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The push for smaller, smarter cancer trials
The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.
The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.
For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).
Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.
Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.
The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.
"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."
Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.
"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."
To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.
"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."
QOL
Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.
"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."
Breast cancer
For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.
Lung cancer
The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.
Colon cancer
The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.
Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.
"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.
She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.
Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."
Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.
The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.
The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.
For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).
Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.
Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.
The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.
"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."
Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.
"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."
To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.
"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."
QOL
Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.
"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."
Breast cancer
For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.
Lung cancer
The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.
Colon cancer
The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.
Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.
"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.
She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.
Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."
Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.
The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.
The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.
For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).
Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.
Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.
The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.
"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."
Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.
"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."
To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.
"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."
QOL
Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.
"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."
Breast cancer
For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.
Lung cancer
The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.
Colon cancer
The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.
Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.
"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.
She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.
Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."
Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
AAD 2014 sessions offer something for everyone
The American Academy’s 2014 annual meeting in Denver will feature new CME sessions and updates on the latest dermatology research.
This year’s program features expert commentary on key issues in medical dermatology, including "Melanoma Multidisciplinary Care 2014: What You Need to Know" on Sunday, March 23, from 1 p.m. to 3 p.m. in Room 705/707 and "Dermatologic Manifestations of New Oncology Drugs," also on Sunday, March 23, from 1 p.m. to 3 p.m. in the Mile High Ballroom 3B. Looking for the latest in aesthetic dermatology? Check out the "Advanced Botulinum Toxin" live demonstration session on Saturday, March 22, from 2 p.m. to 5 p.m. in the Bellco Theater.
There will be expert sessions on pregnancy dermatoses, cutaneous T-cell lymphoma, pediatric dermatology, skin of color, and the latest on treatments for hair and nail conditions. The full scientific session list is available online.
A series of practice management lectures includes topics such as "How to Have an Unforgettably Positive Office Visit" on Saturday, March 22, from 10:00 a.m. to 12:00 p.m. in Room 709/7111 and "Hot Buttons: Recognizing What Sets You Off and Managing Your Triggers" on Sunday, March 23, from 1:00 p.m. to 3:00 p.m. in Room 702.
There is also a mobile device app that meeting attendees can download that contains session schedules, exhibitor and attendee lists, and more.
Can’t attend the meeting? Visit www.eDermatologyNews.com for live conference coverage.
On Twitter @Sknews
The American Academy’s 2014 annual meeting in Denver will feature new CME sessions and updates on the latest dermatology research.
This year’s program features expert commentary on key issues in medical dermatology, including "Melanoma Multidisciplinary Care 2014: What You Need to Know" on Sunday, March 23, from 1 p.m. to 3 p.m. in Room 705/707 and "Dermatologic Manifestations of New Oncology Drugs," also on Sunday, March 23, from 1 p.m. to 3 p.m. in the Mile High Ballroom 3B. Looking for the latest in aesthetic dermatology? Check out the "Advanced Botulinum Toxin" live demonstration session on Saturday, March 22, from 2 p.m. to 5 p.m. in the Bellco Theater.
There will be expert sessions on pregnancy dermatoses, cutaneous T-cell lymphoma, pediatric dermatology, skin of color, and the latest on treatments for hair and nail conditions. The full scientific session list is available online.
A series of practice management lectures includes topics such as "How to Have an Unforgettably Positive Office Visit" on Saturday, March 22, from 10:00 a.m. to 12:00 p.m. in Room 709/7111 and "Hot Buttons: Recognizing What Sets You Off and Managing Your Triggers" on Sunday, March 23, from 1:00 p.m. to 3:00 p.m. in Room 702.
There is also a mobile device app that meeting attendees can download that contains session schedules, exhibitor and attendee lists, and more.
Can’t attend the meeting? Visit www.eDermatologyNews.com for live conference coverage.
On Twitter @Sknews
The American Academy’s 2014 annual meeting in Denver will feature new CME sessions and updates on the latest dermatology research.
This year’s program features expert commentary on key issues in medical dermatology, including "Melanoma Multidisciplinary Care 2014: What You Need to Know" on Sunday, March 23, from 1 p.m. to 3 p.m. in Room 705/707 and "Dermatologic Manifestations of New Oncology Drugs," also on Sunday, March 23, from 1 p.m. to 3 p.m. in the Mile High Ballroom 3B. Looking for the latest in aesthetic dermatology? Check out the "Advanced Botulinum Toxin" live demonstration session on Saturday, March 22, from 2 p.m. to 5 p.m. in the Bellco Theater.
There will be expert sessions on pregnancy dermatoses, cutaneous T-cell lymphoma, pediatric dermatology, skin of color, and the latest on treatments for hair and nail conditions. The full scientific session list is available online.
A series of practice management lectures includes topics such as "How to Have an Unforgettably Positive Office Visit" on Saturday, March 22, from 10:00 a.m. to 12:00 p.m. in Room 709/7111 and "Hot Buttons: Recognizing What Sets You Off and Managing Your Triggers" on Sunday, March 23, from 1:00 p.m. to 3:00 p.m. in Room 702.
There is also a mobile device app that meeting attendees can download that contains session schedules, exhibitor and attendee lists, and more.
Can’t attend the meeting? Visit www.eDermatologyNews.com for live conference coverage.
On Twitter @Sknews
VIDEO: Photodynamic therapy pearls can improve results
CHAMPIONSGATE, FLA. – Do you use photodynamic therapy to treat actinic keratoses? Dr. Joel Cohen has some tips for you. At the Orlando Dermatology Aesthetic and Clinical Conference, Dr. Cohen spoke to us about current strategies for making the most of PDT, and which treatment plans work best for certain patients. What’s next for PDT? Dr. Cohen of the department of dermatology at the University of Colorado, Denver, highlights promising preliminary studies involving different types of combination therapies that can yield cosmetic and medical benefits.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHAMPIONSGATE, FLA. – Do you use photodynamic therapy to treat actinic keratoses? Dr. Joel Cohen has some tips for you. At the Orlando Dermatology Aesthetic and Clinical Conference, Dr. Cohen spoke to us about current strategies for making the most of PDT, and which treatment plans work best for certain patients. What’s next for PDT? Dr. Cohen of the department of dermatology at the University of Colorado, Denver, highlights promising preliminary studies involving different types of combination therapies that can yield cosmetic and medical benefits.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHAMPIONSGATE, FLA. – Do you use photodynamic therapy to treat actinic keratoses? Dr. Joel Cohen has some tips for you. At the Orlando Dermatology Aesthetic and Clinical Conference, Dr. Cohen spoke to us about current strategies for making the most of PDT, and which treatment plans work best for certain patients. What’s next for PDT? Dr. Cohen of the department of dermatology at the University of Colorado, Denver, highlights promising preliminary studies involving different types of combination therapies that can yield cosmetic and medical benefits.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
EXPERT ANALYSIS FROM ODAC
Nivolumab extends survival in advanced melanoma
An immunomodulator that targets the PD-1 pathway effected sustained remission in 31% of patients who took it for advanced melanoma.
Remission lasted a median of 2 years, with 1- and 2-year overall survival of 62% and 43% respectively, wrote Dr. Suzanne Topalian and colleagues.
But perhaps even more exciting, they said, is that the benefit of nivolumab persisted for at least 16 weeks in all patients who had to discontinue therapy.
The report appeared in the March 3 issue of the Journal of Clinical Oncology.
"The persistence of partial tumor regression and stable disease ... suggests that PD-1 blockade may reset the immune equilibrium between tumor and host," wrote Dr. Topalian, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, and her coauthors.
The findings "are consistent with a mechanism by which an effective tumor-selective immune memory response may have been established in some patients, similar to immune memory against specific infectious organisms after antigen exposure," the investigators wrote (J. Clin. Oncol. 2014 March [doi:10.1200/JCO.2013.53.0105]).
PD-1 is an immune checkpoint that helps regulate the autoimmune action of activated T cells. Tumor cells can co-opt this pathway, using it to hide from T cell attack. Blocking PD-1 unmasks tumor cells, allowing the immune system to target them more effectively.
The 2-year follow-up study tracked response rates in 107 patients with advanced melanoma, who were part of a larger study of 306 patients with various solid-tumor cancers. The initial results of the phase I trial were reported at the 2013 meeting of the American Society of Clinical Oncology.
The new report focuses only on the patients with melanoma, who have completed treatment for at least 14 months, and up to 4 years. All of the patients had undergone two to five prior systemic treatments. They received up to 96 weeks of biweekly nivolumab infusions in varying doses.
Median progression-free survival was 3.7 months; 1- and 2-year progression-free survival rates were 36% and 27%, respectively.
About a third of the patients (33; 31%) experienced an objective response to the drug, with a median duration of 2 years. Fifteen of these (45%) occurred within the first 8 weeks of treatment, the investigators wrote. Of these responding patients, 19 (58%) were still responding when the data were analyzed, the authors noted.
