Melanoma

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life.

But a landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients has offered hope, Dr. Steven O'Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference.

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O'Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane) has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O'Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer.

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O'Day said, "because I think it's so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O'Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs' manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells' antitumor activity.

"What's important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient's immune system," Dr. O'Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O'Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O'Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O'Day added.

As expected, the drug's adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O'Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O'Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O'Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O'Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O'Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O'Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It's great science, but it's not really adding to the benefit of the vast majority of patients," Dr. O'Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it's a major step forward."

Dr. O'Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life.

But a landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients has offered hope, Dr. Steven O'Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference.

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O'Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane) has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O'Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer.

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O'Day said, "because I think it's so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O'Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs' manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells' antitumor activity.

"What's important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient's immune system," Dr. O'Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O'Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O'Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O'Day added.

As expected, the drug's adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O'Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O'Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O'Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O'Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O'Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O'Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It's great science, but it's not really adding to the benefit of the vast majority of patients," Dr. O'Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it's a major step forward."

Dr. O'Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life.

But a landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients has offered hope, Dr. Steven O'Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference.

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O'Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane) has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O'Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer.

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O'Day said, "because I think it's so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O'Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs' manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells' antitumor activity.

"What's important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient's immune system," Dr. O'Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O'Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O'Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O'Day added.

As expected, the drug's adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O'Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O'Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O'Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O'Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O'Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O'Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It's great science, but it's not really adding to the benefit of the vast majority of patients," Dr. O'Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it's a major step forward."

Dr. O'Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane)has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O’Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer,

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O’Day said, "because I think it’s so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O‘Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs’ manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells’ antitumor activity.

"What’s important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient’s immune system," Dr. O’Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O’Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O’Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O’Day added.

As expected, the drug’s adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O’Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O’Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O’Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O’Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O’Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O’Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It’s great science, but it’s not really adding to the benefit of the vast majority of patients," Dr. O’Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it’s a major step forward."

Dr. O’Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb.

Community Oncology and this news organization are owned by Elsevier.

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane)has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O’Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer,

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O’Day said, "because I think it’s so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O‘Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs’ manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells’ antitumor activity.

"What’s important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient’s immune system," Dr. O’Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O’Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O’Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O’Day added.

As expected, the drug’s adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O’Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O’Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O’Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O’Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O’Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O’Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It’s great science, but it’s not really adding to the benefit of the vast majority of patients," Dr. O’Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it’s a major step forward."

Dr. O’Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb.

Community Oncology and this news organization are owned by Elsevier.

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.

This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane)has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O’Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer,

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O’Day said, "because I think it’s so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O‘Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs’ manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells’ antitumor activity.

"What’s important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient’s immune system," Dr. O’Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O’Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O’Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O’Day added.

As expected, the drug’s adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O’Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O’Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O’Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O’Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O’Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O’Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It’s great science, but it’s not really adding to the benefit of the vast majority of patients," Dr. O’Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it’s a major step forward."

Dr. O’Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb.

Community Oncology and this news organization are owned by Elsevier.

Adolescent women whose mothers use tanning beds are more likely to be indoor tanners themselves, according to a survey by the American Academy of Dermatology (AAD). 

The AAD survey targeted white, non-Hispanic females aged 14-22, and was conducted online from late December to mid-January. After selecting out for the target population, the survey encompassed responses from some 3,800 women.

Overall, a third said they had used a tanning bed in the past year, with one-quarter going to a tanning salon at least weekly. Eighty percent had tanned outdoors.

Indoor tanners were more than twice as likely to have a family member who used a tanning bed, compared with non-tanning bed users. And, indoor tanners were four times as likely (42%) to indicate that their mothers used tanning beds, compared with those who were not indoor tanners (10%).

Parents knew their daughter was using a tanning bed, said 94% of indoor tanners.

"The survey shows how influential mothers can be on their daughters' behavior, and that is why it's critical for mothers to set a good example by not tanning," said Dr. Ellen S. Marmur, associate professor of dermatology at The Mount Sinai Medical Center in New York, in an AAD statement.

Peer pressure is another factor: tanning bed users were nearly twice as likely to say they felt pressure to be tan (49%), compared with non-users (28%). 

Finally, although the majority said that tanning beds could cause skin cancer, a quarter to a third of younger tanners said they thought indoor tanning was safer than the sun and did not cause cancer. Younger tanners (aged 14-17) were also less likely to report they planned to stop using tanning beds. 

Adolescent women whose mothers use tanning beds are more likely to be indoor tanners themselves, according to a survey by the American Academy of Dermatology (AAD). 

The AAD survey targeted white, non-Hispanic females aged 14-22, and was conducted online from late December to mid-January. After selecting out for the target population, the survey encompassed responses from some 3,800 women.

Overall, a third said they had used a tanning bed in the past year, with one-quarter going to a tanning salon at least weekly. Eighty percent had tanned outdoors.

Indoor tanners were more than twice as likely to have a family member who used a tanning bed, compared with non-tanning bed users. And, indoor tanners were four times as likely (42%) to indicate that their mothers used tanning beds, compared with those who were not indoor tanners (10%).

Parents knew their daughter was using a tanning bed, said 94% of indoor tanners.

"The survey shows how influential mothers can be on their daughters' behavior, and that is why it's critical for mothers to set a good example by not tanning," said Dr. Ellen S. Marmur, associate professor of dermatology at The Mount Sinai Medical Center in New York, in an AAD statement.

Peer pressure is another factor: tanning bed users were nearly twice as likely to say they felt pressure to be tan (49%), compared with non-users (28%). 

Finally, although the majority said that tanning beds could cause skin cancer, a quarter to a third of younger tanners said they thought indoor tanning was safer than the sun and did not cause cancer. Younger tanners (aged 14-17) were also less likely to report they planned to stop using tanning beds. 

Adolescent women whose mothers use tanning beds are more likely to be indoor tanners themselves, according to a survey by the American Academy of Dermatology (AAD). 

The AAD survey targeted white, non-Hispanic females aged 14-22, and was conducted online from late December to mid-January. After selecting out for the target population, the survey encompassed responses from some 3,800 women.

Overall, a third said they had used a tanning bed in the past year, with one-quarter going to a tanning salon at least weekly. Eighty percent had tanned outdoors.

Indoor tanners were more than twice as likely to have a family member who used a tanning bed, compared with non-tanning bed users. And, indoor tanners were four times as likely (42%) to indicate that their mothers used tanning beds, compared with those who were not indoor tanners (10%).

Parents knew their daughter was using a tanning bed, said 94% of indoor tanners.

"The survey shows how influential mothers can be on their daughters' behavior, and that is why it's critical for mothers to set a good example by not tanning," said Dr. Ellen S. Marmur, associate professor of dermatology at The Mount Sinai Medical Center in New York, in an AAD statement.

