Melanoma

WAIKOLOA, HAWAII – Momentum is building – perhaps unstoppably – for creation of a national, population-based melanoma screening program.

"Demand for screening is going up as we speak. The incidence of melanoma is going up dramatically, and it’s really important to understand that this is happening in the absence of formal screening for melanoma. So imagine what would happen if we did screen for melanoma routinely," Dr. Allan C. Halpern observed at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

Also, public awareness is increasing dramatically.

"We’ve spent a lot of time as dermatologists educating the public. And there may be as many as a million people walking around the U.S. right now who’ve personally had melanoma. We want to see them in follow-up visits, and their family members want to see us as well," said Dr. Halpern, chief of the dermatology service at Memorial Sloan Kettering Cancer Center in New York.

The current position of the U.S. Preventive Services Task Force (Ann. Intern. Med. 2009;150:194-8), the American Cancer Society, and other influential organizations is that formal guidelines for population-based screening for melanoma are not warranted at this time, because there is no randomized clinical trial evidence of net benefit. That position could change, however, even in the absence of such evidence. For example, the U.S. Preventive Services Task Force strongly supports cervical cancer screening, even though it has never been subjected to a randomized trial. The task force became convinced that cervical cancer screening works on the basis of observational data showing that by the time 80% of women were screened, mortality due to cervical cancer dropped by nearly 50%, Dr. Halpern noted.

The ‘extraordinary’ German example

The ongoing German national experience with melanoma screening may provide a big push for a shift in U.S. health policy in favor of routine screening for melanoma, according to Dr. Halpern.

The German melanoma screening program is one of the most extraordinary stories in dermatology, he said. The program is mainly the work of one determined and persuasive German dermatologist – Dr. Eckhard Breitbart – who has been pushing for melanoma screening in Germany for 45 years. Dr. Breitbart received funding for a pilot study conducted in Germany’s northernmost state, Schleswig-Holstein. The state’s primary care physicians were persuaded to conduct the first-tier screening of all Schleswig-Holstein residents. They received a financial incentive on a per-case basis, provided they first completed an 8-hour training course. The bottom line: After just 2 years of screening, mortality caused by melanoma dropped by 48% over the next 7 years while remaining unchanged in the neighboring states (Cancer 2012;118:5395-402).

Armed with the data, Dr. Breitbart persuaded the German federal government to expand screening nationally. That program began in 2005.

"I don’t think melanoma mortality will come down by 50% across all of Germany, but if the German data show it comes down by 20%-30%, then it’s the cervical cancer story revisited. I think that would be very strong endorsement that screening for melanoma can save lives," Dr. Halpern said.

He injected a cautionary note, however.

"I must warn you; the German experience may not give us definitive answers. It turns out that Eckhard Breitbart was so persuasive when he went to convince the German government to do the screening program that they ‘knew’ for a fact that it was going to work. So they didn’t allocate any money for an assessment of whether it actually works," Dr. Halpern explained.

Also, the study was limited by the German government’s concern about medical records privacy.

"Trying to get the data on who was screened versus who got melanoma and died of it is proving amazingly difficult. There are actually a bunch of melanoma experts here in the states, including Marty Weinstock and Alan Geller, who have been working closely with the German group to try to get some of the data. We’ll just have to wait and see how the German experience plays out," Dr. Halpern continued.

As pressure for routine melanoma screening mounts in the United States, it’s apparent that there is a major supply-and-demand issue involved. The supply of the medical dermatology workforce is shrinking relative to the growing demand, Dr. Halpern said. Going forward, the most promising solution in his view is to train primary care physicians and physician extenders to perform the screening, as is done in Germany. There is an enormous opportunity here for these nondermatologists to harness the emerging automated imaging and molecular sensing technologies for detection of lesion changes and diagnosis of melanoma, he added.

First do no harm

Dr. Halpern offered a note of caution regarding melanoma screening: Although it sounds great in theory because it’s relatively cheap, the lesions are accessible on the surface of the skin, and there is the potential to save many life-years, it’s also imperative to consider the potential harms. Perhaps the biggest of these, Dr. Halpern said, is the psychological damage caused by turning a patient with an indolent, low-risk melanoma or nonmelanoma skin cancer into a cancer patient.

"We have to be really, really careful to look at the harms involved in screening. To my mind, one of the biggest problems of melanoma screening is the psychological harm we do by giving people cancer. I’m especially bothered about the way we do that with patients who develop melanoma in situ or microinvasive disease," he said.

"Believe me, if I had melanoma in situ or microinvasive melanoma, I would want you to find it and take if off for me. What I don’t want you to do is to turn me into a cancer patient. I don’t think that’s in the patient’s best interest whatsoever. We don’t do it intentionally, but as dermatologists we have this tendency to dramatically overplay the importance of these diagnoses," Dr. Halpern said.

Dr. Halpern reported having financial relationships with Scibase, DermTech, Caliber, and Canfield.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – Momentum is building – perhaps unstoppably – for creation of a national, population-based melanoma screening program.

"Demand for screening is going up as we speak. The incidence of melanoma is going up dramatically, and it’s really important to understand that this is happening in the absence of formal screening for melanoma. So imagine what would happen if we did screen for melanoma routinely," Dr. Allan C. Halpern observed at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

Also, public awareness is increasing dramatically.

"We’ve spent a lot of time as dermatologists educating the public. And there may be as many as a million people walking around the U.S. right now who’ve personally had melanoma. We want to see them in follow-up visits, and their family members want to see us as well," said Dr. Halpern, chief of the dermatology service at Memorial Sloan Kettering Cancer Center in New York.

The current position of the U.S. Preventive Services Task Force (Ann. Intern. Med. 2009;150:194-8), the American Cancer Society, and other influential organizations is that formal guidelines for population-based screening for melanoma are not warranted at this time, because there is no randomized clinical trial evidence of net benefit. That position could change, however, even in the absence of such evidence. For example, the U.S. Preventive Services Task Force strongly supports cervical cancer screening, even though it has never been subjected to a randomized trial. The task force became convinced that cervical cancer screening works on the basis of observational data showing that by the time 80% of women were screened, mortality due to cervical cancer dropped by nearly 50%, Dr. Halpern noted.

The ‘extraordinary’ German example

The ongoing German national experience with melanoma screening may provide a big push for a shift in U.S. health policy in favor of routine screening for melanoma, according to Dr. Halpern.

The German melanoma screening program is one of the most extraordinary stories in dermatology, he said. The program is mainly the work of one determined and persuasive German dermatologist – Dr. Eckhard Breitbart – who has been pushing for melanoma screening in Germany for 45 years. Dr. Breitbart received funding for a pilot study conducted in Germany’s northernmost state, Schleswig-Holstein. The state’s primary care physicians were persuaded to conduct the first-tier screening of all Schleswig-Holstein residents. They received a financial incentive on a per-case basis, provided they first completed an 8-hour training course. The bottom line: After just 2 years of screening, mortality caused by melanoma dropped by 48% over the next 7 years while remaining unchanged in the neighboring states (Cancer 2012;118:5395-402).

Armed with the data, Dr. Breitbart persuaded the German federal government to expand screening nationally. That program began in 2005.

"I don’t think melanoma mortality will come down by 50% across all of Germany, but if the German data show it comes down by 20%-30%, then it’s the cervical cancer story revisited. I think that would be very strong endorsement that screening for melanoma can save lives," Dr. Halpern said.

He injected a cautionary note, however.

"I must warn you; the German experience may not give us definitive answers. It turns out that Eckhard Breitbart was so persuasive when he went to convince the German government to do the screening program that they ‘knew’ for a fact that it was going to work. So they didn’t allocate any money for an assessment of whether it actually works," Dr. Halpern explained.

Also, the study was limited by the German government’s concern about medical records privacy.

"Trying to get the data on who was screened versus who got melanoma and died of it is proving amazingly difficult. There are actually a bunch of melanoma experts here in the states, including Marty Weinstock and Alan Geller, who have been working closely with the German group to try to get some of the data. We’ll just have to wait and see how the German experience plays out," Dr. Halpern continued.

As pressure for routine melanoma screening mounts in the United States, it’s apparent that there is a major supply-and-demand issue involved. The supply of the medical dermatology workforce is shrinking relative to the growing demand, Dr. Halpern said. Going forward, the most promising solution in his view is to train primary care physicians and physician extenders to perform the screening, as is done in Germany. There is an enormous opportunity here for these nondermatologists to harness the emerging automated imaging and molecular sensing technologies for detection of lesion changes and diagnosis of melanoma, he added.

First do no harm

Dr. Halpern offered a note of caution regarding melanoma screening: Although it sounds great in theory because it’s relatively cheap, the lesions are accessible on the surface of the skin, and there is the potential to save many life-years, it’s also imperative to consider the potential harms. Perhaps the biggest of these, Dr. Halpern said, is the psychological damage caused by turning a patient with an indolent, low-risk melanoma or nonmelanoma skin cancer into a cancer patient.

"We have to be really, really careful to look at the harms involved in screening. To my mind, one of the biggest problems of melanoma screening is the psychological harm we do by giving people cancer. I’m especially bothered about the way we do that with patients who develop melanoma in situ or microinvasive disease," he said.

"Believe me, if I had melanoma in situ or microinvasive melanoma, I would want you to find it and take if off for me. What I don’t want you to do is to turn me into a cancer patient. I don’t think that’s in the patient’s best interest whatsoever. We don’t do it intentionally, but as dermatologists we have this tendency to dramatically overplay the importance of these diagnoses," Dr. Halpern said.

