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New guidelines address primary cutaneous T-cell lymphoproliferative disorders
HOLLYWOOD, FLA. – The treatment of patients with lymphomatoid papulosis depends on the presentation, according to new National Comprehensive Cancer Network guidelines for managing primary cutaneous CD30+ T-cell lymphoproliferative disorders.
No treatment is needed in patients with lymphomatoid papulosis (LyP) who present without symptoms because spontaneous remission is extremely common in this disease, and these patients typically won’t have problems with progressive disease, Dr. Andrew D. Zelenetz said at the annual conference of the National Comprehensive Cancer Network.
For those who are symptomatic, topical or systemic treatments are useful in some cases.
Topical steroids "are effective, but not great," commented Dr. Zelenetz, vice chairman of medical informatics at Memorial Sloan Kettering Cancer Center, New York; professor of medicine at Cornell University, New York; and chair of the NCCN Non-Hodgkin's Lymphomas Guidelines panel.
Reported response rates are in the 50%-60% range, he said.
Bexarotene is another treatment option, although experience with this drug is quite limited. The largest series included only 11 patients. Unpublished data from that series at Memorial Sloan Kettering Cancer Center show a response rate of 45% at a maximum oral dose of 600 mg daily, Dr. Zelenetz said.
However, where this is a response, it is "dramatic and quite obvious," he noted, adding that treatment duration needs to be adequate before a patient is considered a nonresponder; the median duration of treatment in the 11-patient series was 35.5 weeks.
In a series of 57 patients from Memorial Sloan Kettering Cancer Center (including the 11 treated systemically with bexarotene), 16 received no therapy; 19 received topical treatment with steroids (13 patients), bexarotene (2 patients), UVB (2 patients), cryotherapy (1 patient), or nitrogen mustard (1 patient); and 5 received systemic treatment with methotrexate.
At follow-up, 14% of patients had no evidence of disease, and, with the exception of one who died of another cause, the remaining patients were alive with disease, Dr. Zelenetz said.
LyP is a rare CD30+ cutaneous lymphoproliferative disorder characterized by self-healing cropped or generalized eruptions of papules that come and go on the trunk or proximal extremities. In rare cases they present as solitary lesions.
"Even though many patients actually have intermittent recurrent disease ... the death rate from LyP is zero. So this is a very manageable disease; don’t overtreat these tumors," he said.
At the other end of the spectrum of CD30+ lymphoproliferative disorders addressed in the new NCCN guidelines is anaplastic large cell lymphoma (ALCL).
Primary cutaneous ALCL is characterized by skin-only presentation that is often localized but which can be disseminated in some cases. Lesions also tend to be larger and "more piled up" than those seen with LyP.
"You can get clustering in a specific area, but we don’t tend to have these big crops of lesions that we see with LyP," Dr. Zelenetz said.
The pathology is also different, with diffuse infiltration of the subcutaneous tissue. The cells are large and anaplastic, and there is intense expression of CD30.
The course of disease is usually indolent, with progression to extracutaneous sites in about 10%-15% of cases.
Nodules or tumors in cases of ALCL are less likely than LyP lesions to regress spontaneously, Dr. Zelenetz said.
This disease must be distinguished from a skin presentation of systemic ALCL, he noted.
"So what’s the big difference? In anaplastic large cell lymphoma that’s systemic, you will have multiple nodules all over and happen to have skin disease. With primary cutaneous ALCL, you have skin only or skin and some regional lymph nodes but nothing beyond that," he said, adding that these primary cutaneous tumors do extremely well nevertheless, with cumulative survival rates above 90%.
Those with systemic ALCL, however, have much lower cumulative survival, in the 25% range.
As with LyP, treatment for primary cutaneous ALCL is based on presentation.
For solitary or grouped lesions, the preferred treatment is surgical excision if needed for diagnosis or radiation if the diagnosis is already established.
Methotrexate is the preferred treatment for multifocal lesions.
The subtype that includes regional lymph nodes is typically treated with very mild chemotherapy including methotrexate or pralatrexate. Radiation can be used for locoregional disease, Dr. Zelenetz said.
An exception to the rule that patients with primary cutaneous ALCL do well is in cases of extensive limb disease. Patients with involvement of a single limb – usually lower extremity, but not always – have poor survival, and their disease is refractory to chemotherapy and radiation. It is unclear why there is a distinction in this presentation, but it is important to be aware of it, he said.
