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FDA proposes ban on indoor tanning for minors
The Food and Drug Administration wants to prohibit indoor tanning for minors and is seeking stricter regulations to enhance the safety of indoor tanning and use of sunlamp products for all users.
“Today’s action is intended to help protect young people from a known and preventable cause of skin cancer and other harms. Individuals under 18 years are at greatest risk of the adverse health consequences of indoor tanning,” said acting FDA Commissioner Stephen Ostroff in a news release outlining the two proposed rules.
Currently, 1.6 million minors tan indoors yearly, according to data from the 2013 National Youth Risk Behavior Survey, cited by the FDA. Although many states require parental consent before minors can use tanning facilities, a national standard is lacking.
An additional measure in the first proposed rule requires adults who use commercial tanning beds to sign a “risk acknowledgment certification” statement before the first tanning session and every 6 months thereafter. These restrictions are appropriate, the FDA statement said, because of the increased risk of skin cancer, notably melanoma, and other risks associated with indoor tanning. According to the proposed rule, some research has found that “doses of UVA radiation emitted by high-power sunlamp products may be up to 10-15 times higher than that of the midday sun, resulting in an intense amount of exposure that does not exist in nature.”
The second proposed ruleis aimed at tanning facilities and sunlamp manufacturers, and contains measures to bring about safer use of tanning devices. These rules would set limits on the amount of light allowed through protective eyewear when tanning, make an emergency “off” switch mandatory on tanning beds, improve warning signs and tanning bulb labeling, and prohibit device modifications without FDA recertification.
According to the FDA, these regulations would affect more than 30,000 tanning salons, health clubs, and spas that offer indoor tanning. “These proposed rules are meant to help adults make their decisions based on truthful information and to ensure manufacturers and tanning facilities take additional steps to improve the safety of these devices,” Dr. Ostroff said.
The rules and opportunities to comment are available starting Monday, Dec. 21 at www.regulations.gov. Public comments will be open for 90 days.
On Twitter @karioakes
The Food and Drug Administration wants to prohibit indoor tanning for minors and is seeking stricter regulations to enhance the safety of indoor tanning and use of sunlamp products for all users.
“Today’s action is intended to help protect young people from a known and preventable cause of skin cancer and other harms. Individuals under 18 years are at greatest risk of the adverse health consequences of indoor tanning,” said acting FDA Commissioner Stephen Ostroff in a news release outlining the two proposed rules.
Currently, 1.6 million minors tan indoors yearly, according to data from the 2013 National Youth Risk Behavior Survey, cited by the FDA. Although many states require parental consent before minors can use tanning facilities, a national standard is lacking.
An additional measure in the first proposed rule requires adults who use commercial tanning beds to sign a “risk acknowledgment certification” statement before the first tanning session and every 6 months thereafter. These restrictions are appropriate, the FDA statement said, because of the increased risk of skin cancer, notably melanoma, and other risks associated with indoor tanning. According to the proposed rule, some research has found that “doses of UVA radiation emitted by high-power sunlamp products may be up to 10-15 times higher than that of the midday sun, resulting in an intense amount of exposure that does not exist in nature.”
The second proposed ruleis aimed at tanning facilities and sunlamp manufacturers, and contains measures to bring about safer use of tanning devices. These rules would set limits on the amount of light allowed through protective eyewear when tanning, make an emergency “off” switch mandatory on tanning beds, improve warning signs and tanning bulb labeling, and prohibit device modifications without FDA recertification.
According to the FDA, these regulations would affect more than 30,000 tanning salons, health clubs, and spas that offer indoor tanning. “These proposed rules are meant to help adults make their decisions based on truthful information and to ensure manufacturers and tanning facilities take additional steps to improve the safety of these devices,” Dr. Ostroff said.
The rules and opportunities to comment are available starting Monday, Dec. 21 at www.regulations.gov. Public comments will be open for 90 days.
On Twitter @karioakes
The Food and Drug Administration wants to prohibit indoor tanning for minors and is seeking stricter regulations to enhance the safety of indoor tanning and use of sunlamp products for all users.
“Today’s action is intended to help protect young people from a known and preventable cause of skin cancer and other harms. Individuals under 18 years are at greatest risk of the adverse health consequences of indoor tanning,” said acting FDA Commissioner Stephen Ostroff in a news release outlining the two proposed rules.
Currently, 1.6 million minors tan indoors yearly, according to data from the 2013 National Youth Risk Behavior Survey, cited by the FDA. Although many states require parental consent before minors can use tanning facilities, a national standard is lacking.
An additional measure in the first proposed rule requires adults who use commercial tanning beds to sign a “risk acknowledgment certification” statement before the first tanning session and every 6 months thereafter. These restrictions are appropriate, the FDA statement said, because of the increased risk of skin cancer, notably melanoma, and other risks associated with indoor tanning. According to the proposed rule, some research has found that “doses of UVA radiation emitted by high-power sunlamp products may be up to 10-15 times higher than that of the midday sun, resulting in an intense amount of exposure that does not exist in nature.”
The second proposed ruleis aimed at tanning facilities and sunlamp manufacturers, and contains measures to bring about safer use of tanning devices. These rules would set limits on the amount of light allowed through protective eyewear when tanning, make an emergency “off” switch mandatory on tanning beds, improve warning signs and tanning bulb labeling, and prohibit device modifications without FDA recertification.
According to the FDA, these regulations would affect more than 30,000 tanning salons, health clubs, and spas that offer indoor tanning. “These proposed rules are meant to help adults make their decisions based on truthful information and to ensure manufacturers and tanning facilities take additional steps to improve the safety of these devices,” Dr. Ostroff said.
The rules and opportunities to comment are available starting Monday, Dec. 21 at www.regulations.gov. Public comments will be open for 90 days.
On Twitter @karioakes
Entering an era of intelligent combination therapy in cancer
The past few decades have witnessed unprecedented advances in our understanding of the molecular underpinnings of cancer. Although indiscriminately cytotoxic therapies like chemo- and radiation therapy remain standard of care for many cancer types, more precise targeted therapies and immune-boosting immunotherapies have added to our arsenal and afforded considerable survival gains. Despite those advances, we are still no closer to a cure, particularly for the most aggressive and insidious cancers that progress rapidly or go undiagnosed until advanced stages of disease. The substantial genetic diversity of tumors and universal nature of drug resistance present the most formidable and enduring challenges to effective cancer treatment.
Click on the PDF icon at the top of this introduction to read the full article.
The past few decades have witnessed unprecedented advances in our understanding of the molecular underpinnings of cancer. Although indiscriminately cytotoxic therapies like chemo- and radiation therapy remain standard of care for many cancer types, more precise targeted therapies and immune-boosting immunotherapies have added to our arsenal and afforded considerable survival gains. Despite those advances, we are still no closer to a cure, particularly for the most aggressive and insidious cancers that progress rapidly or go undiagnosed until advanced stages of disease. The substantial genetic diversity of tumors and universal nature of drug resistance present the most formidable and enduring challenges to effective cancer treatment.
Click on the PDF icon at the top of this introduction to read the full article.
The past few decades have witnessed unprecedented advances in our understanding of the molecular underpinnings of cancer. Although indiscriminately cytotoxic therapies like chemo- and radiation therapy remain standard of care for many cancer types, more precise targeted therapies and immune-boosting immunotherapies have added to our arsenal and afforded considerable survival gains. Despite those advances, we are still no closer to a cure, particularly for the most aggressive and insidious cancers that progress rapidly or go undiagnosed until advanced stages of disease. The substantial genetic diversity of tumors and universal nature of drug resistance present the most formidable and enduring challenges to effective cancer treatment.
Click on the PDF icon at the top of this introduction to read the full article.
Oncology 2015: new therapies and new transitions toward value-based cancer care
The past year has been an exciting one for new oncology and hematology drug approvals and the continued evolution of our oncology delivery system toward high quality and value. In all, at press time in mid-November, the US Food and Drug Administration (FDA) had approved or granted expanded indications for 24 drugs, compared with 19 in the 2 preceding years. Of those 24 approvals, 7 were accelerated and 6 were expanded approvals, and 3 alone were for the immunotherapeutic drug, nivolumab – 2 for non-small-cell lung cancer (NSCLC) and 1 for metastatic melanoma.
Click on the PDF icon at the top of this introduction to read the full article.
The past year has been an exciting one for new oncology and hematology drug approvals and the continued evolution of our oncology delivery system toward high quality and value. In all, at press time in mid-November, the US Food and Drug Administration (FDA) had approved or granted expanded indications for 24 drugs, compared with 19 in the 2 preceding years. Of those 24 approvals, 7 were accelerated and 6 were expanded approvals, and 3 alone were for the immunotherapeutic drug, nivolumab – 2 for non-small-cell lung cancer (NSCLC) and 1 for metastatic melanoma.
Click on the PDF icon at the top of this introduction to read the full article.
The past year has been an exciting one for new oncology and hematology drug approvals and the continued evolution of our oncology delivery system toward high quality and value. In all, at press time in mid-November, the US Food and Drug Administration (FDA) had approved or granted expanded indications for 24 drugs, compared with 19 in the 2 preceding years. Of those 24 approvals, 7 were accelerated and 6 were expanded approvals, and 3 alone were for the immunotherapeutic drug, nivolumab – 2 for non-small-cell lung cancer (NSCLC) and 1 for metastatic melanoma.
Click on the PDF icon at the top of this introduction to read the full article.
FDA approves treatment for chemotherapy ODs, life-threatening toxicities
Uridine triacetate, a pyrimidine analogue, has been approved for the emergency treatment of fluorouracil or capecitabine overdoses in adults and children, and for patients who develop “certain severe or life-threatening toxicities within 4 days of receiving” these treatments, the Food and Drug Administration announced on Dec. 11.
“Today’s approval is a first-of-its-kind therapy that can potentially save lives following overdose or life-threatening toxicity from these chemotherapy agents,” Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement. It will be marketed as Vistogard by Wellstat Therapeutics.
Uridine comes in an oral granule formulation that can be mixed into soft foods or, when necessary, administered via a nasogastric or gastrostomy tube, the prescribing information states. The indication is for use after an overdose “regardless of the presence of symptoms,” and for treating “early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration,” according to the prescribing information.
Uridine blocks cell damage and cell death caused by fluorouracil chemotherapy, according to the statement, which adds that it is up to the patient’s health care provider to “determine when he or she should return to the prescribed chemotherapy after treatment with Vistogard.”
