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Overall survival plateaus at 3 years for ipilimumab-treated melanoma patients
Among patients with advanced melanoma who were treated with ipilimumab, about 20%-26% survived to 3 years, and these patients are likely to have a good long-term outcome, according to a pooled analysis of survival data published online Feb. 9 in the Journal of Clinical Oncology.
Investigators pooled data from ten prospective (including two phase III trials) and two retrospective studies with a total of 1,257 previously treated and 604 treatment-naive patients. At least 3 years after receiving ipilimumab, 254 patients were still alive, with a median follow up for this subset of 69 months. Around year 3, the Kaplan-Meier overall survival (OS) curve began to plateau and extended to 9.9 years for the longest survival follow-up.
“These results suggest that the majority of patients who reached this milestone time point had a low risk of death thereafter,” wrote Dr. Dirk Schadendorf and his associates (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]).
Compared with patients who were previously treated, treatment-naive patients had a higher median overall survival (13.5 months [95% confidence interval, 11.9-15.4] vs. 10.7 months [9.6-11.4]) and higher 3-year-survival rates (26% [21%-30%] vs. 20% [18%-23%]). No definitive conclusion could be drawn from this observation, however, since nonrandomized subsets were used for this analysis. Subset analysis by dose showed similar median OS and 3-year survival rates for ipilimumab 3 mg/kg, 10 mg/kg, and other dosing regimens.
The researchers expanded the study to include overall survival (OS) data from 2,985 patients enrolled in a U.S. multicenter, open-label, expanded-access treatment protocol (EAP). This group included patients with poorer prognostic factors, some of whom were ineligible for clinical trials. The expanded group showed a lower median OS of 9.5 months and 3 year–survival rate of 21%, with the familiar OS curve plateau around 3 years that extended up to 10 years in some patients.
While this analysis only examined overall survival rates, individual ipilimumab studies that tracked patient responses to the drug have shown that some proportion of long-term survivors did not achieve a response. Identifying the specific disease characteristics of the long-term survivors will require further study.
“Considering the historic median OS of approximately 8-10 months and a 5-year survival rate of approximately 10% in advanced melanoma, the results presented herein are encouraging for patients diagnosed with this aggressive disease,” the authors wrote.
Dr. Schadendorf and his associates demonstrate a plateau in the survival curve of ipilimumab-treated patients beginning at about 3 years and representing about 21% of the treatment group. The curve suggests that those who survive to 3 years are highly likely to have a good long-term outcome, which provides a strong motivating factor in the decision to consider ipilimumab treatment. While pooled data adds information far beyond individual trials, a major drawback lies in the loss of control data necessary to isolate the added benefit of the study drug.
An indirect comparison using historic control series, in this case a large cohort documented in the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, can substitute for missing control data in the pooled analysis. Reviewing data for stage IIIc and IV patients, the overall survival Kaplan-Meier curves in this population also show a plateau, but much later than that reported for ipilimumab, at beyond 8 years.
The AJCC melanoma classification gives survival rates at 3, 5, and 10 years of 19%, 13%, and 9%, respectively. Comparison with ipilimumab data suggests that survival at 3 years is similar, but thereafter improves with ipilimumab by 10% over other treatments that were available at the time. This difference is similar to the percentage of patients who achieved objective responses with ipilimumab. Although assessing response rate and progression-free survival in patients treated with ipilimumab presents challenges, the long-term benefits of ipilimumab could be better ascertained if information on the number of patients in the 21% plateau who were disease free or stably maintaining response had been collected.
Evaluation of long-term benefits of ipilimumab should consider toxicities and costs, as it is one of the most costly systemic therapies used for cancer treatment. The phase III trial using the drug at 3 mg/kg demonstrated that the large majority of patients had no serious adverse effects. If older patients and those with advanced disease are candidates, then the 10%-15% of grade 3 or 4 adverse events may translate to hospitalization and added expense, putting health regulatory systems in the position to deny widespread use of the agent despite proven benefit.
As the first agent to benefit overall survival of patients with advanced melanoma, ipilimumab may pave the way to broader improvements in a larger proportion of patients by combining with targeted therapies, such as BRAF and MEK inhibitors, and other new immunotherapies, such as anti-PD-1 antibodies.
Dr. Antoni Ribas is an oncologist with the Jonsson Comprehensive Cancer Center, Los Angles, and Dr. Keith T. Flaherty is an oncologist with Massachusetts General Hospital Cancer Center, Boston. These remarks were part of an editorial accompanying the report (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]). Dr. Ribas has an advisory role with Merck, Amgen, Novartis, GlaxoSmithKline, and Genentech/Roche. Dr. Flaherty has an advisory role with GlaxoSmithKline, Genentech/Roche, Novartis, and Merck.
Dr. Schadendorf and his associates demonstrate a plateau in the survival curve of ipilimumab-treated patients beginning at about 3 years and representing about 21% of the treatment group. The curve suggests that those who survive to 3 years are highly likely to have a good long-term outcome, which provides a strong motivating factor in the decision to consider ipilimumab treatment. While pooled data adds information far beyond individual trials, a major drawback lies in the loss of control data necessary to isolate the added benefit of the study drug.
An indirect comparison using historic control series, in this case a large cohort documented in the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, can substitute for missing control data in the pooled analysis. Reviewing data for stage IIIc and IV patients, the overall survival Kaplan-Meier curves in this population also show a plateau, but much later than that reported for ipilimumab, at beyond 8 years.
The AJCC melanoma classification gives survival rates at 3, 5, and 10 years of 19%, 13%, and 9%, respectively. Comparison with ipilimumab data suggests that survival at 3 years is similar, but thereafter improves with ipilimumab by 10% over other treatments that were available at the time. This difference is similar to the percentage of patients who achieved objective responses with ipilimumab. Although assessing response rate and progression-free survival in patients treated with ipilimumab presents challenges, the long-term benefits of ipilimumab could be better ascertained if information on the number of patients in the 21% plateau who were disease free or stably maintaining response had been collected.
Evaluation of long-term benefits of ipilimumab should consider toxicities and costs, as it is one of the most costly systemic therapies used for cancer treatment. The phase III trial using the drug at 3 mg/kg demonstrated that the large majority of patients had no serious adverse effects. If older patients and those with advanced disease are candidates, then the 10%-15% of grade 3 or 4 adverse events may translate to hospitalization and added expense, putting health regulatory systems in the position to deny widespread use of the agent despite proven benefit.
As the first agent to benefit overall survival of patients with advanced melanoma, ipilimumab may pave the way to broader improvements in a larger proportion of patients by combining with targeted therapies, such as BRAF and MEK inhibitors, and other new immunotherapies, such as anti-PD-1 antibodies.
Dr. Antoni Ribas is an oncologist with the Jonsson Comprehensive Cancer Center, Los Angles, and Dr. Keith T. Flaherty is an oncologist with Massachusetts General Hospital Cancer Center, Boston. These remarks were part of an editorial accompanying the report (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]). Dr. Ribas has an advisory role with Merck, Amgen, Novartis, GlaxoSmithKline, and Genentech/Roche. Dr. Flaherty has an advisory role with GlaxoSmithKline, Genentech/Roche, Novartis, and Merck.
Dr. Schadendorf and his associates demonstrate a plateau in the survival curve of ipilimumab-treated patients beginning at about 3 years and representing about 21% of the treatment group. The curve suggests that those who survive to 3 years are highly likely to have a good long-term outcome, which provides a strong motivating factor in the decision to consider ipilimumab treatment. While pooled data adds information far beyond individual trials, a major drawback lies in the loss of control data necessary to isolate the added benefit of the study drug.
An indirect comparison using historic control series, in this case a large cohort documented in the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, can substitute for missing control data in the pooled analysis. Reviewing data for stage IIIc and IV patients, the overall survival Kaplan-Meier curves in this population also show a plateau, but much later than that reported for ipilimumab, at beyond 8 years.
The AJCC melanoma classification gives survival rates at 3, 5, and 10 years of 19%, 13%, and 9%, respectively. Comparison with ipilimumab data suggests that survival at 3 years is similar, but thereafter improves with ipilimumab by 10% over other treatments that were available at the time. This difference is similar to the percentage of patients who achieved objective responses with ipilimumab. Although assessing response rate and progression-free survival in patients treated with ipilimumab presents challenges, the long-term benefits of ipilimumab could be better ascertained if information on the number of patients in the 21% plateau who were disease free or stably maintaining response had been collected.
Evaluation of long-term benefits of ipilimumab should consider toxicities and costs, as it is one of the most costly systemic therapies used for cancer treatment. The phase III trial using the drug at 3 mg/kg demonstrated that the large majority of patients had no serious adverse effects. If older patients and those with advanced disease are candidates, then the 10%-15% of grade 3 or 4 adverse events may translate to hospitalization and added expense, putting health regulatory systems in the position to deny widespread use of the agent despite proven benefit.
As the first agent to benefit overall survival of patients with advanced melanoma, ipilimumab may pave the way to broader improvements in a larger proportion of patients by combining with targeted therapies, such as BRAF and MEK inhibitors, and other new immunotherapies, such as anti-PD-1 antibodies.
Dr. Antoni Ribas is an oncologist with the Jonsson Comprehensive Cancer Center, Los Angles, and Dr. Keith T. Flaherty is an oncologist with Massachusetts General Hospital Cancer Center, Boston. These remarks were part of an editorial accompanying the report (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]). Dr. Ribas has an advisory role with Merck, Amgen, Novartis, GlaxoSmithKline, and Genentech/Roche. Dr. Flaherty has an advisory role with GlaxoSmithKline, Genentech/Roche, Novartis, and Merck.
Among patients with advanced melanoma who were treated with ipilimumab, about 20%-26% survived to 3 years, and these patients are likely to have a good long-term outcome, according to a pooled analysis of survival data published online Feb. 9 in the Journal of Clinical Oncology.
Investigators pooled data from ten prospective (including two phase III trials) and two retrospective studies with a total of 1,257 previously treated and 604 treatment-naive patients. At least 3 years after receiving ipilimumab, 254 patients were still alive, with a median follow up for this subset of 69 months. Around year 3, the Kaplan-Meier overall survival (OS) curve began to plateau and extended to 9.9 years for the longest survival follow-up.
“These results suggest that the majority of patients who reached this milestone time point had a low risk of death thereafter,” wrote Dr. Dirk Schadendorf and his associates (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]).
Compared with patients who were previously treated, treatment-naive patients had a higher median overall survival (13.5 months [95% confidence interval, 11.9-15.4] vs. 10.7 months [9.6-11.4]) and higher 3-year-survival rates (26% [21%-30%] vs. 20% [18%-23%]). No definitive conclusion could be drawn from this observation, however, since nonrandomized subsets were used for this analysis. Subset analysis by dose showed similar median OS and 3-year survival rates for ipilimumab 3 mg/kg, 10 mg/kg, and other dosing regimens.
The researchers expanded the study to include overall survival (OS) data from 2,985 patients enrolled in a U.S. multicenter, open-label, expanded-access treatment protocol (EAP). This group included patients with poorer prognostic factors, some of whom were ineligible for clinical trials. The expanded group showed a lower median OS of 9.5 months and 3 year–survival rate of 21%, with the familiar OS curve plateau around 3 years that extended up to 10 years in some patients.
While this analysis only examined overall survival rates, individual ipilimumab studies that tracked patient responses to the drug have shown that some proportion of long-term survivors did not achieve a response. Identifying the specific disease characteristics of the long-term survivors will require further study.
“Considering the historic median OS of approximately 8-10 months and a 5-year survival rate of approximately 10% in advanced melanoma, the results presented herein are encouraging for patients diagnosed with this aggressive disease,” the authors wrote.
Among patients with advanced melanoma who were treated with ipilimumab, about 20%-26% survived to 3 years, and these patients are likely to have a good long-term outcome, according to a pooled analysis of survival data published online Feb. 9 in the Journal of Clinical Oncology.
