher than others. App formats with the highest average score (16.5 out of 20) were journals and podcast.

One barrier to utilization of these apps was that a subscription to the journals and podcast was required to obtain access to all available content. Students and trainees can seek out library resources at their academic institutions to take advantage of journal subscriptions available to them at no additional cost. Dermatology residents can take advantage of their complimentary membership in the American Academy of Dermatology for a free subscription to AAD Dialogues in Dermatology (otherwise $179 annually for nonresident members and $320 annually for nonmembers).

On the other hand, learning module was the lowest-rated format (average score, 11.3 out of 20), with only Medical Student: Dermatology qualifying as adequate (total score, 16). This finding is worrisome given that students and residents might look to learning modules for quick targeted lessons on specific topics.

The lowest-scoring app, a clinical decision support tool called Naturelize, received a total score of 7. Although it listed the indications and contraindications for dermal filler types to be used in different locations on the face, there was a clear conflict of interest, oversimplified design, and little evidence-based education, mirroring the current state of cosmetic dermatology training in residency, in which trainees think they are inadequately prepared for aesthetic procedures and comparative effectiveness research is lacking.^9-11

At the opposite end of the spectrum, MyDermPath+ was a reference app with a total score of 20. The app cited credible authors with a medical degree (MD) and had an easy-to-use, well-designed interface, including a reference guide, differential builder, and quiz for a range of topics within dermatology. As a free download without in-app purchases or advertisements, there was no evidence of conflict of interest. The position of a dermatopathology app as the top dermatology education mobile app might reflect an increased emphasis on dermatopathology education in residency as well as a transition to digitization of slides.⁵

The second-highest scoring apps (total score of 19 points) were Dermatology Database and VisualDx. Both were references covering a wide range of dermatology topics. Dermatology Database was a comprehensive search tool for diseases, drugs, procedures, and terms that was simple and entirely free to use but did not cite references. VisualDx, as its name suggests, offered quality clinical images, complete guides with references, and a unique differential builder. An annual subscription is $399.99, but the process to gain free access through a participating academic institution was simple.

Games were a unique mobile app format; however, 2 of 3 games scored in the somewhat adequate range. The game DiagnosUs, which tested users’ ability to differentiate skin cancer and psoriasis from dermatitis on clinical images, would benefit from more comprehensive content as well as professional verification of true diagnoses, which earned the app 2 points in both the content and accuracy categories. The Unusual Suspects tested the ABCDE algorithm in a short learning module, followed by a simple game that involved identification of melanoma in a timed setting. Although the design was novel and interactive, the game was limited to the same 5 melanoma tumors overlaid on pictures of normal skin. The narrow scope earned 1 point for content, the redundancy in the game earned 3 points for design, and the lack of real clinical images earned 2 points for educational objectives. Although game-format mobile apps have the capability to challenge the user’s knowledge with a built-in feedback or reward system, improvements should be made to ensure that apps are equally educational as they are engaging.

AAD Dialogues in Dermatology was the only app in the form of a podcast and provided expert interviews along with disclosures, transcripts, commentary, and references. More than half the content in the app could not be accessed without a subscription, earning 2.5 points in the conflict of interest category. Additionally, several flaws resulted in a design score of 2.5, including inconsistent availability of transcripts, poor quality of sound on some episodes, difficulty distinguishing new episodes from those already played, and a glitch that removed the episode duration. Still, the app was a valuable and comprehensive resource, with clear objectives and cited references. With improvements in content, affordability, and user experience, apps in unique formats such as games and podcasts might appeal to kinesthetic and auditory learners.

An important factor to consider when discussing mobile apps for students and residents is cost. With rising prices of board examinations and preparation materials, supplementary study tools should not come with an exorbitant price tag. Therefore, we limited our evaluation to apps that were free or cost less than $5 to download. Even so, subscriptions and other in-app purchases were an obstacle in one-third of apps, ranging from $4.99 to unlock additional content in Rash Decisions to $69.99 to access most topics in Fitzpatrick’s Color Atlas. The highest-rated app in our study, MyDermPath+, historically cost $19.99 to download but became free with a grant from the Sulzberger Foundation.¹² An initial investment to develop quality apps for the purpose of dermatology education might pay off in the end.

To evaluate the apps from the perspective of the target demographic of this study, 2 medical students—one in the preclinical stage and the other in the clinical stage of medical education—and a dermatology resident graded the apps. Certain limitations exist in this type of study, including differing learning styles, which might influence the types of apps that evaluators found most impactful to their education. Interestingly, some apps earned a higher resident score than student score. In particular, RightSite (a reference that helps with anatomically correct labeling) and Mohs Surgery Appropriate Use Criteria (a clinical decision support tool to determine whether to perform Mohs surgery) each had a 3-point discrepancy (data not shown). A resident might benefit from these practical apps in day-to-day practice, but a student would be less likely to find them useful as a learning tool.

Still, by defining adequate teaching value using specific categories of educational objectives, content, accuracy, design, and conflict of interest, we attempted to minimize the effect of personal preference on the grading process. Although we acknowledge a degree of subjectivity, we found that utilizing a previously published rubric with defined criteria was crucial in remaining unbiased.

Conclusion

Further studies should evaluate additional apps available on Apple’s iPad (tablet), as well as those on other operating systems, including Google’s Android. To ensure the existence of mobile apps as adequate education tools, they should be peer reviewed prior to publication or before widespread use by future and current providers at the minimum. To maximize free access to highly valuable resources available in the palm of their hand, students and trainees should contact the library at their academic institution.

With today’s technology, it is easier than ever to access web-based tools that enrich traditional dermatology education. The literature supports the use of these innovative platforms to enhance learning at the student and trainee levels. A controlled study of pediatric residents showed that online modules effectively supplemented clinical experience with atopic dermatitis.¹ In a randomized diagnostic study of medical students, practice with an image-based web application (app) that teaches rapid recognition of melanoma proved more effective than learning a rule-based algorithm.² Given the visual nature of dermatology, pattern recognition is an essential skill that is fostered through experience and is only made more accessible with technology.

With the added benefit of convenience and accessibility, mobile apps can supplement experiential learning. Mirroring the overall growth of mobile apps, the number of available dermatology apps has increased.³ Dermatology mobile apps serve purposes ranging from quick reference tools to comprehensive modules, journals, and question banks. At an academic hospital in Taiwan, both nondermatology and dermatology trainees’ examination performance improved after 3 weeks of using a smartphone-based wallpaper learning module displaying morphologic characteristics of fungi.⁴ With the expansion of virtual microscopy, mobile apps also have been created as a learning tool for dermatopathology, giving trainees the flexibility and autonomy to view slides on their own time.⁵ Nevertheless, the literature on dermatology mobile apps designed for the education of medical students and trainees is limited, demonstrating a need for further investigation.

Prior studies have reviewed dermatology apps for patients and practicing dermatologists.^6-8 Herein, we focus on mobile apps targeting students and residents learning dermatology. General dermatology reference apps and educational aid apps have grown by 33% and 32%, respectively, from 2014 to 2017.³ As with any resource meant to educate future and current medical providers, there must be an objective review process in place to ensure accurate, unbiased, evidence-based teaching.

Well-organized, comprehensive information and a user-friendly interface are additional factors of importance when selecting an educational mobile app. When discussing supplemental resources, accessibility and affordability also are priorities given the high cost of a medical education at baseline. Overall, there is a need for a standardized method to evaluate the key factors of an educational mobile app that make it appropriate for this demographic. We conducted a search of mobile apps relating to dermatology education for students and residents.

Methods

We searched for publicly available mobile apps relating to dermatology education in the App Store (Apple Inc) from September to November 2019 using the search terms dermatology education, dermoscopy education, melanoma education, skin cancer education, psoriasis education, rosacea education, acne education, eczema education, dermal fillers education, and Mohs surgery education. We excluded apps that were not in English, were created for a conference, cost more than $5 to download, or did not include a specific dermatology education section. In this way, we hoped to evaluate apps that were relevant, accessible, and affordable.

We modeled our study after a review of patient education apps performed by Masud et al⁶ and utilized their quantified grading rubric (scale of 1 to 4). We found their established criteria—educational objectives, content, accuracy, design, and conflict of interest—to be equally applicable for evaluating apps designed for professional education.⁶ Each app earned a minimum of 1 point and a maximum of 4 points per criterion. One point was given if the app did not fulfill the criterion, 2 points for minimally fulfilling the criterion, 3 points for mostly fulfilling the criterion, and 4 points if the criterion was completely fulfilled. Two medical students (E.H. and N.C.)—one at the preclinical stage and the other at the clinical stage of medical education—reviewed the apps using the given rubric, then discussed and resolved any discrepancies in points assigned. A dermatology resident (M.A.) independently reviewed the apps using the given rubric.

The mean of the student score and the resident score was calculated for each category. The sum of the averages for each category was considered the final score for an app, determining its overall quality. Apps with a total score of 5 to 10 were considered poor and inadequate for education. A total score of 10.5 to 15 indicated that an app was somewhat adequate (ie, useful for education in some aspects but falling short in others). Apps that were considered adequate for education, across all or most criteria, received a total score ranging from 15.5 to 20.

Results

Our search generated 130 apps. After applying exclusion criteria, 42 apps were eligible for review. At the time of publication, 36 of these apps were still available. The possible range of scores based on the rubric was 5 to 20. The actual range of scores was 7 to 20. Of the 36 apps, 2 (5.6%) were poor, 16 (44.4%) were somewhat adequate, and 18 (50%) were adequate. Formats included primary resources, such as clinical decision support tools, journals, references, and a podcast (Table 1). Additionally, interactive learning tools included games, learning modules, and apps for self-evaluation (Table 2). Thirty apps covered general dermatology; others focused on skin cancer (n=5) and cosmetic dermatology (n=1). Regarding cost, 29 apps were free to download, whereas 7 charged a fee (mean price, $2.56).

Comment

In addition to the convenience of having an educational tool in their white-coat pocket, learners of dermatology have been shown to benefit from supplementing their curriculum with mobile apps, which sets the stage for formal integration of mobile apps into dermatology teaching in the future.⁸ Prior to widespread adoption, mobile apps must be evaluated for content and utility, starting with an objective rubric.

Without official scientific standards in place, it was unsurprising that only half of the dermatology education applications were classified as adequate in this study. Among the types of apps offered—clinical decision support tools, journals, references, podcast, games, learning modules, and self-evaluation—certain categories scored higher than others. App formats with the highest average score (16.5 out of 20) were journals and podcast.

One barrier to utilization of these apps was that a subscription to the journals and podcast was required to obtain access to all available content. Students and trainees can seek out library resources at their academic institutions to take advantage of journal subscriptions available to them at no additional cost. Dermatology residents can take advantage of their complimentary membership in the American Academy of Dermatology for a free subscription to AAD Dialogues in Dermatology (otherwise $179 annually for nonresident members and $320 annually for nonmembers).

On the other hand, learning module was the lowest-rated format (average score, 11.3 out of 20), with only Medical Student: Dermatology qualifying as adequate (total score, 16). This finding is worrisome given that students and residents might look to learning modules for quick targeted lessons on specific topics.

The lowest-scoring app, a clinical decision support tool called Naturelize, received a total score of 7. Although it listed the indications and contraindications for dermal filler types to be used in different locations on the face, there was a clear conflict of interest, oversimplified design, and little evidence-based education, mirroring the current state of cosmetic dermatology training in residency, in which trainees think they are inadequately prepared for aesthetic procedures and comparative effectiveness research is lacking.^9-11

At the opposite end of the spectrum, MyDermPath+ was a reference app with a total score of 20. The app cited credible authors with a medical degree (MD) and had an easy-to-use, well-designed interface, including a reference guide, differential builder, and quiz for a range of topics within dermatology. As a free download without in-app purchases or advertisements, there was no evidence of conflict of interest. The position of a dermatopathology app as the top dermatology education mobile app might reflect an increased emphasis on dermatopathology education in residency as well as a transition to digitization of slides.⁵

The second-highest scoring apps (total score of 19 points) were Dermatology Database and VisualDx. Both were references covering a wide range of dermatology topics. Dermatology Database was a comprehensive search tool for diseases, drugs, procedures, and terms that was simple and entirely free to use but did not cite references. VisualDx, as its name suggests, offered quality clinical images, complete guides with references, and a unique differential builder. An annual subscription is $399.99, but the process to gain free access through a participating academic institution was simple.