Tumors regressed at various sites, including, in one patient, an unresectable lesion that had eroded through the zygomatic arch into the orbit. Response occurred within 4 months of treatment initiation. This lesion remains in remission. A biopsy showed fibrosis and infiltrating lymphocytes, but no tumor cells. This finding hints that residual tumor seen in some patients’ imaging may in fact be scarring. If that is true, the researchers said, they could have underestimated the real response rate.
Seventeen of the 33 patients who responded discontinued treatment for reasons other than progression. Among these, 12 (71%) maintained their response for 16-56 weeks; in eight of these, response was ongoing at the time of data analysis. Among these is a patient who had metastatic lesions in the adrenal gland, small bowel, and mesenteric lymph nodes.
An additional 7% (7 patients) experienced stable disease for at least 24 weeks at doses of 0.1 to 10 mg/kg. "Unconventional" response patterns not meeting RECIST criteria occurred in four patients, but there was no associated dose pattern; three had received 1 mg/kg and the fourth, 10 mg/kg. Disease progressed in 11 patients treated at doses of 0.1 to 03 mg/kg; none of these responded to a dose escalation, the investigators said.
Nivolumab’s safety data were excellent when compared with other cancer treatments, they noted. Most adverse events occurred within the first 6 months – a hint that close observation and early intervention could minimize their impact. The most common were fatigue (32%), rash (23%), and diarrhea (18%). Grades 3 and 4 adverse events occurred in 24 patients. Treatment-related select adverse events of any grade occurred in 58 (54%). The most common were skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (13%) – not unexpected in an immunomodulating drug. There were no drug-related deaths in the study.
Although this study examined nivolumab as monotherapy, others are looking at a possibly synergistic effect when it’s given with other immunomodulators, and with chemotherapy, kinase inhibitors, or cancer vaccines.
"Innovative, rational treatment combinations based on preclinical evidence may be needed to realize the full therapeutic potential of PD-1 blockade," the investigators said.
Dr. Topalian and several of her coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.
Immunotherapy treatments for cancer might "raise survival curves to new heights," Dr. Geraldine O’Sullivan Coyne wrote in an editorial.
"The continued demonstration of promising clinical outcomes with the use of modern immunotherapy strategies such as nivolumab may allow medical oncologists to have raised expectations for patients with metastatic cancer," wrote Dr. Coyne and her colleagues.
Immune checkpoint inhibitors, including ipilimumab and nivolumab, hold much promise, as exemplified by their large number of complete and near-complete responses, the colleagues wrote. Both drugs showed a flattening of overall survival curves after 2 years, suggesting that at least some patients could derive considerable benefit from longer-term treatment.
"This tail in the curve raises questions about how to increase the number of patients who receive long-term clinical benefit, and how to predict who those patients might be."
Combining one of these drugs with another treatment might even compound its effect, they said. "One promising strategy, referred to as immunogenic intensification, combines one immune checkpoint inhibitor with a different [one] or a therapeutic vaccine ... Hypothetically, vaccine therapy could have a priming or steering effect on the immune system, potentially reducing the need for higher doses of immune checkpoint inhibition or multiple immune checkpoint inhibitors, and lessening the risk of inducing autoimmunity. Such approaches may have the potential to improve clinical outcomes while minimizing adverse effects."
There’s nowhere to go but up for the kinds of cancers being investigated with these drugs, they said.
"Current treatment for metastatic solid tumors ... remains palliative, but perhaps immune checkpoint inhibitors can be part of a strategy to enhance the number of patients who can enjoy sustained, durable responses. ... If future clinical trials validate the findings that have been seen in recent years, perhaps immunotherapy will not just raise expectations, but the all-important survival tail of Kaplan-Meier curves as well."
Dr. Geraldine O’Sullivan Coyne is a medical oncologist at the National Cancer Institute. Neither she nor her co-authors had any financial disclosures.
Immunotherapy treatments for cancer might "raise survival curves to new heights," Dr. Geraldine O’Sullivan Coyne wrote in an editorial.
"The continued demonstration of promising clinical outcomes with the use of modern immunotherapy strategies such as nivolumab may allow medical oncologists to have raised expectations for patients with metastatic cancer," wrote Dr. Coyne and her colleagues.
Immune checkpoint inhibitors, including ipilimumab and nivolumab, hold much promise, as exemplified by their large number of complete and near-complete responses, the colleagues wrote. Both drugs showed a flattening of overall survival curves after 2 years, suggesting that at least some patients could derive considerable benefit from longer-term treatment.
"This tail in the curve raises questions about how to increase the number of patients who receive long-term clinical benefit, and how to predict who those patients might be."
Combining one of these drugs with another treatment might even compound its effect, they said. "One promising strategy, referred to as immunogenic intensification, combines one immune checkpoint inhibitor with a different [one] or a therapeutic vaccine ... Hypothetically, vaccine therapy could have a priming or steering effect on the immune system, potentially reducing the need for higher doses of immune checkpoint inhibition or multiple immune checkpoint inhibitors, and lessening the risk of inducing autoimmunity. Such approaches may have the potential to improve clinical outcomes while minimizing adverse effects."
There’s nowhere to go but up for the kinds of cancers being investigated with these drugs, they said.
"Current treatment for metastatic solid tumors ... remains palliative, but perhaps immune checkpoint inhibitors can be part of a strategy to enhance the number of patients who can enjoy sustained, durable responses. ... If future clinical trials validate the findings that have been seen in recent years, perhaps immunotherapy will not just raise expectations, but the all-important survival tail of Kaplan-Meier curves as well."
Dr. Geraldine O’Sullivan Coyne is a medical oncologist at the National Cancer Institute. Neither she nor her co-authors had any financial disclosures.
Immunotherapy treatments for cancer might "raise survival curves to new heights," Dr. Geraldine O’Sullivan Coyne wrote in an editorial.
"The continued demonstration of promising clinical outcomes with the use of modern immunotherapy strategies such as nivolumab may allow medical oncologists to have raised expectations for patients with metastatic cancer," wrote Dr. Coyne and her colleagues.
Immune checkpoint inhibitors, including ipilimumab and nivolumab, hold much promise, as exemplified by their large number of complete and near-complete responses, the colleagues wrote. Both drugs showed a flattening of overall survival curves after 2 years, suggesting that at least some patients could derive considerable benefit from longer-term treatment.
"This tail in the curve raises questions about how to increase the number of patients who receive long-term clinical benefit, and how to predict who those patients might be."
Combining one of these drugs with another treatment might even compound its effect, they said. "One promising strategy, referred to as immunogenic intensification, combines one immune checkpoint inhibitor with a different [one] or a therapeutic vaccine ... Hypothetically, vaccine therapy could have a priming or steering effect on the immune system, potentially reducing the need for higher doses of immune checkpoint inhibition or multiple immune checkpoint inhibitors, and lessening the risk of inducing autoimmunity. Such approaches may have the potential to improve clinical outcomes while minimizing adverse effects."
There’s nowhere to go but up for the kinds of cancers being investigated with these drugs, they said.
"Current treatment for metastatic solid tumors ... remains palliative, but perhaps immune checkpoint inhibitors can be part of a strategy to enhance the number of patients who can enjoy sustained, durable responses. ... If future clinical trials validate the findings that have been seen in recent years, perhaps immunotherapy will not just raise expectations, but the all-important survival tail of Kaplan-Meier curves as well."
Dr. Geraldine O’Sullivan Coyne is a medical oncologist at the National Cancer Institute. Neither she nor her co-authors had any financial disclosures.
An immunomodulator that targets the PD-1 pathway effected sustained remission in 31% of patients who took it for advanced melanoma.
Remission lasted a median of 2 years, with 1- and 2-year overall survival of 62% and 43% respectively, wrote Dr. Suzanne Topalian and colleagues.
But perhaps even more exciting, they said, is that the benefit of nivolumab persisted for at least 16 weeks in all patients who had to discontinue therapy.
The report appeared in the March 3 issue of the Journal of Clinical Oncology.
"The persistence of partial tumor regression and stable disease ... suggests that PD-1 blockade may reset the immune equilibrium between tumor and host," wrote Dr. Topalian, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, and her coauthors.
The findings "are consistent with a mechanism by which an effective tumor-selective immune memory response may have been established in some patients, similar to immune memory against specific infectious organisms after antigen exposure," the investigators wrote (J. Clin. Oncol. 2014 March [doi:10.1200/JCO.2013.53.0105]).
PD-1 is an immune checkpoint that helps regulate the autoimmune action of activated T cells. Tumor cells can co-opt this pathway, using it to hide from T cell attack. Blocking PD-1 unmasks tumor cells, allowing the immune system to target them more effectively.
The 2-year follow-up study tracked response rates in 107 patients with advanced melanoma, who were part of a larger study of 306 patients with various solid-tumor cancers. The initial results of the phase I trial were reported at the 2013 meeting of the American Society of Clinical Oncology.
The new report focuses only on the patients with melanoma, who have completed treatment for at least 14 months, and up to 4 years. All of the patients had undergone two to five prior systemic treatments. They received up to 96 weeks of biweekly nivolumab infusions in varying doses.
Median progression-free survival was 3.7 months; 1- and 2-year progression-free survival rates were 36% and 27%, respectively.