Investigators pooled data from ten prospective (including two phase III trials) and two retrospective studies with a total of 1,257 previously treated and 604 treatment-naive patients. At least 3 years after receiving ipilimumab, 254 patients were still alive, with a median follow up for this subset of 69 months. Around year 3, the Kaplan-Meier overall survival (OS) curve began to plateau and extended to 9.9 years for the longest survival follow-up.
“These results suggest that the majority of patients who reached this milestone time point had a low risk of death thereafter,” wrote Dr. Dirk Schadendorf and his associates (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]).
Compared with patients who were previously treated, treatment-naive patients had a higher median overall survival (13.5 months [95% confidence interval, 11.9-15.4] vs. 10.7 months [9.6-11.4]) and higher 3-year-survival rates (26% [21%-30%] vs. 20% [18%-23%]). No definitive conclusion could be drawn from this observation, however, since nonrandomized subsets were used for this analysis. Subset analysis by dose showed similar median OS and 3-year survival rates for ipilimumab 3 mg/kg, 10 mg/kg, and other dosing regimens.
The researchers expanded the study to include overall survival (OS) data from 2,985 patients enrolled in a U.S. multicenter, open-label, expanded-access treatment protocol (EAP). This group included patients with poorer prognostic factors, some of whom were ineligible for clinical trials. The expanded group showed a lower median OS of 9.5 months and 3 year–survival rate of 21%, with the familiar OS curve plateau around 3 years that extended up to 10 years in some patients.
While this analysis only examined overall survival rates, individual ipilimumab studies that tracked patient responses to the drug have shown that some proportion of long-term survivors did not achieve a response. Identifying the specific disease characteristics of the long-term survivors will require further study.
“Considering the historic median OS of approximately 8-10 months and a 5-year survival rate of approximately 10% in advanced melanoma, the results presented herein are encouraging for patients diagnosed with this aggressive disease,” the authors wrote.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Ipilimumab-treated advanced melanoma patients alive at 3 years tend to have good long-term outcomes.
Major finding: Around year 3, the Kaplan-Meier OS curve began to plateau and extended to 9.9 years for the longest survival follow-up.
Data source: Pooled overall survival data from 12 studies including 1,861 ipilimumab-treated patients with advanced melanoma.
Disclosures: Dr. Schadendorf disclosed that he is a consultant for Bristol-Myers Squibb. Bristol-Myers Squibb sponsored this study.
Melanoma pathogenesis in patient reveals phenotype-genotype paradox
A melanoma in a dysplastic nevus contained a phenotype-genotype disagreement confounding the exclusive significance of BRAF and NRAS mutations in melanoma pathogenesis, according to Dr. Jean-Marie Tan and associates.
A man in his 50s was diagnosed with a melanoma in a dysplastic nevus after being admitted with a irregularly pigmented melanocytic lesion. Microbiopsy specimens were taken across the lesion and genotyping was carried out on DNA samples for BRAF and NRAS mutations. The melanoma showed only BRAF wild-type, while the dysplastic nevus showed both BRAF wild-type and BRAF V600E mutations. Sequencing in all DNA samples revealed NRAS wild-type genotype, the researchers found.
These conflicting results indicate further studies are required to investigate the importance of other candidate genes linked to melanomagenesis, the investigators concluded.
Read the full article at JAMA Dermatology (doi:10.1001/jamadermatol.2014.3775).
A melanoma in a dysplastic nevus contained a phenotype-genotype disagreement confounding the exclusive significance of BRAF and NRAS mutations in melanoma pathogenesis, according to Dr. Jean-Marie Tan and associates.
A man in his 50s was diagnosed with a melanoma in a dysplastic nevus after being admitted with a irregularly pigmented melanocytic lesion. Microbiopsy specimens were taken across the lesion and genotyping was carried out on DNA samples for BRAF and NRAS mutations. The melanoma showed only BRAF wild-type, while the dysplastic nevus showed both BRAF wild-type and BRAF V600E mutations. Sequencing in all DNA samples revealed NRAS wild-type genotype, the researchers found.
These conflicting results indicate further studies are required to investigate the importance of other candidate genes linked to melanomagenesis, the investigators concluded.
Read the full article at JAMA Dermatology (doi:10.1001/jamadermatol.2014.3775).
A melanoma in a dysplastic nevus contained a phenotype-genotype disagreement confounding the exclusive significance of BRAF and NRAS mutations in melanoma pathogenesis, according to Dr. Jean-Marie Tan and associates.
A man in his 50s was diagnosed with a melanoma in a dysplastic nevus after being admitted with a irregularly pigmented melanocytic lesion. Microbiopsy specimens were taken across the lesion and genotyping was carried out on DNA samples for BRAF and NRAS mutations. The melanoma showed only BRAF wild-type, while the dysplastic nevus showed both BRAF wild-type and BRAF V600E mutations. Sequencing in all DNA samples revealed NRAS wild-type genotype, the researchers found.
These conflicting results indicate further studies are required to investigate the importance of other candidate genes linked to melanomagenesis, the investigators concluded.
Read the full article at JAMA Dermatology (doi:10.1001/jamadermatol.2014.3775).
Xerosis is significant risk during targeted anticancer treatments
Patients receiving targeted anticancer treatments are at a significant risk of developing xerosis, or abnormal dryness, according to Dr. Johannah Valentine and her associates.
In a systematic review and meta-analysis of clinical trials involving 58 targeted agents, nearly 18% of all patients developed xerosis, with 1% of patients developing high-grade xerosis. The incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions, and reporting may vary among physicians and institutions, the researchers said.
Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality-of-life impairment, the investigators recommended.
Read the full article at the Journal of the American Academy of Dermatology (doi:10.1016/j.jaad.2014.12.010).
Patients receiving targeted anticancer treatments are at a significant risk of developing xerosis, or abnormal dryness, according to Dr. Johannah Valentine and her associates.
In a systematic review and meta-analysis of clinical trials involving 58 targeted agents, nearly 18% of all patients developed xerosis, with 1% of patients developing high-grade xerosis. The incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions, and reporting may vary among physicians and institutions, the researchers said.
Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality-of-life impairment, the investigators recommended.
Read the full article at the Journal of the American Academy of Dermatology (doi:10.1016/j.jaad.2014.12.010).
Patients receiving targeted anticancer treatments are at a significant risk of developing xerosis, or abnormal dryness, according to Dr. Johannah Valentine and her associates.
In a systematic review and meta-analysis of clinical trials involving 58 targeted agents, nearly 18% of all patients developed xerosis, with 1% of patients developing high-grade xerosis. The incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions, and reporting may vary among physicians and institutions, the researchers said.
Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality-of-life impairment, the investigators recommended.
Read the full article at the Journal of the American Academy of Dermatology (doi:10.1016/j.jaad.2014.12.010).
Manage Your Dermatology Practice: Managing Difficult Patient Encounters
Difficult patient encounters in the dermatology office can be navigated through honest physician-patient communication regarding problems within the office and insurance coverage. Dr. Gary Goldenberg provides tips on communicating with patients about cosmetic procedures that may be noncovered services as well as diagnoses such as melanoma and psoriasis. He also advises how to work through a long list of questions patients may bring to their visit.
Difficult patient encounters in the dermatology office can be navigated through honest physician-patient communication regarding problems within the office and insurance coverage. Dr. Gary Goldenberg provides tips on communicating with patients about cosmetic procedures that may be noncovered services as well as diagnoses such as melanoma and psoriasis. He also advises how to work through a long list of questions patients may bring to their visit.
Difficult patient encounters in the dermatology office can be navigated through honest physician-patient communication regarding problems within the office and insurance coverage. Dr. Gary Goldenberg provides tips on communicating with patients about cosmetic procedures that may be noncovered services as well as diagnoses such as melanoma and psoriasis. He also advises how to work through a long list of questions patients may bring to their visit.
Teledermoscopy referrals surpass paper for managing skin cancer patients
Smartphone teledermoscopy referrals were faster and allowed for more efficient management of patients with skin cancer, compared with paper referrals, according to Dr. Alexander Börve of the University of Gothenburg, Sweden, and his associates.
The waiting time was significantly shorter using teledermoscopy for patients with various melanomas and carcinomas when surgical treatment was necessary. “Triage decisions were also more reliable with teledermoscopy, and over 40% of the teledermoscopy patients could potentially have avoided face-to-face visits,” the researchers noted (Acta. Derm. Venereol. 2015;95:186-90).
Less than 1% of teledermoscopy referrals were excluded because of poor image quality, they said.
Read the full article at Acta Dermato-Venereologica (doi:10.2340/00015555-1906).
Smartphone teledermoscopy referrals were faster and allowed for more efficient management of patients with skin cancer, compared with paper referrals, according to Dr. Alexander Börve of the University of Gothenburg, Sweden, and his associates.
The waiting time was significantly shorter using teledermoscopy for patients with various melanomas and carcinomas when surgical treatment was necessary. “Triage decisions were also more reliable with teledermoscopy, and over 40% of the teledermoscopy patients could potentially have avoided face-to-face visits,” the researchers noted (Acta. Derm. Venereol. 2015;95:186-90).
Less than 1% of teledermoscopy referrals were excluded because of poor image quality, they said.
Read the full article at Acta Dermato-Venereologica (doi:10.2340/00015555-1906).
Smartphone teledermoscopy referrals were faster and allowed for more efficient management of patients with skin cancer, compared with paper referrals, according to Dr. Alexander Börve of the University of Gothenburg, Sweden, and his associates.
The waiting time was significantly shorter using teledermoscopy for patients with various melanomas and carcinomas when surgical treatment was necessary. “Triage decisions were also more reliable with teledermoscopy, and over 40% of the teledermoscopy patients could potentially have avoided face-to-face visits,” the researchers noted (Acta. Derm. Venereol. 2015;95:186-90).
Less than 1% of teledermoscopy referrals were excluded because of poor image quality, they said.
Read the full article at Acta Dermato-Venereologica (doi:10.2340/00015555-1906).
Vitiligo indicates effective melanoma treatment, predicts survival benefit
The development of vitiligo in melanoma patients on immunotherapy may predict improved survival, according to findings from a systematic review and meta-analysis.
In 137 studies reported between 1995 and 2013 and including 5,737 patients with stage III to IV melanoma who were treated with immunotherapy, the pooled cumulative incidence of vitiligo was 3.4%. In those with vitiligo for whom individual patient data were available, both progression-free and overall survival were significantly improved, compared with those without vitiligo after researchers adjusted for age and sex (hazard ratio, 0.51 and 0.25, respectively), Dr. Hansje-Eva Teulings of the University of Amsterdam and her colleagues reported online Jan. 19 in the Journal of Clinical Oncology.
Immune-related effects after melanoma immunotherapy have been linked to increased clinical efficacy. Vitiligo, which results from “strong antimelanoma immunity that also targets healthy melanocytes as a result of shared expression melanocyte differentiation antigens,” is no exception, but it was unclear whether data from individual studies showing tumor regression and improved survival in those with vitiligo could be extrapolated to all immunotherapy studies, the investigators explained (J. Clin. Oncol. 2015 Jan. 19 [doi:10.1200/JCO.2014.57.4756]).
The current findings highlight the significance of vitiligo as a clinical marker for effective antimelanoma immunity and for improved clinical outcome, they said, concluding that “more awareness of vitiligo induction in patients with melanoma by oncologists may contribute to better recognition of patients with effective antimelanoma immunity and may influence their treatment options and prognosis.”
The development of vitiligo in melanoma patients on immunotherapy may predict improved survival, according to findings from a systematic review and meta-analysis.
In 137 studies reported between 1995 and 2013 and including 5,737 patients with stage III to IV melanoma who were treated with immunotherapy, the pooled cumulative incidence of vitiligo was 3.4%. In those with vitiligo for whom individual patient data were available, both progression-free and overall survival were significantly improved, compared with those without vitiligo after researchers adjusted for age and sex (hazard ratio, 0.51 and 0.25, respectively), Dr. Hansje-Eva Teulings of the University of Amsterdam and her colleagues reported online Jan. 19 in the Journal of Clinical Oncology.