Games were a unique mobile app format; however, 2 of 3 games scored in the somewhat adequate range. The game DiagnosUs, which tested users’ ability to differentiate skin cancer and psoriasis from dermatitis on clinical images, would benefit from more comprehensive content as well as professional verification of true diagnoses, which earned the app 2 points in both the content and accuracy categories. The Unusual Suspects tested the ABCDE algorithm in a short learning module, followed by a simple game that involved identification of melanoma in a timed setting. Although the design was novel and interactive, the game was limited to the same 5 melanoma tumors overlaid on pictures of normal skin. The narrow scope earned 1 point for content, the redundancy in the game earned 3 points for design, and the lack of real clinical images earned 2 points for educational objectives. Although game-format mobile apps have the capability to challenge the user’s knowledge with a built-in feedback or reward system, improvements should be made to ensure that apps are equally educational as they are engaging.

AAD Dialogues in Dermatology was the only app in the form of a podcast and provided expert interviews along with disclosures, transcripts, commentary, and references. More than half the content in the app could not be accessed without a subscription, earning 2.5 points in the conflict of interest category. Additionally, several flaws resulted in a design score of 2.5, including inconsistent availability of transcripts, poor quality of sound on some episodes, difficulty distinguishing new episodes from those already played, and a glitch that removed the episode duration. Still, the app was a valuable and comprehensive resource, with clear objectives and cited references. With improvements in content, affordability, and user experience, apps in unique formats such as games and podcasts might appeal to kinesthetic and auditory learners.

An important factor to consider when discussing mobile apps for students and residents is cost. With rising prices of board examinations and preparation materials, supplementary study tools should not come with an exorbitant price tag. Therefore, we limited our evaluation to apps that were free or cost less than $5 to download. Even so, subscriptions and other in-app purchases were an obstacle in one-third of apps, ranging from $4.99 to unlock additional content in Rash Decisions to $69.99 to access most topics in Fitzpatrick’s Color Atlas. The highest-rated app in our study, MyDermPath+, historically cost $19.99 to download but became free with a grant from the Sulzberger Foundation.¹² An initial investment to develop quality apps for the purpose of dermatology education might pay off in the end.

To evaluate the apps from the perspective of the target demographic of this study, 2 medical students—one in the preclinical stage and the other in the clinical stage of medical education—and a dermatology resident graded the apps. Certain limitations exist in this type of study, including differing learning styles, which might influence the types of apps that evaluators found most impactful to their education. Interestingly, some apps earned a higher resident score than student score. In particular, RightSite (a reference that helps with anatomically correct labeling) and Mohs Surgery Appropriate Use Criteria (a clinical decision support tool to determine whether to perform Mohs surgery) each had a 3-point discrepancy (data not shown). A resident might benefit from these practical apps in day-to-day practice, but a student would be less likely to find them useful as a learning tool.

Still, by defining adequate teaching value using specific categories of educational objectives, content, accuracy, design, and conflict of interest, we attempted to minimize the effect of personal preference on the grading process. Although we acknowledge a degree of subjectivity, we found that utilizing a previously published rubric with defined criteria was crucial in remaining unbiased.

Conclusion

Further studies should evaluate additional apps available on Apple’s iPad (tablet), as well as those on other operating systems, including Google’s Android. To ensure the existence of mobile apps as adequate education tools, they should be peer reviewed prior to publication or before widespread use by future and current providers at the minimum. To maximize free access to highly valuable resources available in the palm of their hand, students and trainees should contact the library at their academic institution.

With today’s technology, it is easier than ever to access web-based tools that enrich traditional dermatology education. The literature supports the use of these innovative platforms to enhance learning at the student and trainee levels. A controlled study of pediatric residents showed that online modules effectively supplemented clinical experience with atopic dermatitis.¹ In a randomized diagnostic study of medical students, practice with an image-based web application (app) that teaches rapid recognition of melanoma proved more effective than learning a rule-based algorithm.² Given the visual nature of dermatology, pattern recognition is an essential skill that is fostered through experience and is only made more accessible with technology.

With the added benefit of convenience and accessibility, mobile apps can supplement experiential learning. Mirroring the overall growth of mobile apps, the number of available dermatology apps has increased.³ Dermatology mobile apps serve purposes ranging from quick reference tools to comprehensive modules, journals, and question banks. At an academic hospital in Taiwan, both nondermatology and dermatology trainees’ examination performance improved after 3 weeks of using a smartphone-based wallpaper learning module displaying morphologic characteristics of fungi.⁴ With the expansion of virtual microscopy, mobile apps also have been created as a learning tool for dermatopathology, giving trainees the flexibility and autonomy to view slides on their own time.⁵ Nevertheless, the literature on dermatology mobile apps designed for the education of medical students and trainees is limited, demonstrating a need for further investigation.

Prior studies have reviewed dermatology apps for patients and practicing dermatologists.^6-8 Herein, we focus on mobile apps targeting students and residents learning dermatology. General dermatology reference apps and educational aid apps have grown by 33% and 32%, respectively, from 2014 to 2017.³ As with any resource meant to educate future and current medical providers, there must be an objective review process in place to ensure accurate, unbiased, evidence-based teaching.

Well-organized, comprehensive information and a user-friendly interface are additional factors of importance when selecting an educational mobile app. When discussing supplemental resources, accessibility and affordability also are priorities given the high cost of a medical education at baseline. Overall, there is a need for a standardized method to evaluate the key factors of an educational mobile app that make it appropriate for this demographic. We conducted a search of mobile apps relating to dermatology education for students and residents.

Methods

We searched for publicly available mobile apps relating to dermatology education in the App Store (Apple Inc) from September to November 2019 using the search terms dermatology education, dermoscopy education, melanoma education, skin cancer education, psoriasis education, rosacea education, acne education, eczema education, dermal fillers education, and Mohs surgery education. We excluded apps that were not in English, were created for a conference, cost more than $5 to download, or did not include a specific dermatology education section. In this way, we hoped to evaluate apps that were relevant, accessible, and affordable.

We modeled our study after a review of patient education apps performed by Masud et al⁶ and utilized their quantified grading rubric (scale of 1 to 4). We found their established criteria—educational objectives, content, accuracy, design, and conflict of interest—to be equally applicable for evaluating apps designed for professional education.⁶ Each app earned a minimum of 1 point and a maximum of 4 points per criterion. One point was given if the app did not fulfill the criterion, 2 points for minimally fulfilling the criterion, 3 points for mostly fulfilling the criterion, and 4 points if the criterion was completely fulfilled. Two medical students (E.H. and N.C.)—one at the preclinical stage and the other at the clinical stage of medical education—reviewed the apps using the given rubric, then discussed and resolved any discrepancies in points assigned. A dermatology resident (M.A.) independently reviewed the apps using the given rubric.

The mean of the student score and the resident score was calculated for each category. The sum of the averages for each category was considered the final score for an app, determining its overall quality. Apps with a total score of 5 to 10 were considered poor and inadequate for education. A total score of 10.5 to 15 indicated that an app was somewhat adequate (ie, useful for education in some aspects but falling short in others). Apps that were considered adequate for education, across all or most criteria, received a total score ranging from 15.5 to 20.

Results

Our search generated 130 apps. After applying exclusion criteria, 42 apps were eligible for review. At the time of publication, 36 of these apps were still available. The possible range of scores based on the rubric was 5 to 20. The actual range of scores was 7 to 20. Of the 36 apps, 2 (5.6%) were poor, 16 (44.4%) were somewhat adequate, and 18 (50%) were adequate. Formats included primary resources, such as clinical decision support tools, journals, references, and a podcast (Table 1). Additionally, interactive learning tools included games, learning modules, and apps for self-evaluation (Table 2). Thirty apps covered general dermatology; others focused on skin cancer (n=5) and cosmetic dermatology (n=1). Regarding cost, 29 apps were free to download, whereas 7 charged a fee (mean price, $2.56).

Comment

In addition to the convenience of having an educational tool in their white-coat pocket, learners of dermatology have been shown to benefit from supplementing their curriculum with mobile apps, which sets the stage for formal integration of mobile apps into dermatology teaching in the future.⁸ Prior to widespread adoption, mobile apps must be evaluated for content and utility, starting with an objective rubric.

Without official scientific standards in place, it was unsurprising that only half of the dermatology education applications were classified as adequate in this study. Among the types of apps offered—clinical decision support tools, journals, references, podcast, games, learning modules, and self-evaluation—certain categories scored higher than others. App formats with the highest average score (16.5 out of 20) were journals and podcast.

One barrier to utilization of these apps was that a subscription to the journals and podcast was required to obtain access to all available content. Students and trainees can seek out library resources at their academic institutions to take advantage of journal subscriptions available to them at no additional cost. Dermatology residents can take advantage of their complimentary membership in the American Academy of Dermatology for a free subscription to AAD Dialogues in Dermatology (otherwise $179 annually for nonresident members and $320 annually for nonmembers).

On the other hand, learning module was the lowest-rated format (average score, 11.3 out of 20), with only Medical Student: Dermatology qualifying as adequate (total score, 16). This finding is worrisome given that students and residents might look to learning modules for quick targeted lessons on specific topics.

The lowest-scoring app, a clinical decision support tool called Naturelize, received a total score of 7. Although it listed the indications and contraindications for dermal filler types to be used in different locations on the face, there was a clear conflict of interest, oversimplified design, and little evidence-based education, mirroring the current state of cosmetic dermatology training in residency, in which trainees think they are inadequately prepared for aesthetic procedures and comparative effectiveness research is lacking.^9-11

At the opposite end of the spectrum, MyDermPath+ was a reference app with a total score of 20. The app cited credible authors with a medical degree (MD) and had an easy-to-use, well-designed interface, including a reference guide, differential builder, and quiz for a range of topics within dermatology. As a free download without in-app purchases or advertisements, there was no evidence of conflict of interest. The position of a dermatopathology app as the top dermatology education mobile app might reflect an increased emphasis on dermatopathology education in residency as well as a transition to digitization of slides.⁵

The second-highest scoring apps (total score of 19 points) were Dermatology Database and VisualDx. Both were references covering a wide range of dermatology topics. Dermatology Database was a comprehensive search tool for diseases, drugs, procedures, and terms that was simple and entirely free to use but did not cite references. VisualDx, as its name suggests, offered quality clinical images, complete guides with references, and a unique differential builder. An annual subscription is $399.99, but the process to gain free access through a participating academic institution was simple.

Games were a unique mobile app format; however, 2 of 3 games scored in the somewhat adequate range. The game DiagnosUs, which tested users’ ability to differentiate skin cancer and psoriasis from dermatitis on clinical images, would benefit from more comprehensive content as well as professional verification of true diagnoses, which earned the app 2 points in both the content and accuracy categories. The Unusual Suspects tested the ABCDE algorithm in a short learning module, followed by a simple game that involved identification of melanoma in a timed setting. Although the design was novel and interactive, the game was limited to the same 5 melanoma tumors overlaid on pictures of normal skin. The narrow scope earned 1 point for content, the redundancy in the game earned 3 points for design, and the lack of real clinical images earned 2 points for educational objectives. Although game-format mobile apps have the capability to challenge the user’s knowledge with a built-in feedback or reward system, improvements should be made to ensure that apps are equally educational as they are engaging.

AAD Dialogues in Dermatology was the only app in the form of a podcast and provided expert interviews along with disclosures, transcripts, commentary, and references. More than half the content in the app could not be accessed without a subscription, earning 2.5 points in the conflict of interest category. Additionally, several flaws resulted in a design score of 2.5, including inconsistent availability of transcripts, poor quality of sound on some episodes, difficulty distinguishing new episodes from those already played, and a glitch that removed the episode duration. Still, the app was a valuable and comprehensive resource, with clear objectives and cited references. With improvements in content, affordability, and user experience, apps in unique formats such as games and podcasts might appeal to kinesthetic and auditory learners.