Uridine was evaluated in two studies of 135 adults and children with cancer, treated with uridine for a fluorouracil or capecitabine overdose, or for early-onset, unusually severe or life-threatening toxicities within 96 hours after receiving fluorouracil (not because of an overdose). Among those treated for an overdose, 97% were alive 30 days after treatment, and among those treated for early-onset severe or life-threatening toxicity, 89% were alive 30 days after treatment. In addition, 33% of the patients resumed chemotherapy within 30 days, according to the FDA statement. Diarrhea, vomiting, and nausea were the most common adverse events associated with treatment.
Uridine was granted orphan drug, priority review, and fast track designations.
Uridine triacetate, a pyrimidine analogue, has been approved for the emergency treatment of fluorouracil or capecitabine overdoses in adults and children, and for patients who develop “certain severe or life-threatening toxicities within 4 days of receiving” these treatments, the Food and Drug Administration announced on Dec. 11.
“Today’s approval is a first-of-its-kind therapy that can potentially save lives following overdose or life-threatening toxicity from these chemotherapy agents,” Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement. It will be marketed as Vistogard by Wellstat Therapeutics.
Uridine comes in an oral granule formulation that can be mixed into soft foods or, when necessary, administered via a nasogastric or gastrostomy tube, the prescribing information states. The indication is for use after an overdose “regardless of the presence of symptoms,” and for treating “early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration,” according to the prescribing information.
Uridine blocks cell damage and cell death caused by fluorouracil chemotherapy, according to the statement, which adds that it is up to the patient’s health care provider to “determine when he or she should return to the prescribed chemotherapy after treatment with Vistogard.”
Uridine was evaluated in two studies of 135 adults and children with cancer, treated with uridine for a fluorouracil or capecitabine overdose, or for early-onset, unusually severe or life-threatening toxicities within 96 hours after receiving fluorouracil (not because of an overdose). Among those treated for an overdose, 97% were alive 30 days after treatment, and among those treated for early-onset severe or life-threatening toxicity, 89% were alive 30 days after treatment. In addition, 33% of the patients resumed chemotherapy within 30 days, according to the FDA statement. Diarrhea, vomiting, and nausea were the most common adverse events associated with treatment.
Uridine was granted orphan drug, priority review, and fast track designations.
Uridine triacetate, a pyrimidine analogue, has been approved for the emergency treatment of fluorouracil or capecitabine overdoses in adults and children, and for patients who develop “certain severe or life-threatening toxicities within 4 days of receiving” these treatments, the Food and Drug Administration announced on Dec. 11.
“Today’s approval is a first-of-its-kind therapy that can potentially save lives following overdose or life-threatening toxicity from these chemotherapy agents,” Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement. It will be marketed as Vistogard by Wellstat Therapeutics.
Uridine comes in an oral granule formulation that can be mixed into soft foods or, when necessary, administered via a nasogastric or gastrostomy tube, the prescribing information states. The indication is for use after an overdose “regardless of the presence of symptoms,” and for treating “early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration,” according to the prescribing information.
Uridine blocks cell damage and cell death caused by fluorouracil chemotherapy, according to the statement, which adds that it is up to the patient’s health care provider to “determine when he or she should return to the prescribed chemotherapy after treatment with Vistogard.”
Uridine was evaluated in two studies of 135 adults and children with cancer, treated with uridine for a fluorouracil or capecitabine overdose, or for early-onset, unusually severe or life-threatening toxicities within 96 hours after receiving fluorouracil (not because of an overdose). Among those treated for an overdose, 97% were alive 30 days after treatment, and among those treated for early-onset severe or life-threatening toxicity, 89% were alive 30 days after treatment. In addition, 33% of the patients resumed chemotherapy within 30 days, according to the FDA statement. Diarrhea, vomiting, and nausea were the most common adverse events associated with treatment.
Uridine was granted orphan drug, priority review, and fast track designations.
Documentation for Mohs Surgery
In 2013, the Centers for Medicare and Medicaid Services (CMS) issued a guidance to reduce reimbursement issues for Mohs micrographic surgery (MMS).1 One crucial question that remains is when and if these documentation guidelines will be formally implemented. The guidelines outlined by the CMS currently are regarded as suggestions until Medicare contractors adopt them into the local coverage determinations (LCDs).
Key Documentation Guidelines
To reduce MMS reimbursement issues, documentation in the patient’s medical record should support the medical necessity of the procedure and reflect the number and anatomic locations of specimens taken and the reason for the procedure should be clearly communicated. The specific tumor type also should be approved for treatment with MMS in the respective LCD.
Nonphysician providers are not authorized by Medicare to perform MMS. To ensure proper coding, both surgery and pathology must be performed by a single physician and should be supported by documentation in the patient’s medical record (eg, relevant chart notes should be made under the provider’s signature). These documentation guidelines are not new but are included in the CMS guidance to reiterate their importance in reducing MMS reimbursement issues.
Per customary clinical practice, the CMS guidance specifies that MMS documentation should include gross description of the tissue removed, including the location, number, and size of the lesions, as well as how many specimens were removed for each stage. However, the guidance diverges from routine MMS documentation requirements in its emphasis on providing a histologic description of the tissue removed. The guidance suggests that the depth of tumor invasion, pathologic pattern, cell morphology (which is not typically specified for skin cancers), and, if present, the existence of perineural invasion or scar tissue should be documented. If these features are constant across stages, they only need to be noted for the first stage.
Adapting Guidelines for Clinical Practice
The CMS guidance may create some conundrums for physicians regarding MMS documentation; for instance, if a tumor is cleared in one stage, as is often the case, no tumor will be seen on glass slides prepared to assess tissue margins during the procedure and therefore documentation of characteristics like depth and pattern will be impossible. Similarly, cell morphology is not a feature that usually is relevant for most squamous and basal cell carcinomas, although it may be useful in certain unusual instances, such as in cases of rare tumors with particular histologic features that may influence management and/or prognosis. When in doubt regarding the appropriate documentation method for MMS, the surgeon should use his or her best judgment based on clinical experience rather than simply following guidelines that may not be applicable.
Final Thoughts
The CMS guidance serves as a reminder of the documentation requirements for MMS and extends current practice by suggesting a detailed microscopic description of the removed tissue. The American Academy of Dermatology has developed a guide to help Mohs surgeons provide the necessary documentation without creating cumbersome chart notes.2 Mohs surgeons should consult the most recent version of the LCD that applies to their geographic area to determine if the new documentation guidelines have been adopted.
- Centers for Medicare and Medicaid Services. Guidance to Reduce Mohs Surgery Reimbursement Issues. Bethesda, MD: Centers for Medicare and Medicaid Services, US Department of Health and Human Services; 2013. MLN Matters SE1318.
- Position statement on documentation of frozen section specimens during Mohs micrographic surgery. American Academy of Dermatology Web site. https://www.aad.org/forms/policies/Uploads/PS/PS%20-%20Documentation%20of%20Frozen%20Section%20Specimens%20during%20Mohs%20Micrographic%20Surgery.pdf. Accessed November 30, 2015.
In 2013, the Centers for Medicare and Medicaid Services (CMS) issued a guidance to reduce reimbursement issues for Mohs micrographic surgery (MMS).1 One crucial question that remains is when and if these documentation guidelines will be formally implemented. The guidelines outlined by the CMS currently are regarded as suggestions until Medicare contractors adopt them into the local coverage determinations (LCDs).
Key Documentation Guidelines
To reduce MMS reimbursement issues, documentation in the patient’s medical record should support the medical necessity of the procedure and reflect the number and anatomic locations of specimens taken and the reason for the procedure should be clearly communicated. The specific tumor type also should be approved for treatment with MMS in the respective LCD.
Nonphysician providers are not authorized by Medicare to perform MMS. To ensure proper coding, both surgery and pathology must be performed by a single physician and should be supported by documentation in the patient’s medical record (eg, relevant chart notes should be made under the provider’s signature). These documentation guidelines are not new but are included in the CMS guidance to reiterate their importance in reducing MMS reimbursement issues.
Per customary clinical practice, the CMS guidance specifies that MMS documentation should include gross description of the tissue removed, including the location, number, and size of the lesions, as well as how many specimens were removed for each stage. However, the guidance diverges from routine MMS documentation requirements in its emphasis on providing a histologic description of the tissue removed. The guidance suggests that the depth of tumor invasion, pathologic pattern, cell morphology (which is not typically specified for skin cancers), and, if present, the existence of perineural invasion or scar tissue should be documented. If these features are constant across stages, they only need to be noted for the first stage.
Adapting Guidelines for Clinical Practice
The CMS guidance may create some conundrums for physicians regarding MMS documentation; for instance, if a tumor is cleared in one stage, as is often the case, no tumor will be seen on glass slides prepared to assess tissue margins during the procedure and therefore documentation of characteristics like depth and pattern will be impossible. Similarly, cell morphology is not a feature that usually is relevant for most squamous and basal cell carcinomas, although it may be useful in certain unusual instances, such as in cases of rare tumors with particular histologic features that may influence management and/or prognosis. When in doubt regarding the appropriate documentation method for MMS, the surgeon should use his or her best judgment based on clinical experience rather than simply following guidelines that may not be applicable.
Final Thoughts
The CMS guidance serves as a reminder of the documentation requirements for MMS and extends current practice by suggesting a detailed microscopic description of the removed tissue. The American Academy of Dermatology has developed a guide to help Mohs surgeons provide the necessary documentation without creating cumbersome chart notes.2 Mohs surgeons should consult the most recent version of the LCD that applies to their geographic area to determine if the new documentation guidelines have been adopted.
In 2013, the Centers for Medicare and Medicaid Services (CMS) issued a guidance to reduce reimbursement issues for Mohs micrographic surgery (MMS).1 One crucial question that remains is when and if these documentation guidelines will be formally implemented. The guidelines outlined by the CMS currently are regarded as suggestions until Medicare contractors adopt them into the local coverage determinations (LCDs).
Key Documentation Guidelines
To reduce MMS reimbursement issues, documentation in the patient’s medical record should support the medical necessity of the procedure and reflect the number and anatomic locations of specimens taken and the reason for the procedure should be clearly communicated. The specific tumor type also should be approved for treatment with MMS in the respective LCD.