About a third of the patients (33; 31%) experienced an objective response to the drug, with a median duration of 2 years. Fifteen of these (45%) occurred within the first 8 weeks of treatment, the investigators wrote. Of these responding patients, 19 (58%) were still responding when the data were analyzed, the authors noted.
Tumors regressed at various sites, including, in one patient, an unresectable lesion that had eroded through the zygomatic arch into the orbit. Response occurred within 4 months of treatment initiation. This lesion remains in remission. A biopsy showed fibrosis and infiltrating lymphocytes, but no tumor cells. This finding hints that residual tumor seen in some patients’ imaging may in fact be scarring. If that is true, the researchers said, they could have underestimated the real response rate.
Seventeen of the 33 patients who responded discontinued treatment for reasons other than progression. Among these, 12 (71%) maintained their response for 16-56 weeks; in eight of these, response was ongoing at the time of data analysis. Among these is a patient who had metastatic lesions in the adrenal gland, small bowel, and mesenteric lymph nodes.
An additional 7% (7 patients) experienced stable disease for at least 24 weeks at doses of 0.1 to 10 mg/kg. "Unconventional" response patterns not meeting RECIST criteria occurred in four patients, but there was no associated dose pattern; three had received 1 mg/kg and the fourth, 10 mg/kg. Disease progressed in 11 patients treated at doses of 0.1 to 03 mg/kg; none of these responded to a dose escalation, the investigators said.
Nivolumab’s safety data were excellent when compared with other cancer treatments, they noted. Most adverse events occurred within the first 6 months – a hint that close observation and early intervention could minimize their impact. The most common were fatigue (32%), rash (23%), and diarrhea (18%). Grades 3 and 4 adverse events occurred in 24 patients. Treatment-related select adverse events of any grade occurred in 58 (54%). The most common were skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (13%) – not unexpected in an immunomodulating drug. There were no drug-related deaths in the study.
Although this study examined nivolumab as monotherapy, others are looking at a possibly synergistic effect when it’s given with other immunomodulators, and with chemotherapy, kinase inhibitors, or cancer vaccines.
"Innovative, rational treatment combinations based on preclinical evidence may be needed to realize the full therapeutic potential of PD-1 blockade," the investigators said.
Dr. Topalian and several of her coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.
An immunomodulator that targets the PD-1 pathway effected sustained remission in 31% of patients who took it for advanced melanoma.
Remission lasted a median of 2 years, with 1- and 2-year overall survival of 62% and 43% respectively, wrote Dr. Suzanne Topalian and colleagues.
But perhaps even more exciting, they said, is that the benefit of nivolumab persisted for at least 16 weeks in all patients who had to discontinue therapy.
The report appeared in the March 3 issue of the Journal of Clinical Oncology.
"The persistence of partial tumor regression and stable disease ... suggests that PD-1 blockade may reset the immune equilibrium between tumor and host," wrote Dr. Topalian, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, and her coauthors.
The findings "are consistent with a mechanism by which an effective tumor-selective immune memory response may have been established in some patients, similar to immune memory against specific infectious organisms after antigen exposure," the investigators wrote (J. Clin. Oncol. 2014 March [doi:10.1200/JCO.2013.53.0105]).
PD-1 is an immune checkpoint that helps regulate the autoimmune action of activated T cells. Tumor cells can co-opt this pathway, using it to hide from T cell attack. Blocking PD-1 unmasks tumor cells, allowing the immune system to target them more effectively.
The 2-year follow-up study tracked response rates in 107 patients with advanced melanoma, who were part of a larger study of 306 patients with various solid-tumor cancers. The initial results of the phase I trial were reported at the 2013 meeting of the American Society of Clinical Oncology.
The new report focuses only on the patients with melanoma, who have completed treatment for at least 14 months, and up to 4 years. All of the patients had undergone two to five prior systemic treatments. They received up to 96 weeks of biweekly nivolumab infusions in varying doses.
Median progression-free survival was 3.7 months; 1- and 2-year progression-free survival rates were 36% and 27%, respectively.
About a third of the patients (33; 31%) experienced an objective response to the drug, with a median duration of 2 years. Fifteen of these (45%) occurred within the first 8 weeks of treatment, the investigators wrote. Of these responding patients, 19 (58%) were still responding when the data were analyzed, the authors noted.
Tumors regressed at various sites, including, in one patient, an unresectable lesion that had eroded through the zygomatic arch into the orbit. Response occurred within 4 months of treatment initiation. This lesion remains in remission. A biopsy showed fibrosis and infiltrating lymphocytes, but no tumor cells. This finding hints that residual tumor seen in some patients’ imaging may in fact be scarring. If that is true, the researchers said, they could have underestimated the real response rate.
Seventeen of the 33 patients who responded discontinued treatment for reasons other than progression. Among these, 12 (71%) maintained their response for 16-56 weeks; in eight of these, response was ongoing at the time of data analysis. Among these is a patient who had metastatic lesions in the adrenal gland, small bowel, and mesenteric lymph nodes.
An additional 7% (7 patients) experienced stable disease for at least 24 weeks at doses of 0.1 to 10 mg/kg. "Unconventional" response patterns not meeting RECIST criteria occurred in four patients, but there was no associated dose pattern; three had received 1 mg/kg and the fourth, 10 mg/kg. Disease progressed in 11 patients treated at doses of 0.1 to 03 mg/kg; none of these responded to a dose escalation, the investigators said.
Nivolumab’s safety data were excellent when compared with other cancer treatments, they noted. Most adverse events occurred within the first 6 months – a hint that close observation and early intervention could minimize their impact. The most common were fatigue (32%), rash (23%), and diarrhea (18%). Grades 3 and 4 adverse events occurred in 24 patients. Treatment-related select adverse events of any grade occurred in 58 (54%). The most common were skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (13%) – not unexpected in an immunomodulating drug. There were no drug-related deaths in the study.
Although this study examined nivolumab as monotherapy, others are looking at a possibly synergistic effect when it’s given with other immunomodulators, and with chemotherapy, kinase inhibitors, or cancer vaccines.
"Innovative, rational treatment combinations based on preclinical evidence may be needed to realize the full therapeutic potential of PD-1 blockade," the investigators said.
Dr. Topalian and several of her coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.
Major finding: The PD-1 receptor inhibitor nivolumab effected sustained response in 31% of those who took it for advanced melanoma.
Data source: A retrospective study of 107 patients with advanced melanoma.
Disclosures: Dr. Topalian and several coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.
Vemurafenib improved survival in BRAF mutation–positive metastatic melanoma
Vemurafenib had a significant survival benefit compared with dacarbazine in adults with treatment-naive, BRAFV600E and BRAFV600K mutation–positive metastatic melanoma, investigators reported in the March issue of Lancet Oncology.
In the phase III trial, 675 patients with BRAFV600 mutations were randomized to receive BRAF inhibitor vemurafenib (960 mg orally b.i.d.) or dacarbazine (1,000 mg/m2 IV every 3 weeks). The median overall survival was 13.6 months among 337 patients randomized to receive vemurafenib, compared with 9.7 months for the 338 patients randomized to receive dacarbazine (hazard ratio, 0.70; 95% confidence interval, 0.57-0.87, P = .0008), reported Dr. Grant McArthur of Peter MacCallum Cancer Centre, East Melbourne, Australia, and his associates.
Researchers followed vemurafenib and dacarbazine patients for a median of 12.5 and 9.5 months, respectively. One-quarter of dacarbazine patients later crossed over to vemurafenib (Lancet Oncol. 2014;15:323-32).
Median progression-free survival times also favored vemurafenib (6.9 months vs. 1.6 months for dacarbazine; HR for vemurafenib, 0.38; 95% CI, 0.32-0.46, P less than .0001). Among those patients available for follow-up at 18 months, after crossover had occurred, the difference in overall survival was insignificant (39% for vemurafenib vs. 34% for dacarbazine), the investigators reported.
Although BRAFV600E is the most common mutation in patients with metastatic melanoma, a substantial proportion of patients carry the BRAFV600K mutation (8.6% in the current study), and data suggest that these patients might be at increased risk for brain and lung metastases and might have a shorter time from diagnosis to metastasis and death than patients with a BRAFVV600E mutation, the investigators said.
Benefit from vemurafenib was found for both types of BRAF mutations. For the 598 patients with BRAFV600E disease (91%), the median overall survival in the vemurafenib group was 13.3 months compared with 10.0 months in the dacarbazine group (HR, 0.75; 95% CI, 0.60-0.93, P = .0085). For the 57 patients with BRAFV600K disease (9%), the median overall survival in the vemurafenib group was 14.5 months (95% CI, 11.2 to not estimable) compared with 7.6 months in the dacarbazine group (HR, 0.43; 95% CI, 0.21-0.90, P = .024), the investigators reported.
Grade 3-4 events included cutaneous squamous cell carcinoma (19%), keratoacanthomas (10%), rash (9%), and abnormal liver function tests (11%) in the vemurafenib group, and neutropenia (9%) in the dacarbazine group. Eight patients (2%) in the vemurafenib group developed new primary melanomas. The death rate due to adverse events was 2% in each group.