Dr. Zelenetz is a scientific adviser for Cancer Genetics Inc. and Gilead and has received consulting fees, honoraria, and/or grant or other research support from Celgene Corp., Cephalon Inc., Genentech Inc., GlaxoSmithKline, Roche Laboratories Inc., sanofi-aventis U.S., and Seattle Genetics Inc.
HOLLYWOOD, FLA. – The treatment of patients with lymphomatoid papulosis depends on the presentation, according to new National Comprehensive Cancer Network guidelines for managing primary cutaneous CD30+ T-cell lymphoproliferative disorders.
No treatment is needed in patients with lymphomatoid papulosis (LyP) who present without symptoms because spontaneous remission is extremely common in this disease, and these patients typically won’t have problems with progressive disease, Dr. Andrew D. Zelenetz said at the annual conference of the National Comprehensive Cancer Network.
For those who are symptomatic, topical or systemic treatments are useful in some cases.
Topical steroids "are effective, but not great," commented Dr. Zelenetz, vice chairman of medical informatics at Memorial Sloan Kettering Cancer Center, New York; professor of medicine at Cornell University, New York; and chair of the NCCN Non-Hodgkin's Lymphomas Guidelines panel.
Reported response rates are in the 50%-60% range, he said.
Bexarotene is another treatment option, although experience with this drug is quite limited. The largest series included only 11 patients. Unpublished data from that series at Memorial Sloan Kettering Cancer Center show a response rate of 45% at a maximum oral dose of 600 mg daily, Dr. Zelenetz said.
However, where this is a response, it is "dramatic and quite obvious," he noted, adding that treatment duration needs to be adequate before a patient is considered a nonresponder; the median duration of treatment in the 11-patient series was 35.5 weeks.
In a series of 57 patients from Memorial Sloan Kettering Cancer Center (including the 11 treated systemically with bexarotene), 16 received no therapy; 19 received topical treatment with steroids (13 patients), bexarotene (2 patients), UVB (2 patients), cryotherapy (1 patient), or nitrogen mustard (1 patient); and 5 received systemic treatment with methotrexate.
At follow-up, 14% of patients had no evidence of disease, and, with the exception of one who died of another cause, the remaining patients were alive with disease, Dr. Zelenetz said.
LyP is a rare CD30+ cutaneous lymphoproliferative disorder characterized by self-healing cropped or generalized eruptions of papules that come and go on the trunk or proximal extremities. In rare cases they present as solitary lesions.
"Even though many patients actually have intermittent recurrent disease ... the death rate from LyP is zero. So this is a very manageable disease; don’t overtreat these tumors," he said.
At the other end of the spectrum of CD30+ lymphoproliferative disorders addressed in the new NCCN guidelines is anaplastic large cell lymphoma (ALCL).
Primary cutaneous ALCL is characterized by skin-only presentation that is often localized but which can be disseminated in some cases. Lesions also tend to be larger and "more piled up" than those seen with LyP.
"You can get clustering in a specific area, but we don’t tend to have these big crops of lesions that we see with LyP," Dr. Zelenetz said.
The pathology is also different, with diffuse infiltration of the subcutaneous tissue. The cells are large and anaplastic, and there is intense expression of CD30.
The course of disease is usually indolent, with progression to extracutaneous sites in about 10%-15% of cases.
Nodules or tumors in cases of ALCL are less likely than LyP lesions to regress spontaneously, Dr. Zelenetz said.
This disease must be distinguished from a skin presentation of systemic ALCL, he noted.
"So what’s the big difference? In anaplastic large cell lymphoma that’s systemic, you will have multiple nodules all over and happen to have skin disease. With primary cutaneous ALCL, you have skin only or skin and some regional lymph nodes but nothing beyond that," he said, adding that these primary cutaneous tumors do extremely well nevertheless, with cumulative survival rates above 90%.
Those with systemic ALCL, however, have much lower cumulative survival, in the 25% range.
As with LyP, treatment for primary cutaneous ALCL is based on presentation.
For solitary or grouped lesions, the preferred treatment is surgical excision if needed for diagnosis or radiation if the diagnosis is already established.
Methotrexate is the preferred treatment for multifocal lesions.
The subtype that includes regional lymph nodes is typically treated with very mild chemotherapy including methotrexate or pralatrexate. Radiation can be used for locoregional disease, Dr. Zelenetz said.
