Melanoma

CHICAGO – Two new oral targeted agents that have yielded positive results in phase III clinical trials are likely to change the treatment landscape for the half of patients with melanoma whose tumors have a mutation of BRAF driving their behavior.

The drugs – trametinib and dabrafenib – both interfere with signaling in the BRAF pathway and respectively reduced the risk of progression or death by 55% and 70% relative to chemotherapy in patients with advanced melanoma harboring common BRAF mutations, according to data presented at the annual meeting of the American Society of Clinical Oncology. These drugs also had good safety profiles.

Thus, trametinib and dabrafenib are likely to join vemurafenib (Zelboraf), the only targeted agent currently approved specifically for the treatment of BRAF-mutant melanoma.

The trials’ findings "show the promise of personalized medicine or precision medicine, using a patient-focused approach that targets treatment to the genetic abnormalities that drive cancer growth and metastatic behavior," Dr. Sylvia Adams of New York University Langone Medical Center commented in a press briefing that she moderated, where the findings were initially reported.

In the first trial, known as METRIC, investigators led by Dr. Caroline Robert, head of the department of dermatology at the Institut Gustave Roussy in Villejuif, France, compared trametinib – an oral selective inhibitor of MEK, which lies downstream of BRAF – with chemotherapy (dacarbazine or paclitaxel) in 322 patients with V600E or V600K BRAF-mutant locally advanced or metastatic melanoma.

Patients in the trametinib group had a higher rate of grade 3 or worse hypertension (12% vs. 3%) and rash (8% vs. 0%). Cases of decreased ejection fraction or ventricular dysfunction (7%) and chorioretinopathy (less than 1%) with the drug were reversible. Of note – in contrast to what has been seen with vemurafenib – none of the patients developed cutaneous squamous cell carcinomas.

Median progression-free survival was longer with trametinib than with chemotherapy (4.8 vs. 1.5 months; hazard ratio, 0.45; P less than .0001), according to data reported at the meeting. (Full results are also being simultaneously published in the New England Journal of Medicine.)

Trametinib reduced the risk of death as well (HR, 0.54; P = .01). "Crossover was allowed," Dr. Robert noted. "That of course can blend the results of overall survival, but even in spite of this crossover in 47% of the patients [in the chemotherapy group], we still have a difference in overall survival.

"Trametinib is the first-in-class MEK inhibitor to show a statistically significant activity in progression-free survival, response rate, and overall survival benefit in a randomized trial and here in this population of BRAF-mutant melanoma patients. The safety profile is very manageable," she commented. "Thus, this phase III trial provides a really positive risk-benefit ratio of trametinib in patients with BRAF-mutant melanoma and delivers an alternate treatment option for these patients."

Dr. Robert said that she didn’t view it as problematic that oncologists may soon have to select among multiple drugs for this patient population. "Let me remind you, for 50 years, we had nothing. And very recently, we have one drug on the market, a BRAF inhibitor; now, hopefully we will have others. So we are very happy to have more than one drug. The future will tell us how to use these drugs, and we are looking forward to try[ing] the combination of BRAF and MEK inhibitors."

Dr. Adams, the press briefing moderator, characterized the findings as "exciting" for two reasons. "Number one, it shows that in metastatic melanoma, MEK pathway–targeted therapy, as seen here for MEK inhibition, is very effective. So there is tumor shrinkage; there is survival benefit for those patients. And second, it also opens the landscape of treatments for BRAF-mutant melanomas and provides patients with additional options."

In the second trial, known as BREAK-3, a team led by Dr. Axel Hauschild, professor of dermatology at the University Hospital in Kiel, Germany, compared dabrafenib, an oral inhibitor of BRAF, with chemotherapy (dacarbazine) in 250 patients with locally advanced or metastatic V600E BRAF-mutant melanoma. In this trial, 68% of patients in the chemotherapy group ultimately crossed over to the other group.

Compared with chemotherapy, dabrafenib improved median progression-free survival (5.1 vs. 2.7 months; HR, 0.30; P less than .0001). The rate of complete or partial response was more than double with the targeted therapy (53% vs. 19%).

"The data for overall survival are very immature; only 12% of the patients have died so far, and therefore the data are not presented here," Dr. Hauschild explained.

Dabrafenib was associated with higher rates of grade 3 or worse hyperkeratosis (2% vs. 0%) and squamous cell carcinoma (5% vs. 0%), whereas chemotherapy was associated with higher rates of grade 3 or worse hematologic adverse events.

"The next step is the combination of dabrafenib and the drug trametinib, not only for stage IV but also for the adjuvant setting," Dr. Hauschild commented. In fact, updated results of a phase I/II trial testing the combination are also being reported at the meeting.

Given the availability of BRAF-targeted therapy today, all melanomas should have mutational testing at minimum for BRAF status, he said. Additionally, clinical trials will be essential to sorting out the various new treatment options.

"It’s not the end of the story for me: It’s the beginning of a completely new era of treatment of metastatic melanoma, and I strongly believe in combinations. Therefore, it’s very much appreciated if patients are brought to clinical trials," he said. "But they need to receive in these clinical trials standard of care. And for BRAF-mutated patients, standard of care is no longer [dacarbazine]; it’s no longer placebo. It needs to be a BRAF inhibitor."

Dr. Adams, the moderator, commented, "This phase III study of dabrafenib confirms that BRAF targeting in mutant melanoma is highly effective as seen by tumor shrinkage in about half of the patients, similar to the [Food and Drug Administration]–approved drug vemurafenib and potentially with less severe skin side effects. We are eagerly awaiting results of combinatorial therapy to see if combinations can actually push out the onset of resistance."

Dr. Robert disclosed that she is a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche. Dr. Hauschild disclosed that he is a consultant to and receives honoraria and research funding from GlaxoSmithKline. Both trials were funded by GlaxoSmithKline. Dr. Adams disclosed that she is a consultant to GlaxoSmithKline.

CHICAGO – Two new oral targeted agents that have yielded positive results in phase III clinical trials are likely to change the treatment landscape for the half of patients with melanoma whose tumors have a mutation of BRAF driving their behavior.

The drugs – trametinib and dabrafenib – both interfere with signaling in the BRAF pathway and respectively reduced the risk of progression or death by 55% and 70% relative to chemotherapy in patients with advanced melanoma harboring common BRAF mutations, according to data presented at the annual meeting of the American Society of Clinical Oncology. These drugs also had good safety profiles.

Thus, trametinib and dabrafenib are likely to join vemurafenib (Zelboraf), the only targeted agent currently approved specifically for the treatment of BRAF-mutant melanoma.

The trials’ findings "show the promise of personalized medicine or precision medicine, using a patient-focused approach that targets treatment to the genetic abnormalities that drive cancer growth and metastatic behavior," Dr. Sylvia Adams of New York University Langone Medical Center commented in a press briefing that she moderated, where the findings were initially reported.

In the first trial, known as METRIC, investigators led by Dr. Caroline Robert, head of the department of dermatology at the Institut Gustave Roussy in Villejuif, France, compared trametinib – an oral selective inhibitor of MEK, which lies downstream of BRAF – with chemotherapy (dacarbazine or paclitaxel) in 322 patients with V600E or V600K BRAF-mutant locally advanced or metastatic melanoma.

Patients in the trametinib group had a higher rate of grade 3 or worse hypertension (12% vs. 3%) and rash (8% vs. 0%). Cases of decreased ejection fraction or ventricular dysfunction (7%) and chorioretinopathy (less than 1%) with the drug were reversible. Of note – in contrast to what has been seen with vemurafenib – none of the patients developed cutaneous squamous cell carcinomas.

Median progression-free survival was longer with trametinib than with chemotherapy (4.8 vs. 1.5 months; hazard ratio, 0.45; P less than .0001), according to data reported at the meeting. (Full results are also being simultaneously published in the New England Journal of Medicine.)