F Hoffman/La Roche/Genentech funded the trial. Dr. McArthur reported providing uncompensated services to Roche/Genentech. Sixteen of his associates reported receiving support from or serving as consultants or advisers to Roche, Roche/Genentech, or Genentech. Three other associates are employees of Roche/Genentech, Roche Molecular Systems, or F Hoffman/La Roche.
Vemurafenib had a significant survival benefit compared with dacarbazine in adults with treatment-naive, BRAFV600E and BRAFV600K mutation–positive metastatic melanoma, investigators reported in the March issue of Lancet Oncology.
In the phase III trial, 675 patients with BRAFV600 mutations were randomized to receive BRAF inhibitor vemurafenib (960 mg orally b.i.d.) or dacarbazine (1,000 mg/m2 IV every 3 weeks). The median overall survival was 13.6 months among 337 patients randomized to receive vemurafenib, compared with 9.7 months for the 338 patients randomized to receive dacarbazine (hazard ratio, 0.70; 95% confidence interval, 0.57-0.87, P = .0008), reported Dr. Grant McArthur of Peter MacCallum Cancer Centre, East Melbourne, Australia, and his associates.
Researchers followed vemurafenib and dacarbazine patients for a median of 12.5 and 9.5 months, respectively. One-quarter of dacarbazine patients later crossed over to vemurafenib (Lancet Oncol. 2014;15:323-32).
Median progression-free survival times also favored vemurafenib (6.9 months vs. 1.6 months for dacarbazine; HR for vemurafenib, 0.38; 95% CI, 0.32-0.46, P less than .0001). Among those patients available for follow-up at 18 months, after crossover had occurred, the difference in overall survival was insignificant (39% for vemurafenib vs. 34% for dacarbazine), the investigators reported.
Although BRAFV600E is the most common mutation in patients with metastatic melanoma, a substantial proportion of patients carry the BRAFV600K mutation (8.6% in the current study), and data suggest that these patients might be at increased risk for brain and lung metastases and might have a shorter time from diagnosis to metastasis and death than patients with a BRAFVV600E mutation, the investigators said.
Benefit from vemurafenib was found for both types of BRAF mutations. For the 598 patients with BRAFV600E disease (91%), the median overall survival in the vemurafenib group was 13.3 months compared with 10.0 months in the dacarbazine group (HR, 0.75; 95% CI, 0.60-0.93, P = .0085). For the 57 patients with BRAFV600K disease (9%), the median overall survival in the vemurafenib group was 14.5 months (95% CI, 11.2 to not estimable) compared with 7.6 months in the dacarbazine group (HR, 0.43; 95% CI, 0.21-0.90, P = .024), the investigators reported.
Grade 3-4 events included cutaneous squamous cell carcinoma (19%), keratoacanthomas (10%), rash (9%), and abnormal liver function tests (11%) in the vemurafenib group, and neutropenia (9%) in the dacarbazine group. Eight patients (2%) in the vemurafenib group developed new primary melanomas. The death rate due to adverse events was 2% in each group.
F Hoffman/La Roche/Genentech funded the trial. Dr. McArthur reported providing uncompensated services to Roche/Genentech. Sixteen of his associates reported receiving support from or serving as consultants or advisers to Roche, Roche/Genentech, or Genentech. Three other associates are employees of Roche/Genentech, Roche Molecular Systems, or F Hoffman/La Roche.
Vemurafenib had a significant survival benefit compared with dacarbazine in adults with treatment-naive, BRAFV600E and BRAFV600K mutation–positive metastatic melanoma, investigators reported in the March issue of Lancet Oncology.
In the phase III trial, 675 patients with BRAFV600 mutations were randomized to receive BRAF inhibitor vemurafenib (960 mg orally b.i.d.) or dacarbazine (1,000 mg/m2 IV every 3 weeks). The median overall survival was 13.6 months among 337 patients randomized to receive vemurafenib, compared with 9.7 months for the 338 patients randomized to receive dacarbazine (hazard ratio, 0.70; 95% confidence interval, 0.57-0.87, P = .0008), reported Dr. Grant McArthur of Peter MacCallum Cancer Centre, East Melbourne, Australia, and his associates.
Researchers followed vemurafenib and dacarbazine patients for a median of 12.5 and 9.5 months, respectively. One-quarter of dacarbazine patients later crossed over to vemurafenib (Lancet Oncol. 2014;15:323-32).
Median progression-free survival times also favored vemurafenib (6.9 months vs. 1.6 months for dacarbazine; HR for vemurafenib, 0.38; 95% CI, 0.32-0.46, P less than .0001). Among those patients available for follow-up at 18 months, after crossover had occurred, the difference in overall survival was insignificant (39% for vemurafenib vs. 34% for dacarbazine), the investigators reported.
Although BRAFV600E is the most common mutation in patients with metastatic melanoma, a substantial proportion of patients carry the BRAFV600K mutation (8.6% in the current study), and data suggest that these patients might be at increased risk for brain and lung metastases and might have a shorter time from diagnosis to metastasis and death than patients with a BRAFVV600E mutation, the investigators said.
Benefit from vemurafenib was found for both types of BRAF mutations. For the 598 patients with BRAFV600E disease (91%), the median overall survival in the vemurafenib group was 13.3 months compared with 10.0 months in the dacarbazine group (HR, 0.75; 95% CI, 0.60-0.93, P = .0085). For the 57 patients with BRAFV600K disease (9%), the median overall survival in the vemurafenib group was 14.5 months (95% CI, 11.2 to not estimable) compared with 7.6 months in the dacarbazine group (HR, 0.43; 95% CI, 0.21-0.90, P = .024), the investigators reported.
Grade 3-4 events included cutaneous squamous cell carcinoma (19%), keratoacanthomas (10%), rash (9%), and abnormal liver function tests (11%) in the vemurafenib group, and neutropenia (9%) in the dacarbazine group. Eight patients (2%) in the vemurafenib group developed new primary melanomas. The death rate due to adverse events was 2% in each group.
F Hoffman/La Roche/Genentech funded the trial. Dr. McArthur reported providing uncompensated services to Roche/Genentech. Sixteen of his associates reported receiving support from or serving as consultants or advisers to Roche, Roche/Genentech, or Genentech. Three other associates are employees of Roche/Genentech, Roche Molecular Systems, or F Hoffman/La Roche.
FROM LANCET ONCOLOGY
Major finding: The median overall survival was 13.6 months for patients receiving vemurafenib compared with 9.7 months for patients receiving dacarbazine (hazard ratio, 0.70; 95% confidence interval, 0.57-0.87, P = .0008).
Data source: A phase III randomized, open-label trial of 675 adults with treatment-naive, BRAFV600E and BRAFV600K mutation–positive metastatic melanoma.
Disclosures: F Hoffman/La Roche/Genentech funded the trial. Dr. McArthur reported providing uncompensated services to Roche/Genentech. Sixteen of his associates reported receiving support from or serving as consultants or advisers to Roche, Roche/Genentech, or Genentech. Three other associates are employees of Roche/Genentech, Roche Molecular Systems, or F Hoffman/La Roche.
Localized Diffuse Melanosis Associated With Melanoma Successfully Treated With Imiquimod Cream 5%: A Case Report and Review of the Literature
Diagnostic and Prognostic Biomarkers and Therapeutic Targets in Melanoma
Counterphobia and Poor Sun Protection Practices in First-Degree Relatives of Melanoma Patients
It is widely accepted that there are several factors that may independently elevate an individual’s risk for melanoma, such as a history of childhood sunburns, family history of melanoma, and poor sun protection practices. Several studies have examined risk behaviors in melanoma patients following their diagnosis and have reported findings such as increased UV exposure patterns, persistent tanning bed use, and sun-protective behaviors similar to those of the general population (Figure).1-4
Although first-degree relatives (FDRs) of melanoma patients are at an increased risk for melanoma, they also have been found to exhibit surprisingly poor sun protection practices. In one retrospective analysis, Geller et al5 found that frequent sunburns, high rates of tanning bed use, and low rates of sunscreen use were common among children of health care workers who reported a personal or family history of skin cancer. An independent study reported that merely 37% (37/100) of FDRs of melanoma patients use sunscreen more than half of the time, and considerably fewer wear protective clothing or seek shade while outdoors.6 Given their increased risk for developing melanoma, it is likely to be assumed that FDRs of melanoma patients practice diligent sun protection. The underlying reasons for the failure of this at-risk population to adhere strongly to sun protection practices warrants special attention.
