Melanoma

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

[email protected]

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

[email protected]

LAS VEGAS – The incidence of melanoma in the United States continues to increase, yet mortality from the disease has been stable and may even be starting to decline, according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.

A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”

Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.

The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”

Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.

Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”

Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”

Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).

“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”

Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.

SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.

[email protected]

Certain myeloablative conditioning regimens are among several novel risk factors for melanoma after allogeneic hematopoietic stem cell transplantation (HCT), according to findings from a nested case-control study.

The study included 140 cases of melanoma and 557 controls matched by age at HCT, sex, primary disease, and survival time. The results showed a significantly increased melanoma risk in HCT survivors who received total body irradiation–based myeloablative conditioning, reduced-intensity conditioning with melphalan, or reduced-intensity conditioning with fludarabine, compared with those who received busulfan-based myeloablative conditioning (odds ratios, 1.77, 2.60, and 2.72, respectively), Megan M. Herr, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues reported in the Journal of the American Academy of Dermatology.

Melanoma risk also was increased in patients who experienced acute graft-versus-host disease (GVHD) with stage 2 or greater skin involvement (OR, 1.92 vs. those with no acute GVHD), chronic GVHD without skin involvement (OR, 1.91 vs. those with no chronic GVHD), or keratinocytic carcinoma (OR, 2.37), and in those who resided in areas with higher ambient ultraviolet radiation (OR for the highest vs. lowest tertile, 1.64).

The UV radiation finding was more pronounced for melanomas occurring 6 or more years after transplant (OR, 3.04 for highest vs. lowest tertile), whereas ambient UV radiation was not associated with melanomas occurring earlier (ORs, 1.37 for less than 3 years and 0.98 at 3-6 years), the investigators noted.

The findings, based on large-scale and detailed clinical data from the Center for International Blood and Marrow Transplant Research for HCT performed during 1985-2012, show that melanoma after HCT has a multifactorial etiology that includes patient-, transplant-, and posttransplant-related factors, they said, noting that the findings also underscore the importance of “prioritization of high-risk survivors for adherence to prevention and screening recommendations.”

Those recommendations call for routine skin examination and photoprotective precautions – particularly in HCT survivors at the highest risk – but studies of screening behaviors suggest that fewer than two-thirds of HCT survivors adhere to these recommendations, they said, concluding that further research on the cost-effectiveness of melanoma screening is warranted, as is investigation into whether current approaches are associated with melanoma risk.

This work was supported by the intramural research program of the National Cancer Institute, the National Institutes of Health, and the Department of Health & Human Services. The authors reported having no conflicts of interest.

[email protected]

SOURCE: Herr MM et al. J Am Acad Dermatol. 2019 Oct 22. doi: 10.1016/j.jaad.2019.10.034.




 

Certain myeloablative conditioning regimens are among several novel risk factors for melanoma after allogeneic hematopoietic stem cell transplantation (HCT), according to findings from a nested case-control study.

The study included 140 cases of melanoma and 557 controls matched by age at HCT, sex, primary disease, and survival time. The results showed a significantly increased melanoma risk in HCT survivors who received total body irradiation–based myeloablative conditioning, reduced-intensity conditioning with melphalan, or reduced-intensity conditioning with fludarabine, compared with those who received busulfan-based myeloablative conditioning (odds ratios, 1.77, 2.60, and 2.72, respectively), Megan M. Herr, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues reported in the Journal of the American Academy of Dermatology.

Melanoma risk also was increased in patients who experienced acute graft-versus-host disease (GVHD) with stage 2 or greater skin involvement (OR, 1.92 vs. those with no acute GVHD), chronic GVHD without skin involvement (OR, 1.91 vs. those with no chronic GVHD), or keratinocytic carcinoma (OR, 2.37), and in those who resided in areas with higher ambient ultraviolet radiation (OR for the highest vs. lowest tertile, 1.64).

The UV radiation finding was more pronounced for melanomas occurring 6 or more years after transplant (OR, 3.04 for highest vs. lowest tertile), whereas ambient UV radiation was not associated with melanomas occurring earlier (ORs, 1.37 for less than 3 years and 0.98 at 3-6 years), the investigators noted.

The findings, based on large-scale and detailed clinical data from the Center for International Blood and Marrow Transplant Research for HCT performed during 1985-2012, show that melanoma after HCT has a multifactorial etiology that includes patient-, transplant-, and posttransplant-related factors, they said, noting that the findings also underscore the importance of “prioritization of high-risk survivors for adherence to prevention and screening recommendations.”

Those recommendations call for routine skin examination and photoprotective precautions – particularly in HCT survivors at the highest risk – but studies of screening behaviors suggest that fewer than two-thirds of HCT survivors adhere to these recommendations, they said, concluding that further research on the cost-effectiveness of melanoma screening is warranted, as is investigation into whether current approaches are associated with melanoma risk.

This work was supported by the intramural research program of the National Cancer Institute, the National Institutes of Health, and the Department of Health & Human Services. The authors reported having no conflicts of interest.

[email protected]

SOURCE: Herr MM et al. J Am Acad Dermatol. 2019 Oct 22. doi: 10.1016/j.jaad.2019.10.034.




 

Certain myeloablative conditioning regimens are among several novel risk factors for melanoma after allogeneic hematopoietic stem cell transplantation (HCT), according to findings from a nested case-control study.

The study included 140 cases of melanoma and 557 controls matched by age at HCT, sex, primary disease, and survival time. The results showed a significantly increased melanoma risk in HCT survivors who received total body irradiation–based myeloablative conditioning, reduced-intensity conditioning with melphalan, or reduced-intensity conditioning with fludarabine, compared with those who received busulfan-based myeloablative conditioning (odds ratios, 1.77, 2.60, and 2.72, respectively), Megan M. Herr, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues reported in the Journal of the American Academy of Dermatology.

Melanoma risk also was increased in patients who experienced acute graft-versus-host disease (GVHD) with stage 2 or greater skin involvement (OR, 1.92 vs. those with no acute GVHD), chronic GVHD without skin involvement (OR, 1.91 vs. those with no chronic GVHD), or keratinocytic carcinoma (OR, 2.37), and in those who resided in areas with higher ambient ultraviolet radiation (OR for the highest vs. lowest tertile, 1.64).

The UV radiation finding was more pronounced for melanomas occurring 6 or more years after transplant (OR, 3.04 for highest vs. lowest tertile), whereas ambient UV radiation was not associated with melanomas occurring earlier (ORs, 1.37 for less than 3 years and 0.98 at 3-6 years), the investigators noted.

The findings, based on large-scale and detailed clinical data from the Center for International Blood and Marrow Transplant Research for HCT performed during 1985-2012, show that melanoma after HCT has a multifactorial etiology that includes patient-, transplant-, and posttransplant-related factors, they said, noting that the findings also underscore the importance of “prioritization of high-risk survivors for adherence to prevention and screening recommendations.”

Those recommendations call for routine skin examination and photoprotective precautions – particularly in HCT survivors at the highest risk – but studies of screening behaviors suggest that fewer than two-thirds of HCT survivors adhere to these recommendations, they said, concluding that further research on the cost-effectiveness of melanoma screening is warranted, as is investigation into whether current approaches are associated with melanoma risk.

This work was supported by the intramural research program of the National Cancer Institute, the National Institutes of Health, and the Department of Health & Human Services. The authors reported having no conflicts of interest.

[email protected]

SOURCE: Herr MM et al. J Am Acad Dermatol. 2019 Oct 22. doi: 10.1016/j.jaad.2019.10.034.




 

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

Dermatologists are increasingly called on to evaluate patients with complex medical problems who are often taking many medications. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system have been developed. Increased skin cancer risk has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature and data regarding the significance and strength of these associations and the molecular pathways by which these medications promote cutaneous tumorigenesis. The association of skin cancer with drugs that either induce photosensitivity—nonsteroidal anti-inflammatory drugs, antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole), voriconazole, thiazides—or suppress the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is therefore not reviewed in this discussion.