An important factor to consider when discussing mobile apps for students and residents is cost. With rising prices of board examinations and preparation materials, supplementary study tools should not come with an exorbitant price tag. Therefore, we limited our evaluation to apps that were free or cost less than $5 to download. Even so, subscriptions and other in-app purchases were an obstacle in one-third of apps, ranging from $4.99 to unlock additional content in Rash Decisions to $69.99 to access most topics in Fitzpatrick’s Color Atlas. The highest-rated app in our study, MyDermPath+, historically cost $19.99 to download but became free with a grant from the Sulzberger Foundation.¹² An initial investment to develop quality apps for the purpose of dermatology education might pay off in the end.

To evaluate the apps from the perspective of the target demographic of this study, 2 medical students—one in the preclinical stage and the other in the clinical stage of medical education—and a dermatology resident graded the apps. Certain limitations exist in this type of study, including differing learning styles, which might influence the types of apps that evaluators found most impactful to their education. Interestingly, some apps earned a higher resident score than student score. In particular, RightSite (a reference that helps with anatomically correct labeling) and Mohs Surgery Appropriate Use Criteria (a clinical decision support tool to determine whether to perform Mohs surgery) each had a 3-point discrepancy (data not shown). A resident might benefit from these practical apps in day-to-day practice, but a student would be less likely to find them useful as a learning tool.

Still, by defining adequate teaching value using specific categories of educational objectives, content, accuracy, design, and conflict of interest, we attempted to minimize the effect of personal preference on the grading process. Although we acknowledge a degree of subjectivity, we found that utilizing a previously published rubric with defined criteria was crucial in remaining unbiased.

Conclusion

Further studies should evaluate additional apps available on Apple’s iPad (tablet), as well as those on other operating systems, including Google’s Android. To ensure the existence of mobile apps as adequate education tools, they should be peer reviewed prior to publication or before widespread use by future and current providers at the minimum. To maximize free access to highly valuable resources available in the palm of their hand, students and trainees should contact the library at their academic institution.

Basal cell carcinoma (BCC) is the most common type of skin cancer frequently encountered in both dermatology and primary care settings.¹ When biopsies of these neoplasms are performed to confirm the diagnosis, pathology reports may indicate positive or negative margin status. No guidelines exist for reporting biopsy margin status for BCC, resulting in varied reporting practices among dermatopathologists. Furthermore, the terminology used to describe margin status can be ambiguous and differs among pathologists; language such as “approaches the margin” or “margins appear free” may be used, with nonuniform interpretation between pathologists and providers, leading to variability in patient management.²

When interpreting a negative margin status on a pathology report, one must question if the BCC extends beyond the margin in unexamined sections of the specimen, which could be the result of an irregular tumor growth pattern or tissue processing. It has been estimated that less than 2% of the peripheral surgical margin is ultimately examined when serial cross-sections are prepared histologically (the bread loaf technique). However, this estimation would depend on several variables, including the number and thickness of sections and the amount of tissue discarded during processing.³ Importantly, reports of a false-negative margin could lead both the clinician and patient to believe that the neoplasm has been completely removed, which could have serious consequences.

Our study sought to determine the reliability of negative biopsy margin status for BCC. We examined BCC biopsy specimens initially determined to have uninvolved margins on routine tissue processing and determined the proportion with truly negative margins after complete tissue block sectioning of the initial biopsy specimen. We felt this technique was a more accurate measurement of true margin status than examination of a re-excision specimen. We also identified any factors that were predictive of positive true margins.

Methods

We conducted a retrospective study evaluating tissue samples collected at Geisinger Health System (Danville, Pennsylvania) from January to December 2016. Specimens were queried via the electronic database system at our institution (CoPath). We included BCC biopsy specimens with negative histologic margins on initial assessment that subsequently had block exhaust levels routinely ordered. These levels are cut every 100 to 150 µm, generating approximately 8 glass slides. We excluded all tumors that did not fit these criteria as well as those in patients younger than 18 years. Data collection was performed utilizing specimen pathology reports in addition to the note from the corresponding clinician office visit from the institution’s electronic medical record (Epic). Appropriate statistical calculations were performed. This study was approved by an institutional review board at our institution, which is required for all research involving human participants. This served to ensure the proper review and storage of patients’ protected health information.

Results

The search yielded a total of 122 specimens from 104 patients after appropriate exclusions. We examined a total of 122 BCC biopsy specimens with negative initial margins: 121 (99.2%) shave biopsies and 1 (0.8%) punch biopsy. Of 122 specimens with negative initial margins, 53 (43.4%) were found to have a truly positive margin based on the presence of either tumor or stroma at the lateral or deep tissue edge after complete tissue block sectioning. Sixty-nine (56.6%) specimens had clear margins and were categorized as truly negative after complete tissue block sectioning. Specimens with positive and negative final margin status did not differ significantly with respect to patient age; gender; biopsy technique; number of gross specimen sections; or tumor characteristics, including location, size, and subtype (Table)(P>.05).

We also examined the type of treatment performed, which varied and included curettage, electrodesiccation and curettage, excision, and Mohs micrographic surgery. Clinicians, who were not made aware of the exhaust level protocol, chose not to pursue further treatment in 6 (4.9%) of the cases because of negative biopsy margins. Four (66.7%) of the 6 providers were physicians, and 2 (33.3%) were advanced practitioners. All of the providers practiced within the Department of Dermatology.

Comment

Our findings support prior smaller studies investigating this topic. A prospective study by Schnebelen et al⁴ examined 27 BCC biopsy specimens and found that 8 (30%) were erroneously classified as negative on routine examination. This study similarly determined true margin status by assessing the margins at complete tissue block exhaustion.⁴ Willardson et al⁵ also demonstrated the poor predictive value of margin status based on the presence of residual BCC in subsequent excisions. They found that 34 (24%) of 143 cases with negative biopsy margins contained residual tumor in the corresponding excision.⁵

Our study revealed that almost half of BCC biopsy specimens that had negative histologic margins with routine sectioning had truly positive margins on complete block exhaustion. This finding was independent of multiple factors, including tumor subtype, indicating that even nonaggressive tumors are prone to false-negative margin reports. We also found that reports of negative margins persuaded some clinicians to forgo definitive treatment. This study serves to remind clinicians of the limitations of margin assessment and provides impetus for dermatopathologists to consider modifying how margin status is reported.

Limitations of this study include a small number of cases and limited generalizability. Institutions that routinely examine more levels of each biopsy specimen may be less likely to erroneously categorize a positive margin as negative. Furthermore, despite exhausting the tissue block, we still may have underestimated the number of cases with truly positive margins, as this method inherently does not allow for complete margin examination.

Acknowledgments
We thank the Geisinger Department of Dermatopathology and the Geisinger Biostatistics & Research Data Core (Danville, Pennsylvania) for their assistance with our project.

Basal cell carcinoma (BCC) is the most common type of skin cancer frequently encountered in both dermatology and primary care settings.¹ When biopsies of these neoplasms are performed to confirm the diagnosis, pathology reports may indicate positive or negative margin status. No guidelines exist for reporting biopsy margin status for BCC, resulting in varied reporting practices among dermatopathologists. Furthermore, the terminology used to describe margin status can be ambiguous and differs among pathologists; language such as “approaches the margin” or “margins appear free” may be used, with nonuniform interpretation between pathologists and providers, leading to variability in patient management.²

When interpreting a negative margin status on a pathology report, one must question if the BCC extends beyond the margin in unexamined sections of the specimen, which could be the result of an irregular tumor growth pattern or tissue processing. It has been estimated that less than 2% of the peripheral surgical margin is ultimately examined when serial cross-sections are prepared histologically (the bread loaf technique). However, this estimation would depend on several variables, including the number and thickness of sections and the amount of tissue discarded during processing.³ Importantly, reports of a false-negative margin could lead both the clinician and patient to believe that the neoplasm has been completely removed, which could have serious consequences.

Our study sought to determine the reliability of negative biopsy margin status for BCC. We examined BCC biopsy specimens initially determined to have uninvolved margins on routine tissue processing and determined the proportion with truly negative margins after complete tissue block sectioning of the initial biopsy specimen. We felt this technique was a more accurate measurement of true margin status than examination of a re-excision specimen. We also identified any factors that were predictive of positive true margins.

Methods

We conducted a retrospective study evaluating tissue samples collected at Geisinger Health System (Danville, Pennsylvania) from January to December 2016. Specimens were queried via the electronic database system at our institution (CoPath). We included BCC biopsy specimens with negative histologic margins on initial assessment that subsequently had block exhaust levels routinely ordered. These levels are cut every 100 to 150 µm, generating approximately 8 glass slides. We excluded all tumors that did not fit these criteria as well as those in patients younger than 18 years. Data collection was performed utilizing specimen pathology reports in addition to the note from the corresponding clinician office visit from the institution’s electronic medical record (Epic). Appropriate statistical calculations were performed. This study was approved by an institutional review board at our institution, which is required for all research involving human participants. This served to ensure the proper review and storage of patients’ protected health information.

Results

The search yielded a total of 122 specimens from 104 patients after appropriate exclusions. We examined a total of 122 BCC biopsy specimens with negative initial margins: 121 (99.2%) shave biopsies and 1 (0.8%) punch biopsy. Of 122 specimens with negative initial margins, 53 (43.4%) were found to have a truly positive margin based on the presence of either tumor or stroma at the lateral or deep tissue edge after complete tissue block sectioning. Sixty-nine (56.6%) specimens had clear margins and were categorized as truly negative after complete tissue block sectioning. Specimens with positive and negative final margin status did not differ significantly with respect to patient age; gender; biopsy technique; number of gross specimen sections; or tumor characteristics, including location, size, and subtype (Table)(P>.05).

We also examined the type of treatment performed, which varied and included curettage, electrodesiccation and curettage, excision, and Mohs micrographic surgery. Clinicians, who were not made aware of the exhaust level protocol, chose not to pursue further treatment in 6 (4.9%) of the cases because of negative biopsy margins. Four (66.7%) of the 6 providers were physicians, and 2 (33.3%) were advanced practitioners. All of the providers practiced within the Department of Dermatology.

Comment

Our findings support prior smaller studies investigating this topic. A prospective study by Schnebelen et al⁴ examined 27 BCC biopsy specimens and found that 8 (30%) were erroneously classified as negative on routine examination. This study similarly determined true margin status by assessing the margins at complete tissue block exhaustion.⁴ Willardson et al⁵ also demonstrated the poor predictive value of margin status based on the presence of residual BCC in subsequent excisions. They found that 34 (24%) of 143 cases with negative biopsy margins contained residual tumor in the corresponding excision.⁵

Our study revealed that almost half of BCC biopsy specimens that had negative histologic margins with routine sectioning had truly positive margins on complete block exhaustion. This finding was independent of multiple factors, including tumor subtype, indicating that even nonaggressive tumors are prone to false-negative margin reports. We also found that reports of negative margins persuaded some clinicians to forgo definitive treatment. This study serves to remind clinicians of the limitations of margin assessment and provides impetus for dermatopathologists to consider modifying how margin status is reported.

Limitations of this study include a small number of cases and limited generalizability. Institutions that routinely examine more levels of each biopsy specimen may be less likely to erroneously categorize a positive margin as negative. Furthermore, despite exhausting the tissue block, we still may have underestimated the number of cases with truly positive margins, as this method inherently does not allow for complete margin examination.

Acknowledgments
We thank the Geisinger Department of Dermatopathology and the Geisinger Biostatistics & Research Data Core (Danville, Pennsylvania) for their assistance with our project.

Basal cell carcinoma (BCC) is the most common type of skin cancer frequently encountered in both dermatology and primary care settings.¹ When biopsies of these neoplasms are performed to confirm the diagnosis, pathology reports may indicate positive or negative margin status. No guidelines exist for reporting biopsy margin status for BCC, resulting in varied reporting practices among dermatopathologists. Furthermore, the terminology used to describe margin status can be ambiguous and differs among pathologists; language such as “approaches the margin” or “margins appear free” may be used, with nonuniform interpretation between pathologists and providers, leading to variability in patient management.²

When interpreting a negative margin status on a pathology report, one must question if the BCC extends beyond the margin in unexamined sections of the specimen, which could be the result of an irregular tumor growth pattern or tissue processing. It has been estimated that less than 2% of the peripheral surgical margin is ultimately examined when serial cross-sections are prepared histologically (the bread loaf technique). However, this estimation would depend on several variables, including the number and thickness of sections and the amount of tissue discarded during processing.³ Importantly, reports of a false-negative margin could lead both the clinician and patient to believe that the neoplasm has been completely removed, which could have serious consequences.