Peer pressure is another factor: tanning bed users were nearly twice as likely to say they felt pressure to be tan (49%), compared with non-users (28%). 

Finally, although the majority said that tanning beds could cause skin cancer, a quarter to a third of younger tanners said they thought indoor tanning was safer than the sun and did not cause cancer. Younger tanners (aged 14-17) were also less likely to report they planned to stop using tanning beds. 

LAS VEGAS – Counties that have up to two dermatologists per 100,000 people have the lowest mortality from melanoma, compared with counties with no dermatologists, according to an analysis of national data.

The analysis also found that having more dermatologists does not decrease melanoma mortality further.

A "dermatologist density" greater than zero and up to one dermatologist per 100,000 people was associated with a 35% reduction in deaths from melanoma compared with counties with no dermatologists, Dr. Jeremy S. Bordeaux reported at the annual meeting of the American College of Mohs Surgery.

Counties with more than one and up to two dermatologists per 100,000 people had an even greater reduction in melanoma mortality – 53% lower than counties with no dermatologists, the multivariate analysis showed. Beyond that, counties with more than two dermatologists had slightly but not significantly higher melanoma mortality rates, compared with counties with more than one and up to two dermatologists.

"Once you get past two per 100,000, it didn't make any difference. If you had 10 per 100,000, it didn't change mortality," said Dr. Bordeaux of the department of dermatology at Case Western Reserve University, Cleveland.

A map of dermatologist density created from U.S. Department of Health and Human Services data showed huge swaths of counties in the middle part of the country with no dermatologists. The study's findings suggest that enticing some dermatologists on the East and West coasts to move to those counties could reduce melanoma mortality.

"If we could get people to go where people don't want to live, I guess that could save lives, but people don’t want to live there for a reason," he said. Perhaps dermatology residency programs could place dermatologists in underserved counties, or loan repayment programs could be tied to contracts to serve in those counties, he suggested.

Dr. Bordeaux and his associates analyzed data from 3,141 U.S. counties from multiple databases, including the National Cancer Institute's Surveillance, Epidemiology and End Results database, the National Program of Cancer Registries, the Centers for Disease Control and Prevention’s National Vital Statistics System, and the U.S. Census Bureau.

Two other factors were associated with decreased melanoma mortality. Counties classified as metropolitan had a 30% lower death rate from melanoma, compared with nonmetropolitan counties. Each hospital that provided oncology services conferred nearly a 2% reduction in melanoma mortality. In Dr. Bordeaux’s county, for example, which has a dozen or so hospitals that offer oncology services, melanoma mortality would be more than 20% lower than in a county with no hospital-based oncology services.

Several factors were associated with higher melanoma mortality. For every 1% increase in the proportion of the population that was white, the melanoma mortality increased 1.5%. Not surprisingly, a higher incidence of melanoma was associated with higher mortality; for each additional case of melanoma per 100,000 people, mortality increased 2.3%. A third factor puzzled Dr. Bordeaux. For each additional percent of the population covered by health insurance, the melanoma mortality rate increased by 1.5%.

Factors that appeared to have no effect on melanoma mortality included the density of primary care providers, the percentage of the population older than 65 years, education level, median household income, and unemployment rate.

Dr. Bordeaux speculated the "plateau effect" that limited mortality reductions to a density of two dermatologists per 100,000 people may reflect the limitations of current therapeutics. Or, areas with greater dermatologist density may represent academic centers, and dermatologists may not be working full time.

Multiple studies have found the need to increase the number of primary care physicians, but the density of primary care physicians did not affect melanoma mortality in the current study, Dr. Bordeaux noted. Other articles in the literature, however, have shown specialist care to be associated with better cancer outcomes in both urology and dermatology.

In one study, higher densities of either dermatologists or internists were associated with better prognosis in patients with melanoma, but a higher density of family physicians was associated with a worse prognosis (J. Amer. Acad. Dermatol. 2009;60:51-8).

Dr. Bordeaux and his fellow investigators had no relevant conflicts of interest to report.

LAS VEGAS – Counties that have up to two dermatologists per 100,000 people have the lowest mortality from melanoma, compared with counties with no dermatologists, according to an analysis of national data.

The analysis also found that having more dermatologists does not decrease melanoma mortality further.

A "dermatologist density" greater than zero and up to one dermatologist per 100,000 people was associated with a 35% reduction in deaths from melanoma compared with counties with no dermatologists, Dr. Jeremy S. Bordeaux reported at the annual meeting of the American College of Mohs Surgery.

Counties with more than one and up to two dermatologists per 100,000 people had an even greater reduction in melanoma mortality – 53% lower than counties with no dermatologists, the multivariate analysis showed. Beyond that, counties with more than two dermatologists had slightly but not significantly higher melanoma mortality rates, compared with counties with more than one and up to two dermatologists.

"Once you get past two per 100,000, it didn't make any difference. If you had 10 per 100,000, it didn't change mortality," said Dr. Bordeaux of the department of dermatology at Case Western Reserve University, Cleveland.

A map of dermatologist density created from U.S. Department of Health and Human Services data showed huge swaths of counties in the middle part of the country with no dermatologists. The study's findings suggest that enticing some dermatologists on the East and West coasts to move to those counties could reduce melanoma mortality.

"If we could get people to go where people don't want to live, I guess that could save lives, but people don’t want to live there for a reason," he said. Perhaps dermatology residency programs could place dermatologists in underserved counties, or loan repayment programs could be tied to contracts to serve in those counties, he suggested.

Dr. Bordeaux and his associates analyzed data from 3,141 U.S. counties from multiple databases, including the National Cancer Institute's Surveillance, Epidemiology and End Results database, the National Program of Cancer Registries, the Centers for Disease Control and Prevention’s National Vital Statistics System, and the U.S. Census Bureau.

Two other factors were associated with decreased melanoma mortality. Counties classified as metropolitan had a 30% lower death rate from melanoma, compared with nonmetropolitan counties. Each hospital that provided oncology services conferred nearly a 2% reduction in melanoma mortality. In Dr. Bordeaux’s county, for example, which has a dozen or so hospitals that offer oncology services, melanoma mortality would be more than 20% lower than in a county with no hospital-based oncology services.

Several factors were associated with higher melanoma mortality. For every 1% increase in the proportion of the population that was white, the melanoma mortality increased 1.5%. Not surprisingly, a higher incidence of melanoma was associated with higher mortality; for each additional case of melanoma per 100,000 people, mortality increased 2.3%. A third factor puzzled Dr. Bordeaux. For each additional percent of the population covered by health insurance, the melanoma mortality rate increased by 1.5%.

Factors that appeared to have no effect on melanoma mortality included the density of primary care providers, the percentage of the population older than 65 years, education level, median household income, and unemployment rate.

