Melanoma

SCOTTSDALE, ARIZ. – Thin melanomas account for most melanoma deaths, even though T4 lesions have the worst prognosis, according to an analysis of melanoma data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

In 2015, a study from Queensland, Australia, reported that more patients died from T1 melanomas than did from T4 melanomas (J Invest Dermatol. 2015 Apr;135:1190-3). But a similar analysis in the United States was not available, so Dr. Shoshana Landow, a dermatologist at the Providence (R.I.) Veterans Affairs Medical Center,and her associates extracted SEER 13 data for invasive melanomas between 1992 through 2003. These registries covered Atlanta, Connecticut, Detroit, rural Georgia, Hawaii, Iowa, Los Angeles, New Mexico, San Francisco-Oakland, San Jose-Monterey, Seattle-Puget Sound, Utah, and the Alaska Native Tumor Registry, according to the SEER website.

©Zerbor/Thinkstock

Among 105,264 recorded melanomas during this period, 37,210 tumors were in situ, the investigators reported in a poster presented at the annual meeting of the Society for Investigative Dermatology. They excluded those cases, as well as 4,789 cases that involved more than one primary melanoma, 8,637 that extended beyond the skin at diagnosis, 5,308 with no record of thickness, and one that was not known to be primary.

That left 49,319 invasive melanomas, of which 35,509 (72%) were T1 (0.01-1.00mm), 7,879 (16%) were T2 (1.01-2.00 mm), 3,948 (8%) were T3 (2.01-4.00 mm), and 1,983 (4%) were T4 (more than 4.00 mm). A total of 17% of the T1 lesions were 0.01-0.25 mm thick at diagnosis, while 42% were 0.26-0.50 mm thick, 25% were 0.51-0.75 mm thick, and 16% were 0.76-1.00 mm thick.

Ten years after diagnosis, 3,660 (7.4%) patients had died of melanoma, according to the study. These deaths included 1,072 T1 patients, 974 T2 patients, 985 T3 patients, and 629 T4 patients. But while T4 lesions accounted for the fewest number of deaths and made up only 4% of all invasive melanomas, the 10-year mortality rate for T4 lesions was nearly 32%, vs. 25% for T3 lesions, 12% for T2 lesions, and 3% for T1 lesions.

Most (42%) T1 lesions were 0.26-0.50 mm thick, 25% of T1 lesions were 0.51-0.75 mm thick, and the remaining T1 lesions were nearly evenly split between the thinnest (0.01-0.25 mm) and the thickest (0.76-1.00mm) categories, the researchers also reported. When considering only the T1 lesions, 10-year mortality rates were 3% for the 0.01-0.25 mm category, 1.9% for the 0.26-0.5 mm category, 3.7% for the 0.51-0.75 mm category, and 5.8% for the 0.76-1.00 mm category.

Thus, the thinnest invasive melanomas had a higher 10-year death rate than did the next-thinnest category, a finding that “demands explanation” and was not caused by ulceration, the researchers noted.

“The greatest total number of deaths was from T1 melanomas and the smallest number from T4, despite the fact that prognosis worsened as melanoma thickened from T1 to T4,” they concluded in their poster. “Our findings highlight the heavy death toll of thin melanomas.”

The authors did not specify funding sources, and had no disclosures.

SCOTTSDALE, ARIZ. – Thin melanomas account for most melanoma deaths, even though T4 lesions have the worst prognosis, according to an analysis of melanoma data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

In 2015, a study from Queensland, Australia, reported that more patients died from T1 melanomas than did from T4 melanomas (J Invest Dermatol. 2015 Apr;135:1190-3). But a similar analysis in the United States was not available, so Dr. Shoshana Landow, a dermatologist at the Providence (R.I.) Veterans Affairs Medical Center,and her associates extracted SEER 13 data for invasive melanomas between 1992 through 2003. These registries covered Atlanta, Connecticut, Detroit, rural Georgia, Hawaii, Iowa, Los Angeles, New Mexico, San Francisco-Oakland, San Jose-Monterey, Seattle-Puget Sound, Utah, and the Alaska Native Tumor Registry, according to the SEER website.