Dr. Halpern reported having financial relationships with Scibase, DermTech, Caliber, and Canfield.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – Momentum is building – perhaps unstoppably – for creation of a national, population-based melanoma screening program.

"Demand for screening is going up as we speak. The incidence of melanoma is going up dramatically, and it’s really important to understand that this is happening in the absence of formal screening for melanoma. So imagine what would happen if we did screen for melanoma routinely," Dr. Allan C. Halpern observed at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

Also, public awareness is increasing dramatically.

"We’ve spent a lot of time as dermatologists educating the public. And there may be as many as a million people walking around the U.S. right now who’ve personally had melanoma. We want to see them in follow-up visits, and their family members want to see us as well," said Dr. Halpern, chief of the dermatology service at Memorial Sloan Kettering Cancer Center in New York.

The current position of the U.S. Preventive Services Task Force (Ann. Intern. Med. 2009;150:194-8), the American Cancer Society, and other influential organizations is that formal guidelines for population-based screening for melanoma are not warranted at this time, because there is no randomized clinical trial evidence of net benefit. That position could change, however, even in the absence of such evidence. For example, the U.S. Preventive Services Task Force strongly supports cervical cancer screening, even though it has never been subjected to a randomized trial. The task force became convinced that cervical cancer screening works on the basis of observational data showing that by the time 80% of women were screened, mortality due to cervical cancer dropped by nearly 50%, Dr. Halpern noted.

The ‘extraordinary’ German example

The ongoing German national experience with melanoma screening may provide a big push for a shift in U.S. health policy in favor of routine screening for melanoma, according to Dr. Halpern.

The German melanoma screening program is one of the most extraordinary stories in dermatology, he said. The program is mainly the work of one determined and persuasive German dermatologist – Dr. Eckhard Breitbart – who has been pushing for melanoma screening in Germany for 45 years. Dr. Breitbart received funding for a pilot study conducted in Germany’s northernmost state, Schleswig-Holstein. The state’s primary care physicians were persuaded to conduct the first-tier screening of all Schleswig-Holstein residents. They received a financial incentive on a per-case basis, provided they first completed an 8-hour training course. The bottom line: After just 2 years of screening, mortality caused by melanoma dropped by 48% over the next 7 years while remaining unchanged in the neighboring states (Cancer 2012;118:5395-402).

Armed with the data, Dr. Breitbart persuaded the German federal government to expand screening nationally. That program began in 2005.

"I don’t think melanoma mortality will come down by 50% across all of Germany, but if the German data show it comes down by 20%-30%, then it’s the cervical cancer story revisited. I think that would be very strong endorsement that screening for melanoma can save lives," Dr. Halpern said.

He injected a cautionary note, however.

"I must warn you; the German experience may not give us definitive answers. It turns out that Eckhard Breitbart was so persuasive when he went to convince the German government to do the screening program that they ‘knew’ for a fact that it was going to work. So they didn’t allocate any money for an assessment of whether it actually works," Dr. Halpern explained.

Also, the study was limited by the German government’s concern about medical records privacy.

"Trying to get the data on who was screened versus who got melanoma and died of it is proving amazingly difficult. There are actually a bunch of melanoma experts here in the states, including Marty Weinstock and Alan Geller, who have been working closely with the German group to try to get some of the data. We’ll just have to wait and see how the German experience plays out," Dr. Halpern continued.

As pressure for routine melanoma screening mounts in the United States, it’s apparent that there is a major supply-and-demand issue involved. The supply of the medical dermatology workforce is shrinking relative to the growing demand, Dr. Halpern said. Going forward, the most promising solution in his view is to train primary care physicians and physician extenders to perform the screening, as is done in Germany. There is an enormous opportunity here for these nondermatologists to harness the emerging automated imaging and molecular sensing technologies for detection of lesion changes and diagnosis of melanoma, he added.

First do no harm

Dr. Halpern offered a note of caution regarding melanoma screening: Although it sounds great in theory because it’s relatively cheap, the lesions are accessible on the surface of the skin, and there is the potential to save many life-years, it’s also imperative to consider the potential harms. Perhaps the biggest of these, Dr. Halpern said, is the psychological damage caused by turning a patient with an indolent, low-risk melanoma or nonmelanoma skin cancer into a cancer patient.

"We have to be really, really careful to look at the harms involved in screening. To my mind, one of the biggest problems of melanoma screening is the psychological harm we do by giving people cancer. I’m especially bothered about the way we do that with patients who develop melanoma in situ or microinvasive disease," he said.

"Believe me, if I had melanoma in situ or microinvasive melanoma, I would want you to find it and take if off for me. What I don’t want you to do is to turn me into a cancer patient. I don’t think that’s in the patient’s best interest whatsoever. We don’t do it intentionally, but as dermatologists we have this tendency to dramatically overplay the importance of these diagnoses," Dr. Halpern said.

Dr. Halpern reported having financial relationships with Scibase, DermTech, Caliber, and Canfield.

SDEF and this news organization are owned by the same parent company.

[email protected]

DENVER - A murine monoclonal antibody had very high sensitivity and specificity for melanomas with the V600E BRAF mutation, and exhibited perfect concordance between the primary and metastatic tumors in individual patients.

In addition to being a valuable screening tool, VE1 (anti-BRAF V600E) could be an extremely useful adjunct to DNA analysis, Michelle Vernali said at the annual meeting of the American Academy of Dermatology.

"I think that the sequential use of immunohistochemistry and molecular analysis will dramatically improve sensitivity and specificity for the detection of BRAF mutations, which is essential for the effective use of BRAF inhibitors," said Ms. Vernali, a fourth-year medical student at the University of North Carolina, Chapel Hill.

According to Roche Diagnostics, the VE1 antibody has demonstrated 100% sensitivity and 99% specificity for BRAF mutations in colon cancer. In addition, it has shown high efficacy in detecting those mutations in thyroid cancer and hairy cell leukemia, and "shows promise" in non–small cell lung cancer and serous ovarian tumors.

According to the company, "The ... antibody has also been said to be a promising tool for patient stratification among individuals presenting with brain metastases."

Ms. Vernali and her colleagues examined the benefit of VE1 staining in 93 patients with metastatic melanoma. Of these, 76 had DNA pyrosequencing of either the primary (19) or metastatic lesion (57). Both primary and metastatic tumor samples were available for 17 patients.

Of the 76 patients with either primary or metastatic lesion samples, DNA pyrosequencing identified 26 that were positive for V600E and 40 that were negative. VE1 staining identified 22 positive samples and 44 negative samples, for a specificity of 100% and a sensitivity of 85%.

Sequencing also identified eight samples positive for V600K, and one each for V600R and V600Q. VE1 did not stain any of these samples.

Among the 17 patients with both primary and metastatic samples, VE1 was in 100% concordance with DNA sequencing, identifying three positive samples and 14 negative samples.

"There was little variability of strength or intensity of the staining, and very little intra-interpreter variance," Ms. Vernali said.

She proposed an algorithm for BRAF testing using VE1 with and without DNA sequencing.

· Insufficient tissue for initial DNA pyrosequencing:

– Stain with VE1.

– Identify BRAF V600E-positive or -negative patients.

· Sufficient tissue for DNA pyrosequencing:

– Stain with VE1.

– Stratify as VE1 positive or negative.

– If VE1 positive, conclude the patient is BRAF V600E positive.

– If VE1 negative, send sample for molecular sequencing to stratify into V600E positive, positive for another BRAF mutation, or BRAF negative.

This algorithm would identify V600E status in patients with tissue samples that would otherwise be insufficient for BRAF testing, she said. "If they had insufficient tissue for DNA sequencing, they could be stratified by immunohistochemistry and if positive, could be treated. Otherwise this is a population that now goes without BRAF-inhibiting therapy."

The algorithm is being tested in some sites already, she added, but needs additional validation before it can be broadly adopted.

Ms. Vernali had no financial disclosures.

[email protected]

DENVER - A murine monoclonal antibody had very high sensitivity and specificity for melanomas with the V600E BRAF mutation, and exhibited perfect concordance between the primary and metastatic tumors in individual patients.

In addition to being a valuable screening tool, VE1 (anti-BRAF V600E) could be an extremely useful adjunct to DNA analysis, Michelle Vernali said at the annual meeting of the American Academy of Dermatology.

"I think that the sequential use of immunohistochemistry and molecular analysis will dramatically improve sensitivity and specificity for the detection of BRAF mutations, which is essential for the effective use of BRAF inhibitors," said Ms. Vernali, a fourth-year medical student at the University of North Carolina, Chapel Hill.

According to Roche Diagnostics, the VE1 antibody has demonstrated 100% sensitivity and 99% specificity for BRAF mutations in colon cancer. In addition, it has shown high efficacy in detecting those mutations in thyroid cancer and hairy cell leukemia, and "shows promise" in non–small cell lung cancer and serous ovarian tumors.

According to the company, "The ... antibody has also been said to be a promising tool for patient stratification among individuals presenting with brain metastases."

Ms. Vernali and her colleagues examined the benefit of VE1 staining in 93 patients with metastatic melanoma. Of these, 76 had DNA pyrosequencing of either the primary (19) or metastatic lesion (57). Both primary and metastatic tumor samples were available for 17 patients.