Dr. Bordeaux speculated the "plateau effect" that limited mortality reductions to a density of two dermatologists per 100,000 people may reflect the limitations of current therapeutics. Or, areas with greater dermatologist density may represent academic centers, and dermatologists may not be working full time.

Multiple studies have found the need to increase the number of primary care physicians, but the density of primary care physicians did not affect melanoma mortality in the current study, Dr. Bordeaux noted. Other articles in the literature, however, have shown specialist care to be associated with better cancer outcomes in both urology and dermatology.

In one study, higher densities of either dermatologists or internists were associated with better prognosis in patients with melanoma, but a higher density of family physicians was associated with a worse prognosis (J. Amer. Acad. Dermatol. 2009;60:51-8).

Dr. Bordeaux and his fellow investigators had no relevant conflicts of interest to report.

LAS VEGAS – Counties that have up to two dermatologists per 100,000 people have the lowest mortality from melanoma, compared with counties with no dermatologists, according to an analysis of national data.

The analysis also found that having more dermatologists does not decrease melanoma mortality further.

A "dermatologist density" greater than zero and up to one dermatologist per 100,000 people was associated with a 35% reduction in deaths from melanoma compared with counties with no dermatologists, Dr. Jeremy S. Bordeaux reported at the annual meeting of the American College of Mohs Surgery.

Counties with more than one and up to two dermatologists per 100,000 people had an even greater reduction in melanoma mortality – 53% lower than counties with no dermatologists, the multivariate analysis showed. Beyond that, counties with more than two dermatologists had slightly but not significantly higher melanoma mortality rates, compared with counties with more than one and up to two dermatologists.

"Once you get past two per 100,000, it didn't make any difference. If you had 10 per 100,000, it didn't change mortality," said Dr. Bordeaux of the department of dermatology at Case Western Reserve University, Cleveland.

A map of dermatologist density created from U.S. Department of Health and Human Services data showed huge swaths of counties in the middle part of the country with no dermatologists. The study's findings suggest that enticing some dermatologists on the East and West coasts to move to those counties could reduce melanoma mortality.

"If we could get people to go where people don't want to live, I guess that could save lives, but people don’t want to live there for a reason," he said. Perhaps dermatology residency programs could place dermatologists in underserved counties, or loan repayment programs could be tied to contracts to serve in those counties, he suggested.

Dr. Bordeaux and his associates analyzed data from 3,141 U.S. counties from multiple databases, including the National Cancer Institute's Surveillance, Epidemiology and End Results database, the National Program of Cancer Registries, the Centers for Disease Control and Prevention’s National Vital Statistics System, and the U.S. Census Bureau.

Two other factors were associated with decreased melanoma mortality. Counties classified as metropolitan had a 30% lower death rate from melanoma, compared with nonmetropolitan counties. Each hospital that provided oncology services conferred nearly a 2% reduction in melanoma mortality. In Dr. Bordeaux’s county, for example, which has a dozen or so hospitals that offer oncology services, melanoma mortality would be more than 20% lower than in a county with no hospital-based oncology services.

Several factors were associated with higher melanoma mortality. For every 1% increase in the proportion of the population that was white, the melanoma mortality increased 1.5%. Not surprisingly, a higher incidence of melanoma was associated with higher mortality; for each additional case of melanoma per 100,000 people, mortality increased 2.3%. A third factor puzzled Dr. Bordeaux. For each additional percent of the population covered by health insurance, the melanoma mortality rate increased by 1.5%.

Factors that appeared to have no effect on melanoma mortality included the density of primary care providers, the percentage of the population older than 65 years, education level, median household income, and unemployment rate.

Dr. Bordeaux speculated the "plateau effect" that limited mortality reductions to a density of two dermatologists per 100,000 people may reflect the limitations of current therapeutics. Or, areas with greater dermatologist density may represent academic centers, and dermatologists may not be working full time.

Multiple studies have found the need to increase the number of primary care physicians, but the density of primary care physicians did not affect melanoma mortality in the current study, Dr. Bordeaux noted. Other articles in the literature, however, have shown specialist care to be associated with better cancer outcomes in both urology and dermatology.

In one study, higher densities of either dermatologists or internists were associated with better prognosis in patients with melanoma, but a higher density of family physicians was associated with a worse prognosis (J. Amer. Acad. Dermatol. 2009;60:51-8).

Dr. Bordeaux and his fellow investigators had no relevant conflicts of interest to report.

A large percentage of young white women use tanning beds or intentionally tan in the sun, despite repeated health warnings, according to a new survey from the American Academy of Dermatology.

"Our survey underscores the importance of educating young women about the very real risks of tanning," noted Dr. Ronald L. Moy, president of the AAD, in a statement.

©Bora Ucak/iStockphoto.com

The online survey of more than 3,800 white, non-Hispanic females aged 14 to 22 years, found that 81% of respondents had tanned outdoors frequently or occasionally in the past year. More than 32% reported using a tanning bed in the past year, while 25% reported using a tanning bed at least weekly.

Meanwhile, 86% of the respondents said that in the past year they never received a spray tan - the safe alternative to UV exposure.

When comparing ages, 18- to 22-year-old women were almost twice as likely (40%) to use indoor tanning beds, compared with 14 to 17 year olds (22%).

"The challenge is that teens have access to indoor tanning salons on almost every corner," noted Dr. Moy in his statement. "A recent survey of 116 U.S. cities found an average of 42 tanning salons per city, which means tanning salons are more prevalent than Starbucks or McDonald's."

Dr. James M. Spencer, of Mount Sinai School of Medicine, New York, was not surprised by the statistics. "It's a fashion," he said. "The media and advertisements make [being] tan desirable," and the media has more impact than physicians.

"We've been trying to get this message out of 20 years … But the public is headed in the wrong direction," said Dr. Spencer.

More than 1 million people in the U.S. tan in salons on an average day. White girls and women, particularly aged 16 to 29 years, make up almost 70% of tanning salon patrons, according to the AAD.

"We are very concerned that this tanning behavior will lead to a continued increase in the incidence of skin cancer in young people and, ultimately, more untimely deaths from this devastating disease," noted Dr. Moy.

Nearly 75% of skin cancer deaths are due to melanoma and rates have been rising over the last 30 years.

More than 30 states either prohibit or require parental consent for minors who want to use indoor tanning devices. The World Health Organization has declared UV radiation from the sun and artificial light sources a known carcinogen and has called for prohibiting minors from indoor tanning.

May has been designated Melanoma/Skin Cancer Detection and Prevention Month.

A large percentage of young white women use tanning beds or intentionally tan in the sun, despite repeated health warnings, according to a new survey from the American Academy of Dermatology.