BRAF Inhibitors

The mitogen-activated protein kinase (MAPK) pathway (also known as the RAS/RAF/MAPK signaling pathway) is important in growth factor–receptor signaling and plays a key role in cell differentiation, survival, and proliferation. Activating mutations in this pathway allow cells to grow and proliferate in a growth factor–independent manner. Twenty percent of human cancers harbor a mutation in the RAS oncogene, an upstream mediator of the pathway.¹ Activating mutations in BRAF, a serine/threonine kinase, predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, 10% to 20% of cholangiocarcinomas, and 5% to 20% of colorectal carcinomas. The most common BRAF mutation in cutaneous melanoma is V600E, which involves a glutamic acid for valine substitution at codon 600. This mutation activates BRAF 500-fold and is present in approximately 50% of melanomas.^1,2

Vemurafenib, a selective BRAF inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in the United States in 2011. Phase 3 trial data demonstrated that vemurafenib resulted in improved survival and decreased risk for disease progression compared to dacarbazine, the former best treatment.³ During phase 1 testing, it became apparent that vemurafenib treatment was associated with a 31% increased risk for squamous cell carcinoma (SCC), most commonly well-differentiated SCC, and keratoacanthomas (KAs).⁴ This association was confirmed in phase 2 and 3 studies, though the incidence was lower. McArthur et al⁵ reported a 19% incidence of cutaneous SCC with extended follow-up analysis of the phase 3 trial. Dabrafenib, another BRAF inhibitor, has been similarly associated with increasing the risk for SCC and KA.

In one study, the mean time to development of SCC after initiating vemurafenib therapy was 10 weeks, with lesions reported as early as 3 weeks. Most patients had clinical signs of chronically sun damaged skin; however, a history of SCC was present in only 17%. Most lesions (63%) were characterized as KAs.⁶

The mechanism for BRAF inhibitor–induced squamoproliferative growth is due to paradoxical activation of the MAPK pathway in cells with wild-type BRAF that harbor upstream-activating mutations in RAS or tyrosine kinase receptors.⁷ In the presence of a BRAF inhibitor, inactivated BRAF forms heterodimers with wild-type CRAF (a BRAF-CRAF heterodimer). The heterodimer forms a complex with the mutant RAS that leads to transactivation of the CRAF molecule,^8,9 resulting in a paradoxical increase in MAPK signaling and consequent ERK phosphorylation and activation through CRAF signaling. RAS, particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, it is thought that vemurafenib potentiates tumorigenesis in subclinical lesions harboring upstream MAPK pathway mutations as opposed to inducing de novo lesions.⁶

Because BRAF inhibitors are remarkably efficacious in the treatment of metastatic melanomas harboring the V600E BRAF mutation, there are no restrictions on their use, despite the known increased risk for SCC. Squamous cell carcinomas tend to be low grade, and all tumors that developed in phase 1 to 3 trials were treated with simple excision. The development of SCC did not necessitate interruption of treatment. Furthermore, the addition of MEK inhibition to BRAF inhibitor therapy reduces the risk for SCC from 19% to 7%.^7,10,11

In addition to SCC, second primary melanomas (SPMs) have been reported in patients treated with BRAF inhibitors. It has been shown that these melanomas occur in melanocytes with wild-type BRAF. It has been postulated that some of these tumors occur in cells that harbor upstream mutations in RAS, whereas others might result from alternate signaling through non-RAF oncogenic pathways.^9,12

Zimmer et al¹ reported 12 SPMs in 11 patients treated with BRAF inhibitor therapy. They reported a median delay of 8 weeks (range, 4–27 weeks) for SPM development. Tumors were detected in early stages; 1 tumor harbored an NRAS mutation.¹

Dalle et al¹³ reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.¹³

The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.² Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.

Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.¹⁴ Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.^15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.¹⁶

Sonic Hedgehog–Inhibiting Agents

Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.¹⁷ The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,^17,18 though long-term utility is limited by drug resistance with extended use in this patient population.^19,20 Several case reports have documented the emergence of KA²¹ and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.^22-24 A larger case-control study by Mohan et al²⁵ showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).

The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.²⁶ Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.²⁵ These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.^25,26

The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro²⁷ examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.²⁷

Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al²⁵ observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.

JAK Inhibitors

Another class of medications potentially associated with increased development of nonmelanoma skin cancer (NMSC) is the JAK inhibitors (also known as jakinibs). Many proinflammatory signaling pathways converge on the JAK family of enzymes—JAK1, JAK2, JAK3, and TYK2. These enzymes operate in cytokine signal transduction by phosphorylating activated cytokine receptors, which allows for recruitment and activation by means of phosphorylation of transcription factors collectively known as signal transducers and activators of transcription (STATs). Phosphorylated STATs dimerize and translocate to the nucleus, acting as direct transcription promoters. Janus kinase inhibitors modulate the immune response by reducing the effect of interleukin and interferon signaling.

Ruxolitinib, a JAK1/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA and is indicated for the treatment of myelofibrosis and polycythemia vera. Additionally, oral and topical JAK inhibitors have shown efficacy in the treatment of psoriasis, rheumatoid arthritis, alopecia areata, vitiligo, and pruritus from atopic dermatitis.²⁸

The JAK-STAT pathway is complex, and the biological activity of the pathway is both proinflammatory and pro–cell survival and proliferation. Because signaling through the pathway can increase angiogenesis and inhibit apoptosis, inhibition of this pathway has been exploited for the treatment of some tumors. However, inhibition of interferon and proinflammatory interleukin signaling also can potentially promote tumor growth by means of inhibition of downstream cytotoxic T-cell signaling, theoretically increasing the risk for NMSC. A study examining the 5-year efficacy of ruxolitinib in myelofibrosis patients (COMFORT-II trial) found that 17.1% of patients developed NMSC compared to only 2.7% of those on the best available therapy. After adjustment by patient exposure, the NMSC rate was still doubled for ruxolitinib-treated patients compared to controls (6.1/100 patient-years and 3.0/100 patient-years, respectively).²⁹ Eighty-week follow-up of the phase 3 clinical trial of ruxolitinib for the treatment of polycythemia vera also noted an increased incidence of NMSC, albeit a more conservative increase. Patients randomized to the ruxolitinib treatment group developed NMSC at a rate of 4.4/100 patient-years, whereas the rate for controls treated with best available therapy was 2.7/100 patient-years.³⁰ In contrast, 5-year follow-up of the COMFORT-I trial, also examining the efficacy of ruxolitinib in myelofibrosis, showed no increased risk for NMSC between ruxolitinib-treated patients and placebo (2.7/100 patient-years and 3.9/100 patient-years, respectively).³¹

A 2017 case series described 5 patients with myelofibrosis who developed multiple skin cancers with aggressive features while receiving ruxolitinib.³² Duration of ruxolitinib therapy ranged from 4 months to 4 years; 3 patients had a history of hydroxyurea exposure, and only 1 patient had a history of NMSC. High-risk cutaneous SCC, undifferentiated pleomorphic sarcoma, and lentigo maligna melanoma (Breslow thickness, 0.45 mm) were among the tumors reported in this series. Although no definitive conclusion can be made regarding the causality of JAK inhibitors in promoting these tumors, the association warrants further investigation. Clinicians should be aware that ruxolitinib might amplify the risk for NMSC in patients with pre-existing genetic or exposure-related susceptibility. Interruption of drug therapy may be necessary in managing patients who develop an aggressive tumor.³²