Immune-related effects after melanoma immunotherapy have been linked to increased clinical efficacy. Vitiligo, which results from “strong antimelanoma immunity that also targets healthy melanocytes as a result of shared expression melanocyte differentiation antigens,” is no exception, but it was unclear whether data from individual studies showing tumor regression and improved survival in those with vitiligo could be extrapolated to all immunotherapy studies, the investigators explained (J. Clin. Oncol. 2015 Jan. 19 [doi:10.1200/JCO.2014.57.4756]).
The current findings highlight the significance of vitiligo as a clinical marker for effective antimelanoma immunity and for improved clinical outcome, they said, concluding that “more awareness of vitiligo induction in patients with melanoma by oncologists may contribute to better recognition of patients with effective antimelanoma immunity and may influence their treatment options and prognosis.”
The development of vitiligo in melanoma patients on immunotherapy may predict improved survival, according to findings from a systematic review and meta-analysis.
In 137 studies reported between 1995 and 2013 and including 5,737 patients with stage III to IV melanoma who were treated with immunotherapy, the pooled cumulative incidence of vitiligo was 3.4%. In those with vitiligo for whom individual patient data were available, both progression-free and overall survival were significantly improved, compared with those without vitiligo after researchers adjusted for age and sex (hazard ratio, 0.51 and 0.25, respectively), Dr. Hansje-Eva Teulings of the University of Amsterdam and her colleagues reported online Jan. 19 in the Journal of Clinical Oncology.
Immune-related effects after melanoma immunotherapy have been linked to increased clinical efficacy. Vitiligo, which results from “strong antimelanoma immunity that also targets healthy melanocytes as a result of shared expression melanocyte differentiation antigens,” is no exception, but it was unclear whether data from individual studies showing tumor regression and improved survival in those with vitiligo could be extrapolated to all immunotherapy studies, the investigators explained (J. Clin. Oncol. 2015 Jan. 19 [doi:10.1200/JCO.2014.57.4756]).
The current findings highlight the significance of vitiligo as a clinical marker for effective antimelanoma immunity and for improved clinical outcome, they said, concluding that “more awareness of vitiligo induction in patients with melanoma by oncologists may contribute to better recognition of patients with effective antimelanoma immunity and may influence their treatment options and prognosis.”
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Vitiligo appears to serve as a clinical marker for effective antimelanoma immunity and improved clinical outcome.
Major finding: Progression-free and overall survival were improved in patients who developed vitiligo (HR, 0.51 and 0.25, respectively).
Data source: A systematic review and meta-analysis of 139 studies including 5,737 patients.
Disclosures: Dr. Teulings reported having no disclosures.
Handheld device illuminates possible routes of melanoma metastases
Investigators using a handheld dermoscopy device that allows visualization of colors, structures, and patterns in skin lesions not evident to the naked eye were able to visualize nonblanching blue and red lines in a branched pattern in two patients with in-transit cutaneous melanoma metastases.
Dr. Michael A. Marchetti and his associates at Memorial Sloan Kettering Cancer Center, New York, reported the “intriguing” visualization of dissemination for cutaneous melanoma metastases in a letter to JAMA Dermatology.
In-transit cutaneous melanoma metastases are those located more than 2 cm from the primary melanoma, but not beyond the regional nodal basin.
The first patient had wide local excision of a primary cutaneous melanoma on the forehead, and a year later, received localized irradiation for satellite skin metastases. A year after that, skin examination revealed six blue macules on the scalp more than 2 cm from the excision scar. Dermoscopy revealed nonblanching bluish lines in a branched pattern. Histopathologic examination of a skin biopsy confirmed in-transit metastatic melanoma with atypical melanocytes present in superficial dermal lymphatics, Dr. Marchetti and his associates reported (JAMA Dermatology 2015;103-5)
The second patient had a history of multiple primary melanomas, the most recent being one on the chest treated with wide local excision. At a follow-up visit 5 years later, skin examination revealed eight blue-gray macules on the chest, all more than 2 cm from the excision scar. Dermoscopy revealed nonblanching, red-bluish, fuzzy, branching lines. Histopathologic examination of a skin biopsy confirmed in-transit metastatic melanoma with atypical melanocytes present in superficial dermal blood vessels, the investigators wrote.
Typical dermoscopic features of cutaneous melanoma metastases include peripheral gray spots, atypical vessels, and a blue nevus-like pattern. The histopathologic findings in these two cases suggest that the dermoscopic color differences correspond to unique microanatomic routes of melanoma dissemination, with blue and red-blue lines corresponding to lymphatic and hematogenous dissemination of tumors, respectively, they said.
“While the factors driving lymphatic vs. hematogenous in-transit dissemination of melanoma remain unknown, as do any differences in their biologic significance, our finding is an intriguing clinical/dermoscopic/histopathologic observation,” the investigators concluded.
On Twitter @nikolaideslaura
Investigators using a handheld dermoscopy device that allows visualization of colors, structures, and patterns in skin lesions not evident to the naked eye were able to visualize nonblanching blue and red lines in a branched pattern in two patients with in-transit cutaneous melanoma metastases.
Dr. Michael A. Marchetti and his associates at Memorial Sloan Kettering Cancer Center, New York, reported the “intriguing” visualization of dissemination for cutaneous melanoma metastases in a letter to JAMA Dermatology.
In-transit cutaneous melanoma metastases are those located more than 2 cm from the primary melanoma, but not beyond the regional nodal basin.
The first patient had wide local excision of a primary cutaneous melanoma on the forehead, and a year later, received localized irradiation for satellite skin metastases. A year after that, skin examination revealed six blue macules on the scalp more than 2 cm from the excision scar. Dermoscopy revealed nonblanching bluish lines in a branched pattern. Histopathologic examination of a skin biopsy confirmed in-transit metastatic melanoma with atypical melanocytes present in superficial dermal lymphatics, Dr. Marchetti and his associates reported (JAMA Dermatology 2015;103-5)
The second patient had a history of multiple primary melanomas, the most recent being one on the chest treated with wide local excision. At a follow-up visit 5 years later, skin examination revealed eight blue-gray macules on the chest, all more than 2 cm from the excision scar. Dermoscopy revealed nonblanching, red-bluish, fuzzy, branching lines. Histopathologic examination of a skin biopsy confirmed in-transit metastatic melanoma with atypical melanocytes present in superficial dermal blood vessels, the investigators wrote.
Typical dermoscopic features of cutaneous melanoma metastases include peripheral gray spots, atypical vessels, and a blue nevus-like pattern. The histopathologic findings in these two cases suggest that the dermoscopic color differences correspond to unique microanatomic routes of melanoma dissemination, with blue and red-blue lines corresponding to lymphatic and hematogenous dissemination of tumors, respectively, they said.
“While the factors driving lymphatic vs. hematogenous in-transit dissemination of melanoma remain unknown, as do any differences in their biologic significance, our finding is an intriguing clinical/dermoscopic/histopathologic observation,” the investigators concluded.
On Twitter @nikolaideslaura
Investigators using a handheld dermoscopy device that allows visualization of colors, structures, and patterns in skin lesions not evident to the naked eye were able to visualize nonblanching blue and red lines in a branched pattern in two patients with in-transit cutaneous melanoma metastases.
Dr. Michael A. Marchetti and his associates at Memorial Sloan Kettering Cancer Center, New York, reported the “intriguing” visualization of dissemination for cutaneous melanoma metastases in a letter to JAMA Dermatology.
In-transit cutaneous melanoma metastases are those located more than 2 cm from the primary melanoma, but not beyond the regional nodal basin.
The first patient had wide local excision of a primary cutaneous melanoma on the forehead, and a year later, received localized irradiation for satellite skin metastases. A year after that, skin examination revealed six blue macules on the scalp more than 2 cm from the excision scar. Dermoscopy revealed nonblanching bluish lines in a branched pattern. Histopathologic examination of a skin biopsy confirmed in-transit metastatic melanoma with atypical melanocytes present in superficial dermal lymphatics, Dr. Marchetti and his associates reported (JAMA Dermatology 2015;103-5)
The second patient had a history of multiple primary melanomas, the most recent being one on the chest treated with wide local excision. At a follow-up visit 5 years later, skin examination revealed eight blue-gray macules on the chest, all more than 2 cm from the excision scar. Dermoscopy revealed nonblanching, red-bluish, fuzzy, branching lines. Histopathologic examination of a skin biopsy confirmed in-transit metastatic melanoma with atypical melanocytes present in superficial dermal blood vessels, the investigators wrote.
Typical dermoscopic features of cutaneous melanoma metastases include peripheral gray spots, atypical vessels, and a blue nevus-like pattern. The histopathologic findings in these two cases suggest that the dermoscopic color differences correspond to unique microanatomic routes of melanoma dissemination, with blue and red-blue lines corresponding to lymphatic and hematogenous dissemination of tumors, respectively, they said.
“While the factors driving lymphatic vs. hematogenous in-transit dissemination of melanoma remain unknown, as do any differences in their biologic significance, our finding is an intriguing clinical/dermoscopic/histopathologic observation,” the investigators concluded.
On Twitter @nikolaideslaura
FROM JAMA DERMATOLOGY
MEK inhibitors can induce skin eruptions with distinctive duskiness
Case reports of unusual drug hypersensitivity to MEK inhibitors, involving skin eruptions with distinctive central duskiness, have been described online in JAMA Dermatology.
Three patients who were receiving different MEK inhibitors (selumetinib, cobimetinib, and trametinib) developed grade 2 or 3 eruptions, all associated with unique duskiness, reported Dr. Urvi Patel and associates at Washington University, St. Louis.
A 60-year-old man with pancreatic cancer who was receiving selumetinib as part of a clinical trial presented with a grade 2 generalized eruption and pruritus 12 days after initiating therapy. He had diffuse targetoid patches with central duskiness. Selumetinib and other study drugs were withheld, the patient was given topical corticosteroid treatment, and the eruption completely resolved after 4 weeks. The patient did not restart the study drugs because of an elevated alkaline phosphatase level and fatigue.
A woman in her 40s who was receiving cobimetinib and other medication for metastatic melanoma developed grade 2 coalescing urticarial patches with surrounding duskiness on day 28 of treatment. Histopathologic examination showed a superficial perivascular lymphocytic infiltrate with rare eosinophils. After treatment was halted for 7 days and a regimen of oral prednisone was started, cobimetinib therapy was reinstituted at a lower dose. There was no recurrence of the eruption 1 year after cobimetinib therapy was restarted, Dr. Patel and associates reported (JAMA Dermatol. 2015 Jan. 14 [doi:10.1001/jamadermatol.2014.3207]).
The third patient, a woman in her 50s with metastatic melanoma, developed a grade 3 eruption 7 weeks into trametinib treatment together with another drug. The worsening urticarial patches and plaques had surrounding diffuse duskiness. After trametinib treatment was withheld for a week, and a regimen of oral prednisone was begun, trametinib therapy was restarted and the eruption did not return.
“As shown in our patients, successful treatment of this MEK inhibitor–associated cutaneous eruption can include a drug holiday and oral corticosteroid therapy, with reinstitution of the drug at a lower dose without recurrence,” Dr. Patel and his associates wrote.
MEK inhibitors target the mitogen-activated protein kinase pathway. Trametinib has been approved for treating advanced melanoma, and more than a dozen other MEK inhibitors are in clinical trials (including selumetinib and cobimetinib) for treatment of melanoma and other solid-organ malignant neoplasms, including pancreatic, hepatocellular, colorectal, and non–small cell lung cancer, the authors noted.
On Twitter @nikolaideslaura
Case reports of unusual drug hypersensitivity to MEK inhibitors, involving skin eruptions with distinctive central duskiness, have been described online in JAMA Dermatology.