©Zerbor/Thinkstock

Among 105,264 recorded melanomas during this period, 37,210 tumors were in situ, the investigators reported in a poster presented at the annual meeting of the Society for Investigative Dermatology. They excluded those cases, as well as 4,789 cases that involved more than one primary melanoma, 8,637 that extended beyond the skin at diagnosis, 5,308 with no record of thickness, and one that was not known to be primary.

That left 49,319 invasive melanomas, of which 35,509 (72%) were T1 (0.01-1.00mm), 7,879 (16%) were T2 (1.01-2.00 mm), 3,948 (8%) were T3 (2.01-4.00 mm), and 1,983 (4%) were T4 (more than 4.00 mm). A total of 17% of the T1 lesions were 0.01-0.25 mm thick at diagnosis, while 42% were 0.26-0.50 mm thick, 25% were 0.51-0.75 mm thick, and 16% were 0.76-1.00 mm thick.

Ten years after diagnosis, 3,660 (7.4%) patients had died of melanoma, according to the study. These deaths included 1,072 T1 patients, 974 T2 patients, 985 T3 patients, and 629 T4 patients. But while T4 lesions accounted for the fewest number of deaths and made up only 4% of all invasive melanomas, the 10-year mortality rate for T4 lesions was nearly 32%, vs. 25% for T3 lesions, 12% for T2 lesions, and 3% for T1 lesions.

Most (42%) T1 lesions were 0.26-0.50 mm thick, 25% of T1 lesions were 0.51-0.75 mm thick, and the remaining T1 lesions were nearly evenly split between the thinnest (0.01-0.25 mm) and the thickest (0.76-1.00mm) categories, the researchers also reported. When considering only the T1 lesions, 10-year mortality rates were 3% for the 0.01-0.25 mm category, 1.9% for the 0.26-0.5 mm category, 3.7% for the 0.51-0.75 mm category, and 5.8% for the 0.76-1.00 mm category.

Thus, the thinnest invasive melanomas had a higher 10-year death rate than did the next-thinnest category, a finding that “demands explanation” and was not caused by ulceration, the researchers noted.

“The greatest total number of deaths was from T1 melanomas and the smallest number from T4, despite the fact that prognosis worsened as melanoma thickened from T1 to T4,” they concluded in their poster. “Our findings highlight the heavy death toll of thin melanomas.”

The authors did not specify funding sources, and had no disclosures.

SCOTTSDALE, ARIZ. – Thin melanomas account for most melanoma deaths, even though T4 lesions have the worst prognosis, according to an analysis of melanoma data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

In 2015, a study from Queensland, Australia, reported that more patients died from T1 melanomas than did from T4 melanomas (J Invest Dermatol. 2015 Apr;135:1190-3). But a similar analysis in the United States was not available, so Dr. Shoshana Landow, a dermatologist at the Providence (R.I.) Veterans Affairs Medical Center,and her associates extracted SEER 13 data for invasive melanomas between 1992 through 2003. These registries covered Atlanta, Connecticut, Detroit, rural Georgia, Hawaii, Iowa, Los Angeles, New Mexico, San Francisco-Oakland, San Jose-Monterey, Seattle-Puget Sound, Utah, and the Alaska Native Tumor Registry, according to the SEER website.

©Zerbor/Thinkstock

Among 105,264 recorded melanomas during this period, 37,210 tumors were in situ, the investigators reported in a poster presented at the annual meeting of the Society for Investigative Dermatology. They excluded those cases, as well as 4,789 cases that involved more than one primary melanoma, 8,637 that extended beyond the skin at diagnosis, 5,308 with no record of thickness, and one that was not known to be primary.

That left 49,319 invasive melanomas, of which 35,509 (72%) were T1 (0.01-1.00mm), 7,879 (16%) were T2 (1.01-2.00 mm), 3,948 (8%) were T3 (2.01-4.00 mm), and 1,983 (4%) were T4 (more than 4.00 mm). A total of 17% of the T1 lesions were 0.01-0.25 mm thick at diagnosis, while 42% were 0.26-0.50 mm thick, 25% were 0.51-0.75 mm thick, and 16% were 0.76-1.00 mm thick.