Trametinib reduced the risk of death as well (HR, 0.54; P = .01). "Crossover was allowed," Dr. Robert noted. "That of course can blend the results of overall survival, but even in spite of this crossover in 47% of the patients [in the chemotherapy group], we still have a difference in overall survival.

"Trametinib is the first-in-class MEK inhibitor to show a statistically significant activity in progression-free survival, response rate, and overall survival benefit in a randomized trial and here in this population of BRAF-mutant melanoma patients. The safety profile is very manageable," she commented. "Thus, this phase III trial provides a really positive risk-benefit ratio of trametinib in patients with BRAF-mutant melanoma and delivers an alternate treatment option for these patients."

Dr. Robert said that she didn’t view it as problematic that oncologists may soon have to select among multiple drugs for this patient population. "Let me remind you, for 50 years, we had nothing. And very recently, we have one drug on the market, a BRAF inhibitor; now, hopefully we will have others. So we are very happy to have more than one drug. The future will tell us how to use these drugs, and we are looking forward to try[ing] the combination of BRAF and MEK inhibitors."

Dr. Adams, the press briefing moderator, characterized the findings as "exciting" for two reasons. "Number one, it shows that in metastatic melanoma, MEK pathway–targeted therapy, as seen here for MEK inhibition, is very effective. So there is tumor shrinkage; there is survival benefit for those patients. And second, it also opens the landscape of treatments for BRAF-mutant melanomas and provides patients with additional options."

In the second trial, known as BREAK-3, a team led by Dr. Axel Hauschild, professor of dermatology at the University Hospital in Kiel, Germany, compared dabrafenib, an oral inhibitor of BRAF, with chemotherapy (dacarbazine) in 250 patients with locally advanced or metastatic V600E BRAF-mutant melanoma. In this trial, 68% of patients in the chemotherapy group ultimately crossed over to the other group.

Compared with chemotherapy, dabrafenib improved median progression-free survival (5.1 vs. 2.7 months; HR, 0.30; P less than .0001). The rate of complete or partial response was more than double with the targeted therapy (53% vs. 19%).

"The data for overall survival are very immature; only 12% of the patients have died so far, and therefore the data are not presented here," Dr. Hauschild explained.

Dabrafenib was associated with higher rates of grade 3 or worse hyperkeratosis (2% vs. 0%) and squamous cell carcinoma (5% vs. 0%), whereas chemotherapy was associated with higher rates of grade 3 or worse hematologic adverse events.

"The next step is the combination of dabrafenib and the drug trametinib, not only for stage IV but also for the adjuvant setting," Dr. Hauschild commented. In fact, updated results of a phase I/II trial testing the combination are also being reported at the meeting.

Given the availability of BRAF-targeted therapy today, all melanomas should have mutational testing at minimum for BRAF status, he said. Additionally, clinical trials will be essential to sorting out the various new treatment options.

"It’s not the end of the story for me: It’s the beginning of a completely new era of treatment of metastatic melanoma, and I strongly believe in combinations. Therefore, it’s very much appreciated if patients are brought to clinical trials," he said. "But they need to receive in these clinical trials standard of care. And for BRAF-mutated patients, standard of care is no longer [dacarbazine]; it’s no longer placebo. It needs to be a BRAF inhibitor."

Dr. Adams, the moderator, commented, "This phase III study of dabrafenib confirms that BRAF targeting in mutant melanoma is highly effective as seen by tumor shrinkage in about half of the patients, similar to the [Food and Drug Administration]–approved drug vemurafenib and potentially with less severe skin side effects. We are eagerly awaiting results of combinatorial therapy to see if combinations can actually push out the onset of resistance."

Dr. Robert disclosed that she is a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche. Dr. Hauschild disclosed that he is a consultant to and receives honoraria and research funding from GlaxoSmithKline. Both trials were funded by GlaxoSmithKline. Dr. Adams disclosed that she is a consultant to GlaxoSmithKline.

CHICAGO – Two new oral targeted agents that have yielded positive results in phase III clinical trials are likely to change the treatment landscape for the half of patients with melanoma whose tumors have a mutation of BRAF driving their behavior.

The drugs – trametinib and dabrafenib – both interfere with signaling in the BRAF pathway and respectively reduced the risk of progression or death by 55% and 70% relative to chemotherapy in patients with advanced melanoma harboring common BRAF mutations, according to data presented at the annual meeting of the American Society of Clinical Oncology. These drugs also had good safety profiles.

Thus, trametinib and dabrafenib are likely to join vemurafenib (Zelboraf), the only targeted agent currently approved specifically for the treatment of BRAF-mutant melanoma.

The trials’ findings "show the promise of personalized medicine or precision medicine, using a patient-focused approach that targets treatment to the genetic abnormalities that drive cancer growth and metastatic behavior," Dr. Sylvia Adams of New York University Langone Medical Center commented in a press briefing that she moderated, where the findings were initially reported.

In the first trial, known as METRIC, investigators led by Dr. Caroline Robert, head of the department of dermatology at the Institut Gustave Roussy in Villejuif, France, compared trametinib – an oral selective inhibitor of MEK, which lies downstream of BRAF – with chemotherapy (dacarbazine or paclitaxel) in 322 patients with V600E or V600K BRAF-mutant locally advanced or metastatic melanoma.

Patients in the trametinib group had a higher rate of grade 3 or worse hypertension (12% vs. 3%) and rash (8% vs. 0%). Cases of decreased ejection fraction or ventricular dysfunction (7%) and chorioretinopathy (less than 1%) with the drug were reversible. Of note – in contrast to what has been seen with vemurafenib – none of the patients developed cutaneous squamous cell carcinomas.

Median progression-free survival was longer with trametinib than with chemotherapy (4.8 vs. 1.5 months; hazard ratio, 0.45; P less than .0001), according to data reported at the meeting. (Full results are also being simultaneously published in the New England Journal of Medicine.)

Trametinib reduced the risk of death as well (HR, 0.54; P = .01). "Crossover was allowed," Dr. Robert noted. "That of course can blend the results of overall survival, but even in spite of this crossover in 47% of the patients [in the chemotherapy group], we still have a difference in overall survival.

"Trametinib is the first-in-class MEK inhibitor to show a statistically significant activity in progression-free survival, response rate, and overall survival benefit in a randomized trial and here in this population of BRAF-mutant melanoma patients. The safety profile is very manageable," she commented. "Thus, this phase III trial provides a really positive risk-benefit ratio of trametinib in patients with BRAF-mutant melanoma and delivers an alternate treatment option for these patients."

Dr. Robert said that she didn’t view it as problematic that oncologists may soon have to select among multiple drugs for this patient population. "Let me remind you, for 50 years, we had nothing. And very recently, we have one drug on the market, a BRAF inhibitor; now, hopefully we will have others. So we are very happy to have more than one drug. The future will tell us how to use these drugs, and we are looking forward to try[ing] the combination of BRAF and MEK inhibitors."

Dr. Adams, the press briefing moderator, characterized the findings as "exciting" for two reasons. "Number one, it shows that in metastatic melanoma, MEK pathway–targeted therapy, as seen here for MEK inhibition, is very effective. So there is tumor shrinkage; there is survival benefit for those patients. And second, it also opens the landscape of treatments for BRAF-mutant melanomas and provides patients with additional options."

In the second trial, known as BREAK-3, a team led by Dr. Axel Hauschild, professor of dermatology at the University Hospital in Kiel, Germany, compared dabrafenib, an oral inhibitor of BRAF, with chemotherapy (dacarbazine) in 250 patients with locally advanced or metastatic V600E BRAF-mutant melanoma. In this trial, 68% of patients in the chemotherapy group ultimately crossed over to the other group.

Compared with chemotherapy, dabrafenib improved median progression-free survival (5.1 vs. 2.7 months; HR, 0.30; P less than .0001). The rate of complete or partial response was more than double with the targeted therapy (53% vs. 19%).