Manne et al7 conducted a survey in a group of FDRs of melanoma patients with self-reported poor sun protection practices to evaluate the demographic, medical, psychological, educational (knowledge of sun protection guidelines), and social influences that correlate with sun protection and sunbathing practices. More effective sun protective behaviors were identified in FDRs with higher education, fewer perceived benefits of sunbathing, more prominent photoaging concerns, and greater sunscreen self-efficacy. The authors concluded that sun-protective behavior in FDRs was not associated with prior knowledge about sunscreen or UV exposure, their relative’s melanoma stage, or physician recommendations for sun protection.7
Factors that have been documented as influencing sun-protective behavior in the general population include knowledge of the benefits of sun protection; attitudes toward tanning and sun protection; subjective norms regarding the beauty and perceived health of a tan; and optimistic bias, which is a cognitive mechanism that causes a person to believe that he/she is at lesser risk for experiencing a negative outcome compared to others. Additionally, sun protection behaviors are influenced by the immediacy of getting the reward (the perceived benefits of tanning) versus the delayed punishment (development of skin cancer).6 Although all of these elements may be important for some individuals, we believe that a subset of FDRs of melanoma patients may be susceptible to the phenomenon known as counterphobia.
Counterphobia is a neurotic response to anxiety in which an individual actively pursues situations that heighten his/her fear rather than fleeing from a feared object or behavior.8 Most insight into counterphobia has come from the experiences of children who have parent(s) with a debilitating or fatal diagnosis. Due to their immature coping mechanisms, some children are at risk for maladaptive behavioral responses. The loss of a parent typically produces severe psychological trauma in all children, but in those who develop counterphobia, it manifests as a heightened fear of death and vulnerability to their parent’s illness. This maladaptive response is dependent on self-identification with the parent, especially among daughters of lost mothers and sons of lost fathers, and this fear remains with the child through adulthood. A survey of 154 motherless daughters found that women aged 19 to 35 years have the highest level of obsessive thoughts of mortality and more than 75% believe they will succumb to their mother’s illness (92% in the case of cancer).9 Despite this fear, children may exhibit health-compromising behaviors related to the diagnoses that led to their parents’ deaths; for example, counterphobia has been identified as a pathologic factor behind sexually promiscuous practices in the children of patients with AIDS, and it also may explain high-risk drinking behavior in a child whose parent died from hepatocellular carcinoma due to a history of alcoholic cirrhosis. Similarly, counterphobia can manifest as the deliberate refusal to undergo a mammogram in a woman whose mother died of breast cancer.9 Psychologists have hypothesized that counterphobic pursuits may result from attempts to master the anxiety associated with fear of injury or death as well as from the notion that attempts at risk-factor reduction are futile, as their death is certain.10
The strong influence of counterphobia on perspectives of health and mortality among individuals affected by early loss of a parent is well documented. An assessment of the subjective life expectancy, death anxiety, and health-related behaviors of college students who lost a parent revealed that these individuals estimated their own life spans to be shorter than college students with 2 living parents.11 Moreover, when students were explicitly instructed to predict their life expectancy based on a purely objective mentality rather than one influenced by personal feelings, the exclusion of emotion yielded a longer projected life span. This finding highlights the magnitude of the psychological forces influencing the ethos of individuals affected by premature parental loss. In the same study, individuals who had experienced early loss of a parent believed they would die of the same condition that caused their parent’s death, a finding accompanied by notably poorer diet and smoking behaviors, which might be expected among those with counterphobic defenses.11
Although Manne et al7 did not find an association between melanoma disease severity and sun-protective behavior in FDRs, the study design did not allow for assessment of potential counterphobic responses, which are most likely to develop in younger individuals who strongly identify with the family member whose disease was disabling or fatal. For example, the study included adult relatives (mean age, 46 years) of melanoma patients diagnosed in the preceding 4 years. Furthermore, fewer than 20% (108/545) of the patients had stage III or IV melanoma, and it was not known if melanoma patients communicated the diagnosis to their family members.7
A practice gap exists in FDRs of melanoma patients who are largely assumed to be practicing adequate, if not heightened, sun protection practices. Given that this group demonstrates poor sun protection practices, it is important to identify reasons for such behavior that may extend beyond what is currently known and may include counterphobia. Based on research performed in other medical conditions, the individuals most at risk for counterphobic responses are young children of patients diagnosed with a disabling or fatal condition, but whether in cases of melanoma counterphobia exists as a maladaptive response and whether such a response may occur in all close relatives, not just offspring, is unknown. Currently, the type of measure(s) that may mitigate poor risk factor modification due to counterphobia, including sun protection practices, is unknown. However, physician knowledge of counterphobic responses as a possibility in close relatives of melanoma patients may improve physician efforts to modify behavior in this unique, high-risk population.
The multimodal pathway of melanoma development suggests that individuals with an underlying genetic predisposition for melanoma who also neglect sun-protective measures are an especially high-risk group.12 As such, targeted education and screening of this patient population may be warranted (Table 1). Although it is incumbent on physicians to incorporate concerted screening, counseling, and focused interventions for newly diagnosed melanoma patients, taking similar measures to counsel and educate immediate relatives who may be at high risk for poor sun protection practices also is encouraged (Table 2).
We believe that recognition of counterphobic behavior is critical in the evaluation of FDRs of melanoma patients. Heightened awareness may bolster primary prevention efforts, especially in our patients with genetic diatheses toward melanoma development.
1. Idorn L, Datta P, Heydenreich J, et al. A 3-year follow-up of sun behavior in patients with cutaneous malignant melanoma [published online ahead of print October 2, 2013]. JAMA Dermatol. doi:10.1001/jamadermatol.2013.5098.
2. Idorn LW, Datta P, Heydenreich J, et al. Sun behaviour after cutaneous malignant melanoma: a study based on ultraviolet radiation measurements and sun diary data [published online ahead of print]. Br J Dermatol. 2013;168:367-373.
3. Mayer D, Layman A, Carlson J. Sun-protection behaviors of melanoma survivors. J Am Acad Dermatol. 2012;66:e9-e10.
4. Lee TK, Brazier AS, Shoveller JA, et al. Sun-related behavior after a diagnosis of cutaneous malignant melanoma. Melanoma Res. 2007;17:51-55.
5. Geller AC, Brooks DR, Colditz GA, et al. Sun protection practices among offspring of women with personal or family history of skin cancer. Pediatrics. 2006;117:e688-e694.
6. Azzarello LM, Dessureault S, Jacobsen PB. Sun-protective behavior among individuals with a family history of melanoma. Cancer Epidemiol Boomarkers Prev. 2006;15:142-145.
7. Manne SL, Coups EJ, Jacobsen PB, et al. Sun protection and sunbathing practices among at-risk family members of patients with melanoma. BMC Public Health. 2011;11:122.
8. Fenichel O. The Psychoanalytic Theory of Neurosis. Oxford, United Kingdom: Taylor & Francis; 1999.
9. Edelman H. Motherless Daughters: The Legacy of Loss. 2nd ed. Cambridge, MA: Da Capo Press; 2006.
10. Poznanski E, Arthur B. The counterphobic defense in children. Child Psychiatry Hum Dev. 1971;1:178-191.
11. Denes-Raj V, Ehrlichman H. Effects of premature parental death on subjective life expectancy, death anxiety, and health behavior. Omega: Journal of Death and Dying. 1991;23:309-321.
12. Hayward NK. Genetics of melanoma predisposition. Oncogene. 2003;22:3053-3062.
13. Arthey S, Clarke VA. Suntanning and sun protection: a review of the psychologial literature. Soc Sci Med. 1995;40:265-274.
It is widely accepted that there are several factors that may independently elevate an individual’s risk for melanoma, such as a history of childhood sunburns, family history of melanoma, and poor sun protection practices. Several studies have examined risk behaviors in melanoma patients following their diagnosis and have reported findings such as increased UV exposure patterns, persistent tanning bed use, and sun-protective behaviors similar to those of the general population (Figure).1-4
Although first-degree relatives (FDRs) of melanoma patients are at an increased risk for melanoma, they also have been found to exhibit surprisingly poor sun protection practices. In one retrospective analysis, Geller et al5 found that frequent sunburns, high rates of tanning bed use, and low rates of sunscreen use were common among children of health care workers who reported a personal or family history of skin cancer. An independent study reported that merely 37% (37/100) of FDRs of melanoma patients use sunscreen more than half of the time, and considerably fewer wear protective clothing or seek shade while outdoors.6 Given their increased risk for developing melanoma, it is likely to be assumed that FDRs of melanoma patients practice diligent sun protection. The underlying reasons for the failure of this at-risk population to adhere strongly to sun protection practices warrants special attention.
Manne et al7 conducted a survey in a group of FDRs of melanoma patients with self-reported poor sun protection practices to evaluate the demographic, medical, psychological, educational (knowledge of sun protection guidelines), and social influences that correlate with sun protection and sunbathing practices. More effective sun protective behaviors were identified in FDRs with higher education, fewer perceived benefits of sunbathing, more prominent photoaging concerns, and greater sunscreen self-efficacy. The authors concluded that sun-protective behavior in FDRs was not associated with prior knowledge about sunscreen or UV exposure, their relative’s melanoma stage, or physician recommendations for sun protection.7
Factors that have been documented as influencing sun-protective behavior in the general population include knowledge of the benefits of sun protection; attitudes toward tanning and sun protection; subjective norms regarding the beauty and perceived health of a tan; and optimistic bias, which is a cognitive mechanism that causes a person to believe that he/she is at lesser risk for experiencing a negative outcome compared to others. Additionally, sun protection behaviors are influenced by the immediacy of getting the reward (the perceived benefits of tanning) versus the delayed punishment (development of skin cancer).6 Although all of these elements may be important for some individuals, we believe that a subset of FDRs of melanoma patients may be susceptible to the phenomenon known as counterphobia.