In contrast, tofacitinib, which specifically inhibits JAK3, carries very low risk, if any, for NMSC when used for the treatment of psoriasis and rheumatoid arthritis. Results from 2 phase 3 trials analyzing the efficacy of tofacitinib in psoriasis demonstrated that only 2 of 1486 patients treated developed NMSC compared to none in the control group.³³ Furthermore, analysis of NMSC across the tofacitinib rheumatoid arthritis clinical program, which included a total of 15,103 patient-years of exposure, demonstrated that the overall NMSC incidence was 0.55 for every 100 patient-years. Of note, the risk in patients receiving high-dose treatment (10 mg vs 5 mg) was nearly doubled in long-term follow-up studies (0.79/100 patient-years and 0.41/100 patient-years, respectively). Overall, the study concluded that treatment with tofacitinib presents no greater increased risk for NMSC than treatment with tumor necrosis factor inhibitors.³³

PDE-5 Inhibitors

Phosphodiesterase 5 inhibitors, such as sildenafil citrate, have been widely prescribed for the treatment of erectile dysfunction. Studies have shown that BRAF-activated melanomas, which occur in approximately 50% to 70% of melanomas, also result in reduced PDE-5 expression.^34-36 In these melanomas, downregulation of PDE-5 results in increased intracellular calcium,³⁶ which has been shown to induce melanoma invasion.^36,37 Given this similarity in molecular pathway between BRAF-activated melanomas and PDE-5 inhibitors, there has been increased concern that PDE-5 inhibitors might be associated with an increased risk for melanoma.

In 2014, Li et al³⁸ published a retrospective analysis suggesting an association with sildenafil and an increased risk for melanoma. Their study utilized the Health Professionals Follow-up Study to identify a statistically significant elevation in the risk for invasive melanoma with both recent sildenafil use (multivariate-adjusted HR=2.24) and use at any time (HR=1.92). These results controlled for confounding variables, such as presence of major chronic disease, use of other erectile dysfunction treatments, family history of melanoma, history of sun exposure, and UV index of the patient’s residence. Notably, the study also found that sildenafil did not affect the incidence of BCC or SCC.³⁸

In 2015, Loeb et al³⁹ also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).³⁹

A 2016 study by Lian et al⁴⁰ looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.⁴⁰

In contrast, a 2017 meta-analysis by Tang et al⁴¹ of 5 studies (3 of which were the aforementioned trials^38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.⁴¹

Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.

Conclusion

Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

Mohs micrographic surgery (MMS) may be a viable alternative to wide margin excision (WME) in selected patients with early-stage invasive melanoma, according to a retrospective cohort study.

In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.

“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.

The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.

In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.

After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).

“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.

The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.

“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.

Mohs micrographic surgery (MMS) may be a viable alternative to wide margin excision (WME) in selected patients with early-stage invasive melanoma, according to a retrospective cohort study.

In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.

“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.

The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.

In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.

After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).

“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.

The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.

“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.

Mohs micrographic surgery (MMS) may be a viable alternative to wide margin excision (WME) in selected patients with early-stage invasive melanoma, according to a retrospective cohort study.

In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.

“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.

The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.

In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.

After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).

“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.

The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.

“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

Join us on Tuesday, October 8, 2019, at 8:00 pm EST on Twitter at #MDedgeChats as we discuss skin cancer, and what’s new in sunscreen, skin of color, and melanoma. 

Special guests include physicians with expertise in dermatology and skin cancer, Anthony Rossi, MD (@DrAnthonyRossi), Julie Amthor Croley, MD, 15k followers on IG (@Drskinandsmiles), and Candrice Heath, MD (@DrCandriceHeath). Background information about the chat can be found below.

What will the conversation cover?

Q1: What are the most common types of skin cancer? 
Q2: What recent research findings can better inform patients about skin cancer risks?
Q3: What’s the difference between melanoma in fair skin vs. darker skin?
Q4: How does the risk of skin cancer differ in people with darker skin?
Q5: Why should sunscreen be used even in the fall and winter?

About Dr. Rossi: 

Dr. Anthony Rossi (@DrAnthonyRossi) is a board-certified dermatologist with fellowship training in Mohs micrographic surgery, cosmetic and laser surgery, and advanced cutaneous oncology at the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College program, both in New York.  He specializes in skin cancer surgery, cosmetic dermatologic surgery, and laser surgery.  

His research includes quality of life in cancer survivors, the use of noninvasive imaging of the skin, and nonsurgical treatments of skin cancer. Additionally, Dr. Rossi is active in dermatologic organizations and advocacy for medicine.

Research and Publications by Dr. Rossi 

About Dr. Heath:
 

Dr. Candrice Heath (@DrCandriceHeath) is Assistant Professor of Dermatology at the Lewis Katz School of Medicine at Temple University in Philadelphia, Pennsylvania with fellowship training in pediatric dermatology at Johns Hopkins University in Baltimore, Maryland. Dr. Heath is triple board certified in pediatrics, dermatology, and pediatric dermatology. She specializes in adult and pediatric dermatology, skin of color, acne, and eczema. Dr. Heath also enjoys educating primary care physicians on the front lines of health care and delivering easy to understand information to consumers. 

Research and publications by Dr. Heath 
Guest host of MDedge podcast: A sunscreen update with Dr. Vincent DeLeo. 
 

About Dr. Croley:  

Dr. Julie Amthor Croley (@Drskinandsmiles) also known as “Dr. Skin and Smiles” has 15,000 followers on Instagram, and is a Chief Dermatology Resident at the University of Texas Medical Branch in Galveston, Texas. She has a special interest in skin cancer and dermatological surgery and hopes to complete a fellowship in Mohs micrographic surgery after residency. In her free time, Dr. Croley enjoys spending time with her husband (an orthopedic surgeon), running and competing in marathons, and spending time on the beach. 

Media coverage by Dr. Croley

Cutaneous melanoma is the most fatal form of skin cancer and is a considerable public health concern in the United States. Early detection and management of skin cancer can lead to decreased morbidity and mortality from skin cancer. As a result, the American Academy of Dermatology Association supports safe sun-protective practices and diligent self-screening for changing lesions.

Sunscreen use is an essential component of sun protection. New regulations from the US Food and Drug Administration (FDA) have left consumers concerned about the safety of sunscreens. According to a recent Cutis editorial from Vincent A. DeLeo, MD, “There is no question that, as physicians, we want to ‘first, do no harm,’ so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data.”

Patients with skin of color experience disproportionately higher morbidity and mortality when diagnosed with melanoma. “Poor prognosis in patients with skin of color is multifactorial and may be due to poor use of sun protection, misconceptions about melanoma risk, atypical clinical presentation, impaired access to care, and delay in diagnosis,” according to a recent Cutis article. 

Population-based skin cancer screening performed exclusively by dermatologists is not practical. Primary care physicians and other experts in melanoma and public health need to be involved in reducing melanoma mortality. 

In this chat, we will provide expert recommendations on the diagnosis of skin cancer, preventive measures, and the latest research discussed among physicians.

Research & Resources

• “Doctor, Do I Need a Skin Check?”
• Assessing the effectiveness of knowledge-based interventions in skin of color populations.
• Melanoma in US Hispanics
• Podcast: Sunscreen update from Dr. Vincent DeLeo
• Windshield and UV exposure  
• Racial, ethnic minorities often don’t practice sun-protective behaviors.
• Sunscreen regulations and advice for your patients.

Join us on Tuesday, October 8, 2019, at 8:00 pm EST on Twitter at #MDedgeChats as we discuss skin cancer, and what’s new in sunscreen, skin of color, and melanoma. 

Special guests include physicians with expertise in dermatology and skin cancer, Anthony Rossi, MD (@DrAnthonyRossi), Julie Amthor Croley, MD, 15k followers on IG (@Drskinandsmiles), and Candrice Heath, MD (@DrCandriceHeath). Background information about the chat can be found below.

What will the conversation cover?