Ten years after diagnosis, 3,660 (7.4%) patients had died of melanoma, according to the study. These deaths included 1,072 T1 patients, 974 T2 patients, 985 T3 patients, and 629 T4 patients. But while T4 lesions accounted for the fewest number of deaths and made up only 4% of all invasive melanomas, the 10-year mortality rate for T4 lesions was nearly 32%, vs. 25% for T3 lesions, 12% for T2 lesions, and 3% for T1 lesions.

Most (42%) T1 lesions were 0.26-0.50 mm thick, 25% of T1 lesions were 0.51-0.75 mm thick, and the remaining T1 lesions were nearly evenly split between the thinnest (0.01-0.25 mm) and the thickest (0.76-1.00mm) categories, the researchers also reported. When considering only the T1 lesions, 10-year mortality rates were 3% for the 0.01-0.25 mm category, 1.9% for the 0.26-0.5 mm category, 3.7% for the 0.51-0.75 mm category, and 5.8% for the 0.76-1.00 mm category.

Thus, the thinnest invasive melanomas had a higher 10-year death rate than did the next-thinnest category, a finding that “demands explanation” and was not caused by ulceration, the researchers noted.

“The greatest total number of deaths was from T1 melanomas and the smallest number from T4, despite the fact that prognosis worsened as melanoma thickened from T1 to T4,” they concluded in their poster. “Our findings highlight the heavy death toll of thin melanomas.”

The authors did not specify funding sources, and had no disclosures.

In the last few years, melanoma treatment has been revolutionized by the development of immune checkpoint–blocking antibodies or immune checkpoint inhibitors. These drugs act through receptor or ligand blockades at certain points along the immunologic cascade to enhance the immune system’s ability to fight malignancies.¹ In 2011, the US Food and Drug Administration approved ipilimumab, an inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA-4), for treatment of patients with unresectable or metastatic melanoma. Other immune-modulating agents followed thereafter. Vemurafenib and dabrafenib, 2 selective BRAF inhibitors, were approved in 2011 and 2013, respectively, and trametinib, a mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 blocker, was approved in 2013. These agents are being used to treat patients with activating BRAF or NRAS mutations.^2,3 Nivolumab and pembrolizumab, which target programmed death receptor-1 (PD-1) and programmed death ligand 1 (PD-L1), respectively, were approved in 2014. Furthermore, phase 2 and 3 trials are ongoing for patients with unresectable stage III or IV melanomas harboring activating c-KIT mutations, which are rare and usually are found in acral or mucosal melanomas. The multikinase inhibitors imatinib, sunitinib, dasatinib, and nilotinib are being used in clinical trials for this purpose and are not yet approved.⁴

Although immune checkpoint inhibitors have shown promising results, they lack direct activity against malignant cells. The nonspecific enhanced immune system response promoted by these drugs has been shown to cause multiple adverse events (AEs). A subset of these side effects has been termed immune-related AEs (irAEs), which occur secondary to reduced tolerance to antigens previously recognized as self-antigens, leading to immune-related side effects.⁵ The majority of these AEs involve the skin and are mild to moderate in severity; however, other organ systems (eg, gastrointestinal, hepatic, endocrine, and neurologic systems) also may be affected. Most of the toxicities have been successfully treated with immunosuppressive agents such as corticosteroids, tumor necrosis factor α antagonists, and mycophenolate mofetil.⁶

Dermatologic Side Effects

The most common AEs associated with immune checkpoint inhibitors are cutaneous reactions, which commonly present after 2 to 3 weeks of treatment.⁷ Approximately 50% of patients receiving ipilimumab (CTLA-4 inhibitor) will experience cutaneous reactions, including erythematous, reticulated, or maculopapular rashes.⁸ Vitiligo and Sweet syndrome also have been observed.^9,10