Of the 76 patients with either primary or metastatic lesion samples, DNA pyrosequencing identified 26 that were positive for V600E and 40 that were negative. VE1 staining identified 22 positive samples and 44 negative samples, for a specificity of 100% and a sensitivity of 85%.

Sequencing also identified eight samples positive for V600K, and one each for V600R and V600Q. VE1 did not stain any of these samples.

Among the 17 patients with both primary and metastatic samples, VE1 was in 100% concordance with DNA sequencing, identifying three positive samples and 14 negative samples.

"There was little variability of strength or intensity of the staining, and very little intra-interpreter variance," Ms. Vernali said.

She proposed an algorithm for BRAF testing using VE1 with and without DNA sequencing.

· Insufficient tissue for initial DNA pyrosequencing:

– Stain with VE1.

– Identify BRAF V600E-positive or -negative patients.

· Sufficient tissue for DNA pyrosequencing:

– Stain with VE1.

– Stratify as VE1 positive or negative.

– If VE1 positive, conclude the patient is BRAF V600E positive.

– If VE1 negative, send sample for molecular sequencing to stratify into V600E positive, positive for another BRAF mutation, or BRAF negative.

This algorithm would identify V600E status in patients with tissue samples that would otherwise be insufficient for BRAF testing, she said. "If they had insufficient tissue for DNA sequencing, they could be stratified by immunohistochemistry and if positive, could be treated. Otherwise this is a population that now goes without BRAF-inhibiting therapy."

The algorithm is being tested in some sites already, she added, but needs additional validation before it can be broadly adopted.

Ms. Vernali had no financial disclosures.

[email protected]

DENVER - A murine monoclonal antibody had very high sensitivity and specificity for melanomas with the V600E BRAF mutation, and exhibited perfect concordance between the primary and metastatic tumors in individual patients.

In addition to being a valuable screening tool, VE1 (anti-BRAF V600E) could be an extremely useful adjunct to DNA analysis, Michelle Vernali said at the annual meeting of the American Academy of Dermatology.

"I think that the sequential use of immunohistochemistry and molecular analysis will dramatically improve sensitivity and specificity for the detection of BRAF mutations, which is essential for the effective use of BRAF inhibitors," said Ms. Vernali, a fourth-year medical student at the University of North Carolina, Chapel Hill.

According to Roche Diagnostics, the VE1 antibody has demonstrated 100% sensitivity and 99% specificity for BRAF mutations in colon cancer. In addition, it has shown high efficacy in detecting those mutations in thyroid cancer and hairy cell leukemia, and "shows promise" in non–small cell lung cancer and serous ovarian tumors.

According to the company, "The ... antibody has also been said to be a promising tool for patient stratification among individuals presenting with brain metastases."

Ms. Vernali and her colleagues examined the benefit of VE1 staining in 93 patients with metastatic melanoma. Of these, 76 had DNA pyrosequencing of either the primary (19) or metastatic lesion (57). Both primary and metastatic tumor samples were available for 17 patients.

Of the 76 patients with either primary or metastatic lesion samples, DNA pyrosequencing identified 26 that were positive for V600E and 40 that were negative. VE1 staining identified 22 positive samples and 44 negative samples, for a specificity of 100% and a sensitivity of 85%.

Sequencing also identified eight samples positive for V600K, and one each for V600R and V600Q. VE1 did not stain any of these samples.

Among the 17 patients with both primary and metastatic samples, VE1 was in 100% concordance with DNA sequencing, identifying three positive samples and 14 negative samples.

"There was little variability of strength or intensity of the staining, and very little intra-interpreter variance," Ms. Vernali said.

She proposed an algorithm for BRAF testing using VE1 with and without DNA sequencing.

· Insufficient tissue for initial DNA pyrosequencing:

– Stain with VE1.

– Identify BRAF V600E-positive or -negative patients.

· Sufficient tissue for DNA pyrosequencing:

– Stain with VE1.

– Stratify as VE1 positive or negative.

– If VE1 positive, conclude the patient is BRAF V600E positive.

– If VE1 negative, send sample for molecular sequencing to stratify into V600E positive, positive for another BRAF mutation, or BRAF negative.

This algorithm would identify V600E status in patients with tissue samples that would otherwise be insufficient for BRAF testing, she said. "If they had insufficient tissue for DNA sequencing, they could be stratified by immunohistochemistry and if positive, could be treated. Otherwise this is a population that now goes without BRAF-inhibiting therapy."

The algorithm is being tested in some sites already, she added, but needs additional validation before it can be broadly adopted.

Ms. Vernali had no financial disclosures.

[email protected]

WASHINGTON – The Food and Drug Administration has taken too long to review and approve new sunscreen ingredients and should be required to clear its current backlog within 8 months and review new products within 11 months, members of Congress said at a hearing April 7.

"Everyone seems to agree that the current system for approving sunscreen ingredients is broken," Rep. Fred Upton (R-Mich.), chairman of the House Energy & Commerce Committee, said at a hearing of his committee’s Subcommittee on Health. H.R. 4250, the Sunscreen Innovation Act, "would help provide a solution to the current backlog of sunscreen ingredients pending at the FDA."

Ingram Publishing/Thinkstockphotos.com

Currently, eight sunscreen ingredients are under review by the FDA, many of which have been approved for use in other countries; some reviews have been ongoing for 3-11 years.

H.R. 4250 was introduced March 13 in the House by Rep. Ed Whitfield (R-Ky.) and Rep. John Dingell (D-Mich.) and as S. 2141 the same day in the Senate by Sen. Jack Reed (D-R.I.) and Sen. Johnny Isakson (R-Ga.).

In addition to eliminating the backlog, the bill would align the sunscreen review process more closely with the new-drug and device approval process. Under the legislation, the FDA Nonprescription Drugs Advisory Committee would review the safety and efficacy of the ingredient and make a recommendation on approval. The FDA would have 45 days to make the final decision for approval.

Rep. Henry Waxman (D-Calif.) said that he worried this would essentially give an advisory committee the power to make an approval decision if the FDA did not act. That would set a bad precedent, said Rep. Waxman, who added that he otherwise supported the Sunscreen Innovation Act.

The American Academy of Dermatology Association supported the legislation.

"A more timely review process has the potential to reduce Americans’ risk for skin cancer by ensuring that they have access to the safest, most effective sunscreens available," Dr. Brett M. Coldiron, AAD president, said in a statement.

Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, said that she agreed that the process should be modernized and that it was no longer serving consumers, manufacturers, or the agency itself.

As Americans have gone from occasional and limited use of sunscreen products to year-round and heavier use of them, new questions have been raised about the short- and long-term effects of these products, Dr. Woodcock said. The FDA "has been actively examining the important scientific questions," such as whether there is systemic exposure to an ingredient, or if an ingredient might be an endocrine disrupter.

The FDA recently sent letters to the makers of two sunscreen ingredients – amiloxate and diethylhexyl butamido triazone – noting that the evidence is not sufficient to establish safety and efficacy, Dr. Woodcock said. The agency is still reviewing six other sunscreen ingredients.

The FDA will hold a public hearing later this year to clarify what information it is seeking to establish the safety and efficacy of sunscreen ingredients, she added.

[email protected] On Twitter @aliciaault

WASHINGTON – The Food and Drug Administration has taken too long to review and approve new sunscreen ingredients and should be required to clear its current backlog within 8 months and review new products within 11 months, members of Congress said at a hearing April 7.

"Everyone seems to agree that the current system for approving sunscreen ingredients is broken," Rep. Fred Upton (R-Mich.), chairman of the House Energy & Commerce Committee, said at a hearing of his committee’s Subcommittee on Health. H.R. 4250, the Sunscreen Innovation Act, "would help provide a solution to the current backlog of sunscreen ingredients pending at the FDA."

Ingram Publishing/Thinkstockphotos.com

Currently, eight sunscreen ingredients are under review by the FDA, many of which have been approved for use in other countries; some reviews have been ongoing for 3-11 years.

H.R. 4250 was introduced March 13 in the House by Rep. Ed Whitfield (R-Ky.) and Rep. John Dingell (D-Mich.) and as S. 2141 the same day in the Senate by Sen. Jack Reed (D-R.I.) and Sen. Johnny Isakson (R-Ga.).

In addition to eliminating the backlog, the bill would align the sunscreen review process more closely with the new-drug and device approval process. Under the legislation, the FDA Nonprescription Drugs Advisory Committee would review the safety and efficacy of the ingredient and make a recommendation on approval. The FDA would have 45 days to make the final decision for approval.

Rep. Henry Waxman (D-Calif.) said that he worried this would essentially give an advisory committee the power to make an approval decision if the FDA did not act. That would set a bad precedent, said Rep. Waxman, who added that he otherwise supported the Sunscreen Innovation Act.

The American Academy of Dermatology Association supported the legislation.

"A more timely review process has the potential to reduce Americans’ risk for skin cancer by ensuring that they have access to the safest, most effective sunscreens available," Dr. Brett M. Coldiron, AAD president, said in a statement.

Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, said that she agreed that the process should be modernized and that it was no longer serving consumers, manufacturers, or the agency itself.

As Americans have gone from occasional and limited use of sunscreen products to year-round and heavier use of them, new questions have been raised about the short- and long-term effects of these products, Dr. Woodcock said. The FDA "has been actively examining the important scientific questions," such as whether there is systemic exposure to an ingredient, or if an ingredient might be an endocrine disrupter.