Our study sought to determine the reliability of negative biopsy margin status for BCC. We examined BCC biopsy specimens initially determined to have uninvolved margins on routine tissue processing and determined the proportion with truly negative margins after complete tissue block sectioning of the initial biopsy specimen. We felt this technique was a more accurate measurement of true margin status than examination of a re-excision specimen. We also identified any factors that were predictive of positive true margins.

Methods

We conducted a retrospective study evaluating tissue samples collected at Geisinger Health System (Danville, Pennsylvania) from January to December 2016. Specimens were queried via the electronic database system at our institution (CoPath). We included BCC biopsy specimens with negative histologic margins on initial assessment that subsequently had block exhaust levels routinely ordered. These levels are cut every 100 to 150 µm, generating approximately 8 glass slides. We excluded all tumors that did not fit these criteria as well as those in patients younger than 18 years. Data collection was performed utilizing specimen pathology reports in addition to the note from the corresponding clinician office visit from the institution’s electronic medical record (Epic). Appropriate statistical calculations were performed. This study was approved by an institutional review board at our institution, which is required for all research involving human participants. This served to ensure the proper review and storage of patients’ protected health information.

Results

The search yielded a total of 122 specimens from 104 patients after appropriate exclusions. We examined a total of 122 BCC biopsy specimens with negative initial margins: 121 (99.2%) shave biopsies and 1 (0.8%) punch biopsy. Of 122 specimens with negative initial margins, 53 (43.4%) were found to have a truly positive margin based on the presence of either tumor or stroma at the lateral or deep tissue edge after complete tissue block sectioning. Sixty-nine (56.6%) specimens had clear margins and were categorized as truly negative after complete tissue block sectioning. Specimens with positive and negative final margin status did not differ significantly with respect to patient age; gender; biopsy technique; number of gross specimen sections; or tumor characteristics, including location, size, and subtype (Table)(P>.05).

We also examined the type of treatment performed, which varied and included curettage, electrodesiccation and curettage, excision, and Mohs micrographic surgery. Clinicians, who were not made aware of the exhaust level protocol, chose not to pursue further treatment in 6 (4.9%) of the cases because of negative biopsy margins. Four (66.7%) of the 6 providers were physicians, and 2 (33.3%) were advanced practitioners. All of the providers practiced within the Department of Dermatology.

Comment

Our findings support prior smaller studies investigating this topic. A prospective study by Schnebelen et al⁴ examined 27 BCC biopsy specimens and found that 8 (30%) were erroneously classified as negative on routine examination. This study similarly determined true margin status by assessing the margins at complete tissue block exhaustion.⁴ Willardson et al⁵ also demonstrated the poor predictive value of margin status based on the presence of residual BCC in subsequent excisions. They found that 34 (24%) of 143 cases with negative biopsy margins contained residual tumor in the corresponding excision.⁵

Our study revealed that almost half of BCC biopsy specimens that had negative histologic margins with routine sectioning had truly positive margins on complete block exhaustion. This finding was independent of multiple factors, including tumor subtype, indicating that even nonaggressive tumors are prone to false-negative margin reports. We also found that reports of negative margins persuaded some clinicians to forgo definitive treatment. This study serves to remind clinicians of the limitations of margin assessment and provides impetus for dermatopathologists to consider modifying how margin status is reported.

Limitations of this study include a small number of cases and limited generalizability. Institutions that routinely examine more levels of each biopsy specimen may be less likely to erroneously categorize a positive margin as negative. Furthermore, despite exhausting the tissue block, we still may have underestimated the number of cases with truly positive margins, as this method inherently does not allow for complete margin examination.

Acknowledgments
We thank the Geisinger Department of Dermatopathology and the Geisinger Biostatistics & Research Data Core (Danville, Pennsylvania) for their assistance with our project.

Neoadjuvant therapy with intralesional talimogene laherparepvec (T-VEC) has durable efficacy in advanced melanoma, according to a phase 2 trial reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

T-VEC is a modified virus that lyses tumor cells locally and induces a systemic immune response. In the phase 2 trial, neoadjuvant T-VEC plus surgery improved 3-year recurrence-free survival, when compared with immediate surgery, in patients with resectable melanoma.

“This is the first neoadjuvant trial for an approved oncolytic virus in melanoma and the largest randomized prospectively controlled neoadjuvant melanoma trial completed to date,” said investigator Reinhard Dummer, MD, of University Hospital Zürich.

The multicenter trial enrolled 150 patients with resectable stage IIIB–IV M1a melanoma (thereby including many with in-transit metastasis) who had at least one injectable lesion.

“This patient population is typically excluded from the trials that are published. Those trials typically focus on lymph node metastasis only,” Dr. Dummer noted.

The patients were randomized evenly to receive six doses over 12 weeks of intralesional T-VEC followed by surgical resection, or to the conventional approach of immediate surgical resection.
 

Survival results

The median follow-up for this interim analysis was 41.3 months.

The 3-year rate of recurrence-free survival, the trial’s primary endpoint, was 46.5% with T-VEC plus surgery and 31.0% with immediate surgery (hazard ratio, 0.67; P = .043). The median duration of recurrence-free survival was 27.5 months and 5.4 months, respectively.

These results were comparable with results seen at 2 years, which were published in Annals of Oncology in 2019. The 2-year rate of recurrence-free survival was 50.5% with T-VEC plus surgery and 31.0% with immediate surgery (HR, 0.66; P = .038).

“These patients appear to be in a plateau phase now,” Dr. Dummer remarked.

The 3-year rate of event-free survival, which excluded any events related to a delay of surgery, was 50.3% for T-VEC and 32.7% for immediate surgery (HR, 0.58, P = .015).

Findings for both outcomes were similar when analyses were repeated after removing events that occurred after receipt of therapy in the adjuvant or metastatic setting.

Finally, the 3-year rate of overall survival was 83.2% with T-VEC plus surgery and 71.6% with immediate surgery (HR, 0.54; P = .061). Respective 2-year values were 88.9% and 77.4% (HR, 0.49; P = .050).

In all, 50.7% of patients in the T-VEC group received subsequent anticancer therapy, compared with 76.8% in the immediate-surgery group. Respective values specifically for subsequent immunotherapy – usually immune checkpoint inhibitors – were 32.9% and 46.4%.

“I think this is a good argument that the effects we see on overall survival and recurrence-free survival are not caused by improved second-line treatments,” Dr. Dummer said.

No new safety signals emerged during the additional year of follow-up. The trial’s final analysis will be conducted after 5 years of follow-up.

“These results build upon the prior 2-year results to support the potential beneficial effect of neoadjuvant T-VEC on advanced resectable melanoma,” Dr. Dummer said.

“In general, if you compare this to the objective outcomes that we see with neoadjuvant ipilimumab-nivolumab, for example, the results do not look very attractive,” he acknowledged.

“However, we have to keep in mind that this is a difficult patient population,” he added, noting that many patients have in-transit metastases that would disqualify them from conventional neoadjuvant therapy. Also, cross-trial comparisons are complicated by the need to allow adjuvant therapy in patients who receive neoadjuvant therapy.

“I would say the combination of ipilimumab-nivolumab should be more powerful, but T-VEC has some impact, and from my understanding, T-VEC would be a perfect partner for a combination, for example, with an anti–[programmed death 1] agent,” Dr. Dummer concluded.
 

‘Impressive’ data support more research

“Neoadjuvant approaches are gaining enthusiasm for patients with locally advanced disease that may not be amenable to simple excision or may require large disfiguring procedures,” said Howard L. Kaufman, MD, of Massachusetts General Hospital and Dana Farber/Harvard Cancer Center, both in Boston, who was not involved in this study.

© Michael Hoetzel

“A treatment option that could induce tumor regression while also promoting immune responses against the tumor is attractive,” Dr. Kaufman added.

“I continue to be impressed with this clinical trial as it demonstrates a consistent improvement in recurrence-free survival, event-free survival, and overall survival for patients treated with neoadjuvant T-VEC and surgery, compared to those who undergo surgery alone,” he said in an interview. “Confirmation that the responses are now maintained for another year is an important milestone.”

Given the study’s fairly small size, large treatment differences would be needed to attain the observed statistical significance, and “this is why the data at 3 years of follow-up is so impressive,” Dr. Kaufman said.

However, benefit of T-VEC’s activity in inducing a systemic immune response may not become fully evident until the end of the trial.

“Overall survival at 5 years is the most relevant endpoint,” Dr. Kaufman maintained.

An important aspect of the study is that it enrolled patients with a range of melanoma stages, including about 18% with stage IV M1a disease, he added.

“This could potentially influence the results, where earlier-stage patients may have a more durable response, compared to higher-stage patients and, thus, the data may be further diluted by the small sample size,” he proposed. “Given this possibility, my sense is that the data is even more impressive since there still appears to be a significant clinical benefit at 3 years, and I would recommend larger studies in patients with earlier-stage melanoma as fertile ground for further oncolytic virus drug development.”

The current trial was funded by Amgen. Dr. Dummer disclosed relationships with Amgen, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Takeda, Pierre Fabre, Sun Pharma, Sanofi, and CatalYm. Dr. Kaufman disclosed employment by Immuneering.

SOURCE: Dummer R et al. SITC 2020, Abstract 432.

Neoadjuvant therapy with intralesional talimogene laherparepvec (T-VEC) has durable efficacy in advanced melanoma, according to a phase 2 trial reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

T-VEC is a modified virus that lyses tumor cells locally and induces a systemic immune response. In the phase 2 trial, neoadjuvant T-VEC plus surgery improved 3-year recurrence-free survival, when compared with immediate surgery, in patients with resectable melanoma.

“This is the first neoadjuvant trial for an approved oncolytic virus in melanoma and the largest randomized prospectively controlled neoadjuvant melanoma trial completed to date,” said investigator Reinhard Dummer, MD, of University Hospital Zürich.

The multicenter trial enrolled 150 patients with resectable stage IIIB–IV M1a melanoma (thereby including many with in-transit metastasis) who had at least one injectable lesion.

“This patient population is typically excluded from the trials that are published. Those trials typically focus on lymph node metastasis only,” Dr. Dummer noted.

The patients were randomized evenly to receive six doses over 12 weeks of intralesional T-VEC followed by surgical resection, or to the conventional approach of immediate surgical resection.
 

Survival results

The median follow-up for this interim analysis was 41.3 months.

The 3-year rate of recurrence-free survival, the trial’s primary endpoint, was 46.5% with T-VEC plus surgery and 31.0% with immediate surgery (hazard ratio, 0.67; P = .043). The median duration of recurrence-free survival was 27.5 months and 5.4 months, respectively.

These results were comparable with results seen at 2 years, which were published in Annals of Oncology in 2019. The 2-year rate of recurrence-free survival was 50.5% with T-VEC plus surgery and 31.0% with immediate surgery (HR, 0.66; P = .038).

“These patients appear to be in a plateau phase now,” Dr. Dummer remarked.

The 3-year rate of event-free survival, which excluded any events related to a delay of surgery, was 50.3% for T-VEC and 32.7% for immediate surgery (HR, 0.58, P = .015).

Findings for both outcomes were similar when analyses were repeated after removing events that occurred after receipt of therapy in the adjuvant or metastatic setting.

Finally, the 3-year rate of overall survival was 83.2% with T-VEC plus surgery and 71.6% with immediate surgery (HR, 0.54; P = .061). Respective 2-year values were 88.9% and 77.4% (HR, 0.49; P = .050).

In all, 50.7% of patients in the T-VEC group received subsequent anticancer therapy, compared with 76.8% in the immediate-surgery group. Respective values specifically for subsequent immunotherapy – usually immune checkpoint inhibitors – were 32.9% and 46.4%.

“I think this is a good argument that the effects we see on overall survival and recurrence-free survival are not caused by improved second-line treatments,” Dr. Dummer said.

No new safety signals emerged during the additional year of follow-up. The trial’s final analysis will be conducted after 5 years of follow-up.

“These results build upon the prior 2-year results to support the potential beneficial effect of neoadjuvant T-VEC on advanced resectable melanoma,” Dr. Dummer said.