"The data for overall survival are very immature; only 12% of the patients have died so far, and therefore the data are not presented here," Dr. Hauschild explained.

Dabrafenib was associated with higher rates of grade 3 or worse hyperkeratosis (2% vs. 0%) and squamous cell carcinoma (5% vs. 0%), whereas chemotherapy was associated with higher rates of grade 3 or worse hematologic adverse events.

"The next step is the combination of dabrafenib and the drug trametinib, not only for stage IV but also for the adjuvant setting," Dr. Hauschild commented. In fact, updated results of a phase I/II trial testing the combination are also being reported at the meeting.

Given the availability of BRAF-targeted therapy today, all melanomas should have mutational testing at minimum for BRAF status, he said. Additionally, clinical trials will be essential to sorting out the various new treatment options.

"It’s not the end of the story for me: It’s the beginning of a completely new era of treatment of metastatic melanoma, and I strongly believe in combinations. Therefore, it’s very much appreciated if patients are brought to clinical trials," he said. "But they need to receive in these clinical trials standard of care. And for BRAF-mutated patients, standard of care is no longer [dacarbazine]; it’s no longer placebo. It needs to be a BRAF inhibitor."

Dr. Adams, the moderator, commented, "This phase III study of dabrafenib confirms that BRAF targeting in mutant melanoma is highly effective as seen by tumor shrinkage in about half of the patients, similar to the [Food and Drug Administration]–approved drug vemurafenib and potentially with less severe skin side effects. We are eagerly awaiting results of combinatorial therapy to see if combinations can actually push out the onset of resistance."

Dr. Robert disclosed that she is a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche. Dr. Hauschild disclosed that he is a consultant to and receives honoraria and research funding from GlaxoSmithKline. Both trials were funded by GlaxoSmithKline. Dr. Adams disclosed that she is a consultant to GlaxoSmithKline.

CHICAGO – Nearly one-quarter of patients with a range of heavily pretreated solid tumors responded to a new immunotherapy called BMS-936558, with some responses persisting for more than 1 year.

"One of the remarkable features about this therapy is that it can induce very durable responses in patients with otherwise treatment-refractory disease," lead author Dr. Suzanne Topalian said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances anti-tumor immunity.

When tested in the phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Topalian, who will present the results at the ASCO meeting.

This sets BMS-936558 apart from other immunotherapies such as ipilimumab (Yervoy), which results in response rates of 10%-15% in metastatic melanoma but also clinically significant toxic effects in 20%-30% of patients.

Three treatment-related deaths occurred as a result of pneumonitis or lung inflammation, although better methods have been developed for aggressive treatment and early recognition of patients at risk for this side effect, she said.

BMS-936558 is also unique in that it was clinically active in lung cancer, which historically has been resistant to immunotherapy. In this subset, the objective response rate was 18%, with 7% achieving stable disease lasting 24 weeks or more. Notably, 55% of patients had received at least three prior lines of therapy, said Dr. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore.

"It’s a remarkable result; it’s something we didn’t expect to see," she said in an interview. "I’ve been in the field of cancer immunotherapy since 1985 and this was a genuine surprise."

Although the data should be interpreted with caution because of the small patient numbers, BMS-936558 appears to be more beneficial in squamous tumors, for which the response rate was 33%, compared with 12% among nonsquamous tumors, she added.

The results represent years of basic science and proof-of-concept that targeting the PD-1 pathway is valuable in cancer therapy. The early phase trial is generating enough excitement to be simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690]), along with a second study involving PD-L1 blockade that reported slightly lower response and adverse event rates (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694]).

Taken together, "these initial observations suggest that antibodies blocking PD-1 or PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," wrote Dr. Antoni Ribas in an editorial accompanying the studies (doi:10.1056/NEJMe1205943).

Dr. Topalian and her associates administered BMS-936558 at doses of 1.0, 3.0, or 10 mg/kg of body weight as an intravenous infusion every 2 weeks for up to 2 years in 296 patients with metastatic melanoma, colorectal, non–small-cell lung cancer, prostate, and renal cancer that had progressed after at least one and up to five previous therapies.

Objective responses were observed in 28% of patients with melanoma and 27% with renal cell cancer, with stable disease reported in 6% and 27%, respectively. Patients with colon and prostate* cancer did not have tumor responses, Dr. Topalian said.

Overall, 31 patients had a response that occurred at least 1 year ago and, of these, 20 responses persisted for more than 1 year.

The most common adverse events were fatigue, rash, diarrhea, pruritus, nausea, decreased appetite or hemoglobin, and pyrexia. Grade 3/4 treatment-related adverse events were similar across all doses, and included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis in addition to pneumonitis.

Ultimately, BMS-936558 may be used first line or in combination with other immunotherapies or targeted therapies in advanced disease, Dr. Topalian said.

"There may be rational ways to combine these agents, that by themselves have limitations, but when combined with PD-1 blockade there is a synergistic effect," she said. "And there is laboratory evidence to suggest that certain kinds of combinations can be synergistic."

A trial evaluating the combination of ipilimumab and BMS-936558 is already underway at Memorial Sloan Kettering Cancer Center, she observed. Phase III trials also are being planned in non–small-cell lung cancer, melanoma, and renal cell cancer.

Finally, an immunohistochemical analysis performed on 42 pretreatment tumor specimens suggests that PD-L1 expression could serve as a potential marker of treatment response. In all, 9 of 25 patients with PD-L1–positive tumors had an objective response, compared with no objective responses among 17 patients with PD-L1–negative tumors (P value = .006).

In his editorial, Dr. Ribas, director of the tumor immunology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, remarked: "The use of PD-1 blockade – with its reduced rate of toxic effects and potential ability to further select patients who have increased likelihood of tumor response – may well have a major effect on cancer treatment."

The study was supported by Bristol-Myers Squibb, Ono Pharmaceuticals, and grants from the National Institutes of Health and the Melanoma Research Alliance. Dr. Topalian also reported consulting for BMS and Amplimmune, and her coauthors reported financial relationships with BMS, including stock ownership, employment, and leadership positions. Dr. Ribas reported no relevant conflicts of interest.

*Correction, 6/21/2012: An earlier version of this story mischaracterized the patients that did not have tumor responses.

CHICAGO – Nearly one-quarter of patients with a range of heavily pretreated solid tumors responded to a new immunotherapy called BMS-936558, with some responses persisting for more than 1 year.

"One of the remarkable features about this therapy is that it can induce very durable responses in patients with otherwise treatment-refractory disease," lead author Dr. Suzanne Topalian said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances anti-tumor immunity.

When tested in the phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Topalian, who will present the results at the ASCO meeting.

This sets BMS-936558 apart from other immunotherapies such as ipilimumab (Yervoy), which results in response rates of 10%-15% in metastatic melanoma but also clinically significant toxic effects in 20%-30% of patients.

Three treatment-related deaths occurred as a result of pneumonitis or lung inflammation, although better methods have been developed for aggressive treatment and early recognition of patients at risk for this side effect, she said.

BMS-936558 is also unique in that it was clinically active in lung cancer, which historically has been resistant to immunotherapy. In this subset, the objective response rate was 18%, with 7% achieving stable disease lasting 24 weeks or more. Notably, 55% of patients had received at least three prior lines of therapy, said Dr. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore.

"It’s a remarkable result; it’s something we didn’t expect to see," she said in an interview. "I’ve been in the field of cancer immunotherapy since 1985 and this was a genuine surprise."

Although the data should be interpreted with caution because of the small patient numbers, BMS-936558 appears to be more beneficial in squamous tumors, for which the response rate was 33%, compared with 12% among nonsquamous tumors, she added.

The results represent years of basic science and proof-of-concept that targeting the PD-1 pathway is valuable in cancer therapy. The early phase trial is generating enough excitement to be simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690]), along with a second study involving PD-L1 blockade that reported slightly lower response and adverse event rates (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694]).