Nonphysician providers are not authorized by Medicare to perform MMS. To ensure proper coding, both surgery and pathology must be performed by a single physician and should be supported by documentation in the patient’s medical record (eg, relevant chart notes should be made under the provider’s signature). These documentation guidelines are not new but are included in the CMS guidance to reiterate their importance in reducing MMS reimbursement issues.
Per customary clinical practice, the CMS guidance specifies that MMS documentation should include gross description of the tissue removed, including the location, number, and size of the lesions, as well as how many specimens were removed for each stage. However, the guidance diverges from routine MMS documentation requirements in its emphasis on providing a histologic description of the tissue removed. The guidance suggests that the depth of tumor invasion, pathologic pattern, cell morphology (which is not typically specified for skin cancers), and, if present, the existence of perineural invasion or scar tissue should be documented. If these features are constant across stages, they only need to be noted for the first stage.
Adapting Guidelines for Clinical Practice
The CMS guidance may create some conundrums for physicians regarding MMS documentation; for instance, if a tumor is cleared in one stage, as is often the case, no tumor will be seen on glass slides prepared to assess tissue margins during the procedure and therefore documentation of characteristics like depth and pattern will be impossible. Similarly, cell morphology is not a feature that usually is relevant for most squamous and basal cell carcinomas, although it may be useful in certain unusual instances, such as in cases of rare tumors with particular histologic features that may influence management and/or prognosis. When in doubt regarding the appropriate documentation method for MMS, the surgeon should use his or her best judgment based on clinical experience rather than simply following guidelines that may not be applicable.
Final Thoughts
The CMS guidance serves as a reminder of the documentation requirements for MMS and extends current practice by suggesting a detailed microscopic description of the removed tissue. The American Academy of Dermatology has developed a guide to help Mohs surgeons provide the necessary documentation without creating cumbersome chart notes.2 Mohs surgeons should consult the most recent version of the LCD that applies to their geographic area to determine if the new documentation guidelines have been adopted.
- Centers for Medicare and Medicaid Services. Guidance to Reduce Mohs Surgery Reimbursement Issues. Bethesda, MD: Centers for Medicare and Medicaid Services, US Department of Health and Human Services; 2013. MLN Matters SE1318.
- Position statement on documentation of frozen section specimens during Mohs micrographic surgery. American Academy of Dermatology Web site. https://www.aad.org/forms/policies/Uploads/PS/PS%20-%20Documentation%20of%20Frozen%20Section%20Specimens%20during%20Mohs%20Micrographic%20Surgery.pdf. Accessed November 30, 2015.
- Centers for Medicare and Medicaid Services. Guidance to Reduce Mohs Surgery Reimbursement Issues. Bethesda, MD: Centers for Medicare and Medicaid Services, US Department of Health and Human Services; 2013. MLN Matters SE1318.
- Position statement on documentation of frozen section specimens during Mohs micrographic surgery. American Academy of Dermatology Web site. https://www.aad.org/forms/policies/Uploads/PS/PS%20-%20Documentation%20of%20Frozen%20Section%20Specimens%20during%20Mohs%20Micrographic%20Surgery.pdf. Accessed November 30, 2015.
EADV: Focus on non-UV triggers of melanoma
COPENHAGEN – Sunlight is recognized as the 800-pound gorilla of melanoma risk, with roughly 65% of all melanomas worldwide attributable to exposure to UV radiation. But what about the other 35%?
About 10% of melanomas are due to an inherited germline mutation, and new germline mutations are being discovered all the time. However, the incidence of melanoma has been rising steadily in industrialized countries since the 1950s, and genetic predisposition can’t explain that phenomenon. Environmental and lifestyle factors are likely to be involved. Indeed, melanomas arising from epigenetic modifications by extrinsic environmental and lifestyle factors other than UV exposure are drawing increasing research attention because of the potential for preventing the malignancy through avoidance of these risk factors, Dr. Veronique del Marmol said at the annual congress of the European Academy of Dermatology and Venereology.
One promising avenue of investigation focuses on microRNAs (miRs) as environmental drivers of melanoma risk. The miRs are important posttranscriptional regulators of gene expression. In particular, overexpression of miR-21 has been shown to accompany the transition of benign melanocytes into melanoma. miR-21 affects numerous genes critical to oncogenesis, including genes promoting sustained proliferation, angiogenesis, evasion from apoptosis, genetic instability, oxidative stress, and invasion and metastasis, as detailed recently [J Transl Med. 2015 Jun 27;13:202] by Dr. Bodo C. Melnik of the department of dermatology, environmental medicine, and health theory, University of Osnabrück (Germany).
Translational work by Dr. Melnik and others has shown that miR-21 expression is upregulated by several elements that investigators have long suspected are associated with an increased risk of melanoma, including smoking, air pollution, polychlorinated biphenyls and other noxious chemicals, chronic inflammation, a high-fat/high-sugar diet, and a sedentary lifestyle. Even cow’s milk has generated suspicion, since bovine miR-21 is identical to human miR-21, noted Dr. del Marmol, head of the department of dermatology at Erasmus Hospital in Brussels and chair of the pan-European Euromelanoma project.
Two noteworthy factors that have generated interest recently are coffee consumption, shown in a large observational study to protect against melanoma, and sildenafil (Viagra), which was shown in an analysis of 25,848 physicians enrolled in the Health Professionals’ Follow-Up Study to be associated with a 2.24-fold increased risk of subsequently developing melanoma during prospective follow-up (JAMA Intern Med. 2014 Jun;174[6]:964-70).
An association between increased risk of melanoma and the use of sildenafil or other phosphodiesterase-5 (PDE-5) inhibitors commonly used by men with erectile dysfunction is biologically plausible, according to Dr. del Marmol. Activation of oncogenic BRAF is a hallmark of 40%-60% of melanomas, and BRAF activation, like sildenafil use, downregulates phosphodiesterase-5A, which increases the invasiveness of melanoma cells.
The coffee connection was identified through an analysis of food frequency questionnaires completed by 447,357 non-Hispanic whites enrolled in the NIH-AARP Diet and Health Study, a prospective study developed at the National Cancer Institute.
During 4.3 million person-years of follow-up, 2,904 individuals were diagnosed with malignant melanoma. In a multivariate analysis, quaffing 4 or more cups of caffeinated coffee daily was associated with a 25% reduction in the risk of developing melanoma. Lesser consumption had no significant impact on melanoma risk (J Natl Cancer Inst. 2015 Jan 20;107[2]: pii: dju421. doi: 10.1093/jnci/dju421].
COPENHAGEN – Sunlight is recognized as the 800-pound gorilla of melanoma risk, with roughly 65% of all melanomas worldwide attributable to exposure to UV radiation. But what about the other 35%?
About 10% of melanomas are due to an inherited germline mutation, and new germline mutations are being discovered all the time. However, the incidence of melanoma has been rising steadily in industrialized countries since the 1950s, and genetic predisposition can’t explain that phenomenon. Environmental and lifestyle factors are likely to be involved. Indeed, melanomas arising from epigenetic modifications by extrinsic environmental and lifestyle factors other than UV exposure are drawing increasing research attention because of the potential for preventing the malignancy through avoidance of these risk factors, Dr. Veronique del Marmol said at the annual congress of the European Academy of Dermatology and Venereology.
One promising avenue of investigation focuses on microRNAs (miRs) as environmental drivers of melanoma risk. The miRs are important posttranscriptional regulators of gene expression. In particular, overexpression of miR-21 has been shown to accompany the transition of benign melanocytes into melanoma. miR-21 affects numerous genes critical to oncogenesis, including genes promoting sustained proliferation, angiogenesis, evasion from apoptosis, genetic instability, oxidative stress, and invasion and metastasis, as detailed recently [J Transl Med. 2015 Jun 27;13:202] by Dr. Bodo C. Melnik of the department of dermatology, environmental medicine, and health theory, University of Osnabrück (Germany).
Translational work by Dr. Melnik and others has shown that miR-21 expression is upregulated by several elements that investigators have long suspected are associated with an increased risk of melanoma, including smoking, air pollution, polychlorinated biphenyls and other noxious chemicals, chronic inflammation, a high-fat/high-sugar diet, and a sedentary lifestyle. Even cow’s milk has generated suspicion, since bovine miR-21 is identical to human miR-21, noted Dr. del Marmol, head of the department of dermatology at Erasmus Hospital in Brussels and chair of the pan-European Euromelanoma project.
Two noteworthy factors that have generated interest recently are coffee consumption, shown in a large observational study to protect against melanoma, and sildenafil (Viagra), which was shown in an analysis of 25,848 physicians enrolled in the Health Professionals’ Follow-Up Study to be associated with a 2.24-fold increased risk of subsequently developing melanoma during prospective follow-up (JAMA Intern Med. 2014 Jun;174[6]:964-70).
An association between increased risk of melanoma and the use of sildenafil or other phosphodiesterase-5 (PDE-5) inhibitors commonly used by men with erectile dysfunction is biologically plausible, according to Dr. del Marmol. Activation of oncogenic BRAF is a hallmark of 40%-60% of melanomas, and BRAF activation, like sildenafil use, downregulates phosphodiesterase-5A, which increases the invasiveness of melanoma cells.
The coffee connection was identified through an analysis of food frequency questionnaires completed by 447,357 non-Hispanic whites enrolled in the NIH-AARP Diet and Health Study, a prospective study developed at the National Cancer Institute.
During 4.3 million person-years of follow-up, 2,904 individuals were diagnosed with malignant melanoma. In a multivariate analysis, quaffing 4 or more cups of caffeinated coffee daily was associated with a 25% reduction in the risk of developing melanoma. Lesser consumption had no significant impact on melanoma risk (J Natl Cancer Inst. 2015 Jan 20;107[2]: pii: dju421. doi: 10.1093/jnci/dju421].
COPENHAGEN – Sunlight is recognized as the 800-pound gorilla of melanoma risk, with roughly 65% of all melanomas worldwide attributable to exposure to UV radiation. But what about the other 35%?
About 10% of melanomas are due to an inherited germline mutation, and new germline mutations are being discovered all the time. However, the incidence of melanoma has been rising steadily in industrialized countries since the 1950s, and genetic predisposition can’t explain that phenomenon. Environmental and lifestyle factors are likely to be involved. Indeed, melanomas arising from epigenetic modifications by extrinsic environmental and lifestyle factors other than UV exposure are drawing increasing research attention because of the potential for preventing the malignancy through avoidance of these risk factors, Dr. Veronique del Marmol said at the annual congress of the European Academy of Dermatology and Venereology.