Q1: What are the most common types of skin cancer? 
Q2: What recent research findings can better inform patients about skin cancer risks?
Q3: What’s the difference between melanoma in fair skin vs. darker skin?
Q4: How does the risk of skin cancer differ in people with darker skin?
Q5: Why should sunscreen be used even in the fall and winter?

About Dr. Rossi: 

Dr. Anthony Rossi (@DrAnthonyRossi) is a board-certified dermatologist with fellowship training in Mohs micrographic surgery, cosmetic and laser surgery, and advanced cutaneous oncology at the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College program, both in New York.  He specializes in skin cancer surgery, cosmetic dermatologic surgery, and laser surgery.  

His research includes quality of life in cancer survivors, the use of noninvasive imaging of the skin, and nonsurgical treatments of skin cancer. Additionally, Dr. Rossi is active in dermatologic organizations and advocacy for medicine.

Research and Publications by Dr. Rossi 

About Dr. Heath:
 

Dr. Candrice Heath (@DrCandriceHeath) is Assistant Professor of Dermatology at the Lewis Katz School of Medicine at Temple University in Philadelphia, Pennsylvania with fellowship training in pediatric dermatology at Johns Hopkins University in Baltimore, Maryland. Dr. Heath is triple board certified in pediatrics, dermatology, and pediatric dermatology. She specializes in adult and pediatric dermatology, skin of color, acne, and eczema. Dr. Heath also enjoys educating primary care physicians on the front lines of health care and delivering easy to understand information to consumers. 

Research and publications by Dr. Heath 
Guest host of MDedge podcast: A sunscreen update with Dr. Vincent DeLeo. 
 

About Dr. Croley:  

Dr. Julie Amthor Croley (@Drskinandsmiles) also known as “Dr. Skin and Smiles” has 15,000 followers on Instagram, and is a Chief Dermatology Resident at the University of Texas Medical Branch in Galveston, Texas. She has a special interest in skin cancer and dermatological surgery and hopes to complete a fellowship in Mohs micrographic surgery after residency. In her free time, Dr. Croley enjoys spending time with her husband (an orthopedic surgeon), running and competing in marathons, and spending time on the beach. 

Media coverage by Dr. Croley

Cutaneous melanoma is the most fatal form of skin cancer and is a considerable public health concern in the United States. Early detection and management of skin cancer can lead to decreased morbidity and mortality from skin cancer. As a result, the American Academy of Dermatology Association supports safe sun-protective practices and diligent self-screening for changing lesions.

Sunscreen use is an essential component of sun protection. New regulations from the US Food and Drug Administration (FDA) have left consumers concerned about the safety of sunscreens. According to a recent Cutis editorial from Vincent A. DeLeo, MD, “There is no question that, as physicians, we want to ‘first, do no harm,’ so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data.”

Patients with skin of color experience disproportionately higher morbidity and mortality when diagnosed with melanoma. “Poor prognosis in patients with skin of color is multifactorial and may be due to poor use of sun protection, misconceptions about melanoma risk, atypical clinical presentation, impaired access to care, and delay in diagnosis,” according to a recent Cutis article. 

Population-based skin cancer screening performed exclusively by dermatologists is not practical. Primary care physicians and other experts in melanoma and public health need to be involved in reducing melanoma mortality. 

In this chat, we will provide expert recommendations on the diagnosis of skin cancer, preventive measures, and the latest research discussed among physicians.

Research & Resources

• “Doctor, Do I Need a Skin Check?”
• Assessing the effectiveness of knowledge-based interventions in skin of color populations.
• Melanoma in US Hispanics
• Podcast: Sunscreen update from Dr. Vincent DeLeo
• Windshield and UV exposure  
• Racial, ethnic minorities often don’t practice sun-protective behaviors.
• Sunscreen regulations and advice for your patients.

Join us on Tuesday, October 8, 2019, at 8:00 pm EST on Twitter at #MDedgeChats as we discuss skin cancer, and what’s new in sunscreen, skin of color, and melanoma. 

Special guests include physicians with expertise in dermatology and skin cancer, Anthony Rossi, MD (@DrAnthonyRossi), Julie Amthor Croley, MD, 15k followers on IG (@Drskinandsmiles), and Candrice Heath, MD (@DrCandriceHeath). Background information about the chat can be found below.

What will the conversation cover?

Q1: What are the most common types of skin cancer? 
Q2: What recent research findings can better inform patients about skin cancer risks?
Q3: What’s the difference between melanoma in fair skin vs. darker skin?
Q4: How does the risk of skin cancer differ in people with darker skin?
Q5: Why should sunscreen be used even in the fall and winter?

About Dr. Rossi: 

Dr. Anthony Rossi (@DrAnthonyRossi) is a board-certified dermatologist with fellowship training in Mohs micrographic surgery, cosmetic and laser surgery, and advanced cutaneous oncology at the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College program, both in New York.  He specializes in skin cancer surgery, cosmetic dermatologic surgery, and laser surgery.  

His research includes quality of life in cancer survivors, the use of noninvasive imaging of the skin, and nonsurgical treatments of skin cancer. Additionally, Dr. Rossi is active in dermatologic organizations and advocacy for medicine.

Research and Publications by Dr. Rossi 

About Dr. Heath:
 

Dr. Candrice Heath (@DrCandriceHeath) is Assistant Professor of Dermatology at the Lewis Katz School of Medicine at Temple University in Philadelphia, Pennsylvania with fellowship training in pediatric dermatology at Johns Hopkins University in Baltimore, Maryland. Dr. Heath is triple board certified in pediatrics, dermatology, and pediatric dermatology. She specializes in adult and pediatric dermatology, skin of color, acne, and eczema. Dr. Heath also enjoys educating primary care physicians on the front lines of health care and delivering easy to understand information to consumers. 

Research and publications by Dr. Heath 
Guest host of MDedge podcast: A sunscreen update with Dr. Vincent DeLeo. 
 

About Dr. Croley:  

Dr. Julie Amthor Croley (@Drskinandsmiles) also known as “Dr. Skin and Smiles” has 15,000 followers on Instagram, and is a Chief Dermatology Resident at the University of Texas Medical Branch in Galveston, Texas. She has a special interest in skin cancer and dermatological surgery and hopes to complete a fellowship in Mohs micrographic surgery after residency. In her free time, Dr. Croley enjoys spending time with her husband (an orthopedic surgeon), running and competing in marathons, and spending time on the beach. 

Media coverage by Dr. Croley

Cutaneous melanoma is the most fatal form of skin cancer and is a considerable public health concern in the United States. Early detection and management of skin cancer can lead to decreased morbidity and mortality from skin cancer. As a result, the American Academy of Dermatology Association supports safe sun-protective practices and diligent self-screening for changing lesions.

Sunscreen use is an essential component of sun protection. New regulations from the US Food and Drug Administration (FDA) have left consumers concerned about the safety of sunscreens. According to a recent Cutis editorial from Vincent A. DeLeo, MD, “There is no question that, as physicians, we want to ‘first, do no harm,’ so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data.”

Patients with skin of color experience disproportionately higher morbidity and mortality when diagnosed with melanoma. “Poor prognosis in patients with skin of color is multifactorial and may be due to poor use of sun protection, misconceptions about melanoma risk, atypical clinical presentation, impaired access to care, and delay in diagnosis,” according to a recent Cutis article. 

Population-based skin cancer screening performed exclusively by dermatologists is not practical. Primary care physicians and other experts in melanoma and public health need to be involved in reducing melanoma mortality. 

In this chat, we will provide expert recommendations on the diagnosis of skin cancer, preventive measures, and the latest research discussed among physicians.

Research & Resources

• “Doctor, Do I Need a Skin Check?”
• Assessing the effectiveness of knowledge-based interventions in skin of color populations.
• Melanoma in US Hispanics
• Podcast: Sunscreen update from Dr. Vincent DeLeo
• Windshield and UV exposure  
• Racial, ethnic minorities often don’t practice sun-protective behaviors.
• Sunscreen regulations and advice for your patients.