“In general, if you compare this to the objective outcomes that we see with neoadjuvant ipilimumab-nivolumab, for example, the results do not look very attractive,” he acknowledged.

“However, we have to keep in mind that this is a difficult patient population,” he added, noting that many patients have in-transit metastases that would disqualify them from conventional neoadjuvant therapy. Also, cross-trial comparisons are complicated by the need to allow adjuvant therapy in patients who receive neoadjuvant therapy.

“I would say the combination of ipilimumab-nivolumab should be more powerful, but T-VEC has some impact, and from my understanding, T-VEC would be a perfect partner for a combination, for example, with an anti–[programmed death 1] agent,” Dr. Dummer concluded.
 

‘Impressive’ data support more research

“Neoadjuvant approaches are gaining enthusiasm for patients with locally advanced disease that may not be amenable to simple excision or may require large disfiguring procedures,” said Howard L. Kaufman, MD, of Massachusetts General Hospital and Dana Farber/Harvard Cancer Center, both in Boston, who was not involved in this study.

© Michael Hoetzel

“A treatment option that could induce tumor regression while also promoting immune responses against the tumor is attractive,” Dr. Kaufman added.

“I continue to be impressed with this clinical trial as it demonstrates a consistent improvement in recurrence-free survival, event-free survival, and overall survival for patients treated with neoadjuvant T-VEC and surgery, compared to those who undergo surgery alone,” he said in an interview. “Confirmation that the responses are now maintained for another year is an important milestone.”

Given the study’s fairly small size, large treatment differences would be needed to attain the observed statistical significance, and “this is why the data at 3 years of follow-up is so impressive,” Dr. Kaufman said.

However, benefit of T-VEC’s activity in inducing a systemic immune response may not become fully evident until the end of the trial.

“Overall survival at 5 years is the most relevant endpoint,” Dr. Kaufman maintained.

An important aspect of the study is that it enrolled patients with a range of melanoma stages, including about 18% with stage IV M1a disease, he added.

“This could potentially influence the results, where earlier-stage patients may have a more durable response, compared to higher-stage patients and, thus, the data may be further diluted by the small sample size,” he proposed. “Given this possibility, my sense is that the data is even more impressive since there still appears to be a significant clinical benefit at 3 years, and I would recommend larger studies in patients with earlier-stage melanoma as fertile ground for further oncolytic virus drug development.”

The current trial was funded by Amgen. Dr. Dummer disclosed relationships with Amgen, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Takeda, Pierre Fabre, Sun Pharma, Sanofi, and CatalYm. Dr. Kaufman disclosed employment by Immuneering.

SOURCE: Dummer R et al. SITC 2020, Abstract 432.

Neoadjuvant therapy with intralesional talimogene laherparepvec (T-VEC) has durable efficacy in advanced melanoma, according to a phase 2 trial reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

T-VEC is a modified virus that lyses tumor cells locally and induces a systemic immune response. In the phase 2 trial, neoadjuvant T-VEC plus surgery improved 3-year recurrence-free survival, when compared with immediate surgery, in patients with resectable melanoma.

“This is the first neoadjuvant trial for an approved oncolytic virus in melanoma and the largest randomized prospectively controlled neoadjuvant melanoma trial completed to date,” said investigator Reinhard Dummer, MD, of University Hospital Zürich.

The multicenter trial enrolled 150 patients with resectable stage IIIB–IV M1a melanoma (thereby including many with in-transit metastasis) who had at least one injectable lesion.

“This patient population is typically excluded from the trials that are published. Those trials typically focus on lymph node metastasis only,” Dr. Dummer noted.

The patients were randomized evenly to receive six doses over 12 weeks of intralesional T-VEC followed by surgical resection, or to the conventional approach of immediate surgical resection.
 

Survival results

The median follow-up for this interim analysis was 41.3 months.

The 3-year rate of recurrence-free survival, the trial’s primary endpoint, was 46.5% with T-VEC plus surgery and 31.0% with immediate surgery (hazard ratio, 0.67; P = .043). The median duration of recurrence-free survival was 27.5 months and 5.4 months, respectively.

These results were comparable with results seen at 2 years, which were published in Annals of Oncology in 2019. The 2-year rate of recurrence-free survival was 50.5% with T-VEC plus surgery and 31.0% with immediate surgery (HR, 0.66; P = .038).

“These patients appear to be in a plateau phase now,” Dr. Dummer remarked.

The 3-year rate of event-free survival, which excluded any events related to a delay of surgery, was 50.3% for T-VEC and 32.7% for immediate surgery (HR, 0.58, P = .015).

Findings for both outcomes were similar when analyses were repeated after removing events that occurred after receipt of therapy in the adjuvant or metastatic setting.

Finally, the 3-year rate of overall survival was 83.2% with T-VEC plus surgery and 71.6% with immediate surgery (HR, 0.54; P = .061). Respective 2-year values were 88.9% and 77.4% (HR, 0.49; P = .050).

In all, 50.7% of patients in the T-VEC group received subsequent anticancer therapy, compared with 76.8% in the immediate-surgery group. Respective values specifically for subsequent immunotherapy – usually immune checkpoint inhibitors – were 32.9% and 46.4%.

“I think this is a good argument that the effects we see on overall survival and recurrence-free survival are not caused by improved second-line treatments,” Dr. Dummer said.

No new safety signals emerged during the additional year of follow-up. The trial’s final analysis will be conducted after 5 years of follow-up.

“These results build upon the prior 2-year results to support the potential beneficial effect of neoadjuvant T-VEC on advanced resectable melanoma,” Dr. Dummer said.

“In general, if you compare this to the objective outcomes that we see with neoadjuvant ipilimumab-nivolumab, for example, the results do not look very attractive,” he acknowledged.

“However, we have to keep in mind that this is a difficult patient population,” he added, noting that many patients have in-transit metastases that would disqualify them from conventional neoadjuvant therapy. Also, cross-trial comparisons are complicated by the need to allow adjuvant therapy in patients who receive neoadjuvant therapy.

“I would say the combination of ipilimumab-nivolumab should be more powerful, but T-VEC has some impact, and from my understanding, T-VEC would be a perfect partner for a combination, for example, with an anti–[programmed death 1] agent,” Dr. Dummer concluded.
 

‘Impressive’ data support more research

“Neoadjuvant approaches are gaining enthusiasm for patients with locally advanced disease that may not be amenable to simple excision or may require large disfiguring procedures,” said Howard L. Kaufman, MD, of Massachusetts General Hospital and Dana Farber/Harvard Cancer Center, both in Boston, who was not involved in this study.

© Michael Hoetzel

“A treatment option that could induce tumor regression while also promoting immune responses against the tumor is attractive,” Dr. Kaufman added.

“I continue to be impressed with this clinical trial as it demonstrates a consistent improvement in recurrence-free survival, event-free survival, and overall survival for patients treated with neoadjuvant T-VEC and surgery, compared to those who undergo surgery alone,” he said in an interview. “Confirmation that the responses are now maintained for another year is an important milestone.”

Given the study’s fairly small size, large treatment differences would be needed to attain the observed statistical significance, and “this is why the data at 3 years of follow-up is so impressive,” Dr. Kaufman said.

However, benefit of T-VEC’s activity in inducing a systemic immune response may not become fully evident until the end of the trial.

“Overall survival at 5 years is the most relevant endpoint,” Dr. Kaufman maintained.

An important aspect of the study is that it enrolled patients with a range of melanoma stages, including about 18% with stage IV M1a disease, he added.

“This could potentially influence the results, where earlier-stage patients may have a more durable response, compared to higher-stage patients and, thus, the data may be further diluted by the small sample size,” he proposed. “Given this possibility, my sense is that the data is even more impressive since there still appears to be a significant clinical benefit at 3 years, and I would recommend larger studies in patients with earlier-stage melanoma as fertile ground for further oncolytic virus drug development.”

The current trial was funded by Amgen. Dr. Dummer disclosed relationships with Amgen, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Takeda, Pierre Fabre, Sun Pharma, Sanofi, and CatalYm. Dr. Kaufman disclosed employment by Immuneering.

SOURCE: Dummer R et al. SITC 2020, Abstract 432.

Rates of cancer increased by 30% from 1973 to 2015 in adolescents and young adults (AYAs) aged 15–39 years in the United States, according to a review of almost a half million cases in the National Institutes of Health’s Surveillance, Epidemiology, and End Results database.

There was an annual increase of 0.537 new cases per 100,000 people, from 57.2 cases per 100,000 in 1973 to 74.2 in 2015.

Kidney carcinoma led with the highest rate increase. There were also marked increases in thyroid and colorectal carcinoma, germ cell and trophoblastic neoplasms, and melanoma, among others.

The report was published online December 1 in JAMA Network Open.

“Clinicians should be on the lookout for these cancers in their adolescent and young adult patients,” said senior investigator Nicholas Zaorsky, MD, an assistant professor of radiation oncology and public health sciences at the Penn State Cancer Institute, Hershey, Pennsylvania.

“Now that there is a better understanding of the types of cancer that are prevalent and rising in this age group, prevention, screening, diagnosis and treatment protocols specifically targeted to this population should be developed,” he said in a press release.

The reasons for the increases are unclear, but environmental and dietary factors, increasing obesity, and changing screening practices are likely in play, the authors comment. In addition, “cancer screening and overdiagnosis are thought to account for much of the increasing rates of thyroid and kidney carcinoma, among others,” they add.

The American Cancer Society (ACS) recently found similar increases in thyroid, kidney, and colorectal cancer among AYAs, as well as an increase in uterine cancer.

It’s important to note, however, that “this phenomenon is largely driven by trends for thyroid cancer, which is thought to be a result of overdiagnosis,” said ACS surveillance researcher Kimberly Miller, MPH, when asked to comment on the new study.

“As such, it is extremely important to also consider trends in cancer mortality rates among this age group, which are declining overall but are increasing for colorectal and uterine cancers. The fact that both incidence and mortality rates are increasing for these two cancers suggests a true increase in disease burden and certainly requires further attention and research,” she said.

Historically, management of cancer in AYAs has fallen somewhere between pediatric and adult oncology, neither of which capture the distinct biological, social, and economic needs of AYAs. Research has also focused on childhood and adult cancers, leaving cancer in AYAs inadequately studied.

The new findings are “valuable to guide more targeted research and interventions specifically to AYAs,” Zaorsky and colleagues say in their report.

Among female patients ― 59.1% of the study population ― incidence increased for 15 cancers, including kidney carcinoma (annual percent change [APC], 3.632), thyroid carcinoma (APC, 3.456), and myeloma, mast cell, and miscellaneous lymphoreticular neoplasms not otherwise specified (APC, 2.805). Rates of five cancers declined, led by astrocytoma not otherwise specified (APC, –3.369) and carcinoma of the gonads (APC, –1.743).

Among male patients, incidence increased for 14 cancers, including kidney carcinoma (APC, 3.572), unspecified soft tissue sarcoma (APC 2.543), and thyroid carcinoma (APC, 2.273). Incidence fell for seven, led by astrocytoma not otherwise specified (APC, –3.759) and carcinoma of the trachea, bronchus, and lung (APC, –2.635).

Increased testicular cancer rates (APC, 1.246) could be related to greater prenatal exposure to estrogen and progesterone or through dairy consumption; increasing survival of premature infants; and greater exposure to cannabis, among other possibilities, the investigators say.

Increases in colorectal cancer might be related to fewer vegetables and more fat and processed meat in the diet; lack of exercise; and increasing obesity. Human papillomavirus infection has also been implicated.

Higher rates of melanoma could be related to tanning bed use.

Declines in some cancers could be related to greater use of oral contraceptives; laws reducing exposure to benzene and other chemicals; and fewer people smoking.

Although kidney carcinoma has increased at the greatest rate, it’s uncommon. Colorectal and thyroid carcinoma, melanoma, non-Hodgkin lymphoma, and germ cell and trophoblastic neoplasms of the gonads contribute more to the overall increase in cancers among AYAs, the investigators note.

Almost 80% of the patients were White; 10.3% were Black.

The study was funded by the National Center for Advancing Translational Sciences. The investigators have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Rates of cancer increased by 30% from 1973 to 2015 in adolescents and young adults (AYAs) aged 15–39 years in the United States, according to a review of almost a half million cases in the National Institutes of Health’s Surveillance, Epidemiology, and End Results database.