One promising avenue of investigation focuses on microRNAs (miRs) as environmental drivers of melanoma risk. The miRs are important posttranscriptional regulators of gene expression. In particular, overexpression of miR-21 has been shown to accompany the transition of benign melanocytes into melanoma. miR-21 affects numerous genes critical to oncogenesis, including genes promoting sustained proliferation, angiogenesis, evasion from apoptosis, genetic instability, oxidative stress, and invasion and metastasis, as detailed recently [J Transl Med. 2015 Jun 27;13:202] by Dr. Bodo C. Melnik of the department of dermatology, environmental medicine, and health theory, University of Osnabrück (Germany).
Translational work by Dr. Melnik and others has shown that miR-21 expression is upregulated by several elements that investigators have long suspected are associated with an increased risk of melanoma, including smoking, air pollution, polychlorinated biphenyls and other noxious chemicals, chronic inflammation, a high-fat/high-sugar diet, and a sedentary lifestyle. Even cow’s milk has generated suspicion, since bovine miR-21 is identical to human miR-21, noted Dr. del Marmol, head of the department of dermatology at Erasmus Hospital in Brussels and chair of the pan-European Euromelanoma project.
Two noteworthy factors that have generated interest recently are coffee consumption, shown in a large observational study to protect against melanoma, and sildenafil (Viagra), which was shown in an analysis of 25,848 physicians enrolled in the Health Professionals’ Follow-Up Study to be associated with a 2.24-fold increased risk of subsequently developing melanoma during prospective follow-up (JAMA Intern Med. 2014 Jun;174[6]:964-70).
An association between increased risk of melanoma and the use of sildenafil or other phosphodiesterase-5 (PDE-5) inhibitors commonly used by men with erectile dysfunction is biologically plausible, according to Dr. del Marmol. Activation of oncogenic BRAF is a hallmark of 40%-60% of melanomas, and BRAF activation, like sildenafil use, downregulates phosphodiesterase-5A, which increases the invasiveness of melanoma cells.
The coffee connection was identified through an analysis of food frequency questionnaires completed by 447,357 non-Hispanic whites enrolled in the NIH-AARP Diet and Health Study, a prospective study developed at the National Cancer Institute.
During 4.3 million person-years of follow-up, 2,904 individuals were diagnosed with malignant melanoma. In a multivariate analysis, quaffing 4 or more cups of caffeinated coffee daily was associated with a 25% reduction in the risk of developing melanoma. Lesser consumption had no significant impact on melanoma risk (J Natl Cancer Inst. 2015 Jan 20;107[2]: pii: dju421. doi: 10.1093/jnci/dju421].
EXPERT ANALYSIS FROM THE EADV CONGRESS
EADV: Fresh insights into Gorlin syndrome
COPENHAGEN – A glimpse into the massive burden imposed upon patients with basal cell nevus syndrome (BCNS) is provided by the initial report from the first U.S. registry of patients affected with the disorder to include individuals who’ve tried the Hedgehog signaling pathway inhibitor vismodegib.
The first 94 patients (average age, 56 years) with BCNS to enroll in the prospective registry had a reported lifetime mean of 312 basal cell carcinomas (BCCs), Dr. Marieke Peters reported at the annual congress of the European Academy of Dermatology and Venereology.
The patients had an average of 36 new BCCs or other tumors in the previous 2 years, and 70% were categorized as having moderate to severe BCNS (also known as Gorlin syndrome), as defined by more than 10 new BCCs during that time period.
Most (94%) of tumors were on sun-exposed areas. Patients reported a lifetime mean of 202 surgical excisions, according to Dr. Peters of Catharina Hospital Eindhoven, the Netherlands.
The median age at diagnosis of BCNS was 15 years, and most patients were diagnosed clinically. Only 26% had undergone genetic testing for PTCH1. (The syndrome is caused by mutations in the PTCH1 gene). Sixty-two percent of subjects reported a family history of BCNS.
Other abnormalities associated with BCNS were common: Eighty percent of patients had jaw cysts, 82% had palmer pitting, 50% had various bone abnormalities, 21% reported ovarian fibromas, 4% reported medulloblastomas, and 4% had other tumors.
Fifty-seven percent of patients had tried vismodegib (Erivedge). However, only 15% were currently on the drug at enrollment; the rest had discontinued it, mainly because of side effects; less frequently because of loss of efficacy due to the development of new mutations. The chief side effects were nausea, vomiting, and diarrhea; less frequent side effects were weight loss, fatigue, muscle cramps, and alopecia, according to the dermatologist.
Gorlin syndrome is a rare autosomal dominant disorder caused mainly by mutations in the PTCH1 gene. The U.S. registry is directed by investigators at Children’s Hospital Oakland Research Institute and Stanford (Calif.) University.
The patient questionnaire used in the BCNS registry is available at https://redcap.stanford.edu/surveys/?s=7MWW9E37ND. For more information about the registry, contact Dr. Ervin Epstein, at eepstein@chori.org.
Dr. Peters reported having no financial conflicts regarding her report. At the time of the EADV meeting, she was a dermatology resident at the Academic Medical Center, Amsterdam.
*This story was updated 12/15/2015.
COPENHAGEN – A glimpse into the massive burden imposed upon patients with basal cell nevus syndrome (BCNS) is provided by the initial report from the first U.S. registry of patients affected with the disorder to include individuals who’ve tried the Hedgehog signaling pathway inhibitor vismodegib.
The first 94 patients (average age, 56 years) with BCNS to enroll in the prospective registry had a reported lifetime mean of 312 basal cell carcinomas (BCCs), Dr. Marieke Peters reported at the annual congress of the European Academy of Dermatology and Venereology.
The patients had an average of 36 new BCCs or other tumors in the previous 2 years, and 70% were categorized as having moderate to severe BCNS (also known as Gorlin syndrome), as defined by more than 10 new BCCs during that time period.
Most (94%) of tumors were on sun-exposed areas. Patients reported a lifetime mean of 202 surgical excisions, according to Dr. Peters of Catharina Hospital Eindhoven, the Netherlands.
The median age at diagnosis of BCNS was 15 years, and most patients were diagnosed clinically. Only 26% had undergone genetic testing for PTCH1. (The syndrome is caused by mutations in the PTCH1 gene). Sixty-two percent of subjects reported a family history of BCNS.
Other abnormalities associated with BCNS were common: Eighty percent of patients had jaw cysts, 82% had palmer pitting, 50% had various bone abnormalities, 21% reported ovarian fibromas, 4% reported medulloblastomas, and 4% had other tumors.
Fifty-seven percent of patients had tried vismodegib (Erivedge). However, only 15% were currently on the drug at enrollment; the rest had discontinued it, mainly because of side effects; less frequently because of loss of efficacy due to the development of new mutations. The chief side effects were nausea, vomiting, and diarrhea; less frequent side effects were weight loss, fatigue, muscle cramps, and alopecia, according to the dermatologist.
Gorlin syndrome is a rare autosomal dominant disorder caused mainly by mutations in the PTCH1 gene. The U.S. registry is directed by investigators at Children’s Hospital Oakland Research Institute and Stanford (Calif.) University.
The patient questionnaire used in the BCNS registry is available at https://redcap.stanford.edu/surveys/?s=7MWW9E37ND. For more information about the registry, contact Dr. Ervin Epstein, at eepstein@chori.org.
Dr. Peters reported having no financial conflicts regarding her report. At the time of the EADV meeting, she was a dermatology resident at the Academic Medical Center, Amsterdam.
*This story was updated 12/15/2015.
COPENHAGEN – A glimpse into the massive burden imposed upon patients with basal cell nevus syndrome (BCNS) is provided by the initial report from the first U.S. registry of patients affected with the disorder to include individuals who’ve tried the Hedgehog signaling pathway inhibitor vismodegib.
The first 94 patients (average age, 56 years) with BCNS to enroll in the prospective registry had a reported lifetime mean of 312 basal cell carcinomas (BCCs), Dr. Marieke Peters reported at the annual congress of the European Academy of Dermatology and Venereology.
The patients had an average of 36 new BCCs or other tumors in the previous 2 years, and 70% were categorized as having moderate to severe BCNS (also known as Gorlin syndrome), as defined by more than 10 new BCCs during that time period.
Most (94%) of tumors were on sun-exposed areas. Patients reported a lifetime mean of 202 surgical excisions, according to Dr. Peters of Catharina Hospital Eindhoven, the Netherlands.
The median age at diagnosis of BCNS was 15 years, and most patients were diagnosed clinically. Only 26% had undergone genetic testing for PTCH1. (The syndrome is caused by mutations in the PTCH1 gene). Sixty-two percent of subjects reported a family history of BCNS.
Other abnormalities associated with BCNS were common: Eighty percent of patients had jaw cysts, 82% had palmer pitting, 50% had various bone abnormalities, 21% reported ovarian fibromas, 4% reported medulloblastomas, and 4% had other tumors.
Fifty-seven percent of patients had tried vismodegib (Erivedge). However, only 15% were currently on the drug at enrollment; the rest had discontinued it, mainly because of side effects; less frequently because of loss of efficacy due to the development of new mutations. The chief side effects were nausea, vomiting, and diarrhea; less frequent side effects were weight loss, fatigue, muscle cramps, and alopecia, according to the dermatologist.
Gorlin syndrome is a rare autosomal dominant disorder caused mainly by mutations in the PTCH1 gene. The U.S. registry is directed by investigators at Children’s Hospital Oakland Research Institute and Stanford (Calif.) University.
The patient questionnaire used in the BCNS registry is available at https://redcap.stanford.edu/surveys/?s=7MWW9E37ND. For more information about the registry, contact Dr. Ervin Epstein, at eepstein@chori.org.
Dr. Peters reported having no financial conflicts regarding her report. At the time of the EADV meeting, she was a dermatology resident at the Academic Medical Center, Amsterdam.
*This story was updated 12/15/2015.
AT THE EADV CONGRESS
Key clinical point: Gorlin syndrome imposes an impressively heavy burden on affected patients.
Major finding: Patients with basal cell nevus syndrome reported a lifetime mean of 312 basal cell carcinomas and 202 surgical excisions.
Data source: The initial report from a prospective U.S. registry of patients with basal cell nevus syndrome, which is still enrolling participants.
Disclosures: The presenter reported having no financial conflicts regarding her study.
Nivolumab approved as first-line, single agent for advanced melanoma
Nivolumab, a programmed death receptor–1 (PD-1) blocking antibody, has been approved as a single agent for the first-line treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma, the manufacturer has announced.