Australian patients with systemic sclerosis were at greater risk for lung cancer, early breast cancer, and early melanoma when compared with the general population in a population-linked cohort study published in Arthritis Care & Research.

Kathleen Morrisroe, MBBS, PhD, of St. Vincent’s Hospital Melbourne and colleagues matched deidentified patient data in the Australian Scleroderma Cohort Study (ASCS) with patients’ respective state cancer registry data between January 2008 and December 2015. The researchers also used the Australian Medical Benefit Schedule (MBS) to track health care costs for hospital admissions, presentations to the ED, other health visits, pathology, and imaging, as well as other associated costs for care, in each state. Based on this information, Dr. Morrisroe and colleagues calculated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) for these patients by comparing them with the general population in Australia.

The results included 1,727 patients with systemic sclerosis (SSc) and cancer in the cohort, which consisted of mostly white (92.1%) women (85.9%) who had limited cutaneous SSc (73.9%). They were a mean of 46.6 years old when they were diagnosed with SSc and had a mean disease duration of 10.9 years. The incidence of cancer was 1.3% per year, and the overall prevalence for the cohort was 14.2%, which was higher than the general Australian population (SIR, 2.15; 95% confidence interval, 1.84-2.49). Breast cancer, melanoma, hematologic cancer, and lung cancer were the most common types of cancers found in the cohort, with early breast cancer (SIR, 3.07; 95% CI, 1.47-5.64), lung cancer (SIR, 3.07; 95% CI, 1.21-3.44), and early melanoma (SIR, 3.40; 95% CI, 1.10-7.93) having a higher incidence than the general population.

Patients with RNA polymerase III (RNAP) autoantibody had a higher incidence of early onset cancer (odds ratio, 2.9; P = .044), defined as a cancer diagnosis within 5 years of SSc diagnosis. Interstitial lung disease was also linked to an increased risk of lung cancer (OR, 2.83; P = .031), which persisted after the researchers performed a multivariate analysis.

Another factor that increased the overall risk of cancer was calcium channel blockers (OR, 1.47; P = .016), which also increased the risk of breast (OR, 1.61; P = .051) and melanoma-specific cancers (OR, 2.01; P = .042), a finding the researchers said was “unexpected, but has been reported in the literature with conflicting results.”

“This association is hypothesized to be related to the role of calcium in cell apoptosis, such as activation of the caspase pathway, induction of endonuclease activity and mitochondrial permeation,” Dr. Morrisroe and colleagues wrote.

SSc patients had more than a doubling of risk of mortality with incident cancer in comparison with SSc patients who did not have cancer (hazard ratio, 2.85; 95% CI, 1.51-5.37; P = .001). The average cost of health care annually for an SSc patient with cancer was AUD $1,496 (P less than .001), the researchers said.

This study was funded in part by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer. Dr. Morrisroe reported receiving support from Arthritis Australia and Royal Australasian College of Physicians Research Establishment Fellowships. Another author reported receiving a fellowship from the National Health and Medical Research Council of Australia. The other authors reported no relevant conflicts of interest.

SOURCE: Morrisroe K et al. Arthritis Care Res. 2019 Sep 20. doi: 10.1002/acr.24076

Australian patients with systemic sclerosis were at greater risk for lung cancer, early breast cancer, and early melanoma when compared with the general population in a population-linked cohort study published in Arthritis Care & Research.

Kathleen Morrisroe, MBBS, PhD, of St. Vincent’s Hospital Melbourne and colleagues matched deidentified patient data in the Australian Scleroderma Cohort Study (ASCS) with patients’ respective state cancer registry data between January 2008 and December 2015. The researchers also used the Australian Medical Benefit Schedule (MBS) to track health care costs for hospital admissions, presentations to the ED, other health visits, pathology, and imaging, as well as other associated costs for care, in each state. Based on this information, Dr. Morrisroe and colleagues calculated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) for these patients by comparing them with the general population in Australia.

The results included 1,727 patients with systemic sclerosis (SSc) and cancer in the cohort, which consisted of mostly white (92.1%) women (85.9%) who had limited cutaneous SSc (73.9%). They were a mean of 46.6 years old when they were diagnosed with SSc and had a mean disease duration of 10.9 years. The incidence of cancer was 1.3% per year, and the overall prevalence for the cohort was 14.2%, which was higher than the general Australian population (SIR, 2.15; 95% confidence interval, 1.84-2.49). Breast cancer, melanoma, hematologic cancer, and lung cancer were the most common types of cancers found in the cohort, with early breast cancer (SIR, 3.07; 95% CI, 1.47-5.64), lung cancer (SIR, 3.07; 95% CI, 1.21-3.44), and early melanoma (SIR, 3.40; 95% CI, 1.10-7.93) having a higher incidence than the general population.

Patients with RNA polymerase III (RNAP) autoantibody had a higher incidence of early onset cancer (odds ratio, 2.9; P = .044), defined as a cancer diagnosis within 5 years of SSc diagnosis. Interstitial lung disease was also linked to an increased risk of lung cancer (OR, 2.83; P = .031), which persisted after the researchers performed a multivariate analysis.

Another factor that increased the overall risk of cancer was calcium channel blockers (OR, 1.47; P = .016), which also increased the risk of breast (OR, 1.61; P = .051) and melanoma-specific cancers (OR, 2.01; P = .042), a finding the researchers said was “unexpected, but has been reported in the literature with conflicting results.”

“This association is hypothesized to be related to the role of calcium in cell apoptosis, such as activation of the caspase pathway, induction of endonuclease activity and mitochondrial permeation,” Dr. Morrisroe and colleagues wrote.

SSc patients had more than a doubling of risk of mortality with incident cancer in comparison with SSc patients who did not have cancer (hazard ratio, 2.85; 95% CI, 1.51-5.37; P = .001). The average cost of health care annually for an SSc patient with cancer was AUD $1,496 (P less than .001), the researchers said.

This study was funded in part by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer. Dr. Morrisroe reported receiving support from Arthritis Australia and Royal Australasian College of Physicians Research Establishment Fellowships. Another author reported receiving a fellowship from the National Health and Medical Research Council of Australia. The other authors reported no relevant conflicts of interest.

SOURCE: Morrisroe K et al. Arthritis Care Res. 2019 Sep 20. doi: 10.1002/acr.24076

Australian patients with systemic sclerosis were at greater risk for lung cancer, early breast cancer, and early melanoma when compared with the general population in a population-linked cohort study published in Arthritis Care & Research.

Kathleen Morrisroe, MBBS, PhD, of St. Vincent’s Hospital Melbourne and colleagues matched deidentified patient data in the Australian Scleroderma Cohort Study (ASCS) with patients’ respective state cancer registry data between January 2008 and December 2015. The researchers also used the Australian Medical Benefit Schedule (MBS) to track health care costs for hospital admissions, presentations to the ED, other health visits, pathology, and imaging, as well as other associated costs for care, in each state. Based on this information, Dr. Morrisroe and colleagues calculated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) for these patients by comparing them with the general population in Australia.

The results included 1,727 patients with systemic sclerosis (SSc) and cancer in the cohort, which consisted of mostly white (92.1%) women (85.9%) who had limited cutaneous SSc (73.9%). They were a mean of 46.6 years old when they were diagnosed with SSc and had a mean disease duration of 10.9 years. The incidence of cancer was 1.3% per year, and the overall prevalence for the cohort was 14.2%, which was higher than the general Australian population (SIR, 2.15; 95% confidence interval, 1.84-2.49). Breast cancer, melanoma, hematologic cancer, and lung cancer were the most common types of cancers found in the cohort, with early breast cancer (SIR, 3.07; 95% CI, 1.47-5.64), lung cancer (SIR, 3.07; 95% CI, 1.21-3.44), and early melanoma (SIR, 3.40; 95% CI, 1.10-7.93) having a higher incidence than the general population.