"Our survey underscores the importance of educating young women about the very real risks of tanning," noted Dr. Ronald L. Moy, president of the AAD, in a statement.

©Bora Ucak/iStockphoto.com

The online survey of more than 3,800 white, non-Hispanic females aged 14 to 22 years, found that 81% of respondents had tanned outdoors frequently or occasionally in the past year. More than 32% reported using a tanning bed in the past year, while 25% reported using a tanning bed at least weekly.

Meanwhile, 86% of the respondents said that in the past year they never received a spray tan - the safe alternative to UV exposure.

When comparing ages, 18- to 22-year-old women were almost twice as likely (40%) to use indoor tanning beds, compared with 14 to 17 year olds (22%).

"The challenge is that teens have access to indoor tanning salons on almost every corner," noted Dr. Moy in his statement. "A recent survey of 116 U.S. cities found an average of 42 tanning salons per city, which means tanning salons are more prevalent than Starbucks or McDonald's."

Dr. James M. Spencer, of Mount Sinai School of Medicine, New York, was not surprised by the statistics. "It's a fashion," he said. "The media and advertisements make [being] tan desirable," and the media has more impact than physicians.

"We've been trying to get this message out of 20 years … But the public is headed in the wrong direction," said Dr. Spencer.

More than 1 million people in the U.S. tan in salons on an average day. White girls and women, particularly aged 16 to 29 years, make up almost 70% of tanning salon patrons, according to the AAD.

"We are very concerned that this tanning behavior will lead to a continued increase in the incidence of skin cancer in young people and, ultimately, more untimely deaths from this devastating disease," noted Dr. Moy.

Nearly 75% of skin cancer deaths are due to melanoma and rates have been rising over the last 30 years.

More than 30 states either prohibit or require parental consent for minors who want to use indoor tanning devices. The World Health Organization has declared UV radiation from the sun and artificial light sources a known carcinogen and has called for prohibiting minors from indoor tanning.

May has been designated Melanoma/Skin Cancer Detection and Prevention Month.

A large percentage of young white women use tanning beds or intentionally tan in the sun, despite repeated health warnings, according to a new survey from the American Academy of Dermatology.

"Our survey underscores the importance of educating young women about the very real risks of tanning," noted Dr. Ronald L. Moy, president of the AAD, in a statement.

©Bora Ucak/iStockphoto.com

The online survey of more than 3,800 white, non-Hispanic females aged 14 to 22 years, found that 81% of respondents had tanned outdoors frequently or occasionally in the past year. More than 32% reported using a tanning bed in the past year, while 25% reported using a tanning bed at least weekly.

Meanwhile, 86% of the respondents said that in the past year they never received a spray tan - the safe alternative to UV exposure.

When comparing ages, 18- to 22-year-old women were almost twice as likely (40%) to use indoor tanning beds, compared with 14 to 17 year olds (22%).

"The challenge is that teens have access to indoor tanning salons on almost every corner," noted Dr. Moy in his statement. "A recent survey of 116 U.S. cities found an average of 42 tanning salons per city, which means tanning salons are more prevalent than Starbucks or McDonald's."

Dr. James M. Spencer, of Mount Sinai School of Medicine, New York, was not surprised by the statistics. "It's a fashion," he said. "The media and advertisements make [being] tan desirable," and the media has more impact than physicians.

"We've been trying to get this message out of 20 years … But the public is headed in the wrong direction," said Dr. Spencer.

More than 1 million people in the U.S. tan in salons on an average day. White girls and women, particularly aged 16 to 29 years, make up almost 70% of tanning salon patrons, according to the AAD.

"We are very concerned that this tanning behavior will lead to a continued increase in the incidence of skin cancer in young people and, ultimately, more untimely deaths from this devastating disease," noted Dr. Moy.

Nearly 75% of skin cancer deaths are due to melanoma and rates have been rising over the last 30 years.

More than 30 states either prohibit or require parental consent for minors who want to use indoor tanning devices. The World Health Organization has declared UV radiation from the sun and artificial light sources a known carcinogen and has called for prohibiting minors from indoor tanning.

May has been designated Melanoma/Skin Cancer Detection and Prevention Month.

April showers bring May patients who may be confused about the safety of sunscreens containing nanoparticles of titanium and zinc.

To help alleviate concerns the Nanodermatology Society released a position statement on the safety of sunscreens containing nanoparticles. Dr. Adam Friedman, vice president of the Society and senior author of the position statement, spoke to The Mole about the safety of nano-based sunscreens.

Photo credit pni via Flickr Creative Commons

The Fears

The concern is that nanoparticles might interact directly with cell DNA and cause damage because of their size and their ability to not only penetrate the skin but to enter the body through the mucosa in the nose, or to be swallowed, Dr. Friedman said.

The Facts

Nanoparticle penetration is limited by size. "One of the things I tell people is that the materials they are using in bench research are different than what is used in over-the-counter products," Dr. Friedman said. "Those used in consumer products are commonly coated, so they aggregate and don't penetrate the skin as easily."

"Thus far, everything that has been done in terms of topical application of the skin, the particles do not penetrate to the point where they could cause problems,” said Dr. Friedman. "Clearly, more needs to be done, and certain clinical situations need to be explored, such as penetration into damaged skin," he noted. When the nanoparticles are aggregated in solution, they are trapped in the upper layers of the skin, where they are sloughed off over time.

"A lot of the fear with respect to the bodily harm from nanomaterials comes from the lung literature and occupational hazards with respect to people inhaling asbestos," he noted.

Another concern about nano-based sunscreens is the potential impact on the environment, Dr. Friedman said. However, a hot-off-the press (April 17) study in Science of the Total Environment by A. Johnson and colleagues found no impact of titanium oxide sunscreens on the environment.

--Heidi Splete (on twitter @hsplete)

April showers bring May patients who may be confused about the safety of sunscreens containing nanoparticles of titanium and zinc.

To help alleviate concerns the Nanodermatology Society released a position statement on the safety of sunscreens containing nanoparticles. Dr. Adam Friedman, vice president of the Society and senior author of the position statement, spoke to The Mole about the safety of nano-based sunscreens.

Photo credit pni via Flickr Creative Commons

The Fears

The concern is that nanoparticles might interact directly with cell DNA and cause damage because of their size and their ability to not only penetrate the skin but to enter the body through the mucosa in the nose, or to be swallowed, Dr. Friedman said.

The Facts

Nanoparticle penetration is limited by size. "One of the things I tell people is that the materials they are using in bench research are different than what is used in over-the-counter products," Dr. Friedman said. "Those used in consumer products are commonly coated, so they aggregate and don't penetrate the skin as easily."