The approval is based on the results of a phase III study, CheckMate 066, which found a significant overall survival (OS) benefit for nivolumab, compared with chemotherapy, as a first-line treatment of patients with BRAF wild-type advanced melanoma, according to a press release issued by Bristol Myers Squibb (BMS) on Nov. 24.
The company markets nivolumab as Opdivo, which was first approved by the Food and Drug Administration in December 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy) treatment and, if BRAF V600 mutation positive, a BRAF inhibitor.
OS was the primary endpoint in the CheckMate 066 trial, which compared treatment with nivolumab (3mg/kg administered intravenously every 2 weeks) to dacarbazine (1,000 mg/m2 administered intravenously every 3 weeks) administered in 418 treatment-naive patients with BRAF wild-type unresectable or metastatic melanoma. In an interim analysis, the median OS for those on dacarbazine was 10.8 months, but was not reached for those on nivolumab (hazard ratio, 0.42; P less than .0001), according to BMS.
The study was stopped early in 2014, after the OS results were noted, the company statement said. At the time the study was designed, ipilimumab had not yet been approved, and dacarbazine was chosen as the comparator because “it represented the standard of care in many regions outside of the U.S.,” the statement added.
Other results included a significantly greater median PFS among those on nivolumab vs. dacarbazine (5.1 months vs. 2.2 months).
In the study, 36% of nivolumab-treated patients had serious adverse reactions; and 41% had grade 3 and 4 adverse reactions, the most common included an increase in gamma-glutamyl transferase in almost 4%, and diarrhea in 3.4%. In addition, 7% stopped treatment permanently because of adverse events, and treatment had to be interrupted in 26%.
The most common adverse reactions reported by those on nivolumab included fatigue, in 49% (vs. 39% of those on dacarbazine) and musculoskeletal pain in 32% (vs. 25%). Rash and pruritus were reported by 28% and 23%, respectively, among those on nivolumab vs. 12% for both rash and pruritus among those on dacarbazine, BMS said.
Nivolumab, a programmed death receptor–1 (PD-1) blocking antibody, has been approved as a single agent for the first-line treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma, the manufacturer has announced.
The approval is based on the results of a phase III study, CheckMate 066, which found a significant overall survival (OS) benefit for nivolumab, compared with chemotherapy, as a first-line treatment of patients with BRAF wild-type advanced melanoma, according to a press release issued by Bristol Myers Squibb (BMS) on Nov. 24.
The company markets nivolumab as Opdivo, which was first approved by the Food and Drug Administration in December 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy) treatment and, if BRAF V600 mutation positive, a BRAF inhibitor.
OS was the primary endpoint in the CheckMate 066 trial, which compared treatment with nivolumab (3mg/kg administered intravenously every 2 weeks) to dacarbazine (1,000 mg/m2 administered intravenously every 3 weeks) administered in 418 treatment-naive patients with BRAF wild-type unresectable or metastatic melanoma. In an interim analysis, the median OS for those on dacarbazine was 10.8 months, but was not reached for those on nivolumab (hazard ratio, 0.42; P less than .0001), according to BMS.
The study was stopped early in 2014, after the OS results were noted, the company statement said. At the time the study was designed, ipilimumab had not yet been approved, and dacarbazine was chosen as the comparator because “it represented the standard of care in many regions outside of the U.S.,” the statement added.
Other results included a significantly greater median PFS among those on nivolumab vs. dacarbazine (5.1 months vs. 2.2 months).
In the study, 36% of nivolumab-treated patients had serious adverse reactions; and 41% had grade 3 and 4 adverse reactions, the most common included an increase in gamma-glutamyl transferase in almost 4%, and diarrhea in 3.4%. In addition, 7% stopped treatment permanently because of adverse events, and treatment had to be interrupted in 26%.
The most common adverse reactions reported by those on nivolumab included fatigue, in 49% (vs. 39% of those on dacarbazine) and musculoskeletal pain in 32% (vs. 25%). Rash and pruritus were reported by 28% and 23%, respectively, among those on nivolumab vs. 12% for both rash and pruritus among those on dacarbazine, BMS said.
Nivolumab, a programmed death receptor–1 (PD-1) blocking antibody, has been approved as a single agent for the first-line treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma, the manufacturer has announced.
The approval is based on the results of a phase III study, CheckMate 066, which found a significant overall survival (OS) benefit for nivolumab, compared with chemotherapy, as a first-line treatment of patients with BRAF wild-type advanced melanoma, according to a press release issued by Bristol Myers Squibb (BMS) on Nov. 24.
The company markets nivolumab as Opdivo, which was first approved by the Food and Drug Administration in December 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy) treatment and, if BRAF V600 mutation positive, a BRAF inhibitor.
OS was the primary endpoint in the CheckMate 066 trial, which compared treatment with nivolumab (3mg/kg administered intravenously every 2 weeks) to dacarbazine (1,000 mg/m2 administered intravenously every 3 weeks) administered in 418 treatment-naive patients with BRAF wild-type unresectable or metastatic melanoma. In an interim analysis, the median OS for those on dacarbazine was 10.8 months, but was not reached for those on nivolumab (hazard ratio, 0.42; P less than .0001), according to BMS.
The study was stopped early in 2014, after the OS results were noted, the company statement said. At the time the study was designed, ipilimumab had not yet been approved, and dacarbazine was chosen as the comparator because “it represented the standard of care in many regions outside of the U.S.,” the statement added.
Other results included a significantly greater median PFS among those on nivolumab vs. dacarbazine (5.1 months vs. 2.2 months).
In the study, 36% of nivolumab-treated patients had serious adverse reactions; and 41% had grade 3 and 4 adverse reactions, the most common included an increase in gamma-glutamyl transferase in almost 4%, and diarrhea in 3.4%. In addition, 7% stopped treatment permanently because of adverse events, and treatment had to be interrupted in 26%.
The most common adverse reactions reported by those on nivolumab included fatigue, in 49% (vs. 39% of those on dacarbazine) and musculoskeletal pain in 32% (vs. 25%). Rash and pruritus were reported by 28% and 23%, respectively, among those on nivolumab vs. 12% for both rash and pruritus among those on dacarbazine, BMS said.
Dermatologists’ management of melanoma varies
CHICAGO – Significant variance exists in management of primary cutaneous melanoma, according to a national survey of 510 dermatologists.
Most dermatologists (36%) preferred a shave biopsy for lesions suspected of being melanoma, despite guidelines from the American Academy of Dermatology (AAD) and National Comprehensive Cancer Network (NCCN) guidelines that recommend narrow excision biopsy.
In all, 31% of dermatologists used a narrow local excision (less than 5 mm margin), 13% saucerization/scoop shave biopsy, 11%, punch biopsy, 3% wide local excision, and 7% other.
“The guidelines and academy are all very clear that one of the goals of the biopsy is to obtain tumor depth, so we were surprised that a significant number of providers use shave biopsy or other methods that may leave a risk of not getting the correct depth,” study co-author Dr. Aaron S. Farberg, a melanoma clinical research fellow at the National Society for Cutaneous Medicine in New York City, said in an interview.
Notably, dermatologists in academic and dermatology-based group practices were significantly less likely than those in multispecialty or solo practice to use narrow excision (23% vs. 42%; P < .001).
Although treatment for melanoma evolves continuously, the authors observed that dermatologists remain at the forefront of melanoma management and play a critical role in patient decision making.
“This study suggests that a knowledge gap may exist representing an educational opportunity to more effectively disseminate and implement recommended approaches,” Dr. Farberg and Dr. Darrell Rigel, of New York University School of Medicine, reported in a poster presentation at the annual meeting of the American Society for Dermatologic Surgery.
The survey also revealed that dermatologists are going beyond suggested surgical margins when excising melanoma.
For malignant melanoma in situ (MMIS), 62% used a 5 mm or less margin, 36% a 6 mm to 10 mm margin, and 2% a 1.1 cm to 1.9 cm margin. For these lesions, the AAD recommends a 0.5 cm-1 cm (5 mm-10 mm) margin and the NCCN a 0.5 cm margin, Drs. Farber and Rigel reported.
Academic dermatologists were significantly more likely than all other practice types to refer patients with MMIS out for excision (18% vs. 10%; P < .05).
For invasive melanoma less than 1 mm in depth, both the AAD and NCCN recommend a 1 cm margin (10 mm). In all, 61% of dermatologists reported using 6 mm to 10 mm margins, with 34% opting for 1.1 cm to 1.9 cm margins, 3% at least 2 cm margins, and 2% no more than 5 mm margins.
No significant difference was found across provider types for treatment of melanomas less than 1 mm in depth.
For invasive melanoma greater than 1 mm in depth, 54% of respondents used 1.1 cm to 1.9 cm margins, with most (67%) referring the patient to another provider. Both national guidelines recommend 1 cm to 2 cm margins for melanomas 1 mm to 2 mm in depth and 2 cm margins for melanoma greater than 2 mm in depth.
Academic dermatologists were significantly more likely than other dermatologists to treat these lesions rather than to refer the patient out (51% vs. 30%; P < .001).
“This is exciting new data that suggests that there still is a variance in early melanoma management,” Dr. Rigel, past president of AAD and ASDS, said in an interview. “The data suggest more studies need to be done to better access why this is occurring.”
Dr. Hensin Tsao, who served on the 2011 AAD guideline working group and is co-chairing the AAD’s pending guideline update, said in an interview that, “Dr. Rigel is well respected in the field and the project will undoubtedly be submitted for publication and subject to further review. It is worthwhile to wait on the final published results and conclusions.”
He agreed, however, with the authors’ suggestion that there is significant variation in practice. Regarding the finding that 36% of respondents use a shave biopsy for suspicious lesions, the AAD guidelines recommend that the entire lesion be removed with a 1 mm to 3 mm margin, which can be accomplished by an elliptical or punch excision with sutures or shave removal to a depth below the anticipated plane of the lesion, Dr. Tsao, of Massachusetts General Hospital in Boston, said.
“It is quite possible that some of the respondents to the questionnaire interpreted ‘shave biopsy’ as a full shave disk excision,” he said. “That said, intentional and routine partial sampling of suspected melanomas would be at odds with the guidelines.”
It is not inappropriate to remove a suspicious lesion, if small enough, with a punch biopsy, Dr. Tsao said, adding, “Perhaps again, the respondents failed to distinguish between partial punch biopsy and punch excision.”