The FDA recently sent letters to the makers of two sunscreen ingredients – amiloxate and diethylhexyl butamido triazone – noting that the evidence is not sufficient to establish safety and efficacy, Dr. Woodcock said. The agency is still reviewing six other sunscreen ingredients.

The FDA will hold a public hearing later this year to clarify what information it is seeking to establish the safety and efficacy of sunscreen ingredients, she added.

[email protected] On Twitter @aliciaault

WASHINGTON – The Food and Drug Administration has taken too long to review and approve new sunscreen ingredients and should be required to clear its current backlog within 8 months and review new products within 11 months, members of Congress said at a hearing April 7.

"Everyone seems to agree that the current system for approving sunscreen ingredients is broken," Rep. Fred Upton (R-Mich.), chairman of the House Energy & Commerce Committee, said at a hearing of his committee’s Subcommittee on Health. H.R. 4250, the Sunscreen Innovation Act, "would help provide a solution to the current backlog of sunscreen ingredients pending at the FDA."

Ingram Publishing/Thinkstockphotos.com

Currently, eight sunscreen ingredients are under review by the FDA, many of which have been approved for use in other countries; some reviews have been ongoing for 3-11 years.

H.R. 4250 was introduced March 13 in the House by Rep. Ed Whitfield (R-Ky.) and Rep. John Dingell (D-Mich.) and as S. 2141 the same day in the Senate by Sen. Jack Reed (D-R.I.) and Sen. Johnny Isakson (R-Ga.).

In addition to eliminating the backlog, the bill would align the sunscreen review process more closely with the new-drug and device approval process. Under the legislation, the FDA Nonprescription Drugs Advisory Committee would review the safety and efficacy of the ingredient and make a recommendation on approval. The FDA would have 45 days to make the final decision for approval.

Rep. Henry Waxman (D-Calif.) said that he worried this would essentially give an advisory committee the power to make an approval decision if the FDA did not act. That would set a bad precedent, said Rep. Waxman, who added that he otherwise supported the Sunscreen Innovation Act.

The American Academy of Dermatology Association supported the legislation.

"A more timely review process has the potential to reduce Americans’ risk for skin cancer by ensuring that they have access to the safest, most effective sunscreens available," Dr. Brett M. Coldiron, AAD president, said in a statement.

Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, said that she agreed that the process should be modernized and that it was no longer serving consumers, manufacturers, or the agency itself.

As Americans have gone from occasional and limited use of sunscreen products to year-round and heavier use of them, new questions have been raised about the short- and long-term effects of these products, Dr. Woodcock said. The FDA "has been actively examining the important scientific questions," such as whether there is systemic exposure to an ingredient, or if an ingredient might be an endocrine disrupter.

The FDA recently sent letters to the makers of two sunscreen ingredients – amiloxate and diethylhexyl butamido triazone – noting that the evidence is not sufficient to establish safety and efficacy, Dr. Woodcock said. The agency is still reviewing six other sunscreen ingredients.

The FDA will hold a public hearing later this year to clarify what information it is seeking to establish the safety and efficacy of sunscreen ingredients, she added.

[email protected] On Twitter @aliciaault

SAN DIEGO – Preliminary findings from two studies presented at the annual meeting of the American Association for Cancer Research suggest that cancer patients whose tumors contained the protein PD-L1 responded favorably to treatment with the investigational checkpoint inhibitor MK-3475.

A highly selective anti–PD-1 immunotherapy being developed by Merck, MK-3475 is designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein.

Both studies are analyses from the ongoing phase 1B KEYNOTE-001 study. In the first analysis, researchers led by Dr. Adil I. Daud evaluated tumor samples from 195 patients with late-stage melanoma who received MK-3475 at three different doses: 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks. Some of the patients had received prior treatment with ipilimumab.

Dr. Daud, codirector of the University of California, San Francisco, melanoma center and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center, and his associates measured the amount of PD-L1 in the tumor samples and considered them PD-L1 positive if at least 1 cell/100 tumors cells stained by immunohistochemistry contained the protein. They also used multiplex flow cytometry to assess absolute CD4 and CD8 T-cell counts and the percentage of activated CD4 and CD8 T-cell counts in peripheral blood.

All study participants had a new tumor biopsy within 2 months before the first dose of MK-3475. Their mean age was 63 years, 76% were male, and 76% had BRAF wild-type tumors. Of the 125 evaluable tumor samples, 89 (71%) were PD-L1 positive and 36 were PD-L1 negative. Disease did not progress for about 50 weeks among patients with PD-L1–positive tumors, compared with about 12 weeks among those with PD-L1–negative tumors. Among the entire study population, the overall response rate was 40%, "which is high for immunotherapy," Dr. Daud said during a press briefing.

Based on cut point of at least 1 cell/100 tumors cells, the response rate among patients with PD-L1–positive tumors was 49%, compared with 13% among patients with PD-L1–negative tumors (P = .0007). At 6 months, 57% of patients with PD-L1–positive tumors had no disease progression, compared with 35% of those whose tumors were PD-L1 negative (P = 0.0051).

Between baseline and week 6, the researchers observed a significant median increase in the percentage of CD8-positive CD4-positive T cells (14.6% vs. 15.7%, respectively) though no significant change in the absolute numbers of circulating T cells was observed.

"Given the high prevalence of PD-L1–positive tumors, the clinical utility of PD-L1 expression in melanoma is not clear at this point, because unselected patients have such a high level of response," Dr. Daud said. Changes in T-cell subtype distribution as a pharmacodynamic marker "supports the proposed MK-3475 mechanism of action."

He characterized the study as "a good foundation to build on, and we think that ongoing studies looking at larger clinical trials will help clarify the role of PD-L1 expression in terms of correlating with response of patients treated with MK-3475. Clinical development of MK-3475, both as monotherapy and as part of combination strategies, is ongoing in multiple solid tumors and hematologic malignancies."

In the second study, Dr. Leena Gandhi presented extended data from an earlier trial of 38 patients with non–small cell lung cancer who were treated with MK-3475. That trial found that higher levels of PD-L1 expression "appeared to correlate with an increased response to MK-3475," Dr. Gandhi, a thoracic oncologist at the Dana-Farber Cancer Institute, Boston, said during a press briefing. The purpose of the current analysis, which included 146 patients, was to determine an optimal cut point for defining whether a tumor is likely to respond to MK-3475 therapy or not. The patients received the agent at three different doses: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. Tumors were assessed by imaging every 9 weeks and by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).

Dr. Gandhi and her associates found that PD-L1 levels of greater than 50% as measured by immunohistochemistry was the best cut-off point for determining whether a tumor is likely to respond to MK-3475. Six months after starting treatment, 41% of patients with tumors that contained high levels of PD-L1 prior to treatment had no disease progression, compared with 17% of those whose tumors contained low levels of PD-L1 (hazard ratio, 0.53; P = .004). This finding is "based on very small numbers of patients with long-term follow-up, so we expect that the final progression-free survival differences may change over time with additional patients," Dr. Gandhi noted.

As for overall survival, 72% of patients with tumors that contained high levels of PD-L1 were alive at 6 months, compared with 53% of those whose tumors contained low levels of PD-L1. This difference trended toward statistical significance (HR, 0.65; P = .134) and may also change as data from additional patients are realized, she said.

Dr. Gandhi noted that data from two ongoing studies will be used to "further explore the relationship between tumor PD-L1 expression and MK-3475 activity in NSCLC patients."

In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, characterized the MK-3475 biomarker as "maturing, but I still think it’s under investigation. I still think we have a ways to go in identifying the best predictive biomarker. I don’t think it’s 100% foolproof by any means."

Both studies were funded by Merck. Dr. Daud disclosed that he has served on the advisory board of Merck and GlaxoSmithKline. Dr. Gandhi said that she had no relevant financial conflicts to disclose.

Dr. LoRusso disclosed that she has received research funding from Agios Pharmaceuticals.

[email protected]

SAN DIEGO – Preliminary findings from two studies presented at the annual meeting of the American Association for Cancer Research suggest that cancer patients whose tumors contained the protein PD-L1 responded favorably to treatment with the investigational checkpoint inhibitor MK-3475.

A highly selective anti–PD-1 immunotherapy being developed by Merck, MK-3475 is designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein.

Both studies are analyses from the ongoing phase 1B KEYNOTE-001 study. In the first analysis, researchers led by Dr. Adil I. Daud evaluated tumor samples from 195 patients with late-stage melanoma who received MK-3475 at three different doses: 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks. Some of the patients had received prior treatment with ipilimumab.

Dr. Daud, codirector of the University of California, San Francisco, melanoma center and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center, and his associates measured the amount of PD-L1 in the tumor samples and considered them PD-L1 positive if at least 1 cell/100 tumors cells stained by immunohistochemistry contained the protein. They also used multiplex flow cytometry to assess absolute CD4 and CD8 T-cell counts and the percentage of activated CD4 and CD8 T-cell counts in peripheral blood.

All study participants had a new tumor biopsy within 2 months before the first dose of MK-3475. Their mean age was 63 years, 76% were male, and 76% had BRAF wild-type tumors. Of the 125 evaluable tumor samples, 89 (71%) were PD-L1 positive and 36 were PD-L1 negative. Disease did not progress for about 50 weeks among patients with PD-L1–positive tumors, compared with about 12 weeks among those with PD-L1–negative tumors. Among the entire study population, the overall response rate was 40%, "which is high for immunotherapy," Dr. Daud said during a press briefing.