"Thus far, everything that has been done in terms of topical application of the skin, the particles do not penetrate to the point where they could cause problems,” said Dr. Friedman. "Clearly, more needs to be done, and certain clinical situations need to be explored, such as penetration into damaged skin," he noted. When the nanoparticles are aggregated in solution, they are trapped in the upper layers of the skin, where they are sloughed off over time.

"A lot of the fear with respect to the bodily harm from nanomaterials comes from the lung literature and occupational hazards with respect to people inhaling asbestos," he noted.

Another concern about nano-based sunscreens is the potential impact on the environment, Dr. Friedman said. However, a hot-off-the press (April 17) study in Science of the Total Environment by A. Johnson and colleagues found no impact of titanium oxide sunscreens on the environment.

--Heidi Splete (on twitter @hsplete)

April showers bring May patients who may be confused about the safety of sunscreens containing nanoparticles of titanium and zinc.

To help alleviate concerns the Nanodermatology Society released a position statement on the safety of sunscreens containing nanoparticles. Dr. Adam Friedman, vice president of the Society and senior author of the position statement, spoke to The Mole about the safety of nano-based sunscreens.

Photo credit pni via Flickr Creative Commons

The Fears

The concern is that nanoparticles might interact directly with cell DNA and cause damage because of their size and their ability to not only penetrate the skin but to enter the body through the mucosa in the nose, or to be swallowed, Dr. Friedman said.

The Facts

Nanoparticle penetration is limited by size. "One of the things I tell people is that the materials they are using in bench research are different than what is used in over-the-counter products," Dr. Friedman said. "Those used in consumer products are commonly coated, so they aggregate and don't penetrate the skin as easily."

"Thus far, everything that has been done in terms of topical application of the skin, the particles do not penetrate to the point where they could cause problems,” said Dr. Friedman. "Clearly, more needs to be done, and certain clinical situations need to be explored, such as penetration into damaged skin," he noted. When the nanoparticles are aggregated in solution, they are trapped in the upper layers of the skin, where they are sloughed off over time.

"A lot of the fear with respect to the bodily harm from nanomaterials comes from the lung literature and occupational hazards with respect to people inhaling asbestos," he noted.

Another concern about nano-based sunscreens is the potential impact on the environment, Dr. Friedman said. However, a hot-off-the press (April 17) study in Science of the Total Environment by A. Johnson and colleagues found no impact of titanium oxide sunscreens on the environment.

--Heidi Splete (on twitter @hsplete)

SAN ANTONIO – Lymphovascular invasion, not sentinel lymph node status, was strongly associated with recurrence and death from Merkel cell carcinoma in a series of 153 patients with clinically localized disease.

Patients without lymphatic vascular invasion (LVI) of their primary tumors did not develop recurrence or die, said Dr. Ryan Fields of the department of surgery at Memorial Sloan-Kettering Cancer Center, New York.

Although sentinel lymph node (SLN) status was not associated with recurrence or death from Merkel cell carcinoma (MCC), patients with a positive SLN were more likely to receive subsequent treatment including complete lymph node dissection, nodal radiation therapy, and/or chemotherapy.

Dr. Fields suggested that one explanation for the surprising lack of association with SLN status may be the additional treatment received by SLN-positive patients was so effective as to interrupt the metastatic cascade and prevent recurrence or death from MCC.

During a discussion of the study, Dr. Kelly McMasters, professor and chair of surgery at the University of Louisville in Kentucky, expressed doubt that adjuvant therapy was so effective as to skew the results and asked whether clinicians should biopsy their next MCC patient or whether this may simply lead them to overtreat their patients.

Dr. Fields acknowledged that the results are puzzling and said that all patients with MCC continue to be offered SLN biopsy at Memorial Sloan-Kettering, where the study was performed. He added that surgeons there are also trying to capture information on LVI to determine in which patients LVI could be used in lieu of SLN biopsy as a prognostic marker.

There is no universally accepted staging system for MCC, a rare cutaneous cancer that has a propensity for lymphatic spread. SLN biopsy has been used in an effort to provide more accurate staging and to guide subsequent treatment, although most studies have been small and did not look at outcome at the time of SLN status, he explained.

A previous analysis of 251 MCC patients treated from 1970 to 2002 at Memorial Sloan-Kettering reported that disease stage was the only independent predictor of survival and that stage-specific survival was decreased in patients with node-positive disease (J. Clin. Oncol. 2005;23:2300-9).

In the current analysis from 1996 to 2010, a total of 153 patients with stage I or II MCC underwent SLN biopsy, of which 45 (29%) were positive and 108 (71%) were negative.

The primary tumor was 2 cm or less (clinical stage I) in 122 patients and more than 2 cm (clinical stage II) in 31 patients. LVI was present in the primary tumor in 75 patients, absent in 69, and unknown in 9.

A positive SLN biopsy was significantly associated with stage II vs. stage I tumors (45% vs. 25%, P = .02), and with LVI vs. LVI absence (55% vs. 4%, P less than .01). Notably, 26% of positive SLNs occurred in tumors 1 cm or less, observed Dr. Fields.

After a median follow-up of 41 months, 16 nodal or distant recurrences occurred, 11 patients died of MCC, and 27 patients died of other causes.

"This highlights the fact that overall survival, which has been used quite a bit as an end point in Merkel cell cancers, is a poor end point measure in this population," Dr. Fields said.

Importantly, there were no nodal recurrences in SLN-positive patients who went on to receive adjuvant nodal radiation therapy after completion lymph node dissection or therapeutic radiotherapy alone.

Only two of the 32 SLN-positive patients (6%) who received no adjuvant chemotherapy developed a distant recurrence, suggesting that unproven adjuvant chemotherapy would be unlikely to benefit this patient population, Dr. Fields said.

Among the 108 patients with a negative SLN, 99 received no further treatment. Of these, 8% experienced a recurrence, which corresponds to a 15% false-negative rate for the SLNB procedure in MCC, he said.

When patients were stratified by tumor characteristics, there was no significant association between SLN-positive and SLN-negative patients in nodal/distant recurrence (P = .86) or death from MCC (P = .89). The association was significantly between stage II and stage I tumors for death (P =.05), but not for recurrence (P = .26).

In contrast, the presence of LVI was significantly associated with both nodal/distant recurrence and death from MCC (both P less than .001), Dr. Fields said. The 2-year confidence intervals of recurrence or death from MCC for LVI-positive patients were 30% and 15%, respectively.

Dr. Fields and his coauthors reported no study support or relevant conflicts of interest.

SAN ANTONIO – Lymphovascular invasion, not sentinel lymph node status, was strongly associated with recurrence and death from Merkel cell carcinoma in a series of 153 patients with clinically localized disease.