Three patients who were receiving different MEK inhibitors (selumetinib, cobimetinib, and trametinib) developed grade 2 or 3 eruptions, all associated with unique duskiness, reported Dr. Urvi Patel and associates at Washington University, St. Louis.
A 60-year-old man with pancreatic cancer who was receiving selumetinib as part of a clinical trial presented with a grade 2 generalized eruption and pruritus 12 days after initiating therapy. He had diffuse targetoid patches with central duskiness. Selumetinib and other study drugs were withheld, the patient was given topical corticosteroid treatment, and the eruption completely resolved after 4 weeks. The patient did not restart the study drugs because of an elevated alkaline phosphatase level and fatigue.
A woman in her 40s who was receiving cobimetinib and other medication for metastatic melanoma developed grade 2 coalescing urticarial patches with surrounding duskiness on day 28 of treatment. Histopathologic examination showed a superficial perivascular lymphocytic infiltrate with rare eosinophils. After treatment was halted for 7 days and a regimen of oral prednisone was started, cobimetinib therapy was reinstituted at a lower dose. There was no recurrence of the eruption 1 year after cobimetinib therapy was restarted, Dr. Patel and associates reported (JAMA Dermatol. 2015 Jan. 14 [doi:10.1001/jamadermatol.2014.3207]).
The third patient, a woman in her 50s with metastatic melanoma, developed a grade 3 eruption 7 weeks into trametinib treatment together with another drug. The worsening urticarial patches and plaques had surrounding diffuse duskiness. After trametinib treatment was withheld for a week, and a regimen of oral prednisone was begun, trametinib therapy was restarted and the eruption did not return.
“As shown in our patients, successful treatment of this MEK inhibitor–associated cutaneous eruption can include a drug holiday and oral corticosteroid therapy, with reinstitution of the drug at a lower dose without recurrence,” Dr. Patel and his associates wrote.
MEK inhibitors target the mitogen-activated protein kinase pathway. Trametinib has been approved for treating advanced melanoma, and more than a dozen other MEK inhibitors are in clinical trials (including selumetinib and cobimetinib) for treatment of melanoma and other solid-organ malignant neoplasms, including pancreatic, hepatocellular, colorectal, and non–small cell lung cancer, the authors noted.
On Twitter @nikolaideslaura
Case reports of unusual drug hypersensitivity to MEK inhibitors, involving skin eruptions with distinctive central duskiness, have been described online in JAMA Dermatology.
Three patients who were receiving different MEK inhibitors (selumetinib, cobimetinib, and trametinib) developed grade 2 or 3 eruptions, all associated with unique duskiness, reported Dr. Urvi Patel and associates at Washington University, St. Louis.
A 60-year-old man with pancreatic cancer who was receiving selumetinib as part of a clinical trial presented with a grade 2 generalized eruption and pruritus 12 days after initiating therapy. He had diffuse targetoid patches with central duskiness. Selumetinib and other study drugs were withheld, the patient was given topical corticosteroid treatment, and the eruption completely resolved after 4 weeks. The patient did not restart the study drugs because of an elevated alkaline phosphatase level and fatigue.
A woman in her 40s who was receiving cobimetinib and other medication for metastatic melanoma developed grade 2 coalescing urticarial patches with surrounding duskiness on day 28 of treatment. Histopathologic examination showed a superficial perivascular lymphocytic infiltrate with rare eosinophils. After treatment was halted for 7 days and a regimen of oral prednisone was started, cobimetinib therapy was reinstituted at a lower dose. There was no recurrence of the eruption 1 year after cobimetinib therapy was restarted, Dr. Patel and associates reported (JAMA Dermatol. 2015 Jan. 14 [doi:10.1001/jamadermatol.2014.3207]).
The third patient, a woman in her 50s with metastatic melanoma, developed a grade 3 eruption 7 weeks into trametinib treatment together with another drug. The worsening urticarial patches and plaques had surrounding diffuse duskiness. After trametinib treatment was withheld for a week, and a regimen of oral prednisone was begun, trametinib therapy was restarted and the eruption did not return.
“As shown in our patients, successful treatment of this MEK inhibitor–associated cutaneous eruption can include a drug holiday and oral corticosteroid therapy, with reinstitution of the drug at a lower dose without recurrence,” Dr. Patel and his associates wrote.
MEK inhibitors target the mitogen-activated protein kinase pathway. Trametinib has been approved for treating advanced melanoma, and more than a dozen other MEK inhibitors are in clinical trials (including selumetinib and cobimetinib) for treatment of melanoma and other solid-organ malignant neoplasms, including pancreatic, hepatocellular, colorectal, and non–small cell lung cancer, the authors noted.
On Twitter @nikolaideslaura
FROM JAMA DERMATOLOGY
Key clinical point: This MEK inhibitor–associated cutaneous eruption can be treated with a drug holiday and oral corticosteroid treatment, restarting the drug at a lower dose without recurrence.
Major finding: Three patients who were receiving different MEK inhibitors (selumetinib, cobimetinib, and trametinib) developed grade 2 or 3 eruptions, all associated with unique duskiness.
Data source: Three case studies of patients receiving different MEK inhibitors.
Disclosures: Dr. Lynn Cornelius has received a research grant from Genentech and is a clinical subinvestigator for GlaxoSmithKline. Dr. Milan J. Anadkat has received honoraria as a speaker and/or consultant from AstraZeneca, Bristol-Myers Squibb, Eisai, ImClone, and Therakos. No other disclosures were reported.
Sunscreens Causing Cancer? The Facts
Skin cancer is the most common form of cancer in the United States and continues to rise in incidence and mortality each year.1 It is common knowledge that UV light plays a major role in the development of skin cancer.2,3 Studies have long demonstrated that using sunscreen on a daily basis can help prevent the development of skin cancer, premature aging, and exacerbation of photodermatoses.4-7 Although there are several photoprotective measures available, sunscreen remains the most popular and widely used among patients.8 Sunscreens that are on the market today contain either organic or inorganic UV filters or a combination of both based on their chemical composition and photoprotection mechanisms.9 Concerns about these ingredients causing cancer have created confusion among consumers. I will attempt to clarify these concerns by critically analyzing available evidence-based data on sunscreen use so that as dermatology residents we will be more knowledgeable about sunscreen safety topics and will be able to provide accurate and up-to-date information to our patients.
Organic UV Filters
Organic UV filters are classified as aromatic compounds that provide photoprotection by absorbing UV light.10 Aside from the photoallergic potential of organic UV filters, controversy has arisen in response to studies reporting their possible hormone disruptive effects.11-18 Although there are several US Food and Drug Administration (FDA)–approved organic UV filters in use today, one of the most commonly manufactured and controversial agents is oxybenzone.10 Claims regarding the estrogenic and antiandrogenic effects of oxybenzone have been investigated with results refuting the claims or concluding that more sensitive studies are needed to determine if these organic ingredients pose such risks.10,19,20 One study demonstrated that nearly 300 years of daily sunscreen application would be needed to reach similar exposure levels of oxybenzone used and described in prior animal studies.21 Additionally, most of the studied adverse effects of UV filters have been evaluated based on oral exposure rather than actual dermal application.11 Although these compounds are absorbed systemically, studies have reported that the amounts are insignificant and noncumulative in the body.10,22-24 Furthermore, the binding affinity of oxybenzone for estrogen receptors has been shown to be much weaker and near insignificant compared to estrogen and estradiol.24,25 Although numerous important studies examining systemic absorption have not shown a clinically significant disruption of hormonal homeostasis or acute toxicity in humans by organic UV filters, further studies are needed.
Inorganic UV Filters
Used as the main active ingredients in sunscreen for decades, titanium dioxide (TiO2) and zinc oxide (ZnO) compounds generally are more photostable and less photoallergic than their organic counterparts.10 In recent years, the safety of these long-used photoprotectors has been questioned because of the development of nanoparticle (<100 nm) formulas that are less opaque on application. Although this formula provides a thin, transparent, and cosmetically appealing medium, there is concern that the metal oxides penetrate the skin and cause local and systemic toxicities.26-28 Several recent scientific studies have shown no percutaneous permeation of these particles in normal adult human skin and reported no causal damage to mammalian cells.10,29-31 Although skin penetration of TiO2 and ZnO has been described as insignificant, focus has shifted to health risks associated with inhaling TiO2 through the use of spray or powder products following statements made by the International Agency for Research on Cancer in 2006.32 Several studies investigating increased health risks, specifically lung cancer, in factory workers who were subjected to TiO2 and ZnO inhalation concluded that exposure was unlikely to pose substantial health risks or subchronic toxicity.33,34 Despite a relatively strong safety profile, a major concern of using these metal oxides as UV filters has been potential free radical formation.35-39 For this reason, the Scientific Committee on Emerging and Newly Identified Health Risks extensively researched and delivered opinions on the use of TiO2 and ZnO in cosmetics, concluding that topical application of either compound does not result in toxicity or other adverse effects.30,40-42 Additionally, an effort has been made by manufacturers to encapsulate nanoparticles with magnesium and other materials to quench the reactive oxygen species along with the human body’s own antioxidant defense system.10 In summary, it appears that the current weight of scientific evidence suggests that percutaneous absorption and toxicity by UV filters in humans may be overestimated and that the use of nanoparticles in sunscreens poses no or negligible potential risks to human health.43,44
Concerns Beyond Organic and Inorganic UV Filters
Beyond these concerns with organic and inorganic UV filters, there are several other claims regarding sunscreen safety that have stirred up controversy, including the side-effect profile of retinyl palmitate, vitamin D deficiency, phototoxicity, environmental effects, futility of sun protection factor levels greater than 50, and increased health risks in children. Although some studies report mixed results, the majority of scientific investigations have addressed and refuted several of these claims, again confirming the relative safety of sunscreen use. It is beyond the scope of this article to further discuss these topics specifically. However, it is worth mentioning that consumer studies report that the actual use of sunscreens is 0.5 mg/cm2 or less compared to the ideal application of 2 mg/cm2, thereby confounding many of the claims made about sunscreen use, such as vitamin D deficiency.45 Sunscreens often contain a combination of several UV filters. To date, only a few existing studies have shown that mixtures of the photoprotective agents discussed might interact and exhibit toxic activity when combined, even when there is no observed adverse toxic effect when used individually in products.46-48
The current FDA ruling on sunscreen labeling does not require manufacturers to state if inorganic UV filters have been formulated into nanoparticles; however, manufacturers are now required to include a statement on all sunscreen labels warning consumers to avoid using sunscreen on damaged or broken skin49 in an effort to prevent the active ingredients from getting under the skin, potentially causing inflammation and/or health risks, because available data do not provide conclusive evidence on increased penetration of open skin.50 Additional information regarding the 2011 FDA sunscreen ruling can be found in a prior Cutis Resident Corner column.51
Final Thoughts
As health care providers, we should take advantage of opportunities to educate our patients about other sun safety practices, such as avoiding excessive sun exposure during peak hours (10 am to 2 pm), seeking shade, and wearing photoprotective clothing (eg, wide-brimmed hats, sunglasses).
The research is quite clear: Using broadband sunscreens that absorb and/or block UV radiation results in reduced damage to the skin’s DNA, a fact that should be considered when taking into account the risks and benefits of sunscreen use.2,3 Although sunscreen use is highly recommended in addition to the other sun protection methods, it is ultimately the patient’s choice. If a patient is still concerned about the active ingredients of UV filters, even given the high probability of safety, there are products available on the market that do not include organic filters or nanoparticles. Given the established benefits of UV protection, the use of sunscreens remain one of the most important photoprotective methods, and with increased usage by the public, continuous monitoring of the overall safety and benefit profile of future products is prudent.
1. Skin cancer statistics. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/cancer/skin/statistics/index.htm. Updated September 2, 2014. Accessed December 30, 2014.