Patients with RNA polymerase III (RNAP) autoantibody had a higher incidence of early onset cancer (odds ratio, 2.9; P = .044), defined as a cancer diagnosis within 5 years of SSc diagnosis. Interstitial lung disease was also linked to an increased risk of lung cancer (OR, 2.83; P = .031), which persisted after the researchers performed a multivariate analysis.

Another factor that increased the overall risk of cancer was calcium channel blockers (OR, 1.47; P = .016), which also increased the risk of breast (OR, 1.61; P = .051) and melanoma-specific cancers (OR, 2.01; P = .042), a finding the researchers said was “unexpected, but has been reported in the literature with conflicting results.”

“This association is hypothesized to be related to the role of calcium in cell apoptosis, such as activation of the caspase pathway, induction of endonuclease activity and mitochondrial permeation,” Dr. Morrisroe and colleagues wrote.

SSc patients had more than a doubling of risk of mortality with incident cancer in comparison with SSc patients who did not have cancer (hazard ratio, 2.85; 95% CI, 1.51-5.37; P = .001). The average cost of health care annually for an SSc patient with cancer was AUD $1,496 (P less than .001), the researchers said.

This study was funded in part by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer. Dr. Morrisroe reported receiving support from Arthritis Australia and Royal Australasian College of Physicians Research Establishment Fellowships. Another author reported receiving a fellowship from the National Health and Medical Research Council of Australia. The other authors reported no relevant conflicts of interest.

SOURCE: Morrisroe K et al. Arthritis Care Res. 2019 Sep 20. doi: 10.1002/acr.24076

Although solar radiation is the most commonly recognized source of UV radiation (UVR), occupational exposures can contribute due to the intensity and chronicity of exposure. Arc welding is a process whereby metal is fused together by heat produced from an electric arc. The electric arc that forms between the electrode and the base metal emits radiation in the full UV spectrum including UVA (400–315 nm), UVB (315–290 nm), and UVC (290–100 nm) wavelengths. Welders, therefore, have an increased risk for broad-spectrum, intense exposure to UVR, which may play a notable role in UV-related skin disease without proper protection. We report 3 welders with skin disease attributed to occupational exposure to UVR.

Case Reports

Patient 1
A 41-year-old man presented for evaluation of treatment-resistant cutaneous lupus. During the 10-year disease course, the patient was treated by both dermatologists and rheumatologists with frequent exacerbations and poor disease control. At the time of presentation, treatment with hydroxychloroquine 200 mg twice daily, azathioprine 50 mg twice daily, intramuscular methylprednisolone acetateinjectable suspension 40 mg, and prednisone 20 mg daily was failing. Physical examination revealed polycyclic erythematous plaques typical of subacute cutaneous lupus erythematosus. A skin biopsy confirmed the diagnosis. Upon further discussion of exacerbating risk factors, the patient noted UVR exposure while working as a welder. Although he had been previously told to avoid sunlight, he did not realize that this recommendation included all forms of UV light. Once this work exposure was eliminated, he was restarted on hydroxychloroquine 200 mg twice daily and topical steroids, and he responded with complete and sustained clearance of disease. When he returned to welding, utilization of sunscreen and sun-protective clothing enabled him to maintain control of his subacute cutaneous lupus erythematosus on oral hydroxychloroquine 200 mg twice daily and topical steroids.

Patient 2
A 55-year-old man presented with numerous actinic keratoses and persistent erythema in a well-demarcated area involving the forehead, temples, and lateral cheeks but sparing the periorbital area. The patient also experienced UVR exposure from welding (up to 4 to 5 times per week during his career spanning more than 20 years). He cited frequent burns in areas where his protective equipment did not cover his skin. He also reported that he often forgoes wearing protective equipment, even though it is available, and only uses safety goggles due to the extreme heat of the working environment as well as the awkwardness of wearing full protective gear while performing certain aspects of the job.

Patient 3
A 63-year-old man presented with a growth on the left side of the upper forehead. A biopsy revealed a squamous cell carcinoma, keratoacanthoma type. He worked as a welder for 40 years until retiring 1 year prior to presentation. He welded daily and always wore a tall face shield. Although the face shield covered most of his face, the scalp and some parts of the upper face were not well protected. In addition to the keratoacanthoma, which presented just outside of the area protected by the face shield, the patient had numerous actinic keratoses on the scalp.

Comment

Welding and UVR Exposure
Arc welders endure large amounts of UVR exposure, which is substantial enough to have notable health effects. The duration of exposure, electrical current used, angle of exposure, amount of ventilation, and the distance from the welding arc play a role in overall UVR exposure.^1,2 Maximum permissible exposure (MPE) limits to UVR have been set by the International Commission on Non-Ionizing Radiation Protection and the National Institute for Occupational Safety and Health.^3,4 The quantity of radiation produced by the arc allows for an exposure time of only a few seconds to minutes before surpassing MPE to UV light.^1,5 Welders are exposed to total-body UVR doses up to 3000 times the MPE, and mean cumulative exposure calculated over an 8-hour workday can reach 9795 mJ/cm².⁶

Workers in close proximity to welders also receive large UVR doses and may not be aware of its hazardous effects. Nearby nonwelders can be exposed to 13 times the MPE of UVR.⁶ At distances up to 10 m from the arc, the irradiance is large enough to reach MPE to UVR in less than 3 hours.¹

Skin and Eye Damage From Welding
Exposure to UVR produced by the welding arc may lead to acute skin or eye reactions, chronic skin or eye disorders, or exacerbation of photosensitive diseases. Common acute problems are photokeratoconjunctivitis (welder’s flash) and skin erythema.^7,8

Actinic elastosis, actinic keratoses, ocular melanoma, and photosensitive diseases represent a spectrum of disorders that can present from chronic UV exposure in welders. In a study by Emmett et al⁷ of 152 welders and 58 controls, actinic elastosis was found to be more frequent in welders than controls. Cases of basal cell carcinoma and squamous cell carcinoma also have been reported in welders.^9,10 However, in the study by Emmett et al,⁷ a statistically significant correlation between welding and skin cancer was not documented. There were limitations in the study, such as small sample size and a young average age of welders.⁷ Future studies may be needed to further clarify the risk for skin cancer in welders.

Although there is no clear association with skin cancer, an increased risk of ocular melanoma in welders is more clearly established. A meta-analysis of 5 studies found that welding was a significant risk factor for ocular melanoma, with an odds ratio of 2.05 (95% confidence interval, 1.20-3.51).¹¹ Other reported eye damage from chronic UVR exposure includes cataracts, chronic conjunctivitis, and retinal damage.^12,13

Case reports of the following photosensitive diseases have been reported to be exacerbated or caused by UV light exposure in welders: discoid lupus erythematosus¹⁴; photodermatitis¹⁵; broadband photosensitivity with decreased minimal erythema dose to UVA, UVB, and UVC¹⁶; UVC-exacerbated atopic dermatitis¹⁷; polymorphous light eruption–like skin eruption¹⁸; and UVA-induced photoallergy to hydrochlorothiazide and ramipril.¹⁹

Prevention of Occupational Exposure to UVR
Occupational Safety and Health Administration guidelines protect workers from excessive exposure to UVR with personal protective equipment (PPE). In addition to UVR protection, PPE needs to protect welders from other risks including trauma from welding debris (slag), fires, electrical burns, and fumes. Online resources from the National Ag Safety Database,²⁰ the American Welding Society,²¹ and Occupational Safety and Health Administration^22,23 are available. These resources advise welders to work in ventilated areas with respirators specific for the metal being welded and to wear clothing and gloves that are not only fire retardant but also UV resistant.^20-23 Additional PPE should protect the head, face, and eyes.