Based on cut point of at least 1 cell/100 tumors cells, the response rate among patients with PD-L1–positive tumors was 49%, compared with 13% among patients with PD-L1–negative tumors (P = .0007). At 6 months, 57% of patients with PD-L1–positive tumors had no disease progression, compared with 35% of those whose tumors were PD-L1 negative (P = 0.0051).

Between baseline and week 6, the researchers observed a significant median increase in the percentage of CD8-positive CD4-positive T cells (14.6% vs. 15.7%, respectively) though no significant change in the absolute numbers of circulating T cells was observed.

"Given the high prevalence of PD-L1–positive tumors, the clinical utility of PD-L1 expression in melanoma is not clear at this point, because unselected patients have such a high level of response," Dr. Daud said. Changes in T-cell subtype distribution as a pharmacodynamic marker "supports the proposed MK-3475 mechanism of action."

He characterized the study as "a good foundation to build on, and we think that ongoing studies looking at larger clinical trials will help clarify the role of PD-L1 expression in terms of correlating with response of patients treated with MK-3475. Clinical development of MK-3475, both as monotherapy and as part of combination strategies, is ongoing in multiple solid tumors and hematologic malignancies."

In the second study, Dr. Leena Gandhi presented extended data from an earlier trial of 38 patients with non–small cell lung cancer who were treated with MK-3475. That trial found that higher levels of PD-L1 expression "appeared to correlate with an increased response to MK-3475," Dr. Gandhi, a thoracic oncologist at the Dana-Farber Cancer Institute, Boston, said during a press briefing. The purpose of the current analysis, which included 146 patients, was to determine an optimal cut point for defining whether a tumor is likely to respond to MK-3475 therapy or not. The patients received the agent at three different doses: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. Tumors were assessed by imaging every 9 weeks and by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).

Dr. Gandhi and her associates found that PD-L1 levels of greater than 50% as measured by immunohistochemistry was the best cut-off point for determining whether a tumor is likely to respond to MK-3475. Six months after starting treatment, 41% of patients with tumors that contained high levels of PD-L1 prior to treatment had no disease progression, compared with 17% of those whose tumors contained low levels of PD-L1 (hazard ratio, 0.53; P = .004). This finding is "based on very small numbers of patients with long-term follow-up, so we expect that the final progression-free survival differences may change over time with additional patients," Dr. Gandhi noted.

As for overall survival, 72% of patients with tumors that contained high levels of PD-L1 were alive at 6 months, compared with 53% of those whose tumors contained low levels of PD-L1. This difference trended toward statistical significance (HR, 0.65; P = .134) and may also change as data from additional patients are realized, she said.

Dr. Gandhi noted that data from two ongoing studies will be used to "further explore the relationship between tumor PD-L1 expression and MK-3475 activity in NSCLC patients."

In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, characterized the MK-3475 biomarker as "maturing, but I still think it’s under investigation. I still think we have a ways to go in identifying the best predictive biomarker. I don’t think it’s 100% foolproof by any means."

Both studies were funded by Merck. Dr. Daud disclosed that he has served on the advisory board of Merck and GlaxoSmithKline. Dr. Gandhi said that she had no relevant financial conflicts to disclose.

Dr. LoRusso disclosed that she has received research funding from Agios Pharmaceuticals.

[email protected]

SAN DIEGO – Preliminary findings from two studies presented at the annual meeting of the American Association for Cancer Research suggest that cancer patients whose tumors contained the protein PD-L1 responded favorably to treatment with the investigational checkpoint inhibitor MK-3475.

A highly selective anti–PD-1 immunotherapy being developed by Merck, MK-3475 is designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein.

Both studies are analyses from the ongoing phase 1B KEYNOTE-001 study. In the first analysis, researchers led by Dr. Adil I. Daud evaluated tumor samples from 195 patients with late-stage melanoma who received MK-3475 at three different doses: 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks. Some of the patients had received prior treatment with ipilimumab.

Dr. Daud, codirector of the University of California, San Francisco, melanoma center and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center, and his associates measured the amount of PD-L1 in the tumor samples and considered them PD-L1 positive if at least 1 cell/100 tumors cells stained by immunohistochemistry contained the protein. They also used multiplex flow cytometry to assess absolute CD4 and CD8 T-cell counts and the percentage of activated CD4 and CD8 T-cell counts in peripheral blood.

All study participants had a new tumor biopsy within 2 months before the first dose of MK-3475. Their mean age was 63 years, 76% were male, and 76% had BRAF wild-type tumors. Of the 125 evaluable tumor samples, 89 (71%) were PD-L1 positive and 36 were PD-L1 negative. Disease did not progress for about 50 weeks among patients with PD-L1–positive tumors, compared with about 12 weeks among those with PD-L1–negative tumors. Among the entire study population, the overall response rate was 40%, "which is high for immunotherapy," Dr. Daud said during a press briefing.

Based on cut point of at least 1 cell/100 tumors cells, the response rate among patients with PD-L1–positive tumors was 49%, compared with 13% among patients with PD-L1–negative tumors (P = .0007). At 6 months, 57% of patients with PD-L1–positive tumors had no disease progression, compared with 35% of those whose tumors were PD-L1 negative (P = 0.0051).

Between baseline and week 6, the researchers observed a significant median increase in the percentage of CD8-positive CD4-positive T cells (14.6% vs. 15.7%, respectively) though no significant change in the absolute numbers of circulating T cells was observed.

"Given the high prevalence of PD-L1–positive tumors, the clinical utility of PD-L1 expression in melanoma is not clear at this point, because unselected patients have such a high level of response," Dr. Daud said. Changes in T-cell subtype distribution as a pharmacodynamic marker "supports the proposed MK-3475 mechanism of action."

He characterized the study as "a good foundation to build on, and we think that ongoing studies looking at larger clinical trials will help clarify the role of PD-L1 expression in terms of correlating with response of patients treated with MK-3475. Clinical development of MK-3475, both as monotherapy and as part of combination strategies, is ongoing in multiple solid tumors and hematologic malignancies."

In the second study, Dr. Leena Gandhi presented extended data from an earlier trial of 38 patients with non–small cell lung cancer who were treated with MK-3475. That trial found that higher levels of PD-L1 expression "appeared to correlate with an increased response to MK-3475," Dr. Gandhi, a thoracic oncologist at the Dana-Farber Cancer Institute, Boston, said during a press briefing. The purpose of the current analysis, which included 146 patients, was to determine an optimal cut point for defining whether a tumor is likely to respond to MK-3475 therapy or not. The patients received the agent at three different doses: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. Tumors were assessed by imaging every 9 weeks and by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).

Dr. Gandhi and her associates found that PD-L1 levels of greater than 50% as measured by immunohistochemistry was the best cut-off point for determining whether a tumor is likely to respond to MK-3475. Six months after starting treatment, 41% of patients with tumors that contained high levels of PD-L1 prior to treatment had no disease progression, compared with 17% of those whose tumors contained low levels of PD-L1 (hazard ratio, 0.53; P = .004). This finding is "based on very small numbers of patients with long-term follow-up, so we expect that the final progression-free survival differences may change over time with additional patients," Dr. Gandhi noted.

As for overall survival, 72% of patients with tumors that contained high levels of PD-L1 were alive at 6 months, compared with 53% of those whose tumors contained low levels of PD-L1. This difference trended toward statistical significance (HR, 0.65; P = .134) and may also change as data from additional patients are realized, she said.

Dr. Gandhi noted that data from two ongoing studies will be used to "further explore the relationship between tumor PD-L1 expression and MK-3475 activity in NSCLC patients."

In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, characterized the MK-3475 biomarker as "maturing, but I still think it’s under investigation. I still think we have a ways to go in identifying the best predictive biomarker. I don’t think it’s 100% foolproof by any means."

Both studies were funded by Merck. Dr. Daud disclosed that he has served on the advisory board of Merck and GlaxoSmithKline. Dr. Gandhi said that she had no relevant financial conflicts to disclose.

Dr. LoRusso disclosed that she has received research funding from Agios Pharmaceuticals.

[email protected]

Prostate tumorigenesis is related to sex hormones, particularly androgens. It also has been suggested that melanoma may be androgen dependent. Postulated mechanisms of pathogenesis include androgen level imbalance (for which early evidence may present as severe teenaged acne), chromosome telomere length alteration (for which increased risk for melanoma is associated with long telomeres), and host immune response modification.

In a December 2013 article published in the Journal of Clinical Oncology, Li et al (2013;31:4394-4399) confirmed that a personal history of prostate cancer was associated with an increased risk for subsequent melanoma. Among patients with prostate cancer whose median age at diagnosis was 68 years or younger, a higher hazard ratio of melanoma was noted. Also, similar to prostate cancer, they observed a positive association between melanoma risk and severe teenaged acne defined by the use of tetracycline for 4 or more years.

What’s the issue?

Are there clinical implications to the confirmation that there is an increased risk for patients with prostate cancer to subsequently develop melanoma? Specifically, should there be increased surveillance for melanoma in these individuals? Perhaps it would be reasonable to regularly perform a complete skin examination in all patients with a history of prostate cancer, especially men who had prostate cancer diagnosed before 68 years of age.

We want to know your views! Tell us what you think.

Prostate tumorigenesis is related to sex hormones, particularly androgens. It also has been suggested that melanoma may be androgen dependent. Postulated mechanisms of pathogenesis include androgen level imbalance (for which early evidence may present as severe teenaged acne), chromosome telomere length alteration (for which increased risk for melanoma is associated with long telomeres), and host immune response modification.