2. World Health Organization, International Agency for Research on Cancer. Solar and ultraviolet radiation. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 55. Lyon, France: International Agency for Research on Cancer; 1992.
3. Green AC, Williams GM, Logan V, et al. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol. 2011;29:257-263.
4. Darlington S, Williams G, Neale R, et al. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol. 2003;139:451-455.
5. Van der Pols JC, Williams GM, Pandeya N, et al. Prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol Biomarkers Prev. 2006;15:2546-2548.
6. Hughes MC, Williams GM, Baker P, et al. Sunscreen and prevention of skin aging: a randomized trial. Ann Intern Med. 2013;158:781-790.
7. Bissonnette R, Nigen S, Bolduc C. Influence of the quantity of sunscreen applied on the ability to protect against ultraviolet-induced polymorphous light eruption. Photodermatol Photoimmunol Photomed. 2012;28:240-243.
8. Cancer trends progress report 2011/2012 update: sun protection. National Cancer Institute Web site. http://progressreport.cancer.gov/doc_detail.asp?pid¡1&did¡2009&chid¡91&coid¡911. Accessed December 30, 2014.
9. Sunscreen Drug Products for Over-the-counter Human Use, 21 CFR §352.10. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=352.10. Updated September 1, 2014. Accessed December 30, 2014.
10. Burnett ME, Wang SQ. Current sunscreen controversies: a critical review. Photodermatol Photoimmunol Photomed. 2011;27:58-67.
11. Krause M, Klit A, Blomberg Jensen M, et al. Sunscreens: are they beneficial for health? an overview of endocrine disrupting properties of UV-filters. Int J Androl. 2012;35:424-436.
12. Schlumpf M, Cotton B, Conscience M, et al. In vitro and in vivo estrogenicity of UV screens. Environ Health Perspect. 2001;109:239-244.
13. Schlumpf M, Schmid P, Durrer S, et al. Endocrine activity and developmental toxicity of cosmetic UV filters–an update. Toxicol. 2004;205:113-122.
14. Schlumpf M, Kypke K, Vökt C, et al. Endocrine active UV filters: developmental toxicity and exposure through breast milk. Chimia. 2008;62:345-351.
15. Nakagawa Y, Suzuki T. Metabolism of 2-hydroxy-4-methoxybenzophenone in isolated rat hepatocytes and xenoestrogenic effects of its metabolites on MCF-7 human breast cancer cells. Chem Biol Interact. 2002;139:115-128.
16. Ma R, Cotton B, Lichtensteiger W, et al. UV filters with antagonistic action at androgen receptors in the MDA-kb2 cell transcriptional-activation assay. Toxicol Sci. 2003;74:43-50.
17. Heneweer M, Muusse M, van den Berg M, et al. Additive estrogenic effects of mixtures of frequently used UV filters on pS2-gene transcription in MCF-7 cells. Toxicol Appl Pharmacol. 2005;208:170-177.
18. Knobler E, Almeida L, Ruzkowski AM, et al. Photoallergy to benzophenone. Arch Dermatol. 1989;125:801-804.
19. Draelos ZD. Are sunscreens safe? J Cosmet Dermatol. 2010;9:1-2.
20. Gilbert E, Pirot F, Bertholle V. Commonly used UV filter toxicity on biological functions: review of last decade studies. Int J of Cosmet Sci. 2013;35:208-219.
21. Wang SQ, Burnett ME, Lim HW. Safety of oxybenzone: putting numbers into perspective. Arch Dermatol. 2011;147:865-866.
22. Mancebo SE, Hu JY, Wang SQ. Sunscreens: a review of health benefits, regulations, and controversies. Dermatol Clin. 2014;32:427-438.
23. Jansen R, Osterwalder U, Wang SQ, et al. Photoprotection: part II. sunscreen: development, efficacy, and controversies. J Am Acad Dermatol. 2013;69:867.e1-867.e14.
24. Janjua NR, Mogensen B, Andersson AM, et al. Systemic absorption of the sunscreens benzo- phenone-3, octyl-methoxycinnamate, and 3-(4-methyl-benzy-lidene) camphor after whole-body topical application and reproductive hormone levels in humans. J Invest Dermatol. 2004;123:57-61.
25. Kadry AM, Chukwuemeka SO, Mohamed S, et al. Pharmacokinetics of benzophenone-3 after oral exposure in male rats. J Appl Toxicol. 1995;15:97-102.
26. Gulson B, McCall M, Korsch M, et al. Small amounts of zinc from zinc oxide particles in sunscreens applied outdoors are absorbed through human skin. Toxicol Sci. 2010;118:140-149.
27. Gulson B, Wong H, Korsch M, et al. Comparison of dermal absorption of zinc from different sunscreen formulations and differing UV exposure based on stable isotope tracing. Sci Total Environ. 2012:420:313-318.
28. Benech-Kieffer F, Meuling WJ, Leclerc C, et al. Percutaneous absorption of Mexoryl SX in human volunteers: comparison with in vitro data. Skin Pharmacol Appl Skin Physiol. 2003;16:343-355.
29. Nash JF. Human safety and efficacy of ultraviolet filters and sunscreen products. Dermatol Clin. 2006;24:35-51.
30. Nohynek GJ, Lademann J, Ribaud C, et al. Grey goo on the skin? nanotechnology, cosmetic and sunscreen safety. Crit Rev Toxicol. 2007;37:251-277.
31. Sadrieh N, Wokovich AM, Gopee NV, et al. Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles. Toxicol Sci. 2010;115:156-166.
32. International Agency for Research on Cancer. Carbon black, titanium dioxide, and talc. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 93. Lyon, France: International Agency for Research on Cancer; 2006.
33. Liao CM, Chiang YH, Chio CP. Model-based assessment for human inhalation exposure risk to airborne nano/fine titanium dioxide particles. Sci Total Environ. 2008:15;407:165-177.
34. Adamcakova-Dodd A, Stebounova LV, Kim JS, et al. Toxicity assessment of zinc oxide nanoparticles using sub-acute and sub-chronic murine inhalation models. Part Fibre Toxicol. 2014;11:15.
35. Wamer WG, Yin JJ, Wei RR. Oxidative damage to nucleic acids photosensitized by titanium dioxide. Free Radic Biol Med. 1997;23:851-858.
36. Nakagawa Y, Wakuri S, Sakamoto K, et al. The photogenotoxicity of titanium dioxide particles. Mutat Res. 1997;394:125-132.
37. Dunford R, Salinaro A, Cai L, et al. Chemical oxidation and DNA damage catalysed by inorganic sunscreen ingredients. FEBS Lett. 1997;418:87-90, 99.
38. Hidaka H, Kobayashi H, Koike T, et al. DNA damage photoinduced by cosmetic pigments and sunscreen agents under solar exposure and artificial UV illumination. J Oleo Sci. 2006;55:249-261.
39. Dufour EK, Kumaravel T, Nohynek GJ, et al. Clastogenicity, photo-clastogenicity or pseudo-photo-clastogenicity: genotoxic effects of zinc oxide in the dark, in pre-irradiated or simultaneously irradiated Chinese hamster ovary cells [published online ahead of print June 21, 2006]. Mutat Res. 2006;607:215-224.
40. Opinion of the Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers concerning titanium dioxide. http://ec.europa.eu/health/archive/ph_risk/committees/sccp/documents/out135_en.pdf. Published October 24, 2000. Accessed December 30, 2014.
41. The Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers opinion concerning zinc oxide. http://ec.europa.eu/health/archive/ph_risk/committees/sccp/documents/out222_en.pdf. Published June 24-25, 2003. Accessed December 30, 2014.
42. Hackenberg S, Friehs G, Kessler M, et al. Nanosized titanium dioxide particles do not induce DNA damage in human peripheral blood lymphocytes. Environ Mol Mutagen. 2010;52:264-268.
43. Bach-Thomsen M, Wulf HC. Sunbather’s application of sunscreen is probably inadequate to obtain the sun protection factor assigned to the preparation. Photodermatol Photoimmunol Photomed. 1993:9;242-244.
44. Nohynek GJ, Antignac E, Re T, et al. Safety assessment of personal care products/cosmetics and their ingredients. Toxicol Appl Pharmacol. 2010:1;243:239-259.
45. Diffey BL. Sunscreens: use and misuse. In: Giacomoni PU, ed. Sun Protection in Man. Vol 3. Amsterdam, the Netherlands: Elsevier Science BV; 2001:521-534.
46. Heneweer M, Muusse M, Van den BM, et al. Additive estrogenic effects of mixtures of frequently used UV-filters on pS2-gene transcription in MCF-7 cells. Toxicol Appl Pharmacol. 2005;208:170-177.
47. Kunz PY, Galicia HF, Fent K. Comparison of in vitro and in vivo estrogenic activity of UV-filters in fish. Toxicol Sci. 2006;90:349-361.
48. Kortenkamp A, Faust M, Scholze M, et al. Low-level exposure to multiple chemicals: reason for human health concerns? Environ Health Perspect. 2007;115(suppl 1):106-114.
49. Labeling and effectiveness testing: sunscreen drug products for over-the-counter human use—small entity compliance guide. US Food and Drug Administration Web site. http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm330694.htm. Published December 2012. Updated May 13, 2014. Accessed December 30, 2014.
50. Schafer-Korting M, Korting HC, Ponce-Poschl E. Liposomal tretinoin for uncomplicated acne vulgaris. Clin Investig. 1994;72:1086-1091.
51. Bronfenbrener R. Simplifying sun safety: a guide to the new FDA sunscreen monograph. Cutis. 2014;93:e17-e19.
Skin cancer is the most common form of cancer in the United States and continues to rise in incidence and mortality each year.1 It is common knowledge that UV light plays a major role in the development of skin cancer.2,3 Studies have long demonstrated that using sunscreen on a daily basis can help prevent the development of skin cancer, premature aging, and exacerbation of photodermatoses.4-7 Although there are several photoprotective measures available, sunscreen remains the most popular and widely used among patients.8 Sunscreens that are on the market today contain either organic or inorganic UV filters or a combination of both based on their chemical composition and photoprotection mechanisms.9 Concerns about these ingredients causing cancer have created confusion among consumers. I will attempt to clarify these concerns by critically analyzing available evidence-based data on sunscreen use so that as dermatology residents we will be more knowledgeable about sunscreen safety topics and will be able to provide accurate and up-to-date information to our patients.
Organic UV Filters
Organic UV filters are classified as aromatic compounds that provide photoprotection by absorbing UV light.10 Aside from the photoallergic potential of organic UV filters, controversy has arisen in response to studies reporting their possible hormone disruptive effects.11-18 Although there are several US Food and Drug Administration (FDA)–approved organic UV filters in use today, one of the most commonly manufactured and controversial agents is oxybenzone.10 Claims regarding the estrogenic and antiandrogenic effects of oxybenzone have been investigated with results refuting the claims or concluding that more sensitive studies are needed to determine if these organic ingredients pose such risks.10,19,20 One study demonstrated that nearly 300 years of daily sunscreen application would be needed to reach similar exposure levels of oxybenzone used and described in prior animal studies.21 Additionally, most of the studied adverse effects of UV filters have been evaluated based on oral exposure rather than actual dermal application.11 Although these compounds are absorbed systemically, studies have reported that the amounts are insignificant and noncumulative in the body.10,22-24 Furthermore, the binding affinity of oxybenzone for estrogen receptors has been shown to be much weaker and near insignificant compared to estrogen and estradiol.24,25 Although numerous important studies examining systemic absorption have not shown a clinically significant disruption of hormonal homeostasis or acute toxicity in humans by organic UV filters, further studies are needed.