Unfortunately, even workers well trained in prevention guidelines may not adequately protect themselves. Some welders forego PPE due to heat, thus exposing themselves to UVR damage in areas that are normally covered. Welders also may forego equipment when working on jobs requiring more detailed welds where clothing, masks, and glasses may be overly bulky and inhibit the worker’s precision. Nontraditional welders, such as artisans or handymen, may not have workplace safety education to be aware of UVR emitted from welding and may not have readily available PPE.

The Figure portrays an amateur welder working without full PPE. Although he is wearing a face shield, he is not wearing fire-retardant clothing, lacks full protective garments, and has no ventilation system.

Conclusion

It is important to recognize welding as an occupation with notable exposure to UVR. Personal protective equipment should be the mainstay of prevention. Sunscreen is a useful adjunct but does not cover UVC that is emitted in the welding arc. Screens and welding blankets can be placed around welders to contain UVR and limit nonwelder exposure. Although UVR hazards should be regulated in the workplace as part of regular safety reviews, the clinician can play a role in recognizing this source of UVR in skin disease and in encouraging the use of PPE.

Although solar radiation is the most commonly recognized source of UV radiation (UVR), occupational exposures can contribute due to the intensity and chronicity of exposure. Arc welding is a process whereby metal is fused together by heat produced from an electric arc. The electric arc that forms between the electrode and the base metal emits radiation in the full UV spectrum including UVA (400–315 nm), UVB (315–290 nm), and UVC (290–100 nm) wavelengths. Welders, therefore, have an increased risk for broad-spectrum, intense exposure to UVR, which may play a notable role in UV-related skin disease without proper protection. We report 3 welders with skin disease attributed to occupational exposure to UVR.

Case Reports

Patient 1
A 41-year-old man presented for evaluation of treatment-resistant cutaneous lupus. During the 10-year disease course, the patient was treated by both dermatologists and rheumatologists with frequent exacerbations and poor disease control. At the time of presentation, treatment with hydroxychloroquine 200 mg twice daily, azathioprine 50 mg twice daily, intramuscular methylprednisolone acetateinjectable suspension 40 mg, and prednisone 20 mg daily was failing. Physical examination revealed polycyclic erythematous plaques typical of subacute cutaneous lupus erythematosus. A skin biopsy confirmed the diagnosis. Upon further discussion of exacerbating risk factors, the patient noted UVR exposure while working as a welder. Although he had been previously told to avoid sunlight, he did not realize that this recommendation included all forms of UV light. Once this work exposure was eliminated, he was restarted on hydroxychloroquine 200 mg twice daily and topical steroids, and he responded with complete and sustained clearance of disease. When he returned to welding, utilization of sunscreen and sun-protective clothing enabled him to maintain control of his subacute cutaneous lupus erythematosus on oral hydroxychloroquine 200 mg twice daily and topical steroids.

Patient 2
A 55-year-old man presented with numerous actinic keratoses and persistent erythema in a well-demarcated area involving the forehead, temples, and lateral cheeks but sparing the periorbital area. The patient also experienced UVR exposure from welding (up to 4 to 5 times per week during his career spanning more than 20 years). He cited frequent burns in areas where his protective equipment did not cover his skin. He also reported that he often forgoes wearing protective equipment, even though it is available, and only uses safety goggles due to the extreme heat of the working environment as well as the awkwardness of wearing full protective gear while performing certain aspects of the job.

Patient 3
A 63-year-old man presented with a growth on the left side of the upper forehead. A biopsy revealed a squamous cell carcinoma, keratoacanthoma type. He worked as a welder for 40 years until retiring 1 year prior to presentation. He welded daily and always wore a tall face shield. Although the face shield covered most of his face, the scalp and some parts of the upper face were not well protected. In addition to the keratoacanthoma, which presented just outside of the area protected by the face shield, the patient had numerous actinic keratoses on the scalp.

Comment

Welding and UVR Exposure
Arc welders endure large amounts of UVR exposure, which is substantial enough to have notable health effects. The duration of exposure, electrical current used, angle of exposure, amount of ventilation, and the distance from the welding arc play a role in overall UVR exposure.^1,2 Maximum permissible exposure (MPE) limits to UVR have been set by the International Commission on Non-Ionizing Radiation Protection and the National Institute for Occupational Safety and Health.^3,4 The quantity of radiation produced by the arc allows for an exposure time of only a few seconds to minutes before surpassing MPE to UV light.^1,5 Welders are exposed to total-body UVR doses up to 3000 times the MPE, and mean cumulative exposure calculated over an 8-hour workday can reach 9795 mJ/cm².⁶

Workers in close proximity to welders also receive large UVR doses and may not be aware of its hazardous effects. Nearby nonwelders can be exposed to 13 times the MPE of UVR.⁶ At distances up to 10 m from the arc, the irradiance is large enough to reach MPE to UVR in less than 3 hours.¹

Skin and Eye Damage From Welding
Exposure to UVR produced by the welding arc may lead to acute skin or eye reactions, chronic skin or eye disorders, or exacerbation of photosensitive diseases. Common acute problems are photokeratoconjunctivitis (welder’s flash) and skin erythema.^7,8

Actinic elastosis, actinic keratoses, ocular melanoma, and photosensitive diseases represent a spectrum of disorders that can present from chronic UV exposure in welders. In a study by Emmett et al⁷ of 152 welders and 58 controls, actinic elastosis was found to be more frequent in welders than controls. Cases of basal cell carcinoma and squamous cell carcinoma also have been reported in welders.^9,10 However, in the study by Emmett et al,⁷ a statistically significant correlation between welding and skin cancer was not documented. There were limitations in the study, such as small sample size and a young average age of welders.⁷ Future studies may be needed to further clarify the risk for skin cancer in welders.

Although there is no clear association with skin cancer, an increased risk of ocular melanoma in welders is more clearly established. A meta-analysis of 5 studies found that welding was a significant risk factor for ocular melanoma, with an odds ratio of 2.05 (95% confidence interval, 1.20-3.51).¹¹ Other reported eye damage from chronic UVR exposure includes cataracts, chronic conjunctivitis, and retinal damage.^12,13

Case reports of the following photosensitive diseases have been reported to be exacerbated or caused by UV light exposure in welders: discoid lupus erythematosus¹⁴; photodermatitis¹⁵; broadband photosensitivity with decreased minimal erythema dose to UVA, UVB, and UVC¹⁶; UVC-exacerbated atopic dermatitis¹⁷; polymorphous light eruption–like skin eruption¹⁸; and UVA-induced photoallergy to hydrochlorothiazide and ramipril.¹⁹

Prevention of Occupational Exposure to UVR
Occupational Safety and Health Administration guidelines protect workers from excessive exposure to UVR with personal protective equipment (PPE). In addition to UVR protection, PPE needs to protect welders from other risks including trauma from welding debris (slag), fires, electrical burns, and fumes. Online resources from the National Ag Safety Database,²⁰ the American Welding Society,²¹ and Occupational Safety and Health Administration^22,23 are available. These resources advise welders to work in ventilated areas with respirators specific for the metal being welded and to wear clothing and gloves that are not only fire retardant but also UV resistant.^20-23 Additional PPE should protect the head, face, and eyes.

Unfortunately, even workers well trained in prevention guidelines may not adequately protect themselves. Some welders forego PPE due to heat, thus exposing themselves to UVR damage in areas that are normally covered. Welders also may forego equipment when working on jobs requiring more detailed welds where clothing, masks, and glasses may be overly bulky and inhibit the worker’s precision. Nontraditional welders, such as artisans or handymen, may not have workplace safety education to be aware of UVR emitted from welding and may not have readily available PPE.