Taken together, "these initial observations suggest that antibodies blocking PD-1 or PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," wrote Dr. Antoni Ribas in an editorial accompanying the studies (doi:10.1056/NEJMe1205943).

Dr. Topalian and her associates administered BMS-936558 at doses of 1.0, 3.0, or 10 mg/kg of body weight as an intravenous infusion every 2 weeks for up to 2 years in 296 patients with metastatic melanoma, colorectal, non–small-cell lung cancer, prostate, and renal cancer that had progressed after at least one and up to five previous therapies.

Objective responses were observed in 28% of patients with melanoma and 27% with renal cell cancer, with stable disease reported in 6% and 27%, respectively. Patients with colon and prostate* cancer did not have tumor responses, Dr. Topalian said.

Overall, 31 patients had a response that occurred at least 1 year ago and, of these, 20 responses persisted for more than 1 year.

The most common adverse events were fatigue, rash, diarrhea, pruritus, nausea, decreased appetite or hemoglobin, and pyrexia. Grade 3/4 treatment-related adverse events were similar across all doses, and included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis in addition to pneumonitis.

Ultimately, BMS-936558 may be used first line or in combination with other immunotherapies or targeted therapies in advanced disease, Dr. Topalian said.

"There may be rational ways to combine these agents, that by themselves have limitations, but when combined with PD-1 blockade there is a synergistic effect," she said. "And there is laboratory evidence to suggest that certain kinds of combinations can be synergistic."

A trial evaluating the combination of ipilimumab and BMS-936558 is already underway at Memorial Sloan Kettering Cancer Center, she observed. Phase III trials also are being planned in non–small-cell lung cancer, melanoma, and renal cell cancer.

Finally, an immunohistochemical analysis performed on 42 pretreatment tumor specimens suggests that PD-L1 expression could serve as a potential marker of treatment response. In all, 9 of 25 patients with PD-L1–positive tumors had an objective response, compared with no objective responses among 17 patients with PD-L1–negative tumors (P value = .006).

In his editorial, Dr. Ribas, director of the tumor immunology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, remarked: "The use of PD-1 blockade – with its reduced rate of toxic effects and potential ability to further select patients who have increased likelihood of tumor response – may well have a major effect on cancer treatment."

The study was supported by Bristol-Myers Squibb, Ono Pharmaceuticals, and grants from the National Institutes of Health and the Melanoma Research Alliance. Dr. Topalian also reported consulting for BMS and Amplimmune, and her coauthors reported financial relationships with BMS, including stock ownership, employment, and leadership positions. Dr. Ribas reported no relevant conflicts of interest.

*Correction, 6/21/2012: An earlier version of this story mischaracterized the patients that did not have tumor responses.

CHICAGO – Nearly one-quarter of patients with a range of heavily pretreated solid tumors responded to a new immunotherapy called BMS-936558, with some responses persisting for more than 1 year.

"One of the remarkable features about this therapy is that it can induce very durable responses in patients with otherwise treatment-refractory disease," lead author Dr. Suzanne Topalian said at a press briefing at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a monoclonal antibody that blocks the programmed death (PD)-1 receptor on the surface of activated T cells. Inhibition of the PD-1 and the PD-1 ligand (PD-L1) pathway rescues exhausted T-cells and enhances anti-tumor immunity.

When tested in the phase I trial, objective responses, defined as complete regression or significant partial regression, were reported in 18%-28% of 236 evaluable patients.

Serious side effects were observed in 14% of the 296 patients in the entire cohort, said Dr. Topalian, who will present the results at the ASCO meeting.

This sets BMS-936558 apart from other immunotherapies such as ipilimumab (Yervoy), which results in response rates of 10%-15% in metastatic melanoma but also clinically significant toxic effects in 20%-30% of patients.

Three treatment-related deaths occurred as a result of pneumonitis or lung inflammation, although better methods have been developed for aggressive treatment and early recognition of patients at risk for this side effect, she said.

BMS-936558 is also unique in that it was clinically active in lung cancer, which historically has been resistant to immunotherapy. In this subset, the objective response rate was 18%, with 7% achieving stable disease lasting 24 weeks or more. Notably, 55% of patients had received at least three prior lines of therapy, said Dr. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore.

"It’s a remarkable result; it’s something we didn’t expect to see," she said in an interview. "I’ve been in the field of cancer immunotherapy since 1985 and this was a genuine surprise."

Although the data should be interpreted with caution because of the small patient numbers, BMS-936558 appears to be more beneficial in squamous tumors, for which the response rate was 33%, compared with 12% among nonsquamous tumors, she added.

The results represent years of basic science and proof-of-concept that targeting the PD-1 pathway is valuable in cancer therapy. The early phase trial is generating enough excitement to be simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200690]), along with a second study involving PD-L1 blockade that reported slightly lower response and adverse event rates (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200694]).

Taken together, "these initial observations suggest that antibodies blocking PD-1 or PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," wrote Dr. Antoni Ribas in an editorial accompanying the studies (doi:10.1056/NEJMe1205943).

Dr. Topalian and her associates administered BMS-936558 at doses of 1.0, 3.0, or 10 mg/kg of body weight as an intravenous infusion every 2 weeks for up to 2 years in 296 patients with metastatic melanoma, colorectal, non–small-cell lung cancer, prostate, and renal cancer that had progressed after at least one and up to five previous therapies.

Objective responses were observed in 28% of patients with melanoma and 27% with renal cell cancer, with stable disease reported in 6% and 27%, respectively. Patients with colon and prostate* cancer did not have tumor responses, Dr. Topalian said.

Overall, 31 patients had a response that occurred at least 1 year ago and, of these, 20 responses persisted for more than 1 year.

The most common adverse events were fatigue, rash, diarrhea, pruritus, nausea, decreased appetite or hemoglobin, and pyrexia. Grade 3/4 treatment-related adverse events were similar across all doses, and included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis in addition to pneumonitis.

Ultimately, BMS-936558 may be used first line or in combination with other immunotherapies or targeted therapies in advanced disease, Dr. Topalian said.

"There may be rational ways to combine these agents, that by themselves have limitations, but when combined with PD-1 blockade there is a synergistic effect," she said. "And there is laboratory evidence to suggest that certain kinds of combinations can be synergistic."

A trial evaluating the combination of ipilimumab and BMS-936558 is already underway at Memorial Sloan Kettering Cancer Center, she observed. Phase III trials also are being planned in non–small-cell lung cancer, melanoma, and renal cell cancer.

Finally, an immunohistochemical analysis performed on 42 pretreatment tumor specimens suggests that PD-L1 expression could serve as a potential marker of treatment response. In all, 9 of 25 patients with PD-L1–positive tumors had an objective response, compared with no objective responses among 17 patients with PD-L1–negative tumors (P value = .006).

In his editorial, Dr. Ribas, director of the tumor immunology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, remarked: "The use of PD-1 blockade – with its reduced rate of toxic effects and potential ability to further select patients who have increased likelihood of tumor response – may well have a major effect on cancer treatment."

The study was supported by Bristol-Myers Squibb, Ono Pharmaceuticals, and grants from the National Institutes of Health and the Melanoma Research Alliance. Dr. Topalian also reported consulting for BMS and Amplimmune, and her coauthors reported financial relationships with BMS, including stock ownership, employment, and leadership positions. Dr. Ribas reported no relevant conflicts of interest.

*Correction, 6/21/2012: An earlier version of this story mischaracterized the patients that did not have tumor responses.

RALEIGH, N.C. – Vismodegib, the Hedgehog pathway inhibitor approved earlier this year for the treatment of advanced basal cell carcinomas, is now being studied for the treatment of newly diagnosed, operable, nodular BCCs.

In the just-completed first part of an ongoing three-part phase II study, 23 of 24 patients (96%) showed a clinical response to 12 weeks of treatment with vismodegib (Erivedge) at the approved dosage of 150 mg once daily, Dr. Ivor Caro reported at the annual meeting of the Society for Investigative Dermatology.