There was an annual increase of 0.537 new cases per 100,000 people, from 57.2 cases per 100,000 in 1973 to 74.2 in 2015.

Kidney carcinoma led with the highest rate increase. There were also marked increases in thyroid and colorectal carcinoma, germ cell and trophoblastic neoplasms, and melanoma, among others.

The report was published online December 1 in JAMA Network Open.

“Clinicians should be on the lookout for these cancers in their adolescent and young adult patients,” said senior investigator Nicholas Zaorsky, MD, an assistant professor of radiation oncology and public health sciences at the Penn State Cancer Institute, Hershey, Pennsylvania.

“Now that there is a better understanding of the types of cancer that are prevalent and rising in this age group, prevention, screening, diagnosis and treatment protocols specifically targeted to this population should be developed,” he said in a press release.

The reasons for the increases are unclear, but environmental and dietary factors, increasing obesity, and changing screening practices are likely in play, the authors comment. In addition, “cancer screening and overdiagnosis are thought to account for much of the increasing rates of thyroid and kidney carcinoma, among others,” they add.

The American Cancer Society (ACS) recently found similar increases in thyroid, kidney, and colorectal cancer among AYAs, as well as an increase in uterine cancer.

It’s important to note, however, that “this phenomenon is largely driven by trends for thyroid cancer, which is thought to be a result of overdiagnosis,” said ACS surveillance researcher Kimberly Miller, MPH, when asked to comment on the new study.

“As such, it is extremely important to also consider trends in cancer mortality rates among this age group, which are declining overall but are increasing for colorectal and uterine cancers. The fact that both incidence and mortality rates are increasing for these two cancers suggests a true increase in disease burden and certainly requires further attention and research,” she said.

Historically, management of cancer in AYAs has fallen somewhere between pediatric and adult oncology, neither of which capture the distinct biological, social, and economic needs of AYAs. Research has also focused on childhood and adult cancers, leaving cancer in AYAs inadequately studied.

The new findings are “valuable to guide more targeted research and interventions specifically to AYAs,” Zaorsky and colleagues say in their report.

Among female patients ― 59.1% of the study population ― incidence increased for 15 cancers, including kidney carcinoma (annual percent change [APC], 3.632), thyroid carcinoma (APC, 3.456), and myeloma, mast cell, and miscellaneous lymphoreticular neoplasms not otherwise specified (APC, 2.805). Rates of five cancers declined, led by astrocytoma not otherwise specified (APC, –3.369) and carcinoma of the gonads (APC, –1.743).

Among male patients, incidence increased for 14 cancers, including kidney carcinoma (APC, 3.572), unspecified soft tissue sarcoma (APC 2.543), and thyroid carcinoma (APC, 2.273). Incidence fell for seven, led by astrocytoma not otherwise specified (APC, –3.759) and carcinoma of the trachea, bronchus, and lung (APC, –2.635).

Increased testicular cancer rates (APC, 1.246) could be related to greater prenatal exposure to estrogen and progesterone or through dairy consumption; increasing survival of premature infants; and greater exposure to cannabis, among other possibilities, the investigators say.

Increases in colorectal cancer might be related to fewer vegetables and more fat and processed meat in the diet; lack of exercise; and increasing obesity. Human papillomavirus infection has also been implicated.

Higher rates of melanoma could be related to tanning bed use.

Declines in some cancers could be related to greater use of oral contraceptives; laws reducing exposure to benzene and other chemicals; and fewer people smoking.

Although kidney carcinoma has increased at the greatest rate, it’s uncommon. Colorectal and thyroid carcinoma, melanoma, non-Hodgkin lymphoma, and germ cell and trophoblastic neoplasms of the gonads contribute more to the overall increase in cancers among AYAs, the investigators note.

Almost 80% of the patients were White; 10.3% were Black.

The study was funded by the National Center for Advancing Translational Sciences. The investigators have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Rates of cancer increased by 30% from 1973 to 2015 in adolescents and young adults (AYAs) aged 15–39 years in the United States, according to a review of almost a half million cases in the National Institutes of Health’s Surveillance, Epidemiology, and End Results database.

There was an annual increase of 0.537 new cases per 100,000 people, from 57.2 cases per 100,000 in 1973 to 74.2 in 2015.

Kidney carcinoma led with the highest rate increase. There were also marked increases in thyroid and colorectal carcinoma, germ cell and trophoblastic neoplasms, and melanoma, among others.

The report was published online December 1 in JAMA Network Open.

“Clinicians should be on the lookout for these cancers in their adolescent and young adult patients,” said senior investigator Nicholas Zaorsky, MD, an assistant professor of radiation oncology and public health sciences at the Penn State Cancer Institute, Hershey, Pennsylvania.

“Now that there is a better understanding of the types of cancer that are prevalent and rising in this age group, prevention, screening, diagnosis and treatment protocols specifically targeted to this population should be developed,” he said in a press release.

The reasons for the increases are unclear, but environmental and dietary factors, increasing obesity, and changing screening practices are likely in play, the authors comment. In addition, “cancer screening and overdiagnosis are thought to account for much of the increasing rates of thyroid and kidney carcinoma, among others,” they add.

The American Cancer Society (ACS) recently found similar increases in thyroid, kidney, and colorectal cancer among AYAs, as well as an increase in uterine cancer.

It’s important to note, however, that “this phenomenon is largely driven by trends for thyroid cancer, which is thought to be a result of overdiagnosis,” said ACS surveillance researcher Kimberly Miller, MPH, when asked to comment on the new study.

“As such, it is extremely important to also consider trends in cancer mortality rates among this age group, which are declining overall but are increasing for colorectal and uterine cancers. The fact that both incidence and mortality rates are increasing for these two cancers suggests a true increase in disease burden and certainly requires further attention and research,” she said.

Historically, management of cancer in AYAs has fallen somewhere between pediatric and adult oncology, neither of which capture the distinct biological, social, and economic needs of AYAs. Research has also focused on childhood and adult cancers, leaving cancer in AYAs inadequately studied.

The new findings are “valuable to guide more targeted research and interventions specifically to AYAs,” Zaorsky and colleagues say in their report.

Among female patients ― 59.1% of the study population ― incidence increased for 15 cancers, including kidney carcinoma (annual percent change [APC], 3.632), thyroid carcinoma (APC, 3.456), and myeloma, mast cell, and miscellaneous lymphoreticular neoplasms not otherwise specified (APC, 2.805). Rates of five cancers declined, led by astrocytoma not otherwise specified (APC, –3.369) and carcinoma of the gonads (APC, –1.743).

Among male patients, incidence increased for 14 cancers, including kidney carcinoma (APC, 3.572), unspecified soft tissue sarcoma (APC 2.543), and thyroid carcinoma (APC, 2.273). Incidence fell for seven, led by astrocytoma not otherwise specified (APC, –3.759) and carcinoma of the trachea, bronchus, and lung (APC, –2.635).

Increased testicular cancer rates (APC, 1.246) could be related to greater prenatal exposure to estrogen and progesterone or through dairy consumption; increasing survival of premature infants; and greater exposure to cannabis, among other possibilities, the investigators say.

Increases in colorectal cancer might be related to fewer vegetables and more fat and processed meat in the diet; lack of exercise; and increasing obesity. Human papillomavirus infection has also been implicated.

Higher rates of melanoma could be related to tanning bed use.

Declines in some cancers could be related to greater use of oral contraceptives; laws reducing exposure to benzene and other chemicals; and fewer people smoking.

Although kidney carcinoma has increased at the greatest rate, it’s uncommon. Colorectal and thyroid carcinoma, melanoma, non-Hodgkin lymphoma, and germ cell and trophoblastic neoplasms of the gonads contribute more to the overall increase in cancers among AYAs, the investigators note.

Almost 80% of the patients were White; 10.3% were Black.

The study was funded by the National Center for Advancing Translational Sciences. The investigators have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The dramatic advances in targeted therapies for late-stage melanoma capture the headlines, but a recent Australian study quietly concluded that the most cost-effective way to lower both the incidence of melanoma and deaths caused by the malignancy over the long haul is through primary prevention in the form of daily sunscreen use, according to Laura Korb Ferris, MD, PhD, a dermatologist and director of clinical trials in the department of dermatology at the University of Pittsburgh.

Wavebreakmedia Ltd/Thinkstock

“I think it’s really important that we recognize the importance of preventing skin cancer, and not just early detection, not just treatment of late disease,” Dr. Ferris said at a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.

She highlighted the Australian cost-effectiveness analysis, which used Markov modeling of data from two published population-based, randomized controlled trials carried out in Queensland, Australia.

The cost-effectiveness study compared the estimated long-term impact of three different approaches to control of melanoma: a primary prevention strategy, which basically consisted of promoting daily sunscreen use and other forms of sun protection; early detection through annual whole-body skin examinations by physicians starting at age 50; and no intervention. The analysis provided estimates of the number of cases of melanoma, deaths caused by melanoma, nonmelanoma skin cancers, and quality of life outcomes over the course of 30 years starting in 50-year-old men and women.

Primary prevention through sun protection was the clear winner, as shown by the results:

• A 44% reduction in the incidence of melanoma, compared with early detection via annual physician skin examinations.
• A 39% reduction in projected melanoma deaths compared with early detection, which in turn achieved only a 2% reduction when compared with no intervention.
• 27% fewer keratinocyte cancers excised than with annual skin examinations.
• A 21.7% reduction in societal costs, compared with an early-detection program.

Daily sunscreen use for primary prevention was also associated with a modest 0.1% increase in quality-adjusted life-years. “Prevention is low cost, low risk, and effective,” Dr. Ferris observed.

The investigators noted that, while residents of the Australian state of Queensland are mainly fair-skinned and confront high UV radiation levels throughout the year, somewhat limiting the generalizability of the study findings, the relationships between the costs of interventional strategies and their outcomes should be proportional in other countries.

True enough, but a strategy of annual skin examinations starting at age 50 years as modeled in the Australian study is not the most productive way to conduct a melanoma early-detection program, Dr. Ferris said. She noted that data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program show that the median age at diagnosis of melanoma in the United States is 65 years, while the median age at death caused by the malignancy is 71 years. That information is helpful in formulating strategies to improve early detection through more focused, higher-yield screening.

UPMC

Case in point: European investigators have estimated that, by screening everyone age 50 years and older, 475 people need to be screened and an average of 19.6 lesions must be biopsied in order to detect one melanoma. But by reserving screening for those age 50 years and up who have any one of three risk factors – a personal history of melanoma, atypical nevi, or at least 40 common nevi – those numbers drop dramatically: 98 people need to be screened and 13.5 lesions biopsied to detect one melanoma. And by further narrowing the screened population to those age 65 years or older with any of the three risk factors, 63 seniors would need to be screened and 9.2 lesions excised to find one melanoma.

Total-body skin examinations are time-consuming for dermatologists. In a recent U.S. study, investigators determined that the additional face-to-face time required per skin cancer detected by doing a total-body skin exam in adults who present to a dermatologist for another reason is 4.5 hours. And that’s just the time involved in detecting any type of skin cancer.

“To get that number for melanoma, multiply by 15 to 20,” Dr. Ferris said.

The investigators also determined that, for each decade of advancing age and increment in lighter skin phototype, the number-needed-to-examine in order to identify one skin cancer of any type decreased.

“By focusing on patients who are older and have fair skin types we can get that time down to about 1 hour,” commented Dr. Ferris, who penned an editorial perspective on the study.

While many dermatologists recommend that people with a high common nevus count undergo frequent screening for melanoma because they are at particularly high risk for invasive disease, a couple of recent studies challenge that notion, she pointed out. One was a retrospective study of 326 consecutive new melanoma patients which found that patients with a higher nevus count had thinner melanomas and a greater likelihood of in situ melanoma. Patients who presented with invasive melanoma had a mean total nevus count of 31.5 lesions, while those with in situ melanoma averaged 57.2 nevi. Each additional nevus was associated with a 4% reduction in the likelihood of invasive melanoma, independent of age and sex.