Counterphobia is a neurotic response to anxiety in which an individual actively pursues situations that heighten his/her fear rather than fleeing from a feared object or behavior.8 Most insight into counterphobia has come from the experiences of children who have parent(s) with a debilitating or fatal diagnosis. Due to their immature coping mechanisms, some children are at risk for maladaptive behavioral responses. The loss of a parent typically produces severe psychological trauma in all children, but in those who develop counterphobia, it manifests as a heightened fear of death and vulnerability to their parent’s illness. This maladaptive response is dependent on self-identification with the parent, especially among daughters of lost mothers and sons of lost fathers, and this fear remains with the child through adulthood. A survey of 154 motherless daughters found that women aged 19 to 35 years have the highest level of obsessive thoughts of mortality and more than 75% believe they will succumb to their mother’s illness (92% in the case of cancer).9 Despite this fear, children may exhibit health-compromising behaviors related to the diagnoses that led to their parents’ deaths; for example, counterphobia has been identified as a pathologic factor behind sexually promiscuous practices in the children of patients with AIDS, and it also may explain high-risk drinking behavior in a child whose parent died from hepatocellular carcinoma due to a history of alcoholic cirrhosis. Similarly, counterphobia can manifest as the deliberate refusal to undergo a mammogram in a woman whose mother died of breast cancer.9 Psychologists have hypothesized that counterphobic pursuits may result from attempts to master the anxiety associated with fear of injury or death as well as from the notion that attempts at risk-factor reduction are futile, as their death is certain.10
The strong influence of counterphobia on perspectives of health and mortality among individuals affected by early loss of a parent is well documented. An assessment of the subjective life expectancy, death anxiety, and health-related behaviors of college students who lost a parent revealed that these individuals estimated their own life spans to be shorter than college students with 2 living parents.11 Moreover, when students were explicitly instructed to predict their life expectancy based on a purely objective mentality rather than one influenced by personal feelings, the exclusion of emotion yielded a longer projected life span. This finding highlights the magnitude of the psychological forces influencing the ethos of individuals affected by premature parental loss. In the same study, individuals who had experienced early loss of a parent believed they would die of the same condition that caused their parent’s death, a finding accompanied by notably poorer diet and smoking behaviors, which might be expected among those with counterphobic defenses.11
Although Manne et al7 did not find an association between melanoma disease severity and sun-protective behavior in FDRs, the study design did not allow for assessment of potential counterphobic responses, which are most likely to develop in younger individuals who strongly identify with the family member whose disease was disabling or fatal. For example, the study included adult relatives (mean age, 46 years) of melanoma patients diagnosed in the preceding 4 years. Furthermore, fewer than 20% (108/545) of the patients had stage III or IV melanoma, and it was not known if melanoma patients communicated the diagnosis to their family members.7
A practice gap exists in FDRs of melanoma patients who are largely assumed to be practicing adequate, if not heightened, sun protection practices. Given that this group demonstrates poor sun protection practices, it is important to identify reasons for such behavior that may extend beyond what is currently known and may include counterphobia. Based on research performed in other medical conditions, the individuals most at risk for counterphobic responses are young children of patients diagnosed with a disabling or fatal condition, but whether in cases of melanoma counterphobia exists as a maladaptive response and whether such a response may occur in all close relatives, not just offspring, is unknown. Currently, the type of measure(s) that may mitigate poor risk factor modification due to counterphobia, including sun protection practices, is unknown. However, physician knowledge of counterphobic responses as a possibility in close relatives of melanoma patients may improve physician efforts to modify behavior in this unique, high-risk population.
The multimodal pathway of melanoma development suggests that individuals with an underlying genetic predisposition for melanoma who also neglect sun-protective measures are an especially high-risk group.12 As such, targeted education and screening of this patient population may be warranted (Table 1). Although it is incumbent on physicians to incorporate concerted screening, counseling, and focused interventions for newly diagnosed melanoma patients, taking similar measures to counsel and educate immediate relatives who may be at high risk for poor sun protection practices also is encouraged (Table 2).
We believe that recognition of counterphobic behavior is critical in the evaluation of FDRs of melanoma patients. Heightened awareness may bolster primary prevention efforts, especially in our patients with genetic diatheses toward melanoma development.
It is widely accepted that there are several factors that may independently elevate an individual’s risk for melanoma, such as a history of childhood sunburns, family history of melanoma, and poor sun protection practices. Several studies have examined risk behaviors in melanoma patients following their diagnosis and have reported findings such as increased UV exposure patterns, persistent tanning bed use, and sun-protective behaviors similar to those of the general population (Figure).1-4
Although first-degree relatives (FDRs) of melanoma patients are at an increased risk for melanoma, they also have been found to exhibit surprisingly poor sun protection practices. In one retrospective analysis, Geller et al5 found that frequent sunburns, high rates of tanning bed use, and low rates of sunscreen use were common among children of health care workers who reported a personal or family history of skin cancer. An independent study reported that merely 37% (37/100) of FDRs of melanoma patients use sunscreen more than half of the time, and considerably fewer wear protective clothing or seek shade while outdoors.6 Given their increased risk for developing melanoma, it is likely to be assumed that FDRs of melanoma patients practice diligent sun protection. The underlying reasons for the failure of this at-risk population to adhere strongly to sun protection practices warrants special attention.
Manne et al7 conducted a survey in a group of FDRs of melanoma patients with self-reported poor sun protection practices to evaluate the demographic, medical, psychological, educational (knowledge of sun protection guidelines), and social influences that correlate with sun protection and sunbathing practices. More effective sun protective behaviors were identified in FDRs with higher education, fewer perceived benefits of sunbathing, more prominent photoaging concerns, and greater sunscreen self-efficacy. The authors concluded that sun-protective behavior in FDRs was not associated with prior knowledge about sunscreen or UV exposure, their relative’s melanoma stage, or physician recommendations for sun protection.7
Factors that have been documented as influencing sun-protective behavior in the general population include knowledge of the benefits of sun protection; attitudes toward tanning and sun protection; subjective norms regarding the beauty and perceived health of a tan; and optimistic bias, which is a cognitive mechanism that causes a person to believe that he/she is at lesser risk for experiencing a negative outcome compared to others. Additionally, sun protection behaviors are influenced by the immediacy of getting the reward (the perceived benefits of tanning) versus the delayed punishment (development of skin cancer).6 Although all of these elements may be important for some individuals, we believe that a subset of FDRs of melanoma patients may be susceptible to the phenomenon known as counterphobia.
Counterphobia is a neurotic response to anxiety in which an individual actively pursues situations that heighten his/her fear rather than fleeing from a feared object or behavior.8 Most insight into counterphobia has come from the experiences of children who have parent(s) with a debilitating or fatal diagnosis. Due to their immature coping mechanisms, some children are at risk for maladaptive behavioral responses. The loss of a parent typically produces severe psychological trauma in all children, but in those who develop counterphobia, it manifests as a heightened fear of death and vulnerability to their parent’s illness. This maladaptive response is dependent on self-identification with the parent, especially among daughters of lost mothers and sons of lost fathers, and this fear remains with the child through adulthood. A survey of 154 motherless daughters found that women aged 19 to 35 years have the highest level of obsessive thoughts of mortality and more than 75% believe they will succumb to their mother’s illness (92% in the case of cancer).9 Despite this fear, children may exhibit health-compromising behaviors related to the diagnoses that led to their parents’ deaths; for example, counterphobia has been identified as a pathologic factor behind sexually promiscuous practices in the children of patients with AIDS, and it also may explain high-risk drinking behavior in a child whose parent died from hepatocellular carcinoma due to a history of alcoholic cirrhosis. Similarly, counterphobia can manifest as the deliberate refusal to undergo a mammogram in a woman whose mother died of breast cancer.9 Psychologists have hypothesized that counterphobic pursuits may result from attempts to master the anxiety associated with fear of injury or death as well as from the notion that attempts at risk-factor reduction are futile, as their death is certain.10
The strong influence of counterphobia on perspectives of health and mortality among individuals affected by early loss of a parent is well documented. An assessment of the subjective life expectancy, death anxiety, and health-related behaviors of college students who lost a parent revealed that these individuals estimated their own life spans to be shorter than college students with 2 living parents.11 Moreover, when students were explicitly instructed to predict their life expectancy based on a purely objective mentality rather than one influenced by personal feelings, the exclusion of emotion yielded a longer projected life span. This finding highlights the magnitude of the psychological forces influencing the ethos of individuals affected by premature parental loss. In the same study, individuals who had experienced early loss of a parent believed they would die of the same condition that caused their parent’s death, a finding accompanied by notably poorer diet and smoking behaviors, which might be expected among those with counterphobic defenses.11
Although Manne et al7 did not find an association between melanoma disease severity and sun-protective behavior in FDRs, the study design did not allow for assessment of potential counterphobic responses, which are most likely to develop in younger individuals who strongly identify with the family member whose disease was disabling or fatal. For example, the study included adult relatives (mean age, 46 years) of melanoma patients diagnosed in the preceding 4 years. Furthermore, fewer than 20% (108/545) of the patients had stage III or IV melanoma, and it was not known if melanoma patients communicated the diagnosis to their family members.7
A practice gap exists in FDRs of melanoma patients who are largely assumed to be practicing adequate, if not heightened, sun protection practices. Given that this group demonstrates poor sun protection practices, it is important to identify reasons for such behavior that may extend beyond what is currently known and may include counterphobia. Based on research performed in other medical conditions, the individuals most at risk for counterphobic responses are young children of patients diagnosed with a disabling or fatal condition, but whether in cases of melanoma counterphobia exists as a maladaptive response and whether such a response may occur in all close relatives, not just offspring, is unknown. Currently, the type of measure(s) that may mitigate poor risk factor modification due to counterphobia, including sun protection practices, is unknown. However, physician knowledge of counterphobic responses as a possibility in close relatives of melanoma patients may improve physician efforts to modify behavior in this unique, high-risk population.