Ten patients (42%) demonstrated complete histologic clearance at 12 weeks as assessed through independent review by two dermatopathologists after Mohs surgery, noted Dr. Caro, a dermatologist employed by Genentech in San Francisco.

Of note, complete histologic clearance didn’t correlate with the investigator-assessed clinical response at the 12-week time point. That is, of the 10 patients with complete histologic clearance of their tumor, only 5 were rated by clinicians as having a complete response. Another four were characterized by clinicians as having a partial response, and one was scored as having stable disease.

Adverse events were common, and rates were consistent with those seen in other studies of vismodegib. Muscle spasms occurred in 19 of 24 patients, dysgeusia or ageusia in 19, alopecia in 9, fatigue in 5, and nausea in 5 patients. Seven patients collectively experienced nine grade 3 adverse events, mostly muscle spasms.

The second part of the ongoing phase II study is aimed at evaluating the durability of vismodegib-induced complete histologic clearances. Twenty-five patients with newly diagnosed operable nodular BCCs are undergoing 12 weeks of once-daily therapy, followed by 24 weeks of observation, then excision for pathologic review and Mohs surgery for margin assessment.

The third part of the study, just now underway, will evaluate a dosing regimen designed to boost treatment efficacy through longer drug exposure while also improving tolerability. Twenty-five patients will receive once-daily vismodegib for 8 weeks, then 4 weeks off, followed by another 8 weeks of vismodegib, then excision and Mohs surgery.

"This approach is based upon the observation that when the drug is discontinued, adverse events recover very rapidly," Dr. Caro explained.

Roughly 80% of the 2.1 million nonmelanoma skin cancers diagnosed annually in the United States are BCCs, and about 60% of them are nodular BCCs. More than 90% of all BCCs have abnormalities in the Hedgehog signaling pathway that promote carcinogenesis and are hence potentially susceptible to vismodegib.

Dr. Caro is an employee of Genentech, sponsor of the phase II study.

RALEIGH, N.C. – Vismodegib, the Hedgehog pathway inhibitor approved earlier this year for the treatment of advanced basal cell carcinomas, is now being studied for the treatment of newly diagnosed, operable, nodular BCCs.

In the just-completed first part of an ongoing three-part phase II study, 23 of 24 patients (96%) showed a clinical response to 12 weeks of treatment with vismodegib (Erivedge) at the approved dosage of 150 mg once daily, Dr. Ivor Caro reported at the annual meeting of the Society for Investigative Dermatology.

Ten patients (42%) demonstrated complete histologic clearance at 12 weeks as assessed through independent review by two dermatopathologists after Mohs surgery, noted Dr. Caro, a dermatologist employed by Genentech in San Francisco.

Of note, complete histologic clearance didn’t correlate with the investigator-assessed clinical response at the 12-week time point. That is, of the 10 patients with complete histologic clearance of their tumor, only 5 were rated by clinicians as having a complete response. Another four were characterized by clinicians as having a partial response, and one was scored as having stable disease.

Adverse events were common, and rates were consistent with those seen in other studies of vismodegib. Muscle spasms occurred in 19 of 24 patients, dysgeusia or ageusia in 19, alopecia in 9, fatigue in 5, and nausea in 5 patients. Seven patients collectively experienced nine grade 3 adverse events, mostly muscle spasms.

The second part of the ongoing phase II study is aimed at evaluating the durability of vismodegib-induced complete histologic clearances. Twenty-five patients with newly diagnosed operable nodular BCCs are undergoing 12 weeks of once-daily therapy, followed by 24 weeks of observation, then excision for pathologic review and Mohs surgery for margin assessment.

The third part of the study, just now underway, will evaluate a dosing regimen designed to boost treatment efficacy through longer drug exposure while also improving tolerability. Twenty-five patients will receive once-daily vismodegib for 8 weeks, then 4 weeks off, followed by another 8 weeks of vismodegib, then excision and Mohs surgery.

"This approach is based upon the observation that when the drug is discontinued, adverse events recover very rapidly," Dr. Caro explained.

Roughly 80% of the 2.1 million nonmelanoma skin cancers diagnosed annually in the United States are BCCs, and about 60% of them are nodular BCCs. More than 90% of all BCCs have abnormalities in the Hedgehog signaling pathway that promote carcinogenesis and are hence potentially susceptible to vismodegib.

Dr. Caro is an employee of Genentech, sponsor of the phase II study.

RALEIGH, N.C. – Vismodegib, the Hedgehog pathway inhibitor approved earlier this year for the treatment of advanced basal cell carcinomas, is now being studied for the treatment of newly diagnosed, operable, nodular BCCs.

In the just-completed first part of an ongoing three-part phase II study, 23 of 24 patients (96%) showed a clinical response to 12 weeks of treatment with vismodegib (Erivedge) at the approved dosage of 150 mg once daily, Dr. Ivor Caro reported at the annual meeting of the Society for Investigative Dermatology.

Ten patients (42%) demonstrated complete histologic clearance at 12 weeks as assessed through independent review by two dermatopathologists after Mohs surgery, noted Dr. Caro, a dermatologist employed by Genentech in San Francisco.

Of note, complete histologic clearance didn’t correlate with the investigator-assessed clinical response at the 12-week time point. That is, of the 10 patients with complete histologic clearance of their tumor, only 5 were rated by clinicians as having a complete response. Another four were characterized by clinicians as having a partial response, and one was scored as having stable disease.

Adverse events were common, and rates were consistent with those seen in other studies of vismodegib. Muscle spasms occurred in 19 of 24 patients, dysgeusia or ageusia in 19, alopecia in 9, fatigue in 5, and nausea in 5 patients. Seven patients collectively experienced nine grade 3 adverse events, mostly muscle spasms.

The second part of the ongoing phase II study is aimed at evaluating the durability of vismodegib-induced complete histologic clearances. Twenty-five patients with newly diagnosed operable nodular BCCs are undergoing 12 weeks of once-daily therapy, followed by 24 weeks of observation, then excision for pathologic review and Mohs surgery for margin assessment.

The third part of the study, just now underway, will evaluate a dosing regimen designed to boost treatment efficacy through longer drug exposure while also improving tolerability. Twenty-five patients will receive once-daily vismodegib for 8 weeks, then 4 weeks off, followed by another 8 weeks of vismodegib, then excision and Mohs surgery.

"This approach is based upon the observation that when the drug is discontinued, adverse events recover very rapidly," Dr. Caro explained.

Roughly 80% of the 2.1 million nonmelanoma skin cancers diagnosed annually in the United States are BCCs, and about 60% of them are nodular BCCs. More than 90% of all BCCs have abnormalities in the Hedgehog signaling pathway that promote carcinogenesis and are hence potentially susceptible to vismodegib.

Dr. Caro is an employee of Genentech, sponsor of the phase II study.

C. William Hanke, MD, MPH, FACP

The history of surgery in dermatology (“dermatologic surgery”) is rich with significant developments and advances by multiple individuals. Only a few of these pioneers can be highlighted in this report because of space limitations. My apologies to colleagues and friends who have not been included or mentioned in this article. The Timeline: Major milestones in the history of dermatologic surgery in this article tells some of the story. The biographic pieces on 15 outstanding physicians add additional detail and perspective. Many major developments have occurred since 2000, but they are beyond the scope of this article.

*For a PDF of the full article, click on the link to the left of this introduction.

C. William Hanke, MD, MPH, FACP

The history of surgery in dermatology (“dermatologic surgery”) is rich with significant developments and advances by multiple individuals. Only a few of these pioneers can be highlighted in this report because of space limitations. My apologies to colleagues and friends who have not been included or mentioned in this article. The Timeline: Major milestones in the history of dermatologic surgery in this article tells some of the story. The biographic pieces on 15 outstanding physicians add additional detail and perspective. Many major developments have occurred since 2000, but they are beyond the scope of this article.

*For a PDF of the full article, click on the link to the left of this introduction.