The Figure portrays an amateur welder working without full PPE. Although he is wearing a face shield, he is not wearing fire-retardant clothing, lacks full protective garments, and has no ventilation system.

Conclusion

It is important to recognize welding as an occupation with notable exposure to UVR. Personal protective equipment should be the mainstay of prevention. Sunscreen is a useful adjunct but does not cover UVC that is emitted in the welding arc. Screens and welding blankets can be placed around welders to contain UVR and limit nonwelder exposure. Although UVR hazards should be regulated in the workplace as part of regular safety reviews, the clinician can play a role in recognizing this source of UVR in skin disease and in encouraging the use of PPE.

Although solar radiation is the most commonly recognized source of UV radiation (UVR), occupational exposures can contribute due to the intensity and chronicity of exposure. Arc welding is a process whereby metal is fused together by heat produced from an electric arc. The electric arc that forms between the electrode and the base metal emits radiation in the full UV spectrum including UVA (400–315 nm), UVB (315–290 nm), and UVC (290–100 nm) wavelengths. Welders, therefore, have an increased risk for broad-spectrum, intense exposure to UVR, which may play a notable role in UV-related skin disease without proper protection. We report 3 welders with skin disease attributed to occupational exposure to UVR.

Case Reports

Patient 1
A 41-year-old man presented for evaluation of treatment-resistant cutaneous lupus. During the 10-year disease course, the patient was treated by both dermatologists and rheumatologists with frequent exacerbations and poor disease control. At the time of presentation, treatment with hydroxychloroquine 200 mg twice daily, azathioprine 50 mg twice daily, intramuscular methylprednisolone acetateinjectable suspension 40 mg, and prednisone 20 mg daily was failing. Physical examination revealed polycyclic erythematous plaques typical of subacute cutaneous lupus erythematosus. A skin biopsy confirmed the diagnosis. Upon further discussion of exacerbating risk factors, the patient noted UVR exposure while working as a welder. Although he had been previously told to avoid sunlight, he did not realize that this recommendation included all forms of UV light. Once this work exposure was eliminated, he was restarted on hydroxychloroquine 200 mg twice daily and topical steroids, and he responded with complete and sustained clearance of disease. When he returned to welding, utilization of sunscreen and sun-protective clothing enabled him to maintain control of his subacute cutaneous lupus erythematosus on oral hydroxychloroquine 200 mg twice daily and topical steroids.

Patient 2
A 55-year-old man presented with numerous actinic keratoses and persistent erythema in a well-demarcated area involving the forehead, temples, and lateral cheeks but sparing the periorbital area. The patient also experienced UVR exposure from welding (up to 4 to 5 times per week during his career spanning more than 20 years). He cited frequent burns in areas where his protective equipment did not cover his skin. He also reported that he often forgoes wearing protective equipment, even though it is available, and only uses safety goggles due to the extreme heat of the working environment as well as the awkwardness of wearing full protective gear while performing certain aspects of the job.

Patient 3
A 63-year-old man presented with a growth on the left side of the upper forehead. A biopsy revealed a squamous cell carcinoma, keratoacanthoma type. He worked as a welder for 40 years until retiring 1 year prior to presentation. He welded daily and always wore a tall face shield. Although the face shield covered most of his face, the scalp and some parts of the upper face were not well protected. In addition to the keratoacanthoma, which presented just outside of the area protected by the face shield, the patient had numerous actinic keratoses on the scalp.

Comment

Welding and UVR Exposure
Arc welders endure large amounts of UVR exposure, which is substantial enough to have notable health effects. The duration of exposure, electrical current used, angle of exposure, amount of ventilation, and the distance from the welding arc play a role in overall UVR exposure.^1,2 Maximum permissible exposure (MPE) limits to UVR have been set by the International Commission on Non-Ionizing Radiation Protection and the National Institute for Occupational Safety and Health.^3,4 The quantity of radiation produced by the arc allows for an exposure time of only a few seconds to minutes before surpassing MPE to UV light.^1,5 Welders are exposed to total-body UVR doses up to 3000 times the MPE, and mean cumulative exposure calculated over an 8-hour workday can reach 9795 mJ/cm².⁶

Workers in close proximity to welders also receive large UVR doses and may not be aware of its hazardous effects. Nearby nonwelders can be exposed to 13 times the MPE of UVR.⁶ At distances up to 10 m from the arc, the irradiance is large enough to reach MPE to UVR in less than 3 hours.¹

Skin and Eye Damage From Welding
Exposure to UVR produced by the welding arc may lead to acute skin or eye reactions, chronic skin or eye disorders, or exacerbation of photosensitive diseases. Common acute problems are photokeratoconjunctivitis (welder’s flash) and skin erythema.^7,8

Actinic elastosis, actinic keratoses, ocular melanoma, and photosensitive diseases represent a spectrum of disorders that can present from chronic UV exposure in welders. In a study by Emmett et al⁷ of 152 welders and 58 controls, actinic elastosis was found to be more frequent in welders than controls. Cases of basal cell carcinoma and squamous cell carcinoma also have been reported in welders.^9,10 However, in the study by Emmett et al,⁷ a statistically significant correlation between welding and skin cancer was not documented. There were limitations in the study, such as small sample size and a young average age of welders.⁷ Future studies may be needed to further clarify the risk for skin cancer in welders.

Although there is no clear association with skin cancer, an increased risk of ocular melanoma in welders is more clearly established. A meta-analysis of 5 studies found that welding was a significant risk factor for ocular melanoma, with an odds ratio of 2.05 (95% confidence interval, 1.20-3.51).¹¹ Other reported eye damage from chronic UVR exposure includes cataracts, chronic conjunctivitis, and retinal damage.^12,13

Case reports of the following photosensitive diseases have been reported to be exacerbated or caused by UV light exposure in welders: discoid lupus erythematosus¹⁴; photodermatitis¹⁵; broadband photosensitivity with decreased minimal erythema dose to UVA, UVB, and UVC¹⁶; UVC-exacerbated atopic dermatitis¹⁷; polymorphous light eruption–like skin eruption¹⁸; and UVA-induced photoallergy to hydrochlorothiazide and ramipril.¹⁹

Prevention of Occupational Exposure to UVR
Occupational Safety and Health Administration guidelines protect workers from excessive exposure to UVR with personal protective equipment (PPE). In addition to UVR protection, PPE needs to protect welders from other risks including trauma from welding debris (slag), fires, electrical burns, and fumes. Online resources from the National Ag Safety Database,²⁰ the American Welding Society,²¹ and Occupational Safety and Health Administration^22,23 are available. These resources advise welders to work in ventilated areas with respirators specific for the metal being welded and to wear clothing and gloves that are not only fire retardant but also UV resistant.^20-23 Additional PPE should protect the head, face, and eyes.

Unfortunately, even workers well trained in prevention guidelines may not adequately protect themselves. Some welders forego PPE due to heat, thus exposing themselves to UVR damage in areas that are normally covered. Welders also may forego equipment when working on jobs requiring more detailed welds where clothing, masks, and glasses may be overly bulky and inhibit the worker’s precision. Nontraditional welders, such as artisans or handymen, may not have workplace safety education to be aware of UVR emitted from welding and may not have readily available PPE.

The Figure portrays an amateur welder working without full PPE. Although he is wearing a face shield, he is not wearing fire-retardant clothing, lacks full protective garments, and has no ventilation system.

Conclusion

It is important to recognize welding as an occupation with notable exposure to UVR. Personal protective equipment should be the mainstay of prevention. Sunscreen is a useful adjunct but does not cover UVC that is emitted in the welding arc. Screens and welding blankets can be placed around welders to contain UVR and limit nonwelder exposure. Although UVR hazards should be regulated in the workplace as part of regular safety reviews, the clinician can play a role in recognizing this source of UVR in skin disease and in encouraging the use of PPE.