An exception to the rule that patients with primary cutaneous ALCL do well is in cases of extensive limb disease. Patients with involvement of a single limb – usually lower extremity, but not always – have poor survival, and their disease is refractory to chemotherapy and radiation. It is unclear why there is a distinction in this presentation, but it is important to be aware of it, he said.
Dr. Zelenetz is a scientific adviser for Cancer Genetics Inc. and Gilead and has received consulting fees, honoraria, and/or grant or other research support from Celgene Corp., Cephalon Inc., Genentech Inc., GlaxoSmithKline, Roche Laboratories Inc., sanofi-aventis U.S., and Seattle Genetics Inc.
HOLLYWOOD, FLA. – The treatment of patients with lymphomatoid papulosis depends on the presentation, according to new National Comprehensive Cancer Network guidelines for managing primary cutaneous CD30+ T-cell lymphoproliferative disorders.
No treatment is needed in patients with lymphomatoid papulosis (LyP) who present without symptoms because spontaneous remission is extremely common in this disease, and these patients typically won’t have problems with progressive disease, Dr. Andrew D. Zelenetz said at the annual conference of the National Comprehensive Cancer Network.
For those who are symptomatic, topical or systemic treatments are useful in some cases.
Topical steroids "are effective, but not great," commented Dr. Zelenetz, vice chairman of medical informatics at Memorial Sloan Kettering Cancer Center, New York; professor of medicine at Cornell University, New York; and chair of the NCCN Non-Hodgkin's Lymphomas Guidelines panel.
Reported response rates are in the 50%-60% range, he said.
Bexarotene is another treatment option, although experience with this drug is quite limited. The largest series included only 11 patients. Unpublished data from that series at Memorial Sloan Kettering Cancer Center show a response rate of 45% at a maximum oral dose of 600 mg daily, Dr. Zelenetz said.
However, where this is a response, it is "dramatic and quite obvious," he noted, adding that treatment duration needs to be adequate before a patient is considered a nonresponder; the median duration of treatment in the 11-patient series was 35.5 weeks.
In a series of 57 patients from Memorial Sloan Kettering Cancer Center (including the 11 treated systemically with bexarotene), 16 received no therapy; 19 received topical treatment with steroids (13 patients), bexarotene (2 patients), UVB (2 patients), cryotherapy (1 patient), or nitrogen mustard (1 patient); and 5 received systemic treatment with methotrexate.
At follow-up, 14% of patients had no evidence of disease, and, with the exception of one who died of another cause, the remaining patients were alive with disease, Dr. Zelenetz said.
LyP is a rare CD30+ cutaneous lymphoproliferative disorder characterized by self-healing cropped or generalized eruptions of papules that come and go on the trunk or proximal extremities. In rare cases they present as solitary lesions.
"Even though many patients actually have intermittent recurrent disease ... the death rate from LyP is zero. So this is a very manageable disease; don’t overtreat these tumors," he said.
At the other end of the spectrum of CD30+ lymphoproliferative disorders addressed in the new NCCN guidelines is anaplastic large cell lymphoma (ALCL).
Primary cutaneous ALCL is characterized by skin-only presentation that is often localized but which can be disseminated in some cases. Lesions also tend to be larger and "more piled up" than those seen with LyP.
"You can get clustering in a specific area, but we don’t tend to have these big crops of lesions that we see with LyP," Dr. Zelenetz said.
The pathology is also different, with diffuse infiltration of the subcutaneous tissue. The cells are large and anaplastic, and there is intense expression of CD30.
The course of disease is usually indolent, with progression to extracutaneous sites in about 10%-15% of cases.
Nodules or tumors in cases of ALCL are less likely than LyP lesions to regress spontaneously, Dr. Zelenetz said.
This disease must be distinguished from a skin presentation of systemic ALCL, he noted.
"So what’s the big difference? In anaplastic large cell lymphoma that’s systemic, you will have multiple nodules all over and happen to have skin disease. With primary cutaneous ALCL, you have skin only or skin and some regional lymph nodes but nothing beyond that," he said, adding that these primary cutaneous tumors do extremely well nevertheless, with cumulative survival rates above 90%.
Those with systemic ALCL, however, have much lower cumulative survival, in the 25% range.
As with LyP, treatment for primary cutaneous ALCL is based on presentation.
For solitary or grouped lesions, the preferred treatment is surgical excision if needed for diagnosis or radiation if the diagnosis is already established.