The multimodal pathway of melanoma development suggests that individuals with an underlying genetic predisposition for melanoma who also neglect sun-protective measures are an especially high-risk group.12 As such, targeted education and screening of this patient population may be warranted (Table 1). Although it is incumbent on physicians to incorporate concerted screening, counseling, and focused interventions for newly diagnosed melanoma patients, taking similar measures to counsel and educate immediate relatives who may be at high risk for poor sun protection practices also is encouraged (Table 2).
We believe that recognition of counterphobic behavior is critical in the evaluation of FDRs of melanoma patients. Heightened awareness may bolster primary prevention efforts, especially in our patients with genetic diatheses toward melanoma development.
1. Idorn L, Datta P, Heydenreich J, et al. A 3-year follow-up of sun behavior in patients with cutaneous malignant melanoma [published online ahead of print October 2, 2013]. JAMA Dermatol. doi:10.1001/jamadermatol.2013.5098.
2. Idorn LW, Datta P, Heydenreich J, et al. Sun behaviour after cutaneous malignant melanoma: a study based on ultraviolet radiation measurements and sun diary data [published online ahead of print]. Br J Dermatol. 2013;168:367-373.
3. Mayer D, Layman A, Carlson J. Sun-protection behaviors of melanoma survivors. J Am Acad Dermatol. 2012;66:e9-e10.
4. Lee TK, Brazier AS, Shoveller JA, et al. Sun-related behavior after a diagnosis of cutaneous malignant melanoma. Melanoma Res. 2007;17:51-55.
5. Geller AC, Brooks DR, Colditz GA, et al. Sun protection practices among offspring of women with personal or family history of skin cancer. Pediatrics. 2006;117:e688-e694.
6. Azzarello LM, Dessureault S, Jacobsen PB. Sun-protective behavior among individuals with a family history of melanoma. Cancer Epidemiol Boomarkers Prev. 2006;15:142-145.
7. Manne SL, Coups EJ, Jacobsen PB, et al. Sun protection and sunbathing practices among at-risk family members of patients with melanoma. BMC Public Health. 2011;11:122.
8. Fenichel O. The Psychoanalytic Theory of Neurosis. Oxford, United Kingdom: Taylor & Francis; 1999.
9. Edelman H. Motherless Daughters: The Legacy of Loss. 2nd ed. Cambridge, MA: Da Capo Press; 2006.
10. Poznanski E, Arthur B. The counterphobic defense in children. Child Psychiatry Hum Dev. 1971;1:178-191.
11. Denes-Raj V, Ehrlichman H. Effects of premature parental death on subjective life expectancy, death anxiety, and health behavior. Omega: Journal of Death and Dying. 1991;23:309-321.
12. Hayward NK. Genetics of melanoma predisposition. Oncogene. 2003;22:3053-3062.
13. Arthey S, Clarke VA. Suntanning and sun protection: a review of the psychologial literature. Soc Sci Med. 1995;40:265-274.
1. Idorn L, Datta P, Heydenreich J, et al. A 3-year follow-up of sun behavior in patients with cutaneous malignant melanoma [published online ahead of print October 2, 2013]. JAMA Dermatol. doi:10.1001/jamadermatol.2013.5098.
2. Idorn LW, Datta P, Heydenreich J, et al. Sun behaviour after cutaneous malignant melanoma: a study based on ultraviolet radiation measurements and sun diary data [published online ahead of print]. Br J Dermatol. 2013;168:367-373.
3. Mayer D, Layman A, Carlson J. Sun-protection behaviors of melanoma survivors. J Am Acad Dermatol. 2012;66:e9-e10.
4. Lee TK, Brazier AS, Shoveller JA, et al. Sun-related behavior after a diagnosis of cutaneous malignant melanoma. Melanoma Res. 2007;17:51-55.
5. Geller AC, Brooks DR, Colditz GA, et al. Sun protection practices among offspring of women with personal or family history of skin cancer. Pediatrics. 2006;117:e688-e694.
6. Azzarello LM, Dessureault S, Jacobsen PB. Sun-protective behavior among individuals with a family history of melanoma. Cancer Epidemiol Boomarkers Prev. 2006;15:142-145.
7. Manne SL, Coups EJ, Jacobsen PB, et al. Sun protection and sunbathing practices among at-risk family members of patients with melanoma. BMC Public Health. 2011;11:122.
8. Fenichel O. The Psychoanalytic Theory of Neurosis. Oxford, United Kingdom: Taylor & Francis; 1999.
9. Edelman H. Motherless Daughters: The Legacy of Loss. 2nd ed. Cambridge, MA: Da Capo Press; 2006.
10. Poznanski E, Arthur B. The counterphobic defense in children. Child Psychiatry Hum Dev. 1971;1:178-191.
11. Denes-Raj V, Ehrlichman H. Effects of premature parental death on subjective life expectancy, death anxiety, and health behavior. Omega: Journal of Death and Dying. 1991;23:309-321.
12. Hayward NK. Genetics of melanoma predisposition. Oncogene. 2003;22:3053-3062.
13. Arthey S, Clarke VA. Suntanning and sun protection: a review of the psychologial literature. Soc Sci Med. 1995;40:265-274.
Aggressive secondary squamous carcinoma appeared during BRAF inhibitor targeted therapy
A woman undergoing BRAF inhibitor targeted therapy for advanced melanoma has presented with invasive spindle cell squamous carcinoma masquerading as a secondary cutaneous squamous cell carcinoma, highlighting the importance of histologic evaluation of these lesions.
"Secondary cutaneous squamous cell carcinomas (cSCCs) are adverse effects of BRAF inhibitor targeted therapy for advanced melanoma," wrote Dr. Daniel N. Cohen and his associates online Feb. 26 in JAMA Dermatology.
The most commonly seen histologic type of secondary cutaneous squamous cell carcinomas is keratoacanthoma-like cSCC (cSCC-KA), which is thought to have a low risk of metastasis or recurrence, said lead author Dr. Cohen of the Vanderbilt University Medical Center, Nashville, Tenn.
In this case report, however, a woman in her 50s with BRAF-mutant metastatic melanoma developed more than 100 new cutaneous squamous proliferations across her face, trunk, and extremities within 4 weeks of starting treatment with the BRAF inhibitor dabrafenib as part of a clinical trial, with some lesions appearing to be a more aggressive type upon analysis.
The lesions began as acrochordons on her face and extremities, as well as new nevi on her torso and axilla. She also developed fever, chills, and fatigue and had enlarging, tender, and bleeding lesions on her trunk and extremities.
Seven large, tender, and indurated lesions were removed using a deep scoop shave biopsy, revealing a biphasic malignant growth pattern (JAMA Dermatology 2014 Feb 26 [doi:10.1001/jamadermatol.2013.7784]).
"The superficial portion demonstrated conventional cSCC-KA features of hyperkeratosis, epidermal acanthosis, and central core of glassy eosinophilic keratin with pseudopapillomatosis and a base with focal invasive lobules of cytologically atypical keratinocytes, consistent with previously reported cSCC-KA" the study authors reported.
However, they added, "in stark contrast to prior reports, the deep aspects of 6 of 7 lesions showed invasive spindled and epithelioid cells with monomorphic elongated nuclei with condensed chromatin and mitoses consistent with spindle cell squamous carcinoma, an aggressive subtype of squamous cell carcinoma."
The cells were strongly immunoreactive for cytokeratin CK5/6 and CK903, and both the squamous and spindle components were vimentin reactive and showed increased proliferation index. In contrast to the usual pattern of a spindle cell melanoma, the spindle tumor cells were also MART-1 and S100 negative.
The authors said this was the first known report of invasive spindle cell squamous carcinoma that mimicked keratoacanthoma-like secondary SCC appearing during BRAF inhibitor therapy and suggested that the discovery has implications for management of secondary squamous cell carcinoma.