Inorganic UV Filters
Used as the main active ingredients in sunscreen for decades, titanium dioxide (TiO2) and zinc oxide (ZnO) compounds generally are more photostable and less photoallergic than their organic counterparts.10 In recent years, the safety of these long-used photoprotectors has been questioned because of the development of nanoparticle (<100 nm) formulas that are less opaque on application. Although this formula provides a thin, transparent, and cosmetically appealing medium, there is concern that the metal oxides penetrate the skin and cause local and systemic toxicities.26-28 Several recent scientific studies have shown no percutaneous permeation of these particles in normal adult human skin and reported no causal damage to mammalian cells.10,29-31 Although skin penetration of TiO2 and ZnO has been described as insignificant, focus has shifted to health risks associated with inhaling TiO2 through the use of spray or powder products following statements made by the International Agency for Research on Cancer in 2006.32 Several studies investigating increased health risks, specifically lung cancer, in factory workers who were subjected to TiO2 and ZnO inhalation concluded that exposure was unlikely to pose substantial health risks or subchronic toxicity.33,34 Despite a relatively strong safety profile, a major concern of using these metal oxides as UV filters has been potential free radical formation.35-39 For this reason, the Scientific Committee on Emerging and Newly Identified Health Risks extensively researched and delivered opinions on the use of TiO2 and ZnO in cosmetics, concluding that topical application of either compound does not result in toxicity or other adverse effects.30,40-42 Additionally, an effort has been made by manufacturers to encapsulate nanoparticles with magnesium and other materials to quench the reactive oxygen species along with the human body’s own antioxidant defense system.10 In summary, it appears that the current weight of scientific evidence suggests that percutaneous absorption and toxicity by UV filters in humans may be overestimated and that the use of nanoparticles in sunscreens poses no or negligible potential risks to human health.43,44
Concerns Beyond Organic and Inorganic UV Filters
Beyond these concerns with organic and inorganic UV filters, there are several other claims regarding sunscreen safety that have stirred up controversy, including the side-effect profile of retinyl palmitate, vitamin D deficiency, phototoxicity, environmental effects, futility of sun protection factor levels greater than 50, and increased health risks in children. Although some studies report mixed results, the majority of scientific investigations have addressed and refuted several of these claims, again confirming the relative safety of sunscreen use. It is beyond the scope of this article to further discuss these topics specifically. However, it is worth mentioning that consumer studies report that the actual use of sunscreens is 0.5 mg/cm2 or less compared to the ideal application of 2 mg/cm2, thereby confounding many of the claims made about sunscreen use, such as vitamin D deficiency.45 Sunscreens often contain a combination of several UV filters. To date, only a few existing studies have shown that mixtures of the photoprotective agents discussed might interact and exhibit toxic activity when combined, even when there is no observed adverse toxic effect when used individually in products.46-48
The current FDA ruling on sunscreen labeling does not require manufacturers to state if inorganic UV filters have been formulated into nanoparticles; however, manufacturers are now required to include a statement on all sunscreen labels warning consumers to avoid using sunscreen on damaged or broken skin49 in an effort to prevent the active ingredients from getting under the skin, potentially causing inflammation and/or health risks, because available data do not provide conclusive evidence on increased penetration of open skin.50 Additional information regarding the 2011 FDA sunscreen ruling can be found in a prior Cutis Resident Corner column.51
Final Thoughts
As health care providers, we should take advantage of opportunities to educate our patients about other sun safety practices, such as avoiding excessive sun exposure during peak hours (10 am to 2 pm), seeking shade, and wearing photoprotective clothing (eg, wide-brimmed hats, sunglasses).
The research is quite clear: Using broadband sunscreens that absorb and/or block UV radiation results in reduced damage to the skin’s DNA, a fact that should be considered when taking into account the risks and benefits of sunscreen use.2,3 Although sunscreen use is highly recommended in addition to the other sun protection methods, it is ultimately the patient’s choice. If a patient is still concerned about the active ingredients of UV filters, even given the high probability of safety, there are products available on the market that do not include organic filters or nanoparticles. Given the established benefits of UV protection, the use of sunscreens remain one of the most important photoprotective methods, and with increased usage by the public, continuous monitoring of the overall safety and benefit profile of future products is prudent.
Skin cancer is the most common form of cancer in the United States and continues to rise in incidence and mortality each year.1 It is common knowledge that UV light plays a major role in the development of skin cancer.2,3 Studies have long demonstrated that using sunscreen on a daily basis can help prevent the development of skin cancer, premature aging, and exacerbation of photodermatoses.4-7 Although there are several photoprotective measures available, sunscreen remains the most popular and widely used among patients.8 Sunscreens that are on the market today contain either organic or inorganic UV filters or a combination of both based on their chemical composition and photoprotection mechanisms.9 Concerns about these ingredients causing cancer have created confusion among consumers. I will attempt to clarify these concerns by critically analyzing available evidence-based data on sunscreen use so that as dermatology residents we will be more knowledgeable about sunscreen safety topics and will be able to provide accurate and up-to-date information to our patients.
Organic UV Filters
Organic UV filters are classified as aromatic compounds that provide photoprotection by absorbing UV light.10 Aside from the photoallergic potential of organic UV filters, controversy has arisen in response to studies reporting their possible hormone disruptive effects.11-18 Although there are several US Food and Drug Administration (FDA)–approved organic UV filters in use today, one of the most commonly manufactured and controversial agents is oxybenzone.10 Claims regarding the estrogenic and antiandrogenic effects of oxybenzone have been investigated with results refuting the claims or concluding that more sensitive studies are needed to determine if these organic ingredients pose such risks.10,19,20 One study demonstrated that nearly 300 years of daily sunscreen application would be needed to reach similar exposure levels of oxybenzone used and described in prior animal studies.21 Additionally, most of the studied adverse effects of UV filters have been evaluated based on oral exposure rather than actual dermal application.11 Although these compounds are absorbed systemically, studies have reported that the amounts are insignificant and noncumulative in the body.10,22-24 Furthermore, the binding affinity of oxybenzone for estrogen receptors has been shown to be much weaker and near insignificant compared to estrogen and estradiol.24,25 Although numerous important studies examining systemic absorption have not shown a clinically significant disruption of hormonal homeostasis or acute toxicity in humans by organic UV filters, further studies are needed.
Inorganic UV Filters
Used as the main active ingredients in sunscreen for decades, titanium dioxide (TiO2) and zinc oxide (ZnO) compounds generally are more photostable and less photoallergic than their organic counterparts.10 In recent years, the safety of these long-used photoprotectors has been questioned because of the development of nanoparticle (<100 nm) formulas that are less opaque on application. Although this formula provides a thin, transparent, and cosmetically appealing medium, there is concern that the metal oxides penetrate the skin and cause local and systemic toxicities.26-28 Several recent scientific studies have shown no percutaneous permeation of these particles in normal adult human skin and reported no causal damage to mammalian cells.10,29-31 Although skin penetration of TiO2 and ZnO has been described as insignificant, focus has shifted to health risks associated with inhaling TiO2 through the use of spray or powder products following statements made by the International Agency for Research on Cancer in 2006.32 Several studies investigating increased health risks, specifically lung cancer, in factory workers who were subjected to TiO2 and ZnO inhalation concluded that exposure was unlikely to pose substantial health risks or subchronic toxicity.33,34 Despite a relatively strong safety profile, a major concern of using these metal oxides as UV filters has been potential free radical formation.35-39 For this reason, the Scientific Committee on Emerging and Newly Identified Health Risks extensively researched and delivered opinions on the use of TiO2 and ZnO in cosmetics, concluding that topical application of either compound does not result in toxicity or other adverse effects.30,40-42 Additionally, an effort has been made by manufacturers to encapsulate nanoparticles with magnesium and other materials to quench the reactive oxygen species along with the human body’s own antioxidant defense system.10 In summary, it appears that the current weight of scientific evidence suggests that percutaneous absorption and toxicity by UV filters in humans may be overestimated and that the use of nanoparticles in sunscreens poses no or negligible potential risks to human health.43,44
Concerns Beyond Organic and Inorganic UV Filters
Beyond these concerns with organic and inorganic UV filters, there are several other claims regarding sunscreen safety that have stirred up controversy, including the side-effect profile of retinyl palmitate, vitamin D deficiency, phototoxicity, environmental effects, futility of sun protection factor levels greater than 50, and increased health risks in children. Although some studies report mixed results, the majority of scientific investigations have addressed and refuted several of these claims, again confirming the relative safety of sunscreen use. It is beyond the scope of this article to further discuss these topics specifically. However, it is worth mentioning that consumer studies report that the actual use of sunscreens is 0.5 mg/cm2 or less compared to the ideal application of 2 mg/cm2, thereby confounding many of the claims made about sunscreen use, such as vitamin D deficiency.45 Sunscreens often contain a combination of several UV filters. To date, only a few existing studies have shown that mixtures of the photoprotective agents discussed might interact and exhibit toxic activity when combined, even when there is no observed adverse toxic effect when used individually in products.46-48
The current FDA ruling on sunscreen labeling does not require manufacturers to state if inorganic UV filters have been formulated into nanoparticles; however, manufacturers are now required to include a statement on all sunscreen labels warning consumers to avoid using sunscreen on damaged or broken skin49 in an effort to prevent the active ingredients from getting under the skin, potentially causing inflammation and/or health risks, because available data do not provide conclusive evidence on increased penetration of open skin.50 Additional information regarding the 2011 FDA sunscreen ruling can be found in a prior Cutis Resident Corner column.51
Final Thoughts
As health care providers, we should take advantage of opportunities to educate our patients about other sun safety practices, such as avoiding excessive sun exposure during peak hours (10 am to 2 pm), seeking shade, and wearing photoprotective clothing (eg, wide-brimmed hats, sunglasses).
The research is quite clear: Using broadband sunscreens that absorb and/or block UV radiation results in reduced damage to the skin’s DNA, a fact that should be considered when taking into account the risks and benefits of sunscreen use.2,3 Although sunscreen use is highly recommended in addition to the other sun protection methods, it is ultimately the patient’s choice. If a patient is still concerned about the active ingredients of UV filters, even given the high probability of safety, there are products available on the market that do not include organic filters or nanoparticles. Given the established benefits of UV protection, the use of sunscreens remain one of the most important photoprotective methods, and with increased usage by the public, continuous monitoring of the overall safety and benefit profile of future products is prudent.
1. Skin cancer statistics. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/cancer/skin/statistics/index.htm. Updated September 2, 2014. Accessed December 30, 2014.
2. World Health Organization, International Agency for Research on Cancer. Solar and ultraviolet radiation. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 55. Lyon, France: International Agency for Research on Cancer; 1992.
3. Green AC, Williams GM, Logan V, et al. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol. 2011;29:257-263.
4. Darlington S, Williams G, Neale R, et al. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol. 2003;139:451-455.
5. Van der Pols JC, Williams GM, Pandeya N, et al. Prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol Biomarkers Prev. 2006;15:2546-2548.
6. Hughes MC, Williams GM, Baker P, et al. Sunscreen and prevention of skin aging: a randomized trial. Ann Intern Med. 2013;158:781-790.
7. Bissonnette R, Nigen S, Bolduc C. Influence of the quantity of sunscreen applied on the ability to protect against ultraviolet-induced polymorphous light eruption. Photodermatol Photoimmunol Photomed. 2012;28:240-243.
8. Cancer trends progress report 2011/2012 update: sun protection. National Cancer Institute Web site. http://progressreport.cancer.gov/doc_detail.asp?pid¡1&did¡2009&chid¡91&coid¡911. Accessed December 30, 2014.
9. Sunscreen Drug Products for Over-the-counter Human Use, 21 CFR §352.10. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=352.10. Updated September 1, 2014. Accessed December 30, 2014.
10. Burnett ME, Wang SQ. Current sunscreen controversies: a critical review. Photodermatol Photoimmunol Photomed. 2011;27:58-67.
11. Krause M, Klit A, Blomberg Jensen M, et al. Sunscreens: are they beneficial for health? an overview of endocrine disrupting properties of UV-filters. Int J Androl. 2012;35:424-436.