Patients without lymphatic vascular invasion (LVI) of their primary tumors did not develop recurrence or die, said Dr. Ryan Fields of the department of surgery at Memorial Sloan-Kettering Cancer Center, New York.

Although sentinel lymph node (SLN) status was not associated with recurrence or death from Merkel cell carcinoma (MCC), patients with a positive SLN were more likely to receive subsequent treatment including complete lymph node dissection, nodal radiation therapy, and/or chemotherapy.

Dr. Fields suggested that one explanation for the surprising lack of association with SLN status may be the additional treatment received by SLN-positive patients was so effective as to interrupt the metastatic cascade and prevent recurrence or death from MCC.

During a discussion of the study, Dr. Kelly McMasters, professor and chair of surgery at the University of Louisville in Kentucky, expressed doubt that adjuvant therapy was so effective as to skew the results and asked whether clinicians should biopsy their next MCC patient or whether this may simply lead them to overtreat their patients.

Dr. Fields acknowledged that the results are puzzling and said that all patients with MCC continue to be offered SLN biopsy at Memorial Sloan-Kettering, where the study was performed. He added that surgeons there are also trying to capture information on LVI to determine in which patients LVI could be used in lieu of SLN biopsy as a prognostic marker.

There is no universally accepted staging system for MCC, a rare cutaneous cancer that has a propensity for lymphatic spread. SLN biopsy has been used in an effort to provide more accurate staging and to guide subsequent treatment, although most studies have been small and did not look at outcome at the time of SLN status, he explained.

A previous analysis of 251 MCC patients treated from 1970 to 2002 at Memorial Sloan-Kettering reported that disease stage was the only independent predictor of survival and that stage-specific survival was decreased in patients with node-positive disease (J. Clin. Oncol. 2005;23:2300-9).

In the current analysis from 1996 to 2010, a total of 153 patients with stage I or II MCC underwent SLN biopsy, of which 45 (29%) were positive and 108 (71%) were negative.

The primary tumor was 2 cm or less (clinical stage I) in 122 patients and more than 2 cm (clinical stage II) in 31 patients. LVI was present in the primary tumor in 75 patients, absent in 69, and unknown in 9.

A positive SLN biopsy was significantly associated with stage II vs. stage I tumors (45% vs. 25%, P = .02), and with LVI vs. LVI absence (55% vs. 4%, P less than .01). Notably, 26% of positive SLNs occurred in tumors 1 cm or less, observed Dr. Fields.

After a median follow-up of 41 months, 16 nodal or distant recurrences occurred, 11 patients died of MCC, and 27 patients died of other causes.

"This highlights the fact that overall survival, which has been used quite a bit as an end point in Merkel cell cancers, is a poor end point measure in this population," Dr. Fields said.

Importantly, there were no nodal recurrences in SLN-positive patients who went on to receive adjuvant nodal radiation therapy after completion lymph node dissection or therapeutic radiotherapy alone.

Only two of the 32 SLN-positive patients (6%) who received no adjuvant chemotherapy developed a distant recurrence, suggesting that unproven adjuvant chemotherapy would be unlikely to benefit this patient population, Dr. Fields said.

Among the 108 patients with a negative SLN, 99 received no further treatment. Of these, 8% experienced a recurrence, which corresponds to a 15% false-negative rate for the SLNB procedure in MCC, he said.

When patients were stratified by tumor characteristics, there was no significant association between SLN-positive and SLN-negative patients in nodal/distant recurrence (P = .86) or death from MCC (P = .89). The association was significantly between stage II and stage I tumors for death (P =.05), but not for recurrence (P = .26).

In contrast, the presence of LVI was significantly associated with both nodal/distant recurrence and death from MCC (both P less than .001), Dr. Fields said. The 2-year confidence intervals of recurrence or death from MCC for LVI-positive patients were 30% and 15%, respectively.

Dr. Fields and his coauthors reported no study support or relevant conflicts of interest.

SAN ANTONIO – Lymphovascular invasion, not sentinel lymph node status, was strongly associated with recurrence and death from Merkel cell carcinoma in a series of 153 patients with clinically localized disease.

Patients without lymphatic vascular invasion (LVI) of their primary tumors did not develop recurrence or die, said Dr. Ryan Fields of the department of surgery at Memorial Sloan-Kettering Cancer Center, New York.

Although sentinel lymph node (SLN) status was not associated with recurrence or death from Merkel cell carcinoma (MCC), patients with a positive SLN were more likely to receive subsequent treatment including complete lymph node dissection, nodal radiation therapy, and/or chemotherapy.

Dr. Fields suggested that one explanation for the surprising lack of association with SLN status may be the additional treatment received by SLN-positive patients was so effective as to interrupt the metastatic cascade and prevent recurrence or death from MCC.

During a discussion of the study, Dr. Kelly McMasters, professor and chair of surgery at the University of Louisville in Kentucky, expressed doubt that adjuvant therapy was so effective as to skew the results and asked whether clinicians should biopsy their next MCC patient or whether this may simply lead them to overtreat their patients.

Dr. Fields acknowledged that the results are puzzling and said that all patients with MCC continue to be offered SLN biopsy at Memorial Sloan-Kettering, where the study was performed. He added that surgeons there are also trying to capture information on LVI to determine in which patients LVI could be used in lieu of SLN biopsy as a prognostic marker.

There is no universally accepted staging system for MCC, a rare cutaneous cancer that has a propensity for lymphatic spread. SLN biopsy has been used in an effort to provide more accurate staging and to guide subsequent treatment, although most studies have been small and did not look at outcome at the time of SLN status, he explained.

A previous analysis of 251 MCC patients treated from 1970 to 2002 at Memorial Sloan-Kettering reported that disease stage was the only independent predictor of survival and that stage-specific survival was decreased in patients with node-positive disease (J. Clin. Oncol. 2005;23:2300-9).

In the current analysis from 1996 to 2010, a total of 153 patients with stage I or II MCC underwent SLN biopsy, of which 45 (29%) were positive and 108 (71%) were negative.

The primary tumor was 2 cm or less (clinical stage I) in 122 patients and more than 2 cm (clinical stage II) in 31 patients. LVI was present in the primary tumor in 75 patients, absent in 69, and unknown in 9.

A positive SLN biopsy was significantly associated with stage II vs. stage I tumors (45% vs. 25%, P = .02), and with LVI vs. LVI absence (55% vs. 4%, P less than .01). Notably, 26% of positive SLNs occurred in tumors 1 cm or less, observed Dr. Fields.

After a median follow-up of 41 months, 16 nodal or distant recurrences occurred, 11 patients died of MCC, and 27 patients died of other causes.

"This highlights the fact that overall survival, which has been used quite a bit as an end point in Merkel cell cancers, is a poor end point measure in this population," Dr. Fields said.