C. William Hanke, MD, MPH, FACP

The history of surgery in dermatology (“dermatologic surgery”) is rich with significant developments and advances by multiple individuals. Only a few of these pioneers can be highlighted in this report because of space limitations. My apologies to colleagues and friends who have not been included or mentioned in this article. The Timeline: Major milestones in the history of dermatologic surgery in this article tells some of the story. The biographic pieces on 15 outstanding physicians add additional detail and perspective. Many major developments have occurred since 2000, but they are beyond the scope of this article.

*For a PDF of the full article, click on the link to the left of this introduction.

Kelley P. Redbord, MD, and C. William Hanke, MD, MPH, FACP

The Stegman Papers is a biography of Dr. Samuel J. Stegman. The papers were collected by Dr. Stegman during his lifetime as a dermatologic surgeon and leader. The manuscript includes a time line of Dr. Stegman’s life and listing of his accomplishments, including significant publications.

*For a PDF of the full article, click on the link to the left of this introduction.

Kelley P. Redbord, MD, and C. William Hanke, MD, MPH, FACP

The Stegman Papers is a biography of Dr. Samuel J. Stegman. The papers were collected by Dr. Stegman during his lifetime as a dermatologic surgeon and leader. The manuscript includes a time line of Dr. Stegman’s life and listing of his accomplishments, including significant publications.

*For a PDF of the full article, click on the link to the left of this introduction.

Kelley P. Redbord, MD, and C. William Hanke, MD, MPH, FACP

The Stegman Papers is a biography of Dr. Samuel J. Stegman. The papers were collected by Dr. Stegman during his lifetime as a dermatologic surgeon and leader. The manuscript includes a time line of Dr. Stegman’s life and listing of his accomplishments, including significant publications.

*For a PDF of the full article, click on the link to the left of this introduction.

Kim Chong, MD, Adil Daud, MD, Susana Ortiz-Urda, MD, PhD, and Sarah T. Arron, MD, PhD; for the UCSF High Risk Skin Cancer Program

Traditional chemotherapy has resulted in only a modest response, if any, for the 3 most common cutaneous malignancies of basal cell carcinoma, squamous cell carcinoma, and melanoma. Recent advances in understanding of the defects in the pathways driving tumorigenesis have changed the way that we think of these cancers and paved the way to targeted therapy for specific tumors. In this review, we will introduce the novel systemic treatments currently available for these cancers in the context of what is understood about the tumor pathogenesis. We will also introduce ongoing studies that will hopefully broaden our options for highly effective and tolerable treatment.

*For a PDF of the full article, click on the link to the left of this introduction.

Kim Chong, MD, Adil Daud, MD, Susana Ortiz-Urda, MD, PhD, and Sarah T. Arron, MD, PhD; for the UCSF High Risk Skin Cancer Program

Traditional chemotherapy has resulted in only a modest response, if any, for the 3 most common cutaneous malignancies of basal cell carcinoma, squamous cell carcinoma, and melanoma. Recent advances in understanding of the defects in the pathways driving tumorigenesis have changed the way that we think of these cancers and paved the way to targeted therapy for specific tumors. In this review, we will introduce the novel systemic treatments currently available for these cancers in the context of what is understood about the tumor pathogenesis. We will also introduce ongoing studies that will hopefully broaden our options for highly effective and tolerable treatment.

*For a PDF of the full article, click on the link to the left of this introduction.

Kim Chong, MD, Adil Daud, MD, Susana Ortiz-Urda, MD, PhD, and Sarah T. Arron, MD, PhD; for the UCSF High Risk Skin Cancer Program

Traditional chemotherapy has resulted in only a modest response, if any, for the 3 most common cutaneous malignancies of basal cell carcinoma, squamous cell carcinoma, and melanoma. Recent advances in understanding of the defects in the pathways driving tumorigenesis have changed the way that we think of these cancers and paved the way to targeted therapy for specific tumors. In this review, we will introduce the novel systemic treatments currently available for these cancers in the context of what is understood about the tumor pathogenesis. We will also introduce ongoing studies that will hopefully broaden our options for highly effective and tolerable treatment.

*For a PDF of the full article, click on the link to the left of this introduction.

It’s a good news/bad news story.

First, the good news: The ozone layer is recovering. The once-ominous news about depletion of the protective ozone surrounding the earth is now much sunnier, Drusilla Hufford of the U.S. Environmental Protection Agency said.

(Photos by D. McNamara)

"It is likely we will have an ozone layer that recovers to what it was before human intervention by 2050 or 2065," Ms. Hufford said at the Florida Society of Dermatology & Dermatologic Surgery (FSDDS) annual meeting.

The bad news is that is still at least 38 years away.

"This is ultimately a self-righting system, but it will not happen immediately," said Ms. Hufford, director of the EPA’s Stratospheric Protection Division. Chlorofluorocarbons (CFCs) and other ozone-depleting substances last a long time. So even though levels are decreasing, we are still at risk of increased UV exposure in the meantime.

Courtesy Drusilla Hufford/EPA

In fact, 2011 featured one of the largest holes in the ozone layer in the Southern hemisphere. NASA compiled a great video of daily satellite images from July to December 2011 that shows the ozone hole forming and dissipating as part of its normal seasonal fluctuation.

Despite the 2011 event, Ms. Hufford remains optimistic. "Global ozone was likely to get a lot worse in absence of the Montreal Protocol, and it has not."

The EPA is going beyond the science to help physicians and others deliver effective sun protection messages. For example, if you are looking for a new angle on your sun protection message, consider pointing your patients to the EPA SunWise site. They can find a daily UV index forecast by city or zip code. Want help convincing patients to move outdoor activities earlier or later in the day to avoid peak sun exposure? The EPA service, provided in conjunction with the National Weather Service, also breaks down UV levels by hour of the day.

If you have a patient who likes technology, they can get even more precise information. Have them scan this QR code from the SunWise program with their smartphone. It provides real-time UV exposure data for their precise location using the phone’s GPS technology.

The question remains: How bad would the future have been if we’d done nothing? NASA scientist Paul Newman and colleagues at NASA’s Goddard Space Flight Center developed ‘The World We Avoided’ simulation to answer that question. It shows what earth could have been like if 193 countries had not signed the Montreal Protocol and agreed to curtail production of ozone depleting chemicals starting about 25 years ago

Here is an excerpt: "The year is 2065. Nearly two-thirds of Earth’s ozone is gone — not just over the poles, but everywhere. The infamous ozone hole over Antarctica, first discovered in the 1980s, is a year-round fixture, with a twin over the North Pole. The ultraviolet (UV) radiation falling on mid-latitude cities like Washington, D.C., is strong enough to cause sunburn in just 5 minutes. DNA-mutating UV radiation is up 650%, with likely harmful effects on plants, animals, and human skin cancer rates."

Ms. Hufford added, "Not only has the Montreal Protocol been enormously successful worldwide in preventing massive destructive of ozone layer, it is also likely helping with climate change."

– Damian McNamara (@MedReporter on Twitter)

It’s a good news/bad news story.

First, the good news: The ozone layer is recovering. The once-ominous news about depletion of the protective ozone surrounding the earth is now much sunnier, Drusilla Hufford of the U.S. Environmental Protection Agency said.

(Photos by D. McNamara)

"It is likely we will have an ozone layer that recovers to what it was before human intervention by 2050 or 2065," Ms. Hufford said at the Florida Society of Dermatology & Dermatologic Surgery (FSDDS) annual meeting.

The bad news is that is still at least 38 years away.

"This is ultimately a self-righting system, but it will not happen immediately," said Ms. Hufford, director of the EPA’s Stratospheric Protection Division. Chlorofluorocarbons (CFCs) and other ozone-depleting substances last a long time. So even though levels are decreasing, we are still at risk of increased UV exposure in the meantime.