12. Schlumpf M, Cotton B, Conscience M, et al. In vitro and in vivo estrogenicity of UV screens. Environ Health Perspect. 2001;109:239-244.
13. Schlumpf M, Schmid P, Durrer S, et al. Endocrine activity and developmental toxicity of cosmetic UV filters–an update. Toxicol. 2004;205:113-122.
14. Schlumpf M, Kypke K, Vökt C, et al. Endocrine active UV filters: developmental toxicity and exposure through breast milk. Chimia. 2008;62:345-351.
15. Nakagawa Y, Suzuki T. Metabolism of 2-hydroxy-4-methoxybenzophenone in isolated rat hepatocytes and xenoestrogenic effects of its metabolites on MCF-7 human breast cancer cells. Chem Biol Interact. 2002;139:115-128.
16. Ma R, Cotton B, Lichtensteiger W, et al. UV filters with antagonistic action at androgen receptors in the MDA-kb2 cell transcriptional-activation assay. Toxicol Sci. 2003;74:43-50.
17. Heneweer M, Muusse M, van den Berg M, et al. Additive estrogenic effects of mixtures of frequently used UV filters on pS2-gene transcription in MCF-7 cells. Toxicol Appl Pharmacol. 2005;208:170-177.
18. Knobler E, Almeida L, Ruzkowski AM, et al. Photoallergy to benzophenone. Arch Dermatol. 1989;125:801-804.
19. Draelos ZD. Are sunscreens safe? J Cosmet Dermatol. 2010;9:1-2.
20. Gilbert E, Pirot F, Bertholle V. Commonly used UV filter toxicity on biological functions: review of last decade studies. Int J of Cosmet Sci. 2013;35:208-219.
21. Wang SQ, Burnett ME, Lim HW. Safety of oxybenzone: putting numbers into perspective. Arch Dermatol. 2011;147:865-866.
22. Mancebo SE, Hu JY, Wang SQ. Sunscreens: a review of health benefits, regulations, and controversies. Dermatol Clin. 2014;32:427-438.
23. Jansen R, Osterwalder U, Wang SQ, et al. Photoprotection: part II. sunscreen: development, efficacy, and controversies. J Am Acad Dermatol. 2013;69:867.e1-867.e14.
24. Janjua NR, Mogensen B, Andersson AM, et al. Systemic absorption of the sunscreens benzo- phenone-3, octyl-methoxycinnamate, and 3-(4-methyl-benzy-lidene) camphor after whole-body topical application and reproductive hormone levels in humans. J Invest Dermatol. 2004;123:57-61.
25. Kadry AM, Chukwuemeka SO, Mohamed S, et al. Pharmacokinetics of benzophenone-3 after oral exposure in male rats. J Appl Toxicol. 1995;15:97-102.
26. Gulson B, McCall M, Korsch M, et al. Small amounts of zinc from zinc oxide particles in sunscreens applied outdoors are absorbed through human skin. Toxicol Sci. 2010;118:140-149.
27. Gulson B, Wong H, Korsch M, et al. Comparison of dermal absorption of zinc from different sunscreen formulations and differing UV exposure based on stable isotope tracing. Sci Total Environ. 2012:420:313-318.
28. Benech-Kieffer F, Meuling WJ, Leclerc C, et al. Percutaneous absorption of Mexoryl SX in human volunteers: comparison with in vitro data. Skin Pharmacol Appl Skin Physiol. 2003;16:343-355.
29. Nash JF. Human safety and efficacy of ultraviolet filters and sunscreen products. Dermatol Clin. 2006;24:35-51.
30. Nohynek GJ, Lademann J, Ribaud C, et al. Grey goo on the skin? nanotechnology, cosmetic and sunscreen safety. Crit Rev Toxicol. 2007;37:251-277.
31. Sadrieh N, Wokovich AM, Gopee NV, et al. Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles. Toxicol Sci. 2010;115:156-166.
32. International Agency for Research on Cancer. Carbon black, titanium dioxide, and talc. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 93. Lyon, France: International Agency for Research on Cancer; 2006.
33. Liao CM, Chiang YH, Chio CP. Model-based assessment for human inhalation exposure risk to airborne nano/fine titanium dioxide particles. Sci Total Environ. 2008:15;407:165-177.
34. Adamcakova-Dodd A, Stebounova LV, Kim JS, et al. Toxicity assessment of zinc oxide nanoparticles using sub-acute and sub-chronic murine inhalation models. Part Fibre Toxicol. 2014;11:15.
35. Wamer WG, Yin JJ, Wei RR. Oxidative damage to nucleic acids photosensitized by titanium dioxide. Free Radic Biol Med. 1997;23:851-858.
36. Nakagawa Y, Wakuri S, Sakamoto K, et al. The photogenotoxicity of titanium dioxide particles. Mutat Res. 1997;394:125-132.
37. Dunford R, Salinaro A, Cai L, et al. Chemical oxidation and DNA damage catalysed by inorganic sunscreen ingredients. FEBS Lett. 1997;418:87-90, 99.
38. Hidaka H, Kobayashi H, Koike T, et al. DNA damage photoinduced by cosmetic pigments and sunscreen agents under solar exposure and artificial UV illumination. J Oleo Sci. 2006;55:249-261.
39. Dufour EK, Kumaravel T, Nohynek GJ, et al. Clastogenicity, photo-clastogenicity or pseudo-photo-clastogenicity: genotoxic effects of zinc oxide in the dark, in pre-irradiated or simultaneously irradiated Chinese hamster ovary cells [published online ahead of print June 21, 2006]. Mutat Res. 2006;607:215-224.
40. Opinion of the Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers concerning titanium dioxide. http://ec.europa.eu/health/archive/ph_risk/committees/sccp/documents/out135_en.pdf. Published October 24, 2000. Accessed December 30, 2014.
41. The Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers opinion concerning zinc oxide. http://ec.europa.eu/health/archive/ph_risk/committees/sccp/documents/out222_en.pdf. Published June 24-25, 2003. Accessed December 30, 2014.
42. Hackenberg S, Friehs G, Kessler M, et al. Nanosized titanium dioxide particles do not induce DNA damage in human peripheral blood lymphocytes. Environ Mol Mutagen. 2010;52:264-268.
43. Bach-Thomsen M, Wulf HC. Sunbather’s application of sunscreen is probably inadequate to obtain the sun protection factor assigned to the preparation. Photodermatol Photoimmunol Photomed. 1993:9;242-244.
44. Nohynek GJ, Antignac E, Re T, et al. Safety assessment of personal care products/cosmetics and their ingredients. Toxicol Appl Pharmacol. 2010:1;243:239-259.
45. Diffey BL. Sunscreens: use and misuse. In: Giacomoni PU, ed. Sun Protection in Man. Vol 3. Amsterdam, the Netherlands: Elsevier Science BV; 2001:521-534.
46. Heneweer M, Muusse M, Van den BM, et al. Additive estrogenic effects of mixtures of frequently used UV-filters on pS2-gene transcription in MCF-7 cells. Toxicol Appl Pharmacol. 2005;208:170-177.
47. Kunz PY, Galicia HF, Fent K. Comparison of in vitro and in vivo estrogenic activity of UV-filters in fish. Toxicol Sci. 2006;90:349-361.
48. Kortenkamp A, Faust M, Scholze M, et al. Low-level exposure to multiple chemicals: reason for human health concerns? Environ Health Perspect. 2007;115(suppl 1):106-114.
49. Labeling and effectiveness testing: sunscreen drug products for over-the-counter human use—small entity compliance guide. US Food and Drug Administration Web site. http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm330694.htm. Published December 2012. Updated May 13, 2014. Accessed December 30, 2014.
50. Schafer-Korting M, Korting HC, Ponce-Poschl E. Liposomal tretinoin for uncomplicated acne vulgaris. Clin Investig. 1994;72:1086-1091.
51. Bronfenbrener R. Simplifying sun safety: a guide to the new FDA sunscreen monograph. Cutis. 2014;93:e17-e19.
1. Skin cancer statistics. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/cancer/skin/statistics/index.htm. Updated September 2, 2014. Accessed December 30, 2014.
2. World Health Organization, International Agency for Research on Cancer. Solar and ultraviolet radiation. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 55. Lyon, France: International Agency for Research on Cancer; 1992.
3. Green AC, Williams GM, Logan V, et al. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol. 2011;29:257-263.
4. Darlington S, Williams G, Neale R, et al. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol. 2003;139:451-455.
5. Van der Pols JC, Williams GM, Pandeya N, et al. Prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol Biomarkers Prev. 2006;15:2546-2548.
6. Hughes MC, Williams GM, Baker P, et al. Sunscreen and prevention of skin aging: a randomized trial. Ann Intern Med. 2013;158:781-790.
7. Bissonnette R, Nigen S, Bolduc C. Influence of the quantity of sunscreen applied on the ability to protect against ultraviolet-induced polymorphous light eruption. Photodermatol Photoimmunol Photomed. 2012;28:240-243.
8. Cancer trends progress report 2011/2012 update: sun protection. National Cancer Institute Web site. http://progressreport.cancer.gov/doc_detail.asp?pid¡1&did¡2009&chid¡91&coid¡911. Accessed December 30, 2014.
9. Sunscreen Drug Products for Over-the-counter Human Use, 21 CFR §352.10. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=352.10. Updated September 1, 2014. Accessed December 30, 2014.
10. Burnett ME, Wang SQ. Current sunscreen controversies: a critical review. Photodermatol Photoimmunol Photomed. 2011;27:58-67.
11. Krause M, Klit A, Blomberg Jensen M, et al. Sunscreens: are they beneficial for health? an overview of endocrine disrupting properties of UV-filters. Int J Androl. 2012;35:424-436.
12. Schlumpf M, Cotton B, Conscience M, et al. In vitro and in vivo estrogenicity of UV screens. Environ Health Perspect. 2001;109:239-244.
13. Schlumpf M, Schmid P, Durrer S, et al. Endocrine activity and developmental toxicity of cosmetic UV filters–an update. Toxicol. 2004;205:113-122.
14. Schlumpf M, Kypke K, Vökt C, et al. Endocrine active UV filters: developmental toxicity and exposure through breast milk. Chimia. 2008;62:345-351.
15. Nakagawa Y, Suzuki T. Metabolism of 2-hydroxy-4-methoxybenzophenone in isolated rat hepatocytes and xenoestrogenic effects of its metabolites on MCF-7 human breast cancer cells. Chem Biol Interact. 2002;139:115-128.
16. Ma R, Cotton B, Lichtensteiger W, et al. UV filters with antagonistic action at androgen receptors in the MDA-kb2 cell transcriptional-activation assay. Toxicol Sci. 2003;74:43-50.
17. Heneweer M, Muusse M, van den Berg M, et al. Additive estrogenic effects of mixtures of frequently used UV filters on pS2-gene transcription in MCF-7 cells. Toxicol Appl Pharmacol. 2005;208:170-177.
18. Knobler E, Almeida L, Ruzkowski AM, et al. Photoallergy to benzophenone. Arch Dermatol. 1989;125:801-804.
19. Draelos ZD. Are sunscreens safe? J Cosmet Dermatol. 2010;9:1-2.
20. Gilbert E, Pirot F, Bertholle V. Commonly used UV filter toxicity on biological functions: review of last decade studies. Int J of Cosmet Sci. 2013;35:208-219.
21. Wang SQ, Burnett ME, Lim HW. Safety of oxybenzone: putting numbers into perspective. Arch Dermatol. 2011;147:865-866.
22. Mancebo SE, Hu JY, Wang SQ. Sunscreens: a review of health benefits, regulations, and controversies. Dermatol Clin. 2014;32:427-438.
23. Jansen R, Osterwalder U, Wang SQ, et al. Photoprotection: part II. sunscreen: development, efficacy, and controversies. J Am Acad Dermatol. 2013;69:867.e1-867.e14.