Antibodies against PD-1 and PD-L1 have been associated with oral mucositis and dry mouth.¹¹ Most patients treated with BRAF, MEK, and KIT inhibitors also experience dermatologic AEs. Rashes caused by BRAF inhibitors commonly are maculopapular to verrucous and hyperkeratotic. Keratoacanthomas, squamous cell carcinomas, and other hyperkeratotic lesions such as verruca vulgaris, actinic keratoses, and milia have been reported, usually in sun-exposed areas.^4,12,13 Other types of keratotic lesions have been observed, such as areolar hyperkeratosis with vemurafenib (BRAF inhibitor).¹⁴ Photosensitivity, panniculitis (eg, erythema nodosum), and mild alopecia also have been reported.¹⁵ Radiosensitization and radiation recall also have been reported in patients treated with BRAF inhibitors.^16-19 Cutaneous reactions observed with MEK inhibitors are acneiform to papulopustular and appear in seborrheic areas such as the face and chest.⁴ In contrast to BRAF inhibitors, increased rates of squamous cell carcinomas and keratoacanthomas have not been reported with MEK inhibitors. Severe cutaneous effects such as toxic epidermal necrolysis and Stevens-Johnson syndrome may occur, and although rare, treatment should be discontinued in these cases.

Gastrointestinal Tract Side Effects

Gastrointestinal (GI) tract side effects commonly result from treatment with immunomodulators, usually occurring after 6 to 7 weeks.⁷ Most patients will experience mild to moderate GI adverse effects (eg, diarrhea), but a few patients have had episodes of colitis, some of which have been fatal.²⁰ Diarrhea and other GI effects are more common in patients treated with ipilimumab, occurring in approximately 30% of patients,²⁰ in comparison to 1% to 2% of those treated with PD-1 and PD-L1 inhibitors.^11,21

Liver abnormalities and asymptomatic elevations in liver enzymes can occur with KIT, BRAF, CTLA-4, and PD-L1 inhibitors.^11,20-23 More serious abnormalities such as symptomatic hepatitis and fever are mostly seen with CTLA-4 inhibitors.

Endocrinologic Side Effects

Immune-related AEs also can affect the pituitary, adrenal, and thyroid glands. These events occur after an average of 9 weeks and usually consist of nausea, headache, and/or fatigue.⁷ Hypophysitis and hypothyroidism are the most common endocrinopathies reported based on characteristic laboratory or radiographic findings and are observed most often with CTLA-4 inhibitors, though they also have been reported with PD-1/PD-L1 blockers.^24,25 Ipilimumab-induced thyrotoxicosis also has been reported, though it is far less common than hypothyroidism.²⁶

Other Side Effects

Other irAEs that are less common include neurologic side effects ranging from Bell palsy²⁷ and Guillain-Barré syndrome²⁰ to paresthesia, as well as pancreatitis,²⁸ ophthalmologic reactions,^29-33 nephritis,^34,35 and hematologic side effects.^36-38 One distinctive AE is lung toxicity, which has been reported with PD-1 inhibitors and presents as cough, dyspnea, or pneumonitis early in treatment.²¹

It is unclear whether immunomodulating agents exacerbate autoimmune diseases. Patients with autoimmune diseases were not included in the clinical trials but reportedly have been treated with ipilimumab without exacerbations. Nevertheless, there has been a report of worsening multiple sclerosis in a melanoma patient treated with ipilimumab.³⁹

Conclusion

Immunomodulators have dramatically improved the survival and care of patients with unresectable melanomas. Because of their mechanism of action, they have the capability to produce substantial toxicity. Although most AEs are mild, lethal side effects can ensue. Therefore, all specialists treating patients with melanoma should be familiar with these side effects and their treatment options, as survival rates and survival times will be increasing over the next few years. Rapid AE identification and treatment can improve patient outcomes and optimize the therapeutic potential of these medications. Because immune checkpoint inhibitors are fairly new, further studies are needed to assess irAEs and the long-term impact in patients treated with immunomodulators.