In a December 2013 article published in the Journal of Clinical Oncology, Li et al (2013;31:4394-4399) confirmed that a personal history of prostate cancer was associated with an increased risk for subsequent melanoma. Among patients with prostate cancer whose median age at diagnosis was 68 years or younger, a higher hazard ratio of melanoma was noted. Also, similar to prostate cancer, they observed a positive association between melanoma risk and severe teenaged acne defined by the use of tetracycline for 4 or more years.

What’s the issue?

Are there clinical implications to the confirmation that there is an increased risk for patients with prostate cancer to subsequently develop melanoma? Specifically, should there be increased surveillance for melanoma in these individuals? Perhaps it would be reasonable to regularly perform a complete skin examination in all patients with a history of prostate cancer, especially men who had prostate cancer diagnosed before 68 years of age.

We want to know your views! Tell us what you think.

Prostate tumorigenesis is related to sex hormones, particularly androgens. It also has been suggested that melanoma may be androgen dependent. Postulated mechanisms of pathogenesis include androgen level imbalance (for which early evidence may present as severe teenaged acne), chromosome telomere length alteration (for which increased risk for melanoma is associated with long telomeres), and host immune response modification.

In a December 2013 article published in the Journal of Clinical Oncology, Li et al (2013;31:4394-4399) confirmed that a personal history of prostate cancer was associated with an increased risk for subsequent melanoma. Among patients with prostate cancer whose median age at diagnosis was 68 years or younger, a higher hazard ratio of melanoma was noted. Also, similar to prostate cancer, they observed a positive association between melanoma risk and severe teenaged acne defined by the use of tetracycline for 4 or more years.

What’s the issue?

Are there clinical implications to the confirmation that there is an increased risk for patients with prostate cancer to subsequently develop melanoma? Specifically, should there be increased surveillance for melanoma in these individuals? Perhaps it would be reasonable to regularly perform a complete skin examination in all patients with a history of prostate cancer, especially men who had prostate cancer diagnosed before 68 years of age.

We want to know your views! Tell us what you think.

DENVER – As many as 25% of Medicare patients with melanoma will experience treatment delays of up to 1.5 months, and 18% may have treatment delays as long as 3 months after a lesion is biopsied, especially if a nondermatologist is performing the excision, based on data from a review of more than 32,000 patients.

Patients who saw dermatologists for their surgery were much less likely to experience a delay in treatment, Dr. Jason Lott said at the annual meeting of the American Academy of Dermatology.

"If a primary care provider was doing the surgery – and many still do their own surgery – patients were 1.6 times more likely to have a delay of more than 1.5 months, and twice as likely to have a delay of more than 3 months," said Dr. Lott of Yale University, New Haven, Conn. "I am making the argument that specialty matters."

Other factors significantly associated with treatment delay included older patient age, comorbidities, tumor stage, and lesion location.

To examine factors contributing to a surgical delay in the United States, Dr. Lott and his colleagues conducted a population-based study of treatment waiting times in more than 32,501 Medicare patients who had been diagnosed with melanoma from 2000 to 2009. The primary outcome was the time between biopsy and surgical treatment.

The most common lesion sites were the head and neck (40%), followed by the extremities and trunk. Compared with head/neck lesions, surgery on the trunk and extremities was significantly less likely to be delayed up to 1.5 months (odds ratio, 0.74).

Melanomas were about equally divided between in situ and localized disease (48% and 44%), with the remainder having distant occurrence. Compared with in situ disease, regional and distant disease were significantly more likely to be treated later, with odds ratios ranging from 1.31 for a delay of up to 1.5 months (regional disease) to 2.15 for a delay of more than 3 months (distant disease).

Older patients had greater delays than did younger patients, with the biggest disparities between those aged 80-84 years and those aged 70-74 years, In the younger group, 54% were treated within 1 month, compared with 50% of the older patients. A delay of up to 3 months occurred in 38% of the younger group and 41% of the older group.

Patients with no medical comorbidities received significantly prompter treatment, with 54% being treated within 1 month compared with 47% of those with three comorbidities.

Expeditious treatment is certainly important to patients, Dr. Lott said, and likely important for achieving optimal outcomes. "Patients don’t like walking around knowing they have a malignancy that’s not treated, with even a marginally increased chance that something bad will happen," he noted.

That risk is not unfounded, Dr. Lott said. The United Kingdom’s "2-week" rule, implemented in 2000, mandates an urgent consultation for suspected malignancies. Patients with suspected melanomas are seen in a special pigmented lesions clinic, and often treated on the same day. In 2007, this practice was shown to positively impact melanoma survival.

Dr. Lott described a retrospective study conducted in the United Kingdom that examined outcomes in 4,399 patients, all of whom were evaluated at a pigmented lesions clinic within 2 weeks of a primary care identification of a suspicious lesion. During the study period, 96 melanomas were identified, and 96% of those were treated within 2 weeks of the primary referral. Most (74%) were excised on the day of the clinic visit.

The authors compared these results with those of 78 melanoma patients who were diagnosed in the 2 years before urgent referral became standard. These patients waited up to 34 days for a referral and up to 74 days for treatment. Patients seen in the clinic had significantly thinner tumors (Breslow thickness 1.68 vs. 2.39 mm). In addition to melanomas, 748 nonmelanoma skin cancers were treated at the clinics.

Among the melanoma patients diagnosed in the clinics, the 5-year survival rate was 82%, compared with 62% in patients diagnosed before the urgent referral.

"Earlier treatment does matter," Dr. Lott said.

Dr. Lott said he had no relevant financial conflicts to disclose.

[email protected]

On Twitter @alz_gal

DENVER – As many as 25% of Medicare patients with melanoma will experience treatment delays of up to 1.5 months, and 18% may have treatment delays as long as 3 months after a lesion is biopsied, especially if a nondermatologist is performing the excision, based on data from a review of more than 32,000 patients.

Patients who saw dermatologists for their surgery were much less likely to experience a delay in treatment, Dr. Jason Lott said at the annual meeting of the American Academy of Dermatology.

"If a primary care provider was doing the surgery – and many still do their own surgery – patients were 1.6 times more likely to have a delay of more than 1.5 months, and twice as likely to have a delay of more than 3 months," said Dr. Lott of Yale University, New Haven, Conn. "I am making the argument that specialty matters."

Other factors significantly associated with treatment delay included older patient age, comorbidities, tumor stage, and lesion location.

To examine factors contributing to a surgical delay in the United States, Dr. Lott and his colleagues conducted a population-based study of treatment waiting times in more than 32,501 Medicare patients who had been diagnosed with melanoma from 2000 to 2009. The primary outcome was the time between biopsy and surgical treatment.

The most common lesion sites were the head and neck (40%), followed by the extremities and trunk. Compared with head/neck lesions, surgery on the trunk and extremities was significantly less likely to be delayed up to 1.5 months (odds ratio, 0.74).

Melanomas were about equally divided between in situ and localized disease (48% and 44%), with the remainder having distant occurrence. Compared with in situ disease, regional and distant disease were significantly more likely to be treated later, with odds ratios ranging from 1.31 for a delay of up to 1.5 months (regional disease) to 2.15 for a delay of more than 3 months (distant disease).

Older patients had greater delays than did younger patients, with the biggest disparities between those aged 80-84 years and those aged 70-74 years, In the younger group, 54% were treated within 1 month, compared with 50% of the older patients. A delay of up to 3 months occurred in 38% of the younger group and 41% of the older group.

Patients with no medical comorbidities received significantly prompter treatment, with 54% being treated within 1 month compared with 47% of those with three comorbidities.

Expeditious treatment is certainly important to patients, Dr. Lott said, and likely important for achieving optimal outcomes. "Patients don’t like walking around knowing they have a malignancy that’s not treated, with even a marginally increased chance that something bad will happen," he noted.

That risk is not unfounded, Dr. Lott said. The United Kingdom’s "2-week" rule, implemented in 2000, mandates an urgent consultation for suspected malignancies. Patients with suspected melanomas are seen in a special pigmented lesions clinic, and often treated on the same day. In 2007, this practice was shown to positively impact melanoma survival.

Dr. Lott described a retrospective study conducted in the United Kingdom that examined outcomes in 4,399 patients, all of whom were evaluated at a pigmented lesions clinic within 2 weeks of a primary care identification of a suspicious lesion. During the study period, 96 melanomas were identified, and 96% of those were treated within 2 weeks of the primary referral. Most (74%) were excised on the day of the clinic visit.

The authors compared these results with those of 78 melanoma patients who were diagnosed in the 2 years before urgent referral became standard. These patients waited up to 34 days for a referral and up to 74 days for treatment. Patients seen in the clinic had significantly thinner tumors (Breslow thickness 1.68 vs. 2.39 mm). In addition to melanomas, 748 nonmelanoma skin cancers were treated at the clinics.

Among the melanoma patients diagnosed in the clinics, the 5-year survival rate was 82%, compared with 62% in patients diagnosed before the urgent referral.

"Earlier treatment does matter," Dr. Lott said.

Dr. Lott said he had no relevant financial conflicts to disclose.

[email protected]

On Twitter @alz_gal

DENVER – As many as 25% of Medicare patients with melanoma will experience treatment delays of up to 1.5 months, and 18% may have treatment delays as long as 3 months after a lesion is biopsied, especially if a nondermatologist is performing the excision, based on data from a review of more than 32,000 patients.