24. Janjua NR, Mogensen B, Andersson AM, et al. Systemic absorption of the sunscreens benzo- phenone-3, octyl-methoxycinnamate, and 3-(4-methyl-benzy-lidene) camphor after whole-body topical application and reproductive hormone levels in humans. J Invest Dermatol. 2004;123:57-61.
25. Kadry AM, Chukwuemeka SO, Mohamed S, et al. Pharmacokinetics of benzophenone-3 after oral exposure in male rats. J Appl Toxicol. 1995;15:97-102.
26. Gulson B, McCall M, Korsch M, et al. Small amounts of zinc from zinc oxide particles in sunscreens applied outdoors are absorbed through human skin. Toxicol Sci. 2010;118:140-149.
27. Gulson B, Wong H, Korsch M, et al. Comparison of dermal absorption of zinc from different sunscreen formulations and differing UV exposure based on stable isotope tracing. Sci Total Environ. 2012:420:313-318.
28. Benech-Kieffer F, Meuling WJ, Leclerc C, et al. Percutaneous absorption of Mexoryl SX in human volunteers: comparison with in vitro data. Skin Pharmacol Appl Skin Physiol. 2003;16:343-355.
29. Nash JF. Human safety and efficacy of ultraviolet filters and sunscreen products. Dermatol Clin. 2006;24:35-51.
30. Nohynek GJ, Lademann J, Ribaud C, et al. Grey goo on the skin? nanotechnology, cosmetic and sunscreen safety. Crit Rev Toxicol. 2007;37:251-277.
31. Sadrieh N, Wokovich AM, Gopee NV, et al. Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles. Toxicol Sci. 2010;115:156-166.
32. International Agency for Research on Cancer. Carbon black, titanium dioxide, and talc. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 93. Lyon, France: International Agency for Research on Cancer; 2006.
33. Liao CM, Chiang YH, Chio CP. Model-based assessment for human inhalation exposure risk to airborne nano/fine titanium dioxide particles. Sci Total Environ. 2008:15;407:165-177.
34. Adamcakova-Dodd A, Stebounova LV, Kim JS, et al. Toxicity assessment of zinc oxide nanoparticles using sub-acute and sub-chronic murine inhalation models. Part Fibre Toxicol. 2014;11:15.
35. Wamer WG, Yin JJ, Wei RR. Oxidative damage to nucleic acids photosensitized by titanium dioxide. Free Radic Biol Med. 1997;23:851-858.
36. Nakagawa Y, Wakuri S, Sakamoto K, et al. The photogenotoxicity of titanium dioxide particles. Mutat Res. 1997;394:125-132.
37. Dunford R, Salinaro A, Cai L, et al. Chemical oxidation and DNA damage catalysed by inorganic sunscreen ingredients. FEBS Lett. 1997;418:87-90, 99.
38. Hidaka H, Kobayashi H, Koike T, et al. DNA damage photoinduced by cosmetic pigments and sunscreen agents under solar exposure and artificial UV illumination. J Oleo Sci. 2006;55:249-261.
39. Dufour EK, Kumaravel T, Nohynek GJ, et al. Clastogenicity, photo-clastogenicity or pseudo-photo-clastogenicity: genotoxic effects of zinc oxide in the dark, in pre-irradiated or simultaneously irradiated Chinese hamster ovary cells [published online ahead of print June 21, 2006]. Mutat Res. 2006;607:215-224.
40. Opinion of the Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers concerning titanium dioxide. http://ec.europa.eu/health/archive/ph_risk/committees/sccp/documents/out135_en.pdf. Published October 24, 2000. Accessed December 30, 2014.
41. The Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers opinion concerning zinc oxide. http://ec.europa.eu/health/archive/ph_risk/committees/sccp/documents/out222_en.pdf. Published June 24-25, 2003. Accessed December 30, 2014.
42. Hackenberg S, Friehs G, Kessler M, et al. Nanosized titanium dioxide particles do not induce DNA damage in human peripheral blood lymphocytes. Environ Mol Mutagen. 2010;52:264-268.
43. Bach-Thomsen M, Wulf HC. Sunbather’s application of sunscreen is probably inadequate to obtain the sun protection factor assigned to the preparation. Photodermatol Photoimmunol Photomed. 1993:9;242-244.
44. Nohynek GJ, Antignac E, Re T, et al. Safety assessment of personal care products/cosmetics and their ingredients. Toxicol Appl Pharmacol. 2010:1;243:239-259.
45. Diffey BL. Sunscreens: use and misuse. In: Giacomoni PU, ed. Sun Protection in Man. Vol 3. Amsterdam, the Netherlands: Elsevier Science BV; 2001:521-534.
46. Heneweer M, Muusse M, Van den BM, et al. Additive estrogenic effects of mixtures of frequently used UV-filters on pS2-gene transcription in MCF-7 cells. Toxicol Appl Pharmacol. 2005;208:170-177.
47. Kunz PY, Galicia HF, Fent K. Comparison of in vitro and in vivo estrogenic activity of UV-filters in fish. Toxicol Sci. 2006;90:349-361.
48. Kortenkamp A, Faust M, Scholze M, et al. Low-level exposure to multiple chemicals: reason for human health concerns? Environ Health Perspect. 2007;115(suppl 1):106-114.
49. Labeling and effectiveness testing: sunscreen drug products for over-the-counter human use—small entity compliance guide. US Food and Drug Administration Web site. http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm330694.htm. Published December 2012. Updated May 13, 2014. Accessed December 30, 2014.
50. Schafer-Korting M, Korting HC, Ponce-Poschl E. Liposomal tretinoin for uncomplicated acne vulgaris. Clin Investig. 1994;72:1086-1091.
51. Bronfenbrener R. Simplifying sun safety: a guide to the new FDA sunscreen monograph. Cutis. 2014;93:e17-e19.
Does Your Dermatology Center Need a Dermatoscenter?
There are anecdotal reports of dogs detecting melanoma and studies of canines being able to not only detect but also distinguish cancer from noncancer. Analysis of volatile compounds or metabolites from exhaled human breath and excreted urine also has been shown to differentiate between patients with certain cancers and healthy individuals. In addition, investigators have demonstrated that melanoma tissue has a volatile profile that is distinct from healthy nonneoplastic skin and nevi.
Abaffy et al (Metabolomics. 2013;9:998-1008) conducted a study that gives further support to the potential for analyzing volatile organic compounds as biomarkers of melanoma. They used the headspace solid phase microextraction method followed by gas chromatography and mass spectrometry to compare the volatile metabolic profiles of melanoma and nonneoplastic healthy-appearing adjacent skin from the same patient. They discovered increased levels of lauric acid (C12:0) and palmitic acid (C16:0) in melanoma and they postulated that the increased levels of these fatty acids were due to cancer-associated upregulation of de novo lipid synthesis.
What’s the issue?
In the 1980s, nail fold capillary microscopy using an ophthalmoscope was occasionally performed to evaluate for disease-associated vascular changes in patients who were being evaluated for connective tissue disorders. Within 2 decades, a dermoscope to assist in the evaluation of not only nail folds but also pigmented and other lesions replaced the ophthalmoscope. The US Food and Drug Administration recently approved a software-driven optical imaging and data analysis device that can be used to obtain additional information to assist the clinician in making a decision whether to biopsy a pigmented lesion.
As our ability to develop more sensitive and specific methods to diagnose melanoma and differentiate it from benign lesions advances, our approach to the evaluation of patients with pigmented lesions shall continue to be modified. Based on the detection of melanoma-associated volatile organic compounds coupled with their potential use as readily accessible tumor-related biomarkers, it is reasonable to speculate: (1) that a handheld office-based device, a dermatoscenter, that can identify melanoma-induced volatile tumor markers shall be developed to evaluate whether pigmented lesions are malignant or benign, and (2) that this device will eventually become an integral component of the dermatologist’s diagnostic armamentarium. Does your dermatology center need a dermatoscenter?
There are anecdotal reports of dogs detecting melanoma and studies of canines being able to not only detect but also distinguish cancer from noncancer. Analysis of volatile compounds or metabolites from exhaled human breath and excreted urine also has been shown to differentiate between patients with certain cancers and healthy individuals. In addition, investigators have demonstrated that melanoma tissue has a volatile profile that is distinct from healthy nonneoplastic skin and nevi.
Abaffy et al (Metabolomics. 2013;9:998-1008) conducted a study that gives further support to the potential for analyzing volatile organic compounds as biomarkers of melanoma. They used the headspace solid phase microextraction method followed by gas chromatography and mass spectrometry to compare the volatile metabolic profiles of melanoma and nonneoplastic healthy-appearing adjacent skin from the same patient. They discovered increased levels of lauric acid (C12:0) and palmitic acid (C16:0) in melanoma and they postulated that the increased levels of these fatty acids were due to cancer-associated upregulation of de novo lipid synthesis.
What’s the issue?
In the 1980s, nail fold capillary microscopy using an ophthalmoscope was occasionally performed to evaluate for disease-associated vascular changes in patients who were being evaluated for connective tissue disorders. Within 2 decades, a dermoscope to assist in the evaluation of not only nail folds but also pigmented and other lesions replaced the ophthalmoscope. The US Food and Drug Administration recently approved a software-driven optical imaging and data analysis device that can be used to obtain additional information to assist the clinician in making a decision whether to biopsy a pigmented lesion.
As our ability to develop more sensitive and specific methods to diagnose melanoma and differentiate it from benign lesions advances, our approach to the evaluation of patients with pigmented lesions shall continue to be modified. Based on the detection of melanoma-associated volatile organic compounds coupled with their potential use as readily accessible tumor-related biomarkers, it is reasonable to speculate: (1) that a handheld office-based device, a dermatoscenter, that can identify melanoma-induced volatile tumor markers shall be developed to evaluate whether pigmented lesions are malignant or benign, and (2) that this device will eventually become an integral component of the dermatologist’s diagnostic armamentarium. Does your dermatology center need a dermatoscenter?
There are anecdotal reports of dogs detecting melanoma and studies of canines being able to not only detect but also distinguish cancer from noncancer. Analysis of volatile compounds or metabolites from exhaled human breath and excreted urine also has been shown to differentiate between patients with certain cancers and healthy individuals. In addition, investigators have demonstrated that melanoma tissue has a volatile profile that is distinct from healthy nonneoplastic skin and nevi.
Abaffy et al (Metabolomics. 2013;9:998-1008) conducted a study that gives further support to the potential for analyzing volatile organic compounds as biomarkers of melanoma. They used the headspace solid phase microextraction method followed by gas chromatography and mass spectrometry to compare the volatile metabolic profiles of melanoma and nonneoplastic healthy-appearing adjacent skin from the same patient. They discovered increased levels of lauric acid (C12:0) and palmitic acid (C16:0) in melanoma and they postulated that the increased levels of these fatty acids were due to cancer-associated upregulation of de novo lipid synthesis.
What’s the issue?
In the 1980s, nail fold capillary microscopy using an ophthalmoscope was occasionally performed to evaluate for disease-associated vascular changes in patients who were being evaluated for connective tissue disorders. Within 2 decades, a dermoscope to assist in the evaluation of not only nail folds but also pigmented and other lesions replaced the ophthalmoscope. The US Food and Drug Administration recently approved a software-driven optical imaging and data analysis device that can be used to obtain additional information to assist the clinician in making a decision whether to biopsy a pigmented lesion.
As our ability to develop more sensitive and specific methods to diagnose melanoma and differentiate it from benign lesions advances, our approach to the evaluation of patients with pigmented lesions shall continue to be modified. Based on the detection of melanoma-associated volatile organic compounds coupled with their potential use as readily accessible tumor-related biomarkers, it is reasonable to speculate: (1) that a handheld office-based device, a dermatoscenter, that can identify melanoma-induced volatile tumor markers shall be developed to evaluate whether pigmented lesions are malignant or benign, and (2) that this device will eventually become an integral component of the dermatologist’s diagnostic armamentarium. Does your dermatology center need a dermatoscenter?