In the last few years, melanoma treatment has been revolutionized by the development of immune checkpoint–blocking antibodies or immune checkpoint inhibitors. These drugs act through receptor or ligand blockades at certain points along the immunologic cascade to enhance the immune system’s ability to fight malignancies.¹ In 2011, the US Food and Drug Administration approved ipilimumab, an inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA-4), for treatment of patients with unresectable or metastatic melanoma. Other immune-modulating agents followed thereafter. Vemurafenib and dabrafenib, 2 selective BRAF inhibitors, were approved in 2011 and 2013, respectively, and trametinib, a mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 blocker, was approved in 2013. These agents are being used to treat patients with activating BRAF or NRAS mutations.^2,3 Nivolumab and pembrolizumab, which target programmed death receptor-1 (PD-1) and programmed death ligand 1 (PD-L1), respectively, were approved in 2014. Furthermore, phase 2 and 3 trials are ongoing for patients with unresectable stage III or IV melanomas harboring activating c-KIT mutations, which are rare and usually are found in acral or mucosal melanomas. The multikinase inhibitors imatinib, sunitinib, dasatinib, and nilotinib are being used in clinical trials for this purpose and are not yet approved.⁴

Although immune checkpoint inhibitors have shown promising results, they lack direct activity against malignant cells. The nonspecific enhanced immune system response promoted by these drugs has been shown to cause multiple adverse events (AEs). A subset of these side effects has been termed immune-related AEs (irAEs), which occur secondary to reduced tolerance to antigens previously recognized as self-antigens, leading to immune-related side effects.⁵ The majority of these AEs involve the skin and are mild to moderate in severity; however, other organ systems (eg, gastrointestinal, hepatic, endocrine, and neurologic systems) also may be affected. Most of the toxicities have been successfully treated with immunosuppressive agents such as corticosteroids, tumor necrosis factor α antagonists, and mycophenolate mofetil.⁶

Dermatologic Side Effects

The most common AEs associated with immune checkpoint inhibitors are cutaneous reactions, which commonly present after 2 to 3 weeks of treatment.⁷ Approximately 50% of patients receiving ipilimumab (CTLA-4 inhibitor) will experience cutaneous reactions, including erythematous, reticulated, or maculopapular rashes.⁸ Vitiligo and Sweet syndrome also have been observed.^9,10

Antibodies against PD-1 and PD-L1 have been associated with oral mucositis and dry mouth.¹¹ Most patients treated with BRAF, MEK, and KIT inhibitors also experience dermatologic AEs. Rashes caused by BRAF inhibitors commonly are maculopapular to verrucous and hyperkeratotic. Keratoacanthomas, squamous cell carcinomas, and other hyperkeratotic lesions such as verruca vulgaris, actinic keratoses, and milia have been reported, usually in sun-exposed areas.^4,12,13 Other types of keratotic lesions have been observed, such as areolar hyperkeratosis with vemurafenib (BRAF inhibitor).¹⁴ Photosensitivity, panniculitis (eg, erythema nodosum), and mild alopecia also have been reported.¹⁵ Radiosensitization and radiation recall also have been reported in patients treated with BRAF inhibitors.^16-19 Cutaneous reactions observed with MEK inhibitors are acneiform to papulopustular and appear in seborrheic areas such as the face and chest.⁴ In contrast to BRAF inhibitors, increased rates of squamous cell carcinomas and keratoacanthomas have not been reported with MEK inhibitors. Severe cutaneous effects such as toxic epidermal necrolysis and Stevens-Johnson syndrome may occur, and although rare, treatment should be discontinued in these cases.

Gastrointestinal Tract Side Effects

Gastrointestinal (GI) tract side effects commonly result from treatment with immunomodulators, usually occurring after 6 to 7 weeks.⁷ Most patients will experience mild to moderate GI adverse effects (eg, diarrhea), but a few patients have had episodes of colitis, some of which have been fatal.²⁰ Diarrhea and other GI effects are more common in patients treated with ipilimumab, occurring in approximately 30% of patients,²⁰ in comparison to 1% to 2% of those treated with PD-1 and PD-L1 inhibitors.^11,21

Liver abnormalities and asymptomatic elevations in liver enzymes can occur with KIT, BRAF, CTLA-4, and PD-L1 inhibitors.^11,20-23 More serious abnormalities such as symptomatic hepatitis and fever are mostly seen with CTLA-4 inhibitors.