"Because the clinical appearance of cSCC-KA and the spindle cell squamous carcinomas in our patient are indistinguishable, histologic evaluation of the entire lesion (via saucerization biopsy or incisional biopsy) is vital to prevent inadequate treatment of a deeply invasive process with a probable higher malignant potential," Dr. Cohen and his associates wrote.
The patient stopped BRAF inhibitor therapy and had no recurrence or new development of cutaneous secondary SCCs. A single later recurrence of melanoma was resected but she remains disease free.
One author declared a consultancy with Bristol-Myers Squibb and Genentech, as well as grant support from Genentech. There were no other financial disclosures reported.
A woman undergoing BRAF inhibitor targeted therapy for advanced melanoma has presented with invasive spindle cell squamous carcinoma masquerading as a secondary cutaneous squamous cell carcinoma, highlighting the importance of histologic evaluation of these lesions.
"Secondary cutaneous squamous cell carcinomas (cSCCs) are adverse effects of BRAF inhibitor targeted therapy for advanced melanoma," wrote Dr. Daniel N. Cohen and his associates online Feb. 26 in JAMA Dermatology.
The most commonly seen histologic type of secondary cutaneous squamous cell carcinomas is keratoacanthoma-like cSCC (cSCC-KA), which is thought to have a low risk of metastasis or recurrence, said lead author Dr. Cohen of the Vanderbilt University Medical Center, Nashville, Tenn.
In this case report, however, a woman in her 50s with BRAF-mutant metastatic melanoma developed more than 100 new cutaneous squamous proliferations across her face, trunk, and extremities within 4 weeks of starting treatment with the BRAF inhibitor dabrafenib as part of a clinical trial, with some lesions appearing to be a more aggressive type upon analysis.
The lesions began as acrochordons on her face and extremities, as well as new nevi on her torso and axilla. She also developed fever, chills, and fatigue and had enlarging, tender, and bleeding lesions on her trunk and extremities.
Seven large, tender, and indurated lesions were removed using a deep scoop shave biopsy, revealing a biphasic malignant growth pattern (JAMA Dermatology 2014 Feb 26 [doi:10.1001/jamadermatol.2013.7784]).
"The superficial portion demonstrated conventional cSCC-KA features of hyperkeratosis, epidermal acanthosis, and central core of glassy eosinophilic keratin with pseudopapillomatosis and a base with focal invasive lobules of cytologically atypical keratinocytes, consistent with previously reported cSCC-KA" the study authors reported.
However, they added, "in stark contrast to prior reports, the deep aspects of 6 of 7 lesions showed invasive spindled and epithelioid cells with monomorphic elongated nuclei with condensed chromatin and mitoses consistent with spindle cell squamous carcinoma, an aggressive subtype of squamous cell carcinoma."
The cells were strongly immunoreactive for cytokeratin CK5/6 and CK903, and both the squamous and spindle components were vimentin reactive and showed increased proliferation index. In contrast to the usual pattern of a spindle cell melanoma, the spindle tumor cells were also MART-1 and S100 negative.
The authors said this was the first known report of invasive spindle cell squamous carcinoma that mimicked keratoacanthoma-like secondary SCC appearing during BRAF inhibitor therapy and suggested that the discovery has implications for management of secondary squamous cell carcinoma.
"Because the clinical appearance of cSCC-KA and the spindle cell squamous carcinomas in our patient are indistinguishable, histologic evaluation of the entire lesion (via saucerization biopsy or incisional biopsy) is vital to prevent inadequate treatment of a deeply invasive process with a probable higher malignant potential," Dr. Cohen and his associates wrote.
The patient stopped BRAF inhibitor therapy and had no recurrence or new development of cutaneous secondary SCCs. A single later recurrence of melanoma was resected but she remains disease free.
One author declared a consultancy with Bristol-Myers Squibb and Genentech, as well as grant support from Genentech. There were no other financial disclosures reported.
A woman undergoing BRAF inhibitor targeted therapy for advanced melanoma has presented with invasive spindle cell squamous carcinoma masquerading as a secondary cutaneous squamous cell carcinoma, highlighting the importance of histologic evaluation of these lesions.
"Secondary cutaneous squamous cell carcinomas (cSCCs) are adverse effects of BRAF inhibitor targeted therapy for advanced melanoma," wrote Dr. Daniel N. Cohen and his associates online Feb. 26 in JAMA Dermatology.
The most commonly seen histologic type of secondary cutaneous squamous cell carcinomas is keratoacanthoma-like cSCC (cSCC-KA), which is thought to have a low risk of metastasis or recurrence, said lead author Dr. Cohen of the Vanderbilt University Medical Center, Nashville, Tenn.
In this case report, however, a woman in her 50s with BRAF-mutant metastatic melanoma developed more than 100 new cutaneous squamous proliferations across her face, trunk, and extremities within 4 weeks of starting treatment with the BRAF inhibitor dabrafenib as part of a clinical trial, with some lesions appearing to be a more aggressive type upon analysis.
The lesions began as acrochordons on her face and extremities, as well as new nevi on her torso and axilla. She also developed fever, chills, and fatigue and had enlarging, tender, and bleeding lesions on her trunk and extremities.
Seven large, tender, and indurated lesions were removed using a deep scoop shave biopsy, revealing a biphasic malignant growth pattern (JAMA Dermatology 2014 Feb 26 [doi:10.1001/jamadermatol.2013.7784]).
"The superficial portion demonstrated conventional cSCC-KA features of hyperkeratosis, epidermal acanthosis, and central core of glassy eosinophilic keratin with pseudopapillomatosis and a base with focal invasive lobules of cytologically atypical keratinocytes, consistent with previously reported cSCC-KA" the study authors reported.
However, they added, "in stark contrast to prior reports, the deep aspects of 6 of 7 lesions showed invasive spindled and epithelioid cells with monomorphic elongated nuclei with condensed chromatin and mitoses consistent with spindle cell squamous carcinoma, an aggressive subtype of squamous cell carcinoma."
The cells were strongly immunoreactive for cytokeratin CK5/6 and CK903, and both the squamous and spindle components were vimentin reactive and showed increased proliferation index. In contrast to the usual pattern of a spindle cell melanoma, the spindle tumor cells were also MART-1 and S100 negative.
The authors said this was the first known report of invasive spindle cell squamous carcinoma that mimicked keratoacanthoma-like secondary SCC appearing during BRAF inhibitor therapy and suggested that the discovery has implications for management of secondary squamous cell carcinoma.
"Because the clinical appearance of cSCC-KA and the spindle cell squamous carcinomas in our patient are indistinguishable, histologic evaluation of the entire lesion (via saucerization biopsy or incisional biopsy) is vital to prevent inadequate treatment of a deeply invasive process with a probable higher malignant potential," Dr. Cohen and his associates wrote.
The patient stopped BRAF inhibitor therapy and had no recurrence or new development of cutaneous secondary SCCs. A single later recurrence of melanoma was resected but she remains disease free.
One author declared a consultancy with Bristol-Myers Squibb and Genentech, as well as grant support from Genentech. There were no other financial disclosures reported.
FROM JAMA DERMATOLOGY
Major finding: A woman undergoing BRAF inhibitor targeted therapy for advanced melanoma has presented with invasive spindle cell squamous carcinoma masquerading as a secondary cutaneous squamous cell carcinoma.
Data source: Case report.
Disclosures: One author declared a consultancy with Bristol-Myers Squibb and Genentech, as well as grant support from Genentech. There were no other financial disclosures reported.
Dabrafenib in advanced melanoma with BRAF V600E mutation
Dabrafenib was recently approved by the US Food and Drug Administration for treatment of unresectable or metastatic melanoma with BRAF V600E mutations as detected by an FDA-approved test. The THxID BRAF assay, for detection of BRAF V600E mutations was concurrently approved. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma, because of the potential risk of tumor promotion. About 50% of melanomas have an activating mutation in the BRAF gene, with about 80%-90% of those having a V600E mutation, and 10%-20% having a V600K mutation.
Click on the PDF icon at the top of this introduction to read the full article.
Dabrafenib was recently approved by the US Food and Drug Administration for treatment of unresectable or metastatic melanoma with BRAF V600E mutations as detected by an FDA-approved test. The THxID BRAF assay, for detection of BRAF V600E mutations was concurrently approved. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma, because of the potential risk of tumor promotion. About 50% of melanomas have an activating mutation in the BRAF gene, with about 80%-90% of those having a V600E mutation, and 10%-20% having a V600K mutation.
Click on the PDF icon at the top of this introduction to read the full article.
Dabrafenib was recently approved by the US Food and Drug Administration for treatment of unresectable or metastatic melanoma with BRAF V600E mutations as detected by an FDA-approved test. The THxID BRAF assay, for detection of BRAF V600E mutations was concurrently approved. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma, because of the potential risk of tumor promotion. About 50% of melanomas have an activating mutation in the BRAF gene, with about 80%-90% of those having a V600E mutation, and 10%-20% having a V600K mutation.
Click on the PDF icon at the top of this introduction to read the full article.