Courtesy Drusilla Hufford/EPA

In fact, 2011 featured one of the largest holes in the ozone layer in the Southern hemisphere. NASA compiled a great video of daily satellite images from July to December 2011 that shows the ozone hole forming and dissipating as part of its normal seasonal fluctuation.

Despite the 2011 event, Ms. Hufford remains optimistic. "Global ozone was likely to get a lot worse in absence of the Montreal Protocol, and it has not."

The EPA is going beyond the science to help physicians and others deliver effective sun protection messages. For example, if you are looking for a new angle on your sun protection message, consider pointing your patients to the EPA SunWise site. They can find a daily UV index forecast by city or zip code. Want help convincing patients to move outdoor activities earlier or later in the day to avoid peak sun exposure? The EPA service, provided in conjunction with the National Weather Service, also breaks down UV levels by hour of the day.

If you have a patient who likes technology, they can get even more precise information. Have them scan this QR code from the SunWise program with their smartphone. It provides real-time UV exposure data for their precise location using the phone’s GPS technology.

The question remains: How bad would the future have been if we’d done nothing? NASA scientist Paul Newman and colleagues at NASA’s Goddard Space Flight Center developed ‘The World We Avoided’ simulation to answer that question. It shows what earth could have been like if 193 countries had not signed the Montreal Protocol and agreed to curtail production of ozone depleting chemicals starting about 25 years ago

Here is an excerpt: "The year is 2065. Nearly two-thirds of Earth’s ozone is gone — not just over the poles, but everywhere. The infamous ozone hole over Antarctica, first discovered in the 1980s, is a year-round fixture, with a twin over the North Pole. The ultraviolet (UV) radiation falling on mid-latitude cities like Washington, D.C., is strong enough to cause sunburn in just 5 minutes. DNA-mutating UV radiation is up 650%, with likely harmful effects on plants, animals, and human skin cancer rates."

Ms. Hufford added, "Not only has the Montreal Protocol been enormously successful worldwide in preventing massive destructive of ozone layer, it is also likely helping with climate change."

– Damian McNamara (@MedReporter on Twitter)

It’s a good news/bad news story.

First, the good news: The ozone layer is recovering. The once-ominous news about depletion of the protective ozone surrounding the earth is now much sunnier, Drusilla Hufford of the U.S. Environmental Protection Agency said.

(Photos by D. McNamara)

"It is likely we will have an ozone layer that recovers to what it was before human intervention by 2050 or 2065," Ms. Hufford said at the Florida Society of Dermatology & Dermatologic Surgery (FSDDS) annual meeting.

The bad news is that is still at least 38 years away.

"This is ultimately a self-righting system, but it will not happen immediately," said Ms. Hufford, director of the EPA’s Stratospheric Protection Division. Chlorofluorocarbons (CFCs) and other ozone-depleting substances last a long time. So even though levels are decreasing, we are still at risk of increased UV exposure in the meantime.

Courtesy Drusilla Hufford/EPA

In fact, 2011 featured one of the largest holes in the ozone layer in the Southern hemisphere. NASA compiled a great video of daily satellite images from July to December 2011 that shows the ozone hole forming and dissipating as part of its normal seasonal fluctuation.

Despite the 2011 event, Ms. Hufford remains optimistic. "Global ozone was likely to get a lot worse in absence of the Montreal Protocol, and it has not."

The EPA is going beyond the science to help physicians and others deliver effective sun protection messages. For example, if you are looking for a new angle on your sun protection message, consider pointing your patients to the EPA SunWise site. They can find a daily UV index forecast by city or zip code. Want help convincing patients to move outdoor activities earlier or later in the day to avoid peak sun exposure? The EPA service, provided in conjunction with the National Weather Service, also breaks down UV levels by hour of the day.

If you have a patient who likes technology, they can get even more precise information. Have them scan this QR code from the SunWise program with their smartphone. It provides real-time UV exposure data for their precise location using the phone’s GPS technology.

The question remains: How bad would the future have been if we’d done nothing? NASA scientist Paul Newman and colleagues at NASA’s Goddard Space Flight Center developed ‘The World We Avoided’ simulation to answer that question. It shows what earth could have been like if 193 countries had not signed the Montreal Protocol and agreed to curtail production of ozone depleting chemicals starting about 25 years ago

Here is an excerpt: "The year is 2065. Nearly two-thirds of Earth’s ozone is gone — not just over the poles, but everywhere. The infamous ozone hole over Antarctica, first discovered in the 1980s, is a year-round fixture, with a twin over the North Pole. The ultraviolet (UV) radiation falling on mid-latitude cities like Washington, D.C., is strong enough to cause sunburn in just 5 minutes. DNA-mutating UV radiation is up 650%, with likely harmful effects on plants, animals, and human skin cancer rates."

Ms. Hufford added, "Not only has the Montreal Protocol been enormously successful worldwide in preventing massive destructive of ozone layer, it is also likely helping with climate change."

– Damian McNamara (@MedReporter on Twitter)

Four dermatology societies joined together to create the first appropriate use criteria for Mohs surgery, consenting that in two-thirds of nearly 300 possible scenarios the micrographic procedure is appropriate.

The American Academy of Dermatology (AAD) developed the appropriate use criteria (AUC) for 270 scenarios for Mohs surgery in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery, and the American Society for Mohs Surgery.

The main driver behind the creation of the 46-page document, which is the first of its kind for any test or treatment option in the field of dermatology, is Medicare, said Dr. Mark J. Zalla, a member of the report’s ad hoc task force that developed the indications.

"The intent of the criteria is to help us maintain the value of Mohs in terms of reimbursement," added Dr. Zalla, who is in private practice in Florence, Ky.

Use of Mohs surgery increased by 400% between 1995 and 2009. (Dermatol. Clin. 2012;30:167-75). "And when Medicare sees use of a specific code increasing significantly over several years, they get concerned," said Dr. Zalla. Some Medicare carriers have already threatened to impose certain criteria for Mohs surgery reimbursement. "And if one carrier does it, it’s possible that [the criteria will become applicable] nationwide," he said.

But Dr. Zalla and advocates for the procedure argue that the sharp increase doesn’t necessarily mean that it is being overutilized. Rather, it’s most likely the result of several factors, including the nation’s skin cancer epidemic and an increase in the number of fellows trained in Mohs surgery.

The ACMS has been ramping up its efforts to raise awareness about the surgery among payers and policy makers. The college has so far spent $20,000 in education lobbying this year, according to the Center for Responsive Politics.

"The bottom line is that dermatologists and Mohs surgeons are the good guys," said Dr. Brett M. Coldiron, president of ACMS and a member of the AUC ad hoc task force. "We are part of the solution, not the problem."

The scenarios represent roughly 85% of anticipated clinical scenarios, the authors noted in their report.

The members of a 17-member rating panel, made up of Mohs surgeons and non-Mohs dermatologists, scored the scenarios on a 9-point scale. Scenarios scoring 7-9 were deemed appropriate, those scoring 4-6 were uncertain, and those scoring 1-3 were inappropriate.

"Those clinical situations for which use of Mohs was rated as uncertain are areas ripe for productive clinical research," said Dr. Suzanne M. Connolly, chair of the AUC task force.

The document breaks down the appropriateness of Mohs surgery by the following skin cancer types:

• For 69 basal cell carcinoma scenarios, 53 were rated appropriate, 6 uncertain, 10 inappropriate.

• For 143 squamous cell carcinoma scenarios, 102 were rated appropriate, 7 uncertain, and 34 inappropriate.

• For 12 lentigo maligna and melanoma in situ scenarios, 10 were rated appropriate, and 2 uncertain.

• For 46 rare cutaneous malignancies scenarios, 35 were rated appropriate, 9 uncertain, and 2 inappropriate.

• Invasive melanoma was not included in the AUC "due to the complexity of the issue," according to the task force.

A small number of low-risk tumors in trunk and extremities were rated as inappropriate for Mohs surgery.