Patients who saw dermatologists for their surgery were much less likely to experience a delay in treatment, Dr. Jason Lott said at the annual meeting of the American Academy of Dermatology.

"If a primary care provider was doing the surgery – and many still do their own surgery – patients were 1.6 times more likely to have a delay of more than 1.5 months, and twice as likely to have a delay of more than 3 months," said Dr. Lott of Yale University, New Haven, Conn. "I am making the argument that specialty matters."

Other factors significantly associated with treatment delay included older patient age, comorbidities, tumor stage, and lesion location.

To examine factors contributing to a surgical delay in the United States, Dr. Lott and his colleagues conducted a population-based study of treatment waiting times in more than 32,501 Medicare patients who had been diagnosed with melanoma from 2000 to 2009. The primary outcome was the time between biopsy and surgical treatment.

The most common lesion sites were the head and neck (40%), followed by the extremities and trunk. Compared with head/neck lesions, surgery on the trunk and extremities was significantly less likely to be delayed up to 1.5 months (odds ratio, 0.74).

Melanomas were about equally divided between in situ and localized disease (48% and 44%), with the remainder having distant occurrence. Compared with in situ disease, regional and distant disease were significantly more likely to be treated later, with odds ratios ranging from 1.31 for a delay of up to 1.5 months (regional disease) to 2.15 for a delay of more than 3 months (distant disease).

Older patients had greater delays than did younger patients, with the biggest disparities between those aged 80-84 years and those aged 70-74 years, In the younger group, 54% were treated within 1 month, compared with 50% of the older patients. A delay of up to 3 months occurred in 38% of the younger group and 41% of the older group.

Patients with no medical comorbidities received significantly prompter treatment, with 54% being treated within 1 month compared with 47% of those with three comorbidities.

Expeditious treatment is certainly important to patients, Dr. Lott said, and likely important for achieving optimal outcomes. "Patients don’t like walking around knowing they have a malignancy that’s not treated, with even a marginally increased chance that something bad will happen," he noted.

That risk is not unfounded, Dr. Lott said. The United Kingdom’s "2-week" rule, implemented in 2000, mandates an urgent consultation for suspected malignancies. Patients with suspected melanomas are seen in a special pigmented lesions clinic, and often treated on the same day. In 2007, this practice was shown to positively impact melanoma survival.

Dr. Lott described a retrospective study conducted in the United Kingdom that examined outcomes in 4,399 patients, all of whom were evaluated at a pigmented lesions clinic within 2 weeks of a primary care identification of a suspicious lesion. During the study period, 96 melanomas were identified, and 96% of those were treated within 2 weeks of the primary referral. Most (74%) were excised on the day of the clinic visit.

The authors compared these results with those of 78 melanoma patients who were diagnosed in the 2 years before urgent referral became standard. These patients waited up to 34 days for a referral and up to 74 days for treatment. Patients seen in the clinic had significantly thinner tumors (Breslow thickness 1.68 vs. 2.39 mm). In addition to melanomas, 748 nonmelanoma skin cancers were treated at the clinics.

Among the melanoma patients diagnosed in the clinics, the 5-year survival rate was 82%, compared with 62% in patients diagnosed before the urgent referral.

"Earlier treatment does matter," Dr. Lott said.

Dr. Lott said he had no relevant financial conflicts to disclose.

[email protected]

On Twitter @alz_gal

DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.

Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.

Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."

As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."

Other topical preparations for actinic keratoses on the market include:

• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."

Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.

• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.

Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.

"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."

Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.

• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.

In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."

Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."

Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.

[email protected]

DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.

Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.

Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."

As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."

Other topical preparations for actinic keratoses on the market include:

• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."

Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.

• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.

Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.

"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."

Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.

• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.

In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."

Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."

Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.

[email protected]

DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.

Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.

Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."

As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."

Other topical preparations for actinic keratoses on the market include:

• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."

Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.

• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.

Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.

"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."

Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.

• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.

In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."

Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."

Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.

[email protected]

WAIKOLOA, HAWAII – The topical immunomodulator imiquimod appears to be beneficial therapy in selected patients with lentigo maligna or lentigo maligna melanoma, according to the largest case series to date.

"Based upon our experience, imiquimod 5% cream is a viable option as primary or adjunctive therapy of lentigo maligna and the in situ component of lentigo maligna melanoma in patients where surgery is really not feasible, or you’ve optimized surgical margins without achieving a clear histologic margin. I emphasize this should only be considered for in situ melanoma; we’re not using it to treat invasive melanoma," Dr. Susan M. Swetter said at the Hawaii Dermatology Seminar sponsored by the Global Academy for Medical Education/Skin Disease Education Foundation.

A cautionary note: Imiquimod (Aldara) for lentigo maligna (LM) is off-label therapy. It’s crucial to discuss with candidates the limitations of nonsurgical treatment for LM and lentigo maligna melanoma (LMM), which includes increased risk of local recurrence because of the lack of margin control, the possibility of a missed invasive melanoma, and the lack of supporting evidence from randomized trials with long-term follow-up.

"When we’re talking about imiquimod as potential treatment for lentigo maligna – and I can’t emphasize this enough – it requires close clinical follow-up, [carefully] documented discussion with the patient, and strong patient compliance. We have had cases of lentigo maligna melanoma where there have been metastases, not because of the in situ component, but because of the initial invasive tumor. You’ve got to follow these patients long term like a hawk. I follow them with Wood’s lamp and dermoscopy, and I biopsy any pigmentation," said Dr. Swetter, professor of dermatology and director of the pigmented lesion and cutaneous melanoma clinic at Stanford (Calif.) University Medical Center.

That being said, there are many scenarios in which surgical excision – the recommended first-line treatment for LM and LMM – might not be feasible. These include the sizable numbers of patients of advanced age who have limiting comorbid medical conditions or cognitive impairment. Also, LM has a strong predilection for the head and neck, and some affected patients avidly wish to avoid potentially disfiguring surgery.

Dr. Swetter presented a retrospective study of 60 patients with 62 LM or LMM lesions treated with imiquimod 5% cream at Stanford or the Veterans Affairs Palo Alto Health Care System. Most she treated personally. Imiquimod was primary therapy in 20 cases and adjuvant therapy following failed surgical attempts to achieve histologic clearance in the rest.

Pathologically, 45% of the lesions were LM, 29% were atypical intraepidermal melanocytic proliferations or poorly evolving LM, and 26% were LMM with histologic transection of LM and excision of the invasive melanoma component. Three-quarters of treated lesions were on the head or neck.

The lesions had a mean Breslow depth of 1.17 mm. Prior to imiquimod, half of the patients had one excision and another 19% had two or more. The mean duration of imiquimod therapy was 10.9 weeks, with a mean post treatment follow-up of 38 months.

"I typically treat to a 2-cm margin around the lesion," the dermatologist noted.

The overall clinical or histologic clearance rate was 86%. This is strikingly similar to the collective 82% rate in 46 reports involving 264 treated patients described in a published review by dermatologists at the University of Colorado, Denver (Dermatol. Surg. 2012;38:937-46).

An inflammatory response to imiquimod was predictive of favorable treatment outcome, especially in patients using the topical agent as primary therapy. Of the 20 patients who used imiquimod as primary therapy, all 16 who experienced clinical and/or histologic clearance had an initial inflammatory response. In contrast, none of the four clinical nonresponders showed an inflammatory response.

Outcomes weren’t quite as good in patients using imiquimod as adjuvant therapy.

"This is likely related to more challenging cases in the adjuvant setting, where the patients may have failed multiple attempts at wide local excision for histologic clearance," Dr. Swetter surmised.

Although the use of imiquimod as treatment for LM remains off label, it’s worth noting that it receives support in major practice guidelines. National Comprehensive Cancer Network guidelines recommend consideration of topical imiquimod or radiotherapy as adjunctive treatment for LM in selected patients after optimal surgery, with a level 2B recommendation. And the American Academy of Dermatology lists imiquimod as among the adjunctive options (J. Am. Acad. Dermatol. 2009; 61:865-7). What’s really needed now, according to Dr. Swetter, is a randomized controlled trial to firmly demonstrate benefit.

Session chair Dr. Allan C. Halpern said he and his colleagues have also been using topical imiquimod to treat LM with impressive results.

"What we’ve been doing, without literature to support it, is a broad shave biopsy, essentially removing the lesion, and then going right in with imiquimod before the patient heals. We’ve gotten some really wonderful clinical results," said Dr. Halpern, chief of the dermatology service at Memorial Sloan-Kettering Cancer Center in New York.

"That said, I think it’s important to remind people that – even with surgery – we do see occasional recurrences of desmoplastic melanomas in association with prior lentigo maligna. There’s no reason to think that’s going to be any less common in the imiquimod era. It’s going to happen to us," he cautioned.

Dr. Swetter reported having no financial conflicts. Dr. Halpern has received research grants from SciBase, DermTech, Caliber, and Canfield.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – The topical immunomodulator imiquimod appears to be beneficial therapy in selected patients with lentigo maligna or lentigo maligna melanoma, according to the largest case series to date.

"Based upon our experience, imiquimod 5% cream is a viable option as primary or adjunctive therapy of lentigo maligna and the in situ component of lentigo maligna melanoma in patients where surgery is really not feasible, or you’ve optimized surgical margins without achieving a clear histologic margin. I emphasize this should only be considered for in situ melanoma; we’re not using it to treat invasive melanoma," Dr. Susan M. Swetter said at the Hawaii Dermatology Seminar sponsored by the Global Academy for Medical Education/Skin Disease Education Foundation.