Endocrinologic Side Effects

Immune-related AEs also can affect the pituitary, adrenal, and thyroid glands. These events occur after an average of 9 weeks and usually consist of nausea, headache, and/or fatigue.⁷ Hypophysitis and hypothyroidism are the most common endocrinopathies reported based on characteristic laboratory or radiographic findings and are observed most often with CTLA-4 inhibitors, though they also have been reported with PD-1/PD-L1 blockers.^24,25 Ipilimumab-induced thyrotoxicosis also has been reported, though it is far less common than hypothyroidism.²⁶

Other Side Effects

Other irAEs that are less common include neurologic side effects ranging from Bell palsy²⁷ and Guillain-Barré syndrome²⁰ to paresthesia, as well as pancreatitis,²⁸ ophthalmologic reactions,^29-33 nephritis,^34,35 and hematologic side effects.^36-38 One distinctive AE is lung toxicity, which has been reported with PD-1 inhibitors and presents as cough, dyspnea, or pneumonitis early in treatment.²¹

It is unclear whether immunomodulating agents exacerbate autoimmune diseases. Patients with autoimmune diseases were not included in the clinical trials but reportedly have been treated with ipilimumab without exacerbations. Nevertheless, there has been a report of worsening multiple sclerosis in a melanoma patient treated with ipilimumab.³⁹

Conclusion

Immunomodulators have dramatically improved the survival and care of patients with unresectable melanomas. Because of their mechanism of action, they have the capability to produce substantial toxicity. Although most AEs are mild, lethal side effects can ensue. Therefore, all specialists treating patients with melanoma should be familiar with these side effects and their treatment options, as survival rates and survival times will be increasing over the next few years. Rapid AE identification and treatment can improve patient outcomes and optimize the therapeutic potential of these medications. Because immune checkpoint inhibitors are fairly new, further studies are needed to assess irAEs and the long-term impact in patients treated with immunomodulators.

In the last few years, melanoma treatment has been revolutionized by the development of immune checkpoint–blocking antibodies or immune checkpoint inhibitors. These drugs act through receptor or ligand blockades at certain points along the immunologic cascade to enhance the immune system’s ability to fight malignancies.¹ In 2011, the US Food and Drug Administration approved ipilimumab, an inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA-4), for treatment of patients with unresectable or metastatic melanoma. Other immune-modulating agents followed thereafter. Vemurafenib and dabrafenib, 2 selective BRAF inhibitors, were approved in 2011 and 2013, respectively, and trametinib, a mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 blocker, was approved in 2013. These agents are being used to treat patients with activating BRAF or NRAS mutations.^2,3 Nivolumab and pembrolizumab, which target programmed death receptor-1 (PD-1) and programmed death ligand 1 (PD-L1), respectively, were approved in 2014. Furthermore, phase 2 and 3 trials are ongoing for patients with unresectable stage III or IV melanomas harboring activating c-KIT mutations, which are rare and usually are found in acral or mucosal melanomas. The multikinase inhibitors imatinib, sunitinib, dasatinib, and nilotinib are being used in clinical trials for this purpose and are not yet approved.⁴

Although immune checkpoint inhibitors have shown promising results, they lack direct activity against malignant cells. The nonspecific enhanced immune system response promoted by these drugs has been shown to cause multiple adverse events (AEs). A subset of these side effects has been termed immune-related AEs (irAEs), which occur secondary to reduced tolerance to antigens previously recognized as self-antigens, leading to immune-related side effects.⁵ The majority of these AEs involve the skin and are mild to moderate in severity; however, other organ systems (eg, gastrointestinal, hepatic, endocrine, and neurologic systems) also may be affected. Most of the toxicities have been successfully treated with immunosuppressive agents such as corticosteroids, tumor necrosis factor α antagonists, and mycophenolate mofetil.⁶