Dr. Zalla said he anticipates a good reaction to the AUC. "There will be some minor changes in practice for some surgeons," he speculated.

Florida dermatologist and Mohs surgeon Terrence A Cronin Jr. noted in an interview that he was not expecting the AUC to change his practice. "But I think, optimistically, that this will help the lay people in the insurance world have a greater understanding of where Mohs is often the best choice for the treatment of skin cancer," noted Dr. Cronin, who was a member of the AUC’s ratings panel.

The document was approved by all four of the societies’ boards during the American Academy of Dermatology’s annual meeting in March. It will be published in the Journal of the American Academy of Dermatology and Dermatologic Surgery later this year.

Four dermatology societies joined together to create the first appropriate use criteria for Mohs surgery, consenting that in two-thirds of nearly 300 possible scenarios the micrographic procedure is appropriate.

The American Academy of Dermatology (AAD) developed the appropriate use criteria (AUC) for 270 scenarios for Mohs surgery in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery, and the American Society for Mohs Surgery.

The main driver behind the creation of the 46-page document, which is the first of its kind for any test or treatment option in the field of dermatology, is Medicare, said Dr. Mark J. Zalla, a member of the report’s ad hoc task force that developed the indications.

"The intent of the criteria is to help us maintain the value of Mohs in terms of reimbursement," added Dr. Zalla, who is in private practice in Florence, Ky.

Use of Mohs surgery increased by 400% between 1995 and 2009. (Dermatol. Clin. 2012;30:167-75). "And when Medicare sees use of a specific code increasing significantly over several years, they get concerned," said Dr. Zalla. Some Medicare carriers have already threatened to impose certain criteria for Mohs surgery reimbursement. "And if one carrier does it, it’s possible that [the criteria will become applicable] nationwide," he said.

But Dr. Zalla and advocates for the procedure argue that the sharp increase doesn’t necessarily mean that it is being overutilized. Rather, it’s most likely the result of several factors, including the nation’s skin cancer epidemic and an increase in the number of fellows trained in Mohs surgery.

The ACMS has been ramping up its efforts to raise awareness about the surgery among payers and policy makers. The college has so far spent $20,000 in education lobbying this year, according to the Center for Responsive Politics.

"The bottom line is that dermatologists and Mohs surgeons are the good guys," said Dr. Brett M. Coldiron, president of ACMS and a member of the AUC ad hoc task force. "We are part of the solution, not the problem."

The scenarios represent roughly 85% of anticipated clinical scenarios, the authors noted in their report.

The members of a 17-member rating panel, made up of Mohs surgeons and non-Mohs dermatologists, scored the scenarios on a 9-point scale. Scenarios scoring 7-9 were deemed appropriate, those scoring 4-6 were uncertain, and those scoring 1-3 were inappropriate.

"Those clinical situations for which use of Mohs was rated as uncertain are areas ripe for productive clinical research," said Dr. Suzanne M. Connolly, chair of the AUC task force.

The document breaks down the appropriateness of Mohs surgery by the following skin cancer types:

• For 69 basal cell carcinoma scenarios, 53 were rated appropriate, 6 uncertain, 10 inappropriate.

• For 143 squamous cell carcinoma scenarios, 102 were rated appropriate, 7 uncertain, and 34 inappropriate.

• For 12 lentigo maligna and melanoma in situ scenarios, 10 were rated appropriate, and 2 uncertain.

• For 46 rare cutaneous malignancies scenarios, 35 were rated appropriate, 9 uncertain, and 2 inappropriate.

• Invasive melanoma was not included in the AUC "due to the complexity of the issue," according to the task force.

A small number of low-risk tumors in trunk and extremities were rated as inappropriate for Mohs surgery.

Dr. Zalla said he anticipates a good reaction to the AUC. "There will be some minor changes in practice for some surgeons," he speculated.

Florida dermatologist and Mohs surgeon Terrence A Cronin Jr. noted in an interview that he was not expecting the AUC to change his practice. "But I think, optimistically, that this will help the lay people in the insurance world have a greater understanding of where Mohs is often the best choice for the treatment of skin cancer," noted Dr. Cronin, who was a member of the AUC’s ratings panel.

The document was approved by all four of the societies’ boards during the American Academy of Dermatology’s annual meeting in March. It will be published in the Journal of the American Academy of Dermatology and Dermatologic Surgery later this year.

Four dermatology societies joined together to create the first appropriate use criteria for Mohs surgery, consenting that in two-thirds of nearly 300 possible scenarios the micrographic procedure is appropriate.

The American Academy of Dermatology (AAD) developed the appropriate use criteria (AUC) for 270 scenarios for Mohs surgery in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery, and the American Society for Mohs Surgery.

The main driver behind the creation of the 46-page document, which is the first of its kind for any test or treatment option in the field of dermatology, is Medicare, said Dr. Mark J. Zalla, a member of the report’s ad hoc task force that developed the indications.

"The intent of the criteria is to help us maintain the value of Mohs in terms of reimbursement," added Dr. Zalla, who is in private practice in Florence, Ky.

Use of Mohs surgery increased by 400% between 1995 and 2009. (Dermatol. Clin. 2012;30:167-75). "And when Medicare sees use of a specific code increasing significantly over several years, they get concerned," said Dr. Zalla. Some Medicare carriers have already threatened to impose certain criteria for Mohs surgery reimbursement. "And if one carrier does it, it’s possible that [the criteria will become applicable] nationwide," he said.

But Dr. Zalla and advocates for the procedure argue that the sharp increase doesn’t necessarily mean that it is being overutilized. Rather, it’s most likely the result of several factors, including the nation’s skin cancer epidemic and an increase in the number of fellows trained in Mohs surgery.

The ACMS has been ramping up its efforts to raise awareness about the surgery among payers and policy makers. The college has so far spent $20,000 in education lobbying this year, according to the Center for Responsive Politics.

"The bottom line is that dermatologists and Mohs surgeons are the good guys," said Dr. Brett M. Coldiron, president of ACMS and a member of the AUC ad hoc task force. "We are part of the solution, not the problem."

The scenarios represent roughly 85% of anticipated clinical scenarios, the authors noted in their report.

The members of a 17-member rating panel, made up of Mohs surgeons and non-Mohs dermatologists, scored the scenarios on a 9-point scale. Scenarios scoring 7-9 were deemed appropriate, those scoring 4-6 were uncertain, and those scoring 1-3 were inappropriate.

"Those clinical situations for which use of Mohs was rated as uncertain are areas ripe for productive clinical research," said Dr. Suzanne M. Connolly, chair of the AUC task force.

The document breaks down the appropriateness of Mohs surgery by the following skin cancer types:

• For 69 basal cell carcinoma scenarios, 53 were rated appropriate, 6 uncertain, 10 inappropriate.

• For 143 squamous cell carcinoma scenarios, 102 were rated appropriate, 7 uncertain, and 34 inappropriate.

• For 12 lentigo maligna and melanoma in situ scenarios, 10 were rated appropriate, and 2 uncertain.

• For 46 rare cutaneous malignancies scenarios, 35 were rated appropriate, 9 uncertain, and 2 inappropriate.

• Invasive melanoma was not included in the AUC "due to the complexity of the issue," according to the task force.

A small number of low-risk tumors in trunk and extremities were rated as inappropriate for Mohs surgery.

Dr. Zalla said he anticipates a good reaction to the AUC. "There will be some minor changes in practice for some surgeons," he speculated.

Florida dermatologist and Mohs surgeon Terrence A Cronin Jr. noted in an interview that he was not expecting the AUC to change his practice. "But I think, optimistically, that this will help the lay people in the insurance world have a greater understanding of where Mohs is often the best choice for the treatment of skin cancer," noted Dr. Cronin, who was a member of the AUC’s ratings panel.

The document was approved by all four of the societies’ boards during the American Academy of Dermatology’s annual meeting in March. It will be published in the Journal of the American Academy of Dermatology and Dermatologic Surgery later this year.