On occasion, the AAD guidelines also make accommodations for an incisional biopsy “of the clinically or dermatoscopically most atypical portion of the lesion.” In this situation, a smaller incisional punch biopsy may be performed of the highly suspicious area.
“There are certainly areas that the investigators have identified which could represent potential knowledge gaps,” Dr. Tsao said. “For instance, 14% of the respondents used a 0.6 cm to 1.0 cm (6 mm-10 mm) margin for melanoma greater than 1 mm.”
Dermatologists’ surveillance of patients in the survey was somewhat less divergent. The most recommended follow-up interval for patients diagnosed within the last 5 years, was 6 months (49%), followed by a 3-month interval (25%), and other (24%). Follow-up was extended to yearly by 63% of dermatologists for patients diagnosed more than five years earlier, Dr. Farberg and Dr. Rigel reported.
Both the AAD and NCCN recommend follow-up every 3 to 12 months for those diagnosed with melanoma within the previous 5 years, while for those diagnosed more than 5 years prior, the AAD recommends follow-up every 3 to 12 months and the NCCN every 12 months.
“Adherence to evidence-based guidelines should lead to improved patient outcomes and quality of care. However, newer studies and emerging data may also justify deviations from existing guidelines, suggesting review of those guidelines may be indicated,” Dr. Farberg and Dr. Rigel concluded.
For example, a prospective series examining surgical margins in 1,072 patients with 1,120 malignant melanoma in situs showed that only 86% were successfully excised with a 6-mm margin, significantly less than the 98.9% clearance achieved with a 9-mm margin, Dr. Farberg told this publication.
That said, a 9-mm margin may not be appropriate for all lesions, such as those on the face, he observed.
The investigators said they hope the survey results will spur on revision of the guidelines, last updated in 2011.
Limitations of the survey include a lack of information on clinical factors such as patient history or anatomic site, the survey may have led to generalized answers, and access to care and reimbursement also may have impacted management, the authors noted.
The response rate to the survey was also low at 8%, with 6,177 practicing U.S. dermatologists surveyed. The demographics of the respondents, however, strongly reflected the full AAD membership, Dr. Farberg said. No significant geographical differences were observed.
CHICAGO – Significant variance exists in management of primary cutaneous melanoma, according to a national survey of 510 dermatologists.
Most dermatologists (36%) preferred a shave biopsy for lesions suspected of being melanoma, despite guidelines from the American Academy of Dermatology (AAD) and National Comprehensive Cancer Network (NCCN) guidelines that recommend narrow excision biopsy.
In all, 31% of dermatologists used a narrow local excision (less than 5 mm margin), 13% saucerization/scoop shave biopsy, 11%, punch biopsy, 3% wide local excision, and 7% other.
“The guidelines and academy are all very clear that one of the goals of the biopsy is to obtain tumor depth, so we were surprised that a significant number of providers use shave biopsy or other methods that may leave a risk of not getting the correct depth,” study co-author Dr. Aaron S. Farberg, a melanoma clinical research fellow at the National Society for Cutaneous Medicine in New York City, said in an interview.
Notably, dermatologists in academic and dermatology-based group practices were significantly less likely than those in multispecialty or solo practice to use narrow excision (23% vs. 42%; P < .001).
Although treatment for melanoma evolves continuously, the authors observed that dermatologists remain at the forefront of melanoma management and play a critical role in patient decision making.
“This study suggests that a knowledge gap may exist representing an educational opportunity to more effectively disseminate and implement recommended approaches,” Dr. Farberg and Dr. Darrell Rigel, of New York University School of Medicine, reported in a poster presentation at the annual meeting of the American Society for Dermatologic Surgery.
The survey also revealed that dermatologists are going beyond suggested surgical margins when excising melanoma.
For malignant melanoma in situ (MMIS), 62% used a 5 mm or less margin, 36% a 6 mm to 10 mm margin, and 2% a 1.1 cm to 1.9 cm margin. For these lesions, the AAD recommends a 0.5 cm-1 cm (5 mm-10 mm) margin and the NCCN a 0.5 cm margin, Drs. Farber and Rigel reported.
Academic dermatologists were significantly more likely than all other practice types to refer patients with MMIS out for excision (18% vs. 10%; P < .05).
For invasive melanoma less than 1 mm in depth, both the AAD and NCCN recommend a 1 cm margin (10 mm). In all, 61% of dermatologists reported using 6 mm to 10 mm margins, with 34% opting for 1.1 cm to 1.9 cm margins, 3% at least 2 cm margins, and 2% no more than 5 mm margins.
No significant difference was found across provider types for treatment of melanomas less than 1 mm in depth.
For invasive melanoma greater than 1 mm in depth, 54% of respondents used 1.1 cm to 1.9 cm margins, with most (67%) referring the patient to another provider. Both national guidelines recommend 1 cm to 2 cm margins for melanomas 1 mm to 2 mm in depth and 2 cm margins for melanoma greater than 2 mm in depth.
Academic dermatologists were significantly more likely than other dermatologists to treat these lesions rather than to refer the patient out (51% vs. 30%; P < .001).
“This is exciting new data that suggests that there still is a variance in early melanoma management,” Dr. Rigel, past president of AAD and ASDS, said in an interview. “The data suggest more studies need to be done to better access why this is occurring.”
Dr. Hensin Tsao, who served on the 2011 AAD guideline working group and is co-chairing the AAD’s pending guideline update, said in an interview that, “Dr. Rigel is well respected in the field and the project will undoubtedly be submitted for publication and subject to further review. It is worthwhile to wait on the final published results and conclusions.”
He agreed, however, with the authors’ suggestion that there is significant variation in practice. Regarding the finding that 36% of respondents use a shave biopsy for suspicious lesions, the AAD guidelines recommend that the entire lesion be removed with a 1 mm to 3 mm margin, which can be accomplished by an elliptical or punch excision with sutures or shave removal to a depth below the anticipated plane of the lesion, Dr. Tsao, of Massachusetts General Hospital in Boston, said.
“It is quite possible that some of the respondents to the questionnaire interpreted ‘shave biopsy’ as a full shave disk excision,” he said. “That said, intentional and routine partial sampling of suspected melanomas would be at odds with the guidelines.”
It is not inappropriate to remove a suspicious lesion, if small enough, with a punch biopsy, Dr. Tsao said, adding, “Perhaps again, the respondents failed to distinguish between partial punch biopsy and punch excision.”
On occasion, the AAD guidelines also make accommodations for an incisional biopsy “of the clinically or dermatoscopically most atypical portion of the lesion.” In this situation, a smaller incisional punch biopsy may be performed of the highly suspicious area.
“There are certainly areas that the investigators have identified which could represent potential knowledge gaps,” Dr. Tsao said. “For instance, 14% of the respondents used a 0.6 cm to 1.0 cm (6 mm-10 mm) margin for melanoma greater than 1 mm.”
Dermatologists’ surveillance of patients in the survey was somewhat less divergent. The most recommended follow-up interval for patients diagnosed within the last 5 years, was 6 months (49%), followed by a 3-month interval (25%), and other (24%). Follow-up was extended to yearly by 63% of dermatologists for patients diagnosed more than five years earlier, Dr. Farberg and Dr. Rigel reported.
Both the AAD and NCCN recommend follow-up every 3 to 12 months for those diagnosed with melanoma within the previous 5 years, while for those diagnosed more than 5 years prior, the AAD recommends follow-up every 3 to 12 months and the NCCN every 12 months.
“Adherence to evidence-based guidelines should lead to improved patient outcomes and quality of care. However, newer studies and emerging data may also justify deviations from existing guidelines, suggesting review of those guidelines may be indicated,” Dr. Farberg and Dr. Rigel concluded.
For example, a prospective series examining surgical margins in 1,072 patients with 1,120 malignant melanoma in situs showed that only 86% were successfully excised with a 6-mm margin, significantly less than the 98.9% clearance achieved with a 9-mm margin, Dr. Farberg told this publication.
That said, a 9-mm margin may not be appropriate for all lesions, such as those on the face, he observed.
The investigators said they hope the survey results will spur on revision of the guidelines, last updated in 2011.
Limitations of the survey include a lack of information on clinical factors such as patient history or anatomic site, the survey may have led to generalized answers, and access to care and reimbursement also may have impacted management, the authors noted.
The response rate to the survey was also low at 8%, with 6,177 practicing U.S. dermatologists surveyed. The demographics of the respondents, however, strongly reflected the full AAD membership, Dr. Farberg said. No significant geographical differences were observed.
CHICAGO – Significant variance exists in management of primary cutaneous melanoma, according to a national survey of 510 dermatologists.
Most dermatologists (36%) preferred a shave biopsy for lesions suspected of being melanoma, despite guidelines from the American Academy of Dermatology (AAD) and National Comprehensive Cancer Network (NCCN) guidelines that recommend narrow excision biopsy.
In all, 31% of dermatologists used a narrow local excision (less than 5 mm margin), 13% saucerization/scoop shave biopsy, 11%, punch biopsy, 3% wide local excision, and 7% other.
“The guidelines and academy are all very clear that one of the goals of the biopsy is to obtain tumor depth, so we were surprised that a significant number of providers use shave biopsy or other methods that may leave a risk of not getting the correct depth,” study co-author Dr. Aaron S. Farberg, a melanoma clinical research fellow at the National Society for Cutaneous Medicine in New York City, said in an interview.
Notably, dermatologists in academic and dermatology-based group practices were significantly less likely than those in multispecialty or solo practice to use narrow excision (23% vs. 42%; P < .001).
Although treatment for melanoma evolves continuously, the authors observed that dermatologists remain at the forefront of melanoma management and play a critical role in patient decision making.
“This study suggests that a knowledge gap may exist representing an educational opportunity to more effectively disseminate and implement recommended approaches,” Dr. Farberg and Dr. Darrell Rigel, of New York University School of Medicine, reported in a poster presentation at the annual meeting of the American Society for Dermatologic Surgery.
The survey also revealed that dermatologists are going beyond suggested surgical margins when excising melanoma.
For malignant melanoma in situ (MMIS), 62% used a 5 mm or less margin, 36% a 6 mm to 10 mm margin, and 2% a 1.1 cm to 1.9 cm margin. For these lesions, the AAD recommends a 0.5 cm-1 cm (5 mm-10 mm) margin and the NCCN a 0.5 cm margin, Drs. Farber and Rigel reported.