A cautionary note: Imiquimod (Aldara) for lentigo maligna (LM) is off-label therapy. It’s crucial to discuss with candidates the limitations of nonsurgical treatment for LM and lentigo maligna melanoma (LMM), which includes increased risk of local recurrence because of the lack of margin control, the possibility of a missed invasive melanoma, and the lack of supporting evidence from randomized trials with long-term follow-up.

"When we’re talking about imiquimod as potential treatment for lentigo maligna – and I can’t emphasize this enough – it requires close clinical follow-up, [carefully] documented discussion with the patient, and strong patient compliance. We have had cases of lentigo maligna melanoma where there have been metastases, not because of the in situ component, but because of the initial invasive tumor. You’ve got to follow these patients long term like a hawk. I follow them with Wood’s lamp and dermoscopy, and I biopsy any pigmentation," said Dr. Swetter, professor of dermatology and director of the pigmented lesion and cutaneous melanoma clinic at Stanford (Calif.) University Medical Center.

That being said, there are many scenarios in which surgical excision – the recommended first-line treatment for LM and LMM – might not be feasible. These include the sizable numbers of patients of advanced age who have limiting comorbid medical conditions or cognitive impairment. Also, LM has a strong predilection for the head and neck, and some affected patients avidly wish to avoid potentially disfiguring surgery.

Dr. Swetter presented a retrospective study of 60 patients with 62 LM or LMM lesions treated with imiquimod 5% cream at Stanford or the Veterans Affairs Palo Alto Health Care System. Most she treated personally. Imiquimod was primary therapy in 20 cases and adjuvant therapy following failed surgical attempts to achieve histologic clearance in the rest.

Pathologically, 45% of the lesions were LM, 29% were atypical intraepidermal melanocytic proliferations or poorly evolving LM, and 26% were LMM with histologic transection of LM and excision of the invasive melanoma component. Three-quarters of treated lesions were on the head or neck.

The lesions had a mean Breslow depth of 1.17 mm. Prior to imiquimod, half of the patients had one excision and another 19% had two or more. The mean duration of imiquimod therapy was 10.9 weeks, with a mean post treatment follow-up of 38 months.

"I typically treat to a 2-cm margin around the lesion," the dermatologist noted.

The overall clinical or histologic clearance rate was 86%. This is strikingly similar to the collective 82% rate in 46 reports involving 264 treated patients described in a published review by dermatologists at the University of Colorado, Denver (Dermatol. Surg. 2012;38:937-46).

An inflammatory response to imiquimod was predictive of favorable treatment outcome, especially in patients using the topical agent as primary therapy. Of the 20 patients who used imiquimod as primary therapy, all 16 who experienced clinical and/or histologic clearance had an initial inflammatory response. In contrast, none of the four clinical nonresponders showed an inflammatory response.

Outcomes weren’t quite as good in patients using imiquimod as adjuvant therapy.

"This is likely related to more challenging cases in the adjuvant setting, where the patients may have failed multiple attempts at wide local excision for histologic clearance," Dr. Swetter surmised.

Although the use of imiquimod as treatment for LM remains off label, it’s worth noting that it receives support in major practice guidelines. National Comprehensive Cancer Network guidelines recommend consideration of topical imiquimod or radiotherapy as adjunctive treatment for LM in selected patients after optimal surgery, with a level 2B recommendation. And the American Academy of Dermatology lists imiquimod as among the adjunctive options (J. Am. Acad. Dermatol. 2009; 61:865-7). What’s really needed now, according to Dr. Swetter, is a randomized controlled trial to firmly demonstrate benefit.

Session chair Dr. Allan C. Halpern said he and his colleagues have also been using topical imiquimod to treat LM with impressive results.

"What we’ve been doing, without literature to support it, is a broad shave biopsy, essentially removing the lesion, and then going right in with imiquimod before the patient heals. We’ve gotten some really wonderful clinical results," said Dr. Halpern, chief of the dermatology service at Memorial Sloan-Kettering Cancer Center in New York.

"That said, I think it’s important to remind people that – even with surgery – we do see occasional recurrences of desmoplastic melanomas in association with prior lentigo maligna. There’s no reason to think that’s going to be any less common in the imiquimod era. It’s going to happen to us," he cautioned.

Dr. Swetter reported having no financial conflicts. Dr. Halpern has received research grants from SciBase, DermTech, Caliber, and Canfield.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – The topical immunomodulator imiquimod appears to be beneficial therapy in selected patients with lentigo maligna or lentigo maligna melanoma, according to the largest case series to date.

"Based upon our experience, imiquimod 5% cream is a viable option as primary or adjunctive therapy of lentigo maligna and the in situ component of lentigo maligna melanoma in patients where surgery is really not feasible, or you’ve optimized surgical margins without achieving a clear histologic margin. I emphasize this should only be considered for in situ melanoma; we’re not using it to treat invasive melanoma," Dr. Susan M. Swetter said at the Hawaii Dermatology Seminar sponsored by the Global Academy for Medical Education/Skin Disease Education Foundation.

A cautionary note: Imiquimod (Aldara) for lentigo maligna (LM) is off-label therapy. It’s crucial to discuss with candidates the limitations of nonsurgical treatment for LM and lentigo maligna melanoma (LMM), which includes increased risk of local recurrence because of the lack of margin control, the possibility of a missed invasive melanoma, and the lack of supporting evidence from randomized trials with long-term follow-up.

"When we’re talking about imiquimod as potential treatment for lentigo maligna – and I can’t emphasize this enough – it requires close clinical follow-up, [carefully] documented discussion with the patient, and strong patient compliance. We have had cases of lentigo maligna melanoma where there have been metastases, not because of the in situ component, but because of the initial invasive tumor. You’ve got to follow these patients long term like a hawk. I follow them with Wood’s lamp and dermoscopy, and I biopsy any pigmentation," said Dr. Swetter, professor of dermatology and director of the pigmented lesion and cutaneous melanoma clinic at Stanford (Calif.) University Medical Center.

That being said, there are many scenarios in which surgical excision – the recommended first-line treatment for LM and LMM – might not be feasible. These include the sizable numbers of patients of advanced age who have limiting comorbid medical conditions or cognitive impairment. Also, LM has a strong predilection for the head and neck, and some affected patients avidly wish to avoid potentially disfiguring surgery.

Dr. Swetter presented a retrospective study of 60 patients with 62 LM or LMM lesions treated with imiquimod 5% cream at Stanford or the Veterans Affairs Palo Alto Health Care System. Most she treated personally. Imiquimod was primary therapy in 20 cases and adjuvant therapy following failed surgical attempts to achieve histologic clearance in the rest.

Pathologically, 45% of the lesions were LM, 29% were atypical intraepidermal melanocytic proliferations or poorly evolving LM, and 26% were LMM with histologic transection of LM and excision of the invasive melanoma component. Three-quarters of treated lesions were on the head or neck.

The lesions had a mean Breslow depth of 1.17 mm. Prior to imiquimod, half of the patients had one excision and another 19% had two or more. The mean duration of imiquimod therapy was 10.9 weeks, with a mean post treatment follow-up of 38 months.

"I typically treat to a 2-cm margin around the lesion," the dermatologist noted.

The overall clinical or histologic clearance rate was 86%. This is strikingly similar to the collective 82% rate in 46 reports involving 264 treated patients described in a published review by dermatologists at the University of Colorado, Denver (Dermatol. Surg. 2012;38:937-46).

An inflammatory response to imiquimod was predictive of favorable treatment outcome, especially in patients using the topical agent as primary therapy. Of the 20 patients who used imiquimod as primary therapy, all 16 who experienced clinical and/or histologic clearance had an initial inflammatory response. In contrast, none of the four clinical nonresponders showed an inflammatory response.

Outcomes weren’t quite as good in patients using imiquimod as adjuvant therapy.

"This is likely related to more challenging cases in the adjuvant setting, where the patients may have failed multiple attempts at wide local excision for histologic clearance," Dr. Swetter surmised.

Although the use of imiquimod as treatment for LM remains off label, it’s worth noting that it receives support in major practice guidelines. National Comprehensive Cancer Network guidelines recommend consideration of topical imiquimod or radiotherapy as adjunctive treatment for LM in selected patients after optimal surgery, with a level 2B recommendation. And the American Academy of Dermatology lists imiquimod as among the adjunctive options (J. Am. Acad. Dermatol. 2009; 61:865-7). What’s really needed now, according to Dr. Swetter, is a randomized controlled trial to firmly demonstrate benefit.

Session chair Dr. Allan C. Halpern said he and his colleagues have also been using topical imiquimod to treat LM with impressive results.

"What we’ve been doing, without literature to support it, is a broad shave biopsy, essentially removing the lesion, and then going right in with imiquimod before the patient heals. We’ve gotten some really wonderful clinical results," said Dr. Halpern, chief of the dermatology service at Memorial Sloan-Kettering Cancer Center in New York.

"That said, I think it’s important to remind people that – even with surgery – we do see occasional recurrences of desmoplastic melanomas in association with prior lentigo maligna. There’s no reason to think that’s going to be any less common in the imiquimod era. It’s going to happen to us," he cautioned.

Dr. Swetter reported having no financial conflicts. Dr. Halpern has received research grants from SciBase, DermTech, Caliber, and Canfield.

SDEF and this news organization are owned by the same parent company.

[email protected]