Dermatologic Side Effects

The most common AEs associated with immune checkpoint inhibitors are cutaneous reactions, which commonly present after 2 to 3 weeks of treatment.⁷ Approximately 50% of patients receiving ipilimumab (CTLA-4 inhibitor) will experience cutaneous reactions, including erythematous, reticulated, or maculopapular rashes.⁸ Vitiligo and Sweet syndrome also have been observed.^9,10

Antibodies against PD-1 and PD-L1 have been associated with oral mucositis and dry mouth.¹¹ Most patients treated with BRAF, MEK, and KIT inhibitors also experience dermatologic AEs. Rashes caused by BRAF inhibitors commonly are maculopapular to verrucous and hyperkeratotic. Keratoacanthomas, squamous cell carcinomas, and other hyperkeratotic lesions such as verruca vulgaris, actinic keratoses, and milia have been reported, usually in sun-exposed areas.^4,12,13 Other types of keratotic lesions have been observed, such as areolar hyperkeratosis with vemurafenib (BRAF inhibitor).¹⁴ Photosensitivity, panniculitis (eg, erythema nodosum), and mild alopecia also have been reported.¹⁵ Radiosensitization and radiation recall also have been reported in patients treated with BRAF inhibitors.^16-19 Cutaneous reactions observed with MEK inhibitors are acneiform to papulopustular and appear in seborrheic areas such as the face and chest.⁴ In contrast to BRAF inhibitors, increased rates of squamous cell carcinomas and keratoacanthomas have not been reported with MEK inhibitors. Severe cutaneous effects such as toxic epidermal necrolysis and Stevens-Johnson syndrome may occur, and although rare, treatment should be discontinued in these cases.

Gastrointestinal Tract Side Effects

Gastrointestinal (GI) tract side effects commonly result from treatment with immunomodulators, usually occurring after 6 to 7 weeks.⁷ Most patients will experience mild to moderate GI adverse effects (eg, diarrhea), but a few patients have had episodes of colitis, some of which have been fatal.²⁰ Diarrhea and other GI effects are more common in patients treated with ipilimumab, occurring in approximately 30% of patients,²⁰ in comparison to 1% to 2% of those treated with PD-1 and PD-L1 inhibitors.^11,21

Liver abnormalities and asymptomatic elevations in liver enzymes can occur with KIT, BRAF, CTLA-4, and PD-L1 inhibitors.^11,20-23 More serious abnormalities such as symptomatic hepatitis and fever are mostly seen with CTLA-4 inhibitors.

Endocrinologic Side Effects

Immune-related AEs also can affect the pituitary, adrenal, and thyroid glands. These events occur after an average of 9 weeks and usually consist of nausea, headache, and/or fatigue.⁷ Hypophysitis and hypothyroidism are the most common endocrinopathies reported based on characteristic laboratory or radiographic findings and are observed most often with CTLA-4 inhibitors, though they also have been reported with PD-1/PD-L1 blockers.^24,25 Ipilimumab-induced thyrotoxicosis also has been reported, though it is far less common than hypothyroidism.²⁶

Other Side Effects

Other irAEs that are less common include neurologic side effects ranging from Bell palsy²⁷ and Guillain-Barré syndrome²⁰ to paresthesia, as well as pancreatitis,²⁸ ophthalmologic reactions,^29-33 nephritis,^34,35 and hematologic side effects.^36-38 One distinctive AE is lung toxicity, which has been reported with PD-1 inhibitors and presents as cough, dyspnea, or pneumonitis early in treatment.²¹

It is unclear whether immunomodulating agents exacerbate autoimmune diseases. Patients with autoimmune diseases were not included in the clinical trials but reportedly have been treated with ipilimumab without exacerbations. Nevertheless, there has been a report of worsening multiple sclerosis in a melanoma patient treated with ipilimumab.³⁹

Conclusion

Immunomodulators have dramatically improved the survival and care of patients with unresectable melanomas. Because of their mechanism of action, they have the capability to produce substantial toxicity. Although most AEs are mild, lethal side effects can ensue. Therefore, all specialists treating patients with melanoma should be familiar with these side effects and their treatment options, as survival rates and survival times will be increasing over the next few years. Rapid AE identification and treatment can improve patient outcomes and optimize the