Academic dermatologists were significantly more likely than all other practice types to refer patients with MMIS out for excision (18% vs. 10%; P < .05).
For invasive melanoma less than 1 mm in depth, both the AAD and NCCN recommend a 1 cm margin (10 mm). In all, 61% of dermatologists reported using 6 mm to 10 mm margins, with 34% opting for 1.1 cm to 1.9 cm margins, 3% at least 2 cm margins, and 2% no more than 5 mm margins.
No significant difference was found across provider types for treatment of melanomas less than 1 mm in depth.
For invasive melanoma greater than 1 mm in depth, 54% of respondents used 1.1 cm to 1.9 cm margins, with most (67%) referring the patient to another provider. Both national guidelines recommend 1 cm to 2 cm margins for melanomas 1 mm to 2 mm in depth and 2 cm margins for melanoma greater than 2 mm in depth.
Academic dermatologists were significantly more likely than other dermatologists to treat these lesions rather than to refer the patient out (51% vs. 30%; P < .001).
“This is exciting new data that suggests that there still is a variance in early melanoma management,” Dr. Rigel, past president of AAD and ASDS, said in an interview. “The data suggest more studies need to be done to better access why this is occurring.”
Dr. Hensin Tsao, who served on the 2011 AAD guideline working group and is co-chairing the AAD’s pending guideline update, said in an interview that, “Dr. Rigel is well respected in the field and the project will undoubtedly be submitted for publication and subject to further review. It is worthwhile to wait on the final published results and conclusions.”
He agreed, however, with the authors’ suggestion that there is significant variation in practice. Regarding the finding that 36% of respondents use a shave biopsy for suspicious lesions, the AAD guidelines recommend that the entire lesion be removed with a 1 mm to 3 mm margin, which can be accomplished by an elliptical or punch excision with sutures or shave removal to a depth below the anticipated plane of the lesion, Dr. Tsao, of Massachusetts General Hospital in Boston, said.
“It is quite possible that some of the respondents to the questionnaire interpreted ‘shave biopsy’ as a full shave disk excision,” he said. “That said, intentional and routine partial sampling of suspected melanomas would be at odds with the guidelines.”
It is not inappropriate to remove a suspicious lesion, if small enough, with a punch biopsy, Dr. Tsao said, adding, “Perhaps again, the respondents failed to distinguish between partial punch biopsy and punch excision.”
On occasion, the AAD guidelines also make accommodations for an incisional biopsy “of the clinically or dermatoscopically most atypical portion of the lesion.” In this situation, a smaller incisional punch biopsy may be performed of the highly suspicious area.
“There are certainly areas that the investigators have identified which could represent potential knowledge gaps,” Dr. Tsao said. “For instance, 14% of the respondents used a 0.6 cm to 1.0 cm (6 mm-10 mm) margin for melanoma greater than 1 mm.”
Dermatologists’ surveillance of patients in the survey was somewhat less divergent. The most recommended follow-up interval for patients diagnosed within the last 5 years, was 6 months (49%), followed by a 3-month interval (25%), and other (24%). Follow-up was extended to yearly by 63% of dermatologists for patients diagnosed more than five years earlier, Dr. Farberg and Dr. Rigel reported.
Both the AAD and NCCN recommend follow-up every 3 to 12 months for those diagnosed with melanoma within the previous 5 years, while for those diagnosed more than 5 years prior, the AAD recommends follow-up every 3 to 12 months and the NCCN every 12 months.
“Adherence to evidence-based guidelines should lead to improved patient outcomes and quality of care. However, newer studies and emerging data may also justify deviations from existing guidelines, suggesting review of those guidelines may be indicated,” Dr. Farberg and Dr. Rigel concluded.
For example, a prospective series examining surgical margins in 1,072 patients with 1,120 malignant melanoma in situs showed that only 86% were successfully excised with a 6-mm margin, significantly less than the 98.9% clearance achieved with a 9-mm margin, Dr. Farberg told this publication.
That said, a 9-mm margin may not be appropriate for all lesions, such as those on the face, he observed.
The investigators said they hope the survey results will spur on revision of the guidelines, last updated in 2011.
Limitations of the survey include a lack of information on clinical factors such as patient history or anatomic site, the survey may have led to generalized answers, and access to care and reimbursement also may have impacted management, the authors noted.
The response rate to the survey was also low at 8%, with 6,177 practicing U.S. dermatologists surveyed. The demographics of the respondents, however, strongly reflected the full AAD membership, Dr. Farberg said. No significant geographical differences were observed.
AT THE ASDS ANNUAL MEETING
Key clinical point: Significant variance exists in dermatologists’ management of melanoma.
Major finding: Only 31% of dermatologists used narrow excision as recommended to biopsy suspicious lesions.
Data source: Survey of 510 U.S. practicing dermatologists.
Disclosures: The authors reported having no financial disclosures.
Immune-related events with checkpoint inhibitors are manageable
BOSTON– Immune-related adverse events associated with checkpoint inhibitor therapy are generally mild to moderate and transient, but some less common side effects can be serious or even fatal, according to an immunotherapy researcher.
“Rapid identification of these side effects and initiation of systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition,” said Dr. Antoine Italiano from the Institut Bergonié in Bordeaux, France.
There is also evidence to suggest that immune-related adverse events (irAEs) associated with the programmed-death 1 (PD-1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) may be predictive of favorable outcomes. In contrast, although there was early clinical evidence to suggest that adverse reactions to immune checkpoint inhibition with cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies such as ipilimumab (Yervoy) correlate with outcomes, more recent evidence suggests that toxicity with this class of agents is not predictive of efficacy, Dr. Italiano said at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.
“Correlation between safety profile and outcome must be confirmed by further studies,” he said, adding that “further studies are also needed to identify patients at high risk of poor tolerability.”
Immune-related adverse events associated with anti-CTLA-4 therapy generally involve organ systems such as the skin, digestive tract, and endocrine system. Rare adverse events reported with these agents include renal injury, sarcoidosis, uveitis, and myelitis, among others.
The events tend to arise around 10 weeks of therapy, following three cycles with either ipilimumab or the investigational agent tremelimumab. Late-occurring events, defined as those that arise more than 70 days after the last infusion, are uncommon, occurring in less than 7% of patients.
Most irAEs seen with anti-CTLA-4 therapy are reversible within about 6 weeks, although some events, such as hypophysitis (autoimmune inflammation of the pituitary gland), can take significantly longer to resolve, Dr. Italiano said.
He cited a recent systematic review and meta-analysis showing that among patients treated with any anti-CTLA-4, the overall incidence of all-grade irAEs was 72%, and the overall incidence of high-grade irAEs was 24%. This study also showed that there was a dose-dependent risk of developing irAEs with ipilimumab, with the incidence of all grades of events at 61% for the 3 mg/kg dose, and 79% for the 10 mg/kg dose.
Two potential biomarkers for gastrointestinal irAEs, the neutrophil-activation markers CD177 and CEACAM1, were identified in a 2013 study. This finding suggests a possible role of neutrophils in ipilimumab-associated GI irAEs, Dr. Italiano noted.
Evidence from early clinical studies of ipilimumab in metastatic melanoma suggested that irAEs correlated with outcomes, but a study published in October 2015 seems to debunk this notion, showing that among 298 patients treated with ipilimumab, neither time to treatment failure nor overall survival were affected by the occurrence of irAEs, he added.
As to whether therapy with anti-CTLA-4 antibodies is safe for treatment of cancer for patients with autoimmune diseases or immunodeficient states, the jury is still out, because these patients were typically excluded from clinical trials.
“But there are a few recent case reports suggesting that treating patients with autoimmune disease with ipilimumab is safe and does not induce exacerbation of the symptoms of the underlying autoimmune disease,” Dr. Italiano said.
PD-1 inhibitors
Adverse events common to the PD-1 inhibitors pembrolizumab and nivolumab and occurring in more than 5% of patients with each include fatigue/asthenia, decreased appetite, diarrhea, rash, pruritus, nausea, and arthralgia.
In clinical trials of the agents for treatment of melanoma, vitiligo was the most common irAE, occurring in 7%-8% of patients. Other events, occurring in similar frequency across the various trials, included hypo- or hyperthyroidism, pneumonitis, colitis, hepatitis, renal failure/nephritis, uveitis/iritis, and hypophysitis.
The time to first occurrence and resolution of irAEs with the PD-1 inhibitors varies by organ system, with skin toxicity occurring within the few weeks of therapy, peaking at about 15 weeks, and resolving by about 25 weeks. Gastrointestinal toxicities crop up at about 10 weeks, but quickly resolve.
Among the less common (less than 10%) irAEs, hepatic and pulmonary events seen to occur around week 8 or 9 and resolve within 2-4 weeks, whereas endocrine events start showing up around week 10, peak at about 25 weeks, and resolve around 40 weeks.
Among patients treated with PD-1 inhibitors for non–small cell lung cancer, the adverse-event profile is similar to that seen in treatment of patients with melanoma, except for the absence of vitiligo, Dr. Italiano noted.
In contrast to the CTLA-4 inhibitors, irAEs seen with the PD-1 inhibitors, especially cutaneous events, appear to be associated with favorable outcomes.
For example, in a prospective, single-center observational study of pembrolizumab in 67 patients with metastatic melanoma, 17 developed vitiligo, and 12 of these patients had an objective response (18% complete and 53% partial responses). The objective response rate in this group was 71%, compared with 28% (14 of 50 patients) for those who did not develop vitiligo.
In a second, retrospective study of 83 patients enrolled in clinical trials of pembrolizumab for melanoma, non–small cell lung cancer, prostate cancer, and Merkel cell carcinoma, patients in each of three pembrolizumab dosing groups who developed cutaneous AEs had significantly longer progression-free intervals than patients who did not develop cutaneous AEs.
A similar correlation between cutaneous events with nivolumab and favorable outcomes was seen in a study of pooled data on 148 patients with resected or unresectable metastatic melanoma. The investigators found that both rash and vitiligo correlated significantly with better overall survival.
BOSTON– Immune-related adverse events associated with checkpoint inhibitor therapy are generally mild to moderate and transient, but some less common side effects can be serious or even fatal, according to an immunotherapy researcher.
“Rapid identification of these side effects and initiation of systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition,” said Dr. Antoine Italiano from the Institut Bergonié in Bordeaux, France.