The other study included 566 newly diagnosed melanoma patients in two U.S. centers. Among the 56% of patients who were younger than 60 years, those who had more than 50 total nevi were 68% less likely to have a thick melanoma in a logistic regression analysis that controlled for demographic factors, as well as anatomic location of the melanoma, histologic subtype, and skin cancer screening frequency. In contrast, younger patients with more than 5 atypical nevi were 2.43-fold more likely to have thicker melanomas than were those with no such lesions. The lesson, according to the investigators, is that total nevus count isn’t a reliable determinant of a patient’s risk status or the need for skin examinations.

Dr. Ferris reported no financial conflicts of interest regarding her presentation.

Global Academy for Medical Education and this news organization are owned by the same company.

bjancin@mdedge.com

The dramatic advances in targeted therapies for late-stage melanoma capture the headlines, but a recent Australian study quietly concluded that the most cost-effective way to lower both the incidence of melanoma and deaths caused by the malignancy over the long haul is through primary prevention in the form of daily sunscreen use, according to Laura Korb Ferris, MD, PhD, a dermatologist and director of clinical trials in the department of dermatology at the University of Pittsburgh.

Wavebreakmedia Ltd/Thinkstock

“I think it’s really important that we recognize the importance of preventing skin cancer, and not just early detection, not just treatment of late disease,” Dr. Ferris said at a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.

She highlighted the Australian cost-effectiveness analysis, which used Markov modeling of data from two published population-based, randomized controlled trials carried out in Queensland, Australia.

The cost-effectiveness study compared the estimated long-term impact of three different approaches to control of melanoma: a primary prevention strategy, which basically consisted of promoting daily sunscreen use and other forms of sun protection; early detection through annual whole-body skin examinations by physicians starting at age 50; and no intervention. The analysis provided estimates of the number of cases of melanoma, deaths caused by melanoma, nonmelanoma skin cancers, and quality of life outcomes over the course of 30 years starting in 50-year-old men and women.

Primary prevention through sun protection was the clear winner, as shown by the results:

• A 44% reduction in the incidence of melanoma, compared with early detection via annual physician skin examinations.
• A 39% reduction in projected melanoma deaths compared with early detection, which in turn achieved only a 2% reduction when compared with no intervention.
• 27% fewer keratinocyte cancers excised than with annual skin examinations.
• A 21.7% reduction in societal costs, compared with an early-detection program.

Daily sunscreen use for primary prevention was also associated with a modest 0.1% increase in quality-adjusted life-years. “Prevention is low cost, low risk, and effective,” Dr. Ferris observed.

The investigators noted that, while residents of the Australian state of Queensland are mainly fair-skinned and confront high UV radiation levels throughout the year, somewhat limiting the generalizability of the study findings, the relationships between the costs of interventional strategies and their outcomes should be proportional in other countries.

True enough, but a strategy of annual skin examinations starting at age 50 years as modeled in the Australian study is not the most productive way to conduct a melanoma early-detection program, Dr. Ferris said. She noted that data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program show that the median age at diagnosis of melanoma in the United States is 65 years, while the median age at death caused by the malignancy is 71 years. That information is helpful in formulating strategies to improve early detection through more focused, higher-yield screening.

UPMC

Case in point: European investigators have estimated that, by screening everyone age 50 years and older, 475 people need to be screened and an average of 19.6 lesions must be biopsied in order to detect one melanoma. But by reserving screening for those age 50 years and up who have any one of three risk factors – a personal history of melanoma, atypical nevi, or at least 40 common nevi – those numbers drop dramatically: 98 people need to be screened and 13.5 lesions biopsied to detect one melanoma. And by further narrowing the screened population to those age 65 years or older with any of the three risk factors, 63 seniors would need to be screened and 9.2 lesions excised to find one melanoma.

Total-body skin examinations are time-consuming for dermatologists. In a recent U.S. study, investigators determined that the additional face-to-face time required per skin cancer detected by doing a total-body skin exam in adults who present to a dermatologist for another reason is 4.5 hours. And that’s just the time involved in detecting any type of skin cancer.

“To get that number for melanoma, multiply by 15 to 20,” Dr. Ferris said.

The investigators also determined that, for each decade of advancing age and increment in lighter skin phototype, the number-needed-to-examine in order to identify one skin cancer of any type decreased.

“By focusing on patients who are older and have fair skin types we can get that time down to about 1 hour,” commented Dr. Ferris, who penned an editorial perspective on the study.

While many dermatologists recommend that people with a high common nevus count undergo frequent screening for melanoma because they are at particularly high risk for invasive disease, a couple of recent studies challenge that notion, she pointed out. One was a retrospective study of 326 consecutive new melanoma patients which found that patients with a higher nevus count had thinner melanomas and a greater likelihood of in situ melanoma. Patients who presented with invasive melanoma had a mean total nevus count of 31.5 lesions, while those with in situ melanoma averaged 57.2 nevi. Each additional nevus was associated with a 4% reduction in the likelihood of invasive melanoma, independent of age and sex.

The other study included 566 newly diagnosed melanoma patients in two U.S. centers. Among the 56% of patients who were younger than 60 years, those who had more than 50 total nevi were 68% less likely to have a thick melanoma in a logistic regression analysis that controlled for demographic factors, as well as anatomic location of the melanoma, histologic subtype, and skin cancer screening frequency. In contrast, younger patients with more than 5 atypical nevi were 2.43-fold more likely to have thicker melanomas than were those with no such lesions. The lesson, according to the investigators, is that total nevus count isn’t a reliable determinant of a patient’s risk status or the need for skin examinations.

Dr. Ferris reported no financial conflicts of interest regarding her presentation.

Global Academy for Medical Education and this news organization are owned by the same company.

bjancin@mdedge.com

The dramatic advances in targeted therapies for late-stage melanoma capture the headlines, but a recent Australian study quietly concluded that the most cost-effective way to lower both the incidence of melanoma and deaths caused by the malignancy over the long haul is through primary prevention in the form of daily sunscreen use, according to Laura Korb Ferris, MD, PhD, a dermatologist and director of clinical trials in the department of dermatology at the University of Pittsburgh.

Wavebreakmedia Ltd/Thinkstock

“I think it’s really important that we recognize the importance of preventing skin cancer, and not just early detection, not just treatment of late disease,” Dr. Ferris said at a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.

She highlighted the Australian cost-effectiveness analysis, which used Markov modeling of data from two published population-based, randomized controlled trials carried out in Queensland, Australia.

The cost-effectiveness study compared the estimated long-term impact of three different approaches to control of melanoma: a primary prevention strategy, which basically consisted of promoting daily sunscreen use and other forms of sun protection; early detection through annual whole-body skin examinations by physicians starting at age 50; and no intervention. The analysis provided estimates of the number of cases of melanoma, deaths caused by melanoma, nonmelanoma skin cancers, and quality of life outcomes over the course of 30 years starting in 50-year-old men and women.

Primary prevention through sun protection was the clear winner, as shown by the results:

• A 44% reduction in the incidence of melanoma, compared with early detection via annual physician skin examinations.
• A 39% reduction in projected melanoma deaths compared with early detection, which in turn achieved only a 2% reduction when compared with no intervention.
• 27% fewer keratinocyte cancers excised than with annual skin examinations.
• A 21.7% reduction in societal costs, compared with an early-detection program.

Daily sunscreen use for primary prevention was also associated with a modest 0.1% increase in quality-adjusted life-years. “Prevention is low cost, low risk, and effective,” Dr. Ferris observed.

The investigators noted that, while residents of the Australian state of Queensland are mainly fair-skinned and confront high UV radiation levels throughout the year, somewhat limiting the generalizability of the study findings, the relationships between the costs of interventional strategies and their outcomes should be proportional in other countries.

True enough, but a strategy of annual skin examinations starting at age 50 years as modeled in the Australian study is not the most productive way to conduct a melanoma early-detection program, Dr. Ferris said. She noted that data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program show that the median age at diagnosis of melanoma in the United States is 65 years, while the median age at death caused by the malignancy is 71 years. That information is helpful in formulating strategies to improve early detection through more focused, higher-yield screening.

UPMC

Case in point: European investigators have estimated that, by screening everyone age 50 years and older, 475 people need to be screened and an average of 19.6 lesions must be biopsied in order to detect one melanoma. But by reserving screening for those age 50 years and up who have any one of three risk factors – a personal history of melanoma, atypical nevi, or at least 40 common nevi – those numbers drop dramatically: 98 people need to be screened and 13.5 lesions biopsied to detect one melanoma. And by further narrowing the screened population to those age 65 years or older with any of the three risk factors, 63 seniors would need to be screened and 9.2 lesions excised to find one melanoma.

Total-body skin examinations are time-consuming for dermatologists. In a recent U.S. study, investigators determined that the additional face-to-face time required per skin cancer detected by doing a total-body skin exam in adults who present to a dermatologist for another reason is 4.5 hours. And that’s just the time involved in detecting any type of skin cancer.

“To get that number for melanoma, multiply by 15 to 20,” Dr. Ferris said.

The investigators also determined that, for each decade of advancing age and increment in lighter skin phototype, the number-needed-to-examine in order to identify one skin cancer of any type decreased.

“By focusing on patients who are older and have fair skin types we can get that time down to about 1 hour,” commented Dr. Ferris, who penned an editorial perspective on the study.

While many dermatologists recommend that people with a high common nevus count undergo frequent screening for melanoma because they are at particularly high risk for invasive disease, a couple of recent studies challenge that notion, she pointed out. One was a retrospective study of 326 consecutive new melanoma patients which found that patients with a higher nevus count had thinner melanomas and a greater likelihood of in situ melanoma. Patients who presented with invasive melanoma had a mean total nevus count of 31.5 lesions, while those with in situ melanoma averaged 57.2 nevi. Each additional nevus was associated with a 4% reduction in the likelihood of invasive melanoma, independent of age and sex.

The other study included 566 newly diagnosed melanoma patients in two U.S. centers. Among the 56% of patients who were younger than 60 years, those who had more than 50 total nevi were 68% less likely to have a thick melanoma in a logistic regression analysis that controlled for demographic factors, as well as anatomic location of the melanoma, histologic subtype, and skin cancer screening frequency. In contrast, younger patients with more than 5 atypical nevi were 2.43-fold more likely to have thicker melanomas than were those with no such lesions. The lesson, according to the investigators, is that total nevus count isn’t a reliable determinant of a patient’s risk status or the need for skin examinations.

Dr. Ferris reported no financial conflicts of interest regarding her presentation.

Global Academy for Medical Education and this news organization are owned by the same company.

bjancin@mdedge.com

To the Editor:

A 32-year-old man presented to the dermatology clinic with multiple asymptomatic blue lesions on the arms and upper torso of 15 years’ duration. His medical history was notable for a recent diagnosis of malignant melanoma following excision of a mole on the upper back 4 months prior. He reported that the mole had been present since childhood, but his sister noticed that it increased in size and changed in color over the course of a year. Physical examination showed multiple blue subcutaneous nodules on the bilateral arms and lower back. The nodules were soft and nontender, and some had telangiectasia on the overlying skin.

Given the atypical distribution of nodules and the patient’s recent history of melanoma, there was concern for cutaneous metastases. A punch biopsy of one of the nodules on the right upper arm was performed. Microscopic examination of the biopsy specimen revealed a proliferation of multiple cavernous vessels surrounded by several rows of monotonous round cells with moderate eosinophilic cytoplasm and monomorphic nuclei, which was consistent with a diagnosis of glomangioma (Figure 1). Immunohistochemical analysis showed diffuse positive staining for smooth muscle actin (Figure 2); CD34 immunostain was positive in endothelial cells and negative in tumor cells (Figure 3).

Glomus tumors arise from modified smooth muscle cells located in glomus bodies. The glomus body is a component of the dermis involved in regulation of body temperature that is composed of an afferent arteriole and an efferent venule. The arterial end of this apparatus, known as the Sucquet-Hoyer canal, is surrounded by glomus cells that have a contractile capability similar to smooth muscle cells. Glomus tumors usually present as painful masses on the fingers with a typical subungual location and almost always are solitary.¹ Glomangiomas, sometimes known as glomuvenous malformations, tend to be larger and usually are painless. They mostly are found on the trunk and extremities and can appear in groups.^2,3 Histopathologically, glomus tumors are circumscribed lesions that show a predominance of glomus cells surrounding inconspicuous blood vessels. Glomangiomas are less well-circumscribed and show a more vascular architecture with prominent dilated vessels and a smaller number of glomus cells.⁴

We present a case of a patient with multiple glomangiomas. There are few reports of multiple glomangiomas in the literature. This case is particularly interesting in that our patient had a history of malignant melanoma, and there was a concern for skin metastases. Despite the patient’s personal history of blue lesions that predated the diagnosis of melanoma for many years, we could not exclude the possibility of cutaneous metastases without performing biopsies.