Importantly, there were no nodal recurrences in SLN-positive patients who went on to receive adjuvant nodal radiation therapy after completion lymph node dissection or therapeutic radiotherapy alone.

Only two of the 32 SLN-positive patients (6%) who received no adjuvant chemotherapy developed a distant recurrence, suggesting that unproven adjuvant chemotherapy would be unlikely to benefit this patient population, Dr. Fields said.

Among the 108 patients with a negative SLN, 99 received no further treatment. Of these, 8% experienced a recurrence, which corresponds to a 15% false-negative rate for the SLNB procedure in MCC, he said.

When patients were stratified by tumor characteristics, there was no significant association between SLN-positive and SLN-negative patients in nodal/distant recurrence (P = .86) or death from MCC (P = .89). The association was significantly between stage II and stage I tumors for death (P =.05), but not for recurrence (P = .26).

In contrast, the presence of LVI was significantly associated with both nodal/distant recurrence and death from MCC (both P less than .001), Dr. Fields said. The 2-year confidence intervals of recurrence or death from MCC for LVI-positive patients were 30% and 15%, respectively.

Dr. Fields and his coauthors reported no study support or relevant conflicts of interest.

SAN ANTONIO – Lymphovascular invasion, not sentinel lymph node status, was strongly associated with recurrence and death from Merkel cell carcinoma in a series of 153 patients with clinically localized disease.

Patients without lymphatic vascular invasion (LVI) of their primary tumors did not develop recurrence or die, said Dr. Ryan Fields of the department of surgery at Memorial Sloan-Kettering Cancer Center, New York.

Although sentinel lymph node (SLN) status was not associated with recurrence or death from Merkel cell carcinoma (MCC), patients with a positive SLN were more likely to receive subsequent treatment including complete lymph node dissection, nodal radiation therapy, and/or chemotherapy.

Dr. Fields suggested that one explanation for the surprising lack of association with SLN status may be the additional treatment received by SLN-positive patients was so effective as to interrupt the metastatic cascade and prevent recurrence or death from MCC.

During a discussion of the study, Dr. Kelly McMasters, professor and chair of surgery at the University of Louisville in Kentucky, expressed doubt that adjuvant therapy was so effective as to skew the results and asked whether clinicians should biopsy their next MCC patient or whether this may simply lead them to over treat their patients.

Dr. Fields acknowledged that the results are puzzling and said that all patients with MCC continue to be offered SLN biopsy at Memorial Sloan-Kettering, where the study was performed. He added that surgeons there are also trying to capture information on LVI to determine in which patients LVI could be used in lieu of SLN biopsy as a prognostic marker.

There is no universally accepted staging system for MCC, a rare cutaneous cancer that has a propensity for lymphatic spread. SLN biopsy has been used in an effort to provide more accurate staging and to guide subsequent treatment, although most studies have been small and did not look at outcome at the time of SLN status, he explained.

A previous analysis of 251 MCC patients treated from 1970 to 2002 at Memorial Sloan-Kettering reported that disease stage was the only independent predictor of survival and that stage-specific survival was decreased in patients with node-positive disease (J. Clin. Oncol. 2005;23:2300-9).

In the current analysis from 1996 to 2010, a total of 153 patients with stage I or II MCC underwent SLN biopsy, of which 45 (29%) were positive and 108 (71%) were negative.

The primary tumor was 2 cm or less (clinical stage I) in 122 patients and more than 2 cm (clinical stage II) in 31 patients. LVI was present in the primary tumor in 75 patients, absent in 69, and unknown in 9.

A positive SLN biopsy was significantly associated with stage II vs. stage I tumors (45% vs. 25%, P = .02), and with LVI vs. LVI absence (55% vs. 4%, P less than .01). Notably, 26% of positive SLNs occurred in tumors 1 cm or less, observed Dr. Fields.

After a median follow-up of 41 months, 16 nodal or distant recurrences occurred, 11 patients died of MCC, and 27 patients died of other causes.

"This highlights the fact that overall survival, which has been used quite a bit as an end point in Merkel cell cancers, is a poor end point measure in this population," Dr. Fields said.

Importantly, there were no nodal recurrences in SLN-positive patients who went on to receive adjuvant nodal radiation therapy after completion lymph node dissection or therapeutic radiotherapy alone.

Only two of the 32 SLN-positive patients (6%) who received no adjuvant chemotherapy developed a distant recurrence, suggesting that unproven adjuvant chemotherapy would be unlikely to benefit this patient population, Dr. Fields said.

Among the 108 patients with a negative SLN, 99 received no further treatment. Of these, 8% experienced a recurrence, which corresponds to a 15% false-negative rate for the SLNB procedure in MCC, he said.

When patients were stratified by tumor characteristics, there was no significant association between SLN-positive and SLN-negative patients in nodal/distant recurrence (P = .86) or death from MCC (P = .89). The association was significantly between stage II and stage I tumors for death (P =.05), but not for recurrence (P = .26).

In contrast, the presence of LVI was significantly associated with both nodal/distant recurrence and death from MCC (both P less than .001), Dr. Fields said. The 2-year confidence intervals of recurrence or death from MCC for LVI-positive patients were 30% and 15%, respectively.

Dr. Fields and his coauthors reported no study support or relevant conflicts of interest.

SAN ANTONIO – Lymphovascular invasion, not sentinel lymph node status, was strongly associated with recurrence and death from Merkel cell carcinoma in a series of 153 patients with clinically localized disease.

Patients without lymphatic vascular invasion (LVI) of their primary tumors did not develop recurrence or die, said Dr. Ryan Fields of the department of surgery at Memorial Sloan-Kettering Cancer Center, New York.

Although sentinel lymph node (SLN) status was not associated with recurrence or death from Merkel cell carcinoma (MCC), patients with a positive SLN were more likely to receive subsequent treatment including complete lymph node dissection, nodal radiation therapy, and/or chemotherapy.

Dr. Fields suggested that one explanation for the surprising lack of association with SLN status may be the additional treatment received by SLN-positive patients was so effective as to interrupt the metastatic cascade and prevent recurrence or death from MCC.

During a discussion of the study, Dr. Kelly McMasters, professor and chair of surgery at the University of Louisville in Kentucky, expressed doubt that adjuvant therapy was so effective as to skew the results and asked whether clinicians should biopsy their next MCC patient or whether this may simply lead them to over treat their patients.

Dr. Fields acknowledged that the results are puzzling and said that all patients with MCC continue to be offered SLN biopsy at Memorial Sloan-Kettering, where the study was performed. He added that surgeons there are also trying to capture information on LVI to determine in which patients LVI could be used in lieu of SLN biopsy as a prognostic marker.