There is also evidence to suggest that immune-related adverse events (irAEs) associated with the programmed-death 1 (PD-1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) may be predictive of favorable outcomes. In contrast, although there was early clinical evidence to suggest that adverse reactions to immune checkpoint inhibition with cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies such as ipilimumab (Yervoy) correlate with outcomes, more recent evidence suggests that toxicity with this class of agents is not predictive of efficacy, Dr. Italiano said at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.
“Correlation between safety profile and outcome must be confirmed by further studies,” he said, adding that “further studies are also needed to identify patients at high risk of poor tolerability.”
Immune-related adverse events associated with anti-CTLA-4 therapy generally involve organ systems such as the skin, digestive tract, and endocrine system. Rare adverse events reported with these agents include renal injury, sarcoidosis, uveitis, and myelitis, among others.
The events tend to arise around 10 weeks of therapy, following three cycles with either ipilimumab or the investigational agent tremelimumab. Late-occurring events, defined as those that arise more than 70 days after the last infusion, are uncommon, occurring in less than 7% of patients.
Most irAEs seen with anti-CTLA-4 therapy are reversible within about 6 weeks, although some events, such as hypophysitis (autoimmune inflammation of the pituitary gland), can take significantly longer to resolve, Dr. Italiano said.
He cited a recent systematic review and meta-analysis showing that among patients treated with any anti-CTLA-4, the overall incidence of all-grade irAEs was 72%, and the overall incidence of high-grade irAEs was 24%. This study also showed that there was a dose-dependent risk of developing irAEs with ipilimumab, with the incidence of all grades of events at 61% for the 3 mg/kg dose, and 79% for the 10 mg/kg dose.
Two potential biomarkers for gastrointestinal irAEs, the neutrophil-activation markers CD177 and CEACAM1, were identified in a 2013 study. This finding suggests a possible role of neutrophils in ipilimumab-associated GI irAEs, Dr. Italiano noted.
Evidence from early clinical studies of ipilimumab in metastatic melanoma suggested that irAEs correlated with outcomes, but a study published in October 2015 seems to debunk this notion, showing that among 298 patients treated with ipilimumab, neither time to treatment failure nor overall survival were affected by the occurrence of irAEs, he added.
As to whether therapy with anti-CTLA-4 antibodies is safe for treatment of cancer for patients with autoimmune diseases or immunodeficient states, the jury is still out, because these patients were typically excluded from clinical trials.
“But there are a few recent case reports suggesting that treating patients with autoimmune disease with ipilimumab is safe and does not induce exacerbation of the symptoms of the underlying autoimmune disease,” Dr. Italiano said.
PD-1 inhibitors
Adverse events common to the PD-1 inhibitors pembrolizumab and nivolumab and occurring in more than 5% of patients with each include fatigue/asthenia, decreased appetite, diarrhea, rash, pruritus, nausea, and arthralgia.
In clinical trials of the agents for treatment of melanoma, vitiligo was the most common irAE, occurring in 7%-8% of patients. Other events, occurring in similar frequency across the various trials, included hypo- or hyperthyroidism, pneumonitis, colitis, hepatitis, renal failure/nephritis, uveitis/iritis, and hypophysitis.
The time to first occurrence and resolution of irAEs with the PD-1 inhibitors varies by organ system, with skin toxicity occurring within the few weeks of therapy, peaking at about 15 weeks, and resolving by about 25 weeks. Gastrointestinal toxicities crop up at about 10 weeks, but quickly resolve.
Among the less common (less than 10%) irAEs, hepatic and pulmonary events seen to occur around week 8 or 9 and resolve within 2-4 weeks, whereas endocrine events start showing up around week 10, peak at about 25 weeks, and resolve around 40 weeks.
Among patients treated with PD-1 inhibitors for non–small cell lung cancer, the adverse-event profile is similar to that seen in treatment of patients with melanoma, except for the absence of vitiligo, Dr. Italiano noted.
In contrast to the CTLA-4 inhibitors, irAEs seen with the PD-1 inhibitors, especially cutaneous events, appear to be associated with favorable outcomes.
For example, in a prospective, single-center observational study of pembrolizumab in 67 patients with metastatic melanoma, 17 developed vitiligo, and 12 of these patients had an objective response (18% complete and 53% partial responses). The objective response rate in this group was 71%, compared with 28% (14 of 50 patients) for those who did not develop vitiligo.
In a second, retrospective study of 83 patients enrolled in clinical trials of pembrolizumab for melanoma, non–small cell lung cancer, prostate cancer, and Merkel cell carcinoma, patients in each of three pembrolizumab dosing groups who developed cutaneous AEs had significantly longer progression-free intervals than patients who did not develop cutaneous AEs.
A similar correlation between cutaneous events with nivolumab and favorable outcomes was seen in a study of pooled data on 148 patients with resected or unresectable metastatic melanoma. The investigators found that both rash and vitiligo correlated significantly with better overall survival.
BOSTON– Immune-related adverse events associated with checkpoint inhibitor therapy are generally mild to moderate and transient, but some less common side effects can be serious or even fatal, according to an immunotherapy researcher.
“Rapid identification of these side effects and initiation of systemic immunosuppression can improve outcomes without compromising the efficacy of immune-checkpoint inhibition,” said Dr. Antoine Italiano from the Institut Bergonié in Bordeaux, France.
There is also evidence to suggest that immune-related adverse events (irAEs) associated with the programmed-death 1 (PD-1) inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) may be predictive of favorable outcomes. In contrast, although there was early clinical evidence to suggest that adverse reactions to immune checkpoint inhibition with cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies such as ipilimumab (Yervoy) correlate with outcomes, more recent evidence suggests that toxicity with this class of agents is not predictive of efficacy, Dr. Italiano said at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.
“Correlation between safety profile and outcome must be confirmed by further studies,” he said, adding that “further studies are also needed to identify patients at high risk of poor tolerability.”
Immune-related adverse events associated with anti-CTLA-4 therapy generally involve organ systems such as the skin, digestive tract, and endocrine system. Rare adverse events reported with these agents include renal injury, sarcoidosis, uveitis, and myelitis, among others.
The events tend to arise around 10 weeks of therapy, following three cycles with either ipilimumab or the investigational agent tremelimumab. Late-occurring events, defined as those that arise more than 70 days after the last infusion, are uncommon, occurring in less than 7% of patients.
Most irAEs seen with anti-CTLA-4 therapy are reversible within about 6 weeks, although some events, such as hypophysitis (autoimmune inflammation of the pituitary gland), can take significantly longer to resolve, Dr. Italiano said.
He cited a recent systematic review and meta-analysis showing that among patients treated with any anti-CTLA-4, the overall incidence of all-grade irAEs was 72%, and the overall incidence of high-grade irAEs was 24%. This study also showed that there was a dose-dependent risk of developing irAEs with ipilimumab, with the incidence of all grades of events at 61% for the 3 mg/kg dose, and 79% for the 10 mg/kg dose.
Two potential biomarkers for gastrointestinal irAEs, the neutrophil-activation markers CD177 and CEACAM1, were identified in a 2013 study. This finding suggests a possible role of neutrophils in ipilimumab-associated GI irAEs, Dr. Italiano noted.
Evidence from early clinical studies of ipilimumab in metastatic melanoma suggested that irAEs correlated with outcomes, but a study published in October 2015 seems to debunk this notion, showing that among 298 patients treated with ipilimumab, neither time to treatment failure nor overall survival were affected by the occurrence of irAEs, he added.
As to whether therapy with anti-CTLA-4 antibodies is safe for treatment of cancer for patients with autoimmune diseases or immunodeficient states, the jury is still out, because these patients were typically excluded from clinical trials.
“But there are a few recent case reports suggesting that treating patients with autoimmune disease with ipilimumab is safe and does not induce exacerbation of the symptoms of the underlying autoimmune disease,” Dr. Italiano said.
PD-1 inhibitors
Adverse events common to the PD-1 inhibitors pembrolizumab and nivolumab and occurring in more than 5% of patients with each include fatigue/asthenia, decreased appetite, diarrhea, rash, pruritus, nausea, and arthralgia.
In clinical trials of the agents for treatment of melanoma, vitiligo was the most common irAE, occurring in 7%-8% of patients. Other events, occurring in similar frequency across the various trials, included hypo- or hyperthyroidism, pneumonitis, colitis, hepatitis, renal failure/nephritis, uveitis/iritis, and hypophysitis.
The time to first occurrence and resolution of irAEs with the PD-1 inhibitors varies by organ system, with skin toxicity occurring within the few weeks of therapy, peaking at about 15 weeks, and resolving by about 25 weeks. Gastrointestinal toxicities crop up at about 10 weeks, but quickly resolve.
Among the less common (less than 10%) irAEs, hepatic and pulmonary events seen to occur around week 8 or 9 and resolve within 2-4 weeks, whereas endocrine events start showing up around week 10, peak at about 25 weeks, and resolve around 40 weeks.
Among patients treated with PD-1 inhibitors for non–small cell lung cancer, the adverse-event profile is similar to that seen in treatment of patients with melanoma, except for the absence of vitiligo, Dr. Italiano noted.
In contrast to the CTLA-4 inhibitors, irAEs seen with the PD-1 inhibitors, especially cutaneous events, appear to be associated with favorable outcomes.
For example, in a prospective, single-center observational study of pembrolizumab in 67 patients with metastatic melanoma, 17 developed vitiligo, and 12 of these patients had an objective response (18% complete and 53% partial responses). The objective response rate in this group was 71%, compared with 28% (14 of 50 patients) for those who did not develop vitiligo.
In a second, retrospective study of 83 patients enrolled in clinical trials of pembrolizumab for melanoma, non–small cell lung cancer, prostate cancer, and Merkel cell carcinoma, patients in each of three pembrolizumab dosing groups who developed cutaneous AEs had significantly longer progression-free intervals than patients who did not develop cutaneous AEs.
A similar correlation between cutaneous events with nivolumab and favorable outcomes was seen in a study of pooled data on 148 patients with resected or unresectable metastatic melanoma. The investigators found that both rash and vitiligo correlated significantly with better overall survival.
AT AACR–NCI–EORTC
Key clinical point: Inhibitors of CTLA-4 and PD-1/PD-L1 are associated with manageable immune-related adverse events.
Major finding: Cutaneous adverse events with PD-1 inhibitor therapy appear to be predictive of favorable outcomes.
Data source: Review of current knowledge of the immune-related adverse events associated with checkpoint inhibitors.
Disclosures: Dr. Italiano reported no conflicts of interest.