Methotrexate is the preferred treatment for multifocal lesions.
The subtype that includes regional lymph nodes is typically treated with very mild chemotherapy including methotrexate or pralatrexate. Radiation can be used for locoregional disease, Dr. Zelenetz said.
An exception to the rule that patients with primary cutaneous ALCL do well is in cases of extensive limb disease. Patients with involvement of a single limb – usually lower extremity, but not always – have poor survival, and their disease is refractory to chemotherapy and radiation. It is unclear why there is a distinction in this presentation, but it is important to be aware of it, he said.
Dr. Zelenetz is a scientific adviser for Cancer Genetics Inc. and Gilead and has received consulting fees, honoraria, and/or grant or other research support from Celgene Corp., Cephalon Inc., Genentech Inc., GlaxoSmithKline, Roche Laboratories Inc., sanofi-aventis U.S., and Seattle Genetics Inc.
AT THE NCCN ANNUAL CONFERENCE
Monoclonal antibody pinpoints BRAF status in melanoma
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.
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.
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.
AT THE AAD ANNUAL MEETING
Major finding: A monoclonal antibody showed 100% specificity and 85% sensitivity for identifying V600E BRAF mutations in metastatic melanoma.
Data source: The prospective study comprised 93 patients.
Disclosures: Ms. Vernali had no financial disclosures.
First-Degree Relatives of Melanoma Patients May Experience Counterphobia
House panel chides FDA for inaction on sunscreens
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."
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.
aault@frontlinemedcom.com 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."
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.
aault@frontlinemedcom.com 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."
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.
aault@frontlinemedcom.com On Twitter @aliciaault
AT AN ENERGY AND COMMERCE SUBCOMMITTEE HEARING
Patients with PD-L1–positive tumors had better response to immune checkpoint inhibitor
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.
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.
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.
AT THE AACR ANNUAL MEETING
Major finding: Overall response to MK-3475 among melanoma patients with PD-L1–positive tumors was 49%, compared with 13% among patients with PD-L1–negative tumors (P = .0007). In a separate study, 41% of NSCLC 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 (P = .004).
Data source: Two studies of 341 patients from the ongoing phase 1B KEYNOTE-001 study.
Disclosures: The 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.
Increased Risk for Melanoma in Men With Prostate Cancer: Implications for Clinical Practice?
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.
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.
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.
Substantial delay seen in melanoma surgery for Medicare patients
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.
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.
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.
On Twitter @alz_gal
AT THE AAD ANNUAL MEETING
Major finding: Melanoma excision delays were significantly less common when the diagnostic physician was a dermatologist, rather than a nondermatologist (OR, 0.67 for more than 1.5 months; 0.58 for more than 3 months).
Data source: A Medicare database study involving more than 32,000 patients with melanoma.
Disclosures: Dr. Lott said he had no relevant financial disclosures.
What’s old is new again for actinic keratoses treatment
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.
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.
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.
EXPERT ANALYSIS FROM THE AAD ANNUAL MEETING
New study supports imiquimod for lentigo maligna
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.
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.
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.
EXPERT ANALYSIS FROM SDEF HAWAII DERMATOLOGY SEMINAR
Immunotherapy for melanoma progresses with some interesting response patterns
HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.
Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.
In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).
A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.
The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).
It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.
He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.
However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.
"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.
In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).
At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.
Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.
"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.
He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.
Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).
Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."
Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.
In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.
For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.
As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.
"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.
Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.
A simplified treatment algorithm can be used to help select the appropriate treatment, he added.
For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).
For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.
The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.
Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.
As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.
A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.
"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.
Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.
HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.
Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.
In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).
A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.
The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).
It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.
He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.
However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.
"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.
In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).
At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.
Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.
"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.
He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.
Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).
Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."
Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.
In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.
For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.
As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.
"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.
Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.
A simplified treatment algorithm can be used to help select the appropriate treatment, he added.
For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).
For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.
The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.
Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.
As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.
A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.
"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.
Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.
HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.
Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.
In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).
A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.
The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).
It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.
He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.
However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.
"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.
In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).
At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.
Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.
"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.
He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.
Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).
Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."
Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.
In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.
For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.
As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.
"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.
Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.
A simplified treatment algorithm can be used to help select the appropriate treatment, he added.
For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).
For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.
The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.
Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.
As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.
A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.
"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.
Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.
EXPERT ANALYSIS FROM THE NCCN ANNUAL CONFERENCE