Tumors of glomus cell origin usually are benign. It has been suggested to replace the term glomangioma with glomuvenous malformations to emphasize the hamartomatous nature of these lesions.⁵ Glomuvenous malformations, or glomangiomas, can occur sporadically or can be inherited as a familial disorder. Inheritable glomangioma has been linked to the chromosome 1p21-22 locus and mutations in the glomulin gene, GLMN, with variable penetrance.⁶ Our patient did not report a family history of such lesions.

Glomangiomas typically are solitary but rarely can present as multiple lesions in fewer than 10% of cases.⁷ Multiple glomangiomas are classified into 3 subtypes: localized, disseminated, and congenital plaque type. Localized multiple glomangiomas present as blue nodules confined to 1 anatomic location such as the hand or arm. Disseminated glomangiomas are more widely distributed and involve more than 1 anatomic location.⁸ Plaque-type glomangiomas consist of numerous confluent lesions occurring either as solitary or multiple plaques.² Clinically, glomangiomas manifest as painless to mildly painful cutaneous nodules. Compared to venous malformations, glomangiomas are less compressible under external pressure.

Histopathologically, glomangiomas appear as nonencapsulated tumors with large, irregular, prominent vessels lined by glomus cells. Glomus cells may be so sparse that the distinction from venous malformations and hemangiomas becomes difficult. Immunohistochemistry can play an important role in diagnosis. As modified smooth muscle cells, glomus cells stain positive with a-smooth muscle actin, while CD34 highlights the vascular endothelium.¹The clinical differential diagnosis of multiple blue or violaceous subcutaneous nodules includes blue rubber bleb nevus syndrome, Maffucci syndrome, glomus tumor, pyogenic granuloma, hemangioma, spiradenoma, angiolipoma, leiomyoma, or hemangiopericytoma.^9-12

Different treatment modalities are available for solitary glomangiomas, including surgical excision, sclerotherapy, and laser application. Treatment of multiple glomangiomas may not be feasible, and excision of isolated symptomatic lesions may be the only option; however, it is crucial to reach the correct diagnosis in these patients to avoid improper treatments and interventions.

To the Editor:

A 32-year-old man presented to the dermatology clinic with multiple asymptomatic blue lesions on the arms and upper torso of 15 years’ duration. His medical history was notable for a recent diagnosis of malignant melanoma following excision of a mole on the upper back 4 months prior. He reported that the mole had been present since childhood, but his sister noticed that it increased in size and changed in color over the course of a year. Physical examination showed multiple blue subcutaneous nodules on the bilateral arms and lower back. The nodules were soft and nontender, and some had telangiectasia on the overlying skin.

Given the atypical distribution of nodules and the patient’s recent history of melanoma, there was concern for cutaneous metastases. A punch biopsy of one of the nodules on the right upper arm was performed. Microscopic examination of the biopsy specimen revealed a proliferation of multiple cavernous vessels surrounded by several rows of monotonous round cells with moderate eosinophilic cytoplasm and monomorphic nuclei, which was consistent with a diagnosis of glomangioma (Figure 1). Immunohistochemical analysis showed diffuse positive staining for smooth muscle actin (Figure 2); CD34 immunostain was positive in endothelial cells and negative in tumor cells (Figure 3).

Glomus tumors arise from modified smooth muscle cells located in glomus bodies. The glomus body is a component of the dermis involved in regulation of body temperature that is composed of an afferent arteriole and an efferent venule. The arterial end of this apparatus, known as the Sucquet-Hoyer canal, is surrounded by glomus cells that have a contractile capability similar to smooth muscle cells. Glomus tumors usually present as painful masses on the fingers with a typical subungual location and almost always are solitary.¹ Glomangiomas, sometimes known as glomuvenous malformations, tend to be larger and usually are painless. They mostly are found on the trunk and extremities and can appear in groups.^2,3 Histopathologically, glomus tumors are circumscribed lesions that show a predominance of glomus cells surrounding inconspicuous blood vessels. Glomangiomas are less well-circumscribed and show a more vascular architecture with prominent dilated vessels and a smaller number of glomus cells.⁴

We present a case of a patient with multiple glomangiomas. There are few reports of multiple glomangiomas in the literature. This case is particularly interesting in that our patient had a history of malignant melanoma, and there was a concern for skin metastases. Despite the patient’s personal history of blue lesions that predated the diagnosis of melanoma for many years, we could not exclude the possibility of cutaneous metastases without performing biopsies.

Tumors of glomus cell origin usually are benign. It has been suggested to replace the term glomangioma with glomuvenous malformations to emphasize the hamartomatous nature of these lesions.⁵ Glomuvenous malformations, or glomangiomas, can occur sporadically or can be inherited as a familial disorder. Inheritable glomangioma has been linked to the chromosome 1p21-22 locus and mutations in the glomulin gene, GLMN, with variable penetrance.⁶ Our patient did not report a family history of such lesions.

Glomangiomas typically are solitary but rarely can present as multiple lesions in fewer than 10% of cases.⁷ Multiple glomangiomas are classified into 3 subtypes: localized, disseminated, and congenital plaque type. Localized multiple glomangiomas present as blue nodules confined to 1 anatomic location such as the hand or arm. Disseminated glomangiomas are more widely distributed and involve more than 1 anatomic location.⁸ Plaque-type glomangiomas consist of numerous confluent lesions occurring either as solitary or multiple plaques.² Clinically, glomangiomas manifest as painless to mildly painful cutaneous nodules. Compared to venous malformations, glomangiomas are less compressible under external pressure.

Histopathologically, glomangiomas appear as nonencapsulated tumors with large, irregular, prominent vessels lined by glomus cells. Glomus cells may be so sparse that the distinction from venous malformations and hemangiomas becomes difficult. Immunohistochemistry can play an important role in diagnosis. As modified smooth muscle cells, glomus cells stain positive with a-smooth muscle actin, while CD34 highlights the vascular endothelium.¹The clinical differential diagnosis of multiple blue or violaceous subcutaneous nodules includes blue rubber bleb nevus syndrome, Maffucci syndrome, glomus tumor, pyogenic granuloma, hemangioma, spiradenoma, angiolipoma, leiomyoma, or hemangiopericytoma.^9-12

Different treatment modalities are available for solitary glomangiomas, including surgical excision, sclerotherapy, and laser application. Treatment of multiple glomangiomas may not be feasible, and excision of isolated symptomatic lesions may be the only option; however, it is crucial to reach the correct diagnosis in these patients to avoid improper treatments and interventions.

To the Editor:

A 32-year-old man presented to the dermatology clinic with multiple asymptomatic blue lesions on the arms and upper torso of 15 years’ duration. His medical history was notable for a recent diagnosis of malignant melanoma following excision of a mole on the upper back 4 months prior. He reported that the mole had been present since childhood, but his sister noticed that it increased in size and changed in color over the course of a year. Physical examination showed multiple blue subcutaneous nodules on the bilateral arms and lower back. The nodules were soft and nontender, and some had telangiectasia on the overlying skin.

Given the atypical distribution of nodules and the patient’s recent history of melanoma, there was concern for cutaneous metastases. A punch biopsy of one of the nodules on the right upper arm was performed. Microscopic examination of the biopsy specimen revealed a proliferation of multiple cavernous vessels surrounded by several rows of monotonous round cells with moderate eosinophilic cytoplasm and monomorphic nuclei, which was consistent with a diagnosis of glomangioma (Figure 1). Immunohistochemical analysis showed diffuse positive staining for smooth muscle actin (Figure 2); CD34 immunostain was positive in endothelial cells and negative in tumor cells (Figure 3).

Glomus tumors arise from modified smooth muscle cells located in glomus bodies. The glomus body is a component of the dermis involved in regulation of body temperature that is composed of an afferent arteriole and an efferent venule. The arterial end of this apparatus, known as the Sucquet-Hoyer canal, is surrounded by glomus cells that have a contractile capability similar to smooth muscle cells. Glomus tumors usually present as painful masses on the fingers with a typical subungual location and almost always are solitary.¹ Glomangiomas, sometimes known as glomuvenous malformations, tend to be larger and usually are painless. They mostly are found on the trunk and extremities and can appear in groups.^2,3 Histopathologically, glomus tumors are circumscribed lesions that show a predominance of glomus cells surrounding inconspicuous blood vessels. Glomangiomas are less well-circumscribed and show a more vascular architecture with prominent dilated vessels and a smaller number of glomus cells.⁴

We present a case of a patient with multiple glomangiomas. There are few reports of multiple glomangiomas in the literature. This case is particularly interesting in that our patient had a history of malignant melanoma, and there was a concern for skin metastases. Despite the patient’s personal history of blue lesions that predated the diagnosis of melanoma for many years, we could not exclude the possibility of cutaneous metastases without performing biopsies.

Tumors of glomus cell origin usually are benign. It has been suggested to replace the term glomangioma with glomuvenous malformations to emphasize the hamartomatous nature of these lesions.⁵ Glomuvenous malformations, or glomangiomas, can occur sporadically or can be inherited as a familial disorder. Inheritable glomangioma has been linked to the chromosome 1p21-22 locus and mutations in the glomulin gene, GLMN, with variable penetrance.⁶ Our patient did not report a family history of such lesions.

Glomangiomas typically are solitary but rarely can present as multiple lesions in fewer than 10% of cases.⁷ Multiple glomangiomas are classified into 3 subtypes: localized, disseminated, and congenital plaque type. Localized multiple glomangiomas present as blue nodules confined to 1 anatomic location such as the hand or arm. Disseminated glomangiomas are more widely distributed and involve more than 1 anatomic location.⁸ Plaque-type glomangiomas consist of numerous confluent lesions occurring either as solitary or multiple plaques.² Clinically, glomangiomas manifest as painless to mildly painful cutaneous nodules. Compared to venous malformations, glomangiomas are less compressible under external pressure.

Histopathologically, glomangiomas appear as nonencapsulated tumors with large, irregular, prominent vessels lined by glomus cells. Glomus cells may be so sparse that the distinction from venous malformations and hemangiomas becomes difficult. Immunohistochemistry can play an important role in diagnosis. As modified smooth muscle cells, glomus cells stain positive with a-smooth muscle actin, while CD34 highlights the vascular endothelium.¹The clinical differential diagnosis of multiple blue or violaceous subcutaneous nodules includes blue rubber bleb nevus syndrome, Maffucci syndrome, glomus tumor, pyogenic granuloma, hemangioma, spiradenoma, angiolipoma, leiomyoma, or hemangiopericytoma.^9-12

Different treatment modalities are available for solitary glomangiomas, including surgical excision, sclerotherapy, and laser application. Treatment of multiple glomangiomas may not be feasible, and excision of isolated symptomatic lesions may be the only option; however, it is crucial to reach the correct diagnosis in these patients to avoid improper treatments and interventions.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.

A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.

The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.

CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.

These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.

“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
 

Patients, treatment, and response

The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.

The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.

At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.

“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”

Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
 

Survival and safety

Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).

The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.

Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.

Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
 

Another treatment option?

“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.

“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.

However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.

Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.

The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.

SOURCE: Davar D et al. SITC 2020, Abstract 303.

A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.

The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.

CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.

These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.

“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
 

Patients, treatment, and response

The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.

The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.

At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.

“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”

Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
 

Survival and safety

Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).

The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.

Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.

Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
 

Another treatment option?

“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.

“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.

However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.

Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.

The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.

SOURCE: Davar D et al. SITC 2020, Abstract 303.

A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.

The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.

CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.

These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.

“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
 

Patients, treatment, and response

The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.

The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.

At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.

“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”

Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
 

Survival and safety

Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).

The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.

Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.

Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
 

Another treatment option?

“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.

“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.

However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.

Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.

The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.

SOURCE: Davar D et al. SITC 2020, Abstract 303.