There is no universally accepted staging system for MCC, a rare cutaneous cancer that has a propensity for lymphatic spread. SLN biopsy has been used in an effort to provide more accurate staging and to guide subsequent treatment, although most studies have been small and did not look at outcome at the time of SLN status, he explained.

A previous analysis of 251 MCC patients treated from 1970 to 2002 at Memorial Sloan-Kettering reported that disease stage was the only independent predictor of survival and that stage-specific survival was decreased in patients with node-positive disease (J. Clin. Oncol. 2005;23:2300-9).

In the current analysis from 1996 to 2010, a total of 153 patients with stage I or II MCC underwent SLN biopsy, of which 45 (29%) were positive and 108 (71%) were negative.

The primary tumor was 2 cm or less (clinical stage I) in 122 patients and more than 2 cm (clinical stage II) in 31 patients. LVI was present in the primary tumor in 75 patients, absent in 69, and unknown in 9.

A positive SLN biopsy was significantly associated with stage II vs. stage I tumors (45% vs. 25%, P = .02), and with LVI vs. LVI absence (55% vs. 4%, P less than .01). Notably, 26% of positive SLNs occurred in tumors 1 cm or less, observed Dr. Fields.

After a median follow-up of 41 months, 16 nodal or distant recurrences occurred, 11 patients died of MCC, and 27 patients died of other causes.

"This highlights the fact that overall survival, which has been used quite a bit as an end point in Merkel cell cancers, is a poor end point measure in this population," Dr. Fields said.

Importantly, there were no nodal recurrences in SLN-positive patients who went on to receive adjuvant nodal radiation therapy after completion lymph node dissection or therapeutic radiotherapy alone.

Only two of the 32 SLN-positive patients (6%) who received no adjuvant chemotherapy developed a distant recurrence, suggesting that unproven adjuvant chemotherapy would be unlikely to benefit this patient population, Dr. Fields said.

Among the 108 patients with a negative SLN, 99 received no further treatment. Of these, 8% experienced a recurrence, which corresponds to a 15% false-negative rate for the SLNB procedure in MCC, he said.

When patients were stratified by tumor characteristics, there was no significant association between SLN-positive and SLN-negative patients in nodal/distant recurrence (P = .86) or death from MCC (P = .89). The association was significantly between stage II and stage I tumors for death (P =.05), but not for recurrence (P = .26).

In contrast, the presence of LVI was significantly associated with both nodal/distant recurrence and death from MCC (both P less than .001), Dr. Fields said. The 2-year confidence intervals of recurrence or death from MCC for LVI-positive patients were 30% and 15%, respectively.

Dr. Fields and his coauthors reported no study support or relevant conflicts of interest.

SAN ANTONIO – Lymphovascular invasion, not sentinel lymph node status, was strongly associated with recurrence and death from Merkel cell carcinoma in a series of 153 patients with clinically localized disease.

Patients without lymphatic vascular invasion (LVI) of their primary tumors did not develop recurrence or die, said Dr. Ryan Fields of the department of surgery at Memorial Sloan-Kettering Cancer Center, New York.

Although sentinel lymph node (SLN) status was not associated with recurrence or death from Merkel cell carcinoma (MCC), patients with a positive SLN were more likely to receive subsequent treatment including complete lymph node dissection, nodal radiation therapy, and/or chemotherapy.

Dr. Fields suggested that one explanation for the surprising lack of association with SLN status may be the additional treatment received by SLN-positive patients was so effective as to interrupt the metastatic cascade and prevent recurrence or death from MCC.

During a discussion of the study, Dr. Kelly McMasters, professor and chair of surgery at the University of Louisville in Kentucky, expressed doubt that adjuvant therapy was so effective as to skew the results and asked whether clinicians should biopsy their next MCC patient or whether this may simply lead them to over treat their patients.

Dr. Fields acknowledged that the results are puzzling and said that all patients with MCC continue to be offered SLN biopsy at Memorial Sloan-Kettering, where the study was performed. He added that surgeons there are also trying to capture information on LVI to determine in which patients LVI could be used in lieu of SLN biopsy as a prognostic marker.

There is no universally accepted staging system for MCC, a rare cutaneous cancer that has a propensity for lymphatic spread. SLN biopsy has been used in an effort to provide more accurate staging and to guide subsequent treatment, although most studies have been small and did not look at outcome at the time of SLN status, he explained.

A previous analysis of 251 MCC patients treated from 1970 to 2002 at Memorial Sloan-Kettering reported that disease stage was the only independent predictor of survival and that stage-specific survival was decreased in patients with node-positive disease (J. Clin. Oncol. 2005;23:2300-9).

In the current analysis from 1996 to 2010, a total of 153 patients with stage I or II MCC underwent SLN biopsy, of which 45 (29%) were positive and 108 (71%) were negative.

The primary tumor was 2 cm or less (clinical stage I) in 122 patients and more than 2 cm (clinical stage II) in 31 patients. LVI was present in the primary tumor in 75 patients, absent in 69, and unknown in 9.

A positive SLN biopsy was significantly associated with stage II vs. stage I tumors (45% vs. 25%, P = .02), and with LVI vs. LVI absence (55% vs. 4%, P less than .01). Notably, 26% of positive SLNs occurred in tumors 1 cm or less, observed Dr. Fields.

After a median follow-up of 41 months, 16 nodal or distant recurrences occurred, 11 patients died of MCC, and 27 patients died of other causes.

"This highlights the fact that overall survival, which has been used quite a bit as an end point in Merkel cell cancers, is a poor end point measure in this population," Dr. Fields said.

Importantly, there were no nodal recurrences in SLN-positive patients who went on to receive adjuvant nodal radiation therapy after completion lymph node dissection or therapeutic radiotherapy alone.

Only two of the 32 SLN-positive patients (6%) who received no adjuvant chemotherapy developed a distant recurrence, suggesting that unproven adjuvant chemotherapy would be unlikely to benefit this patient population, Dr. Fields said.

Among the 108 patients with a negative SLN, 99 received no further treatment. Of these, 8% experienced a recurrence, which corresponds to a 15% false-negative rate for the SLNB procedure in MCC, he said.

When patients were stratified by tumor characteristics, there was no significant association between SLN-positive and SLN-negative patients in nodal/distant recurrence (P = .86) or death from MCC (P = .89). The association was significantly between stage II and stage I tumors for death (P =.05), but not for recurrence (P = .26).

In contrast, the presence of LVI was significantly associated with both nodal/distant recurrence and death from MCC (both P less than .001), Dr. Fields said. The 2-year confidence intervals of recurrence or death from MCC for LVI-positive patients were 30% and 15%, respectively.

Dr. Fields and his coauthors reported no study support or relevant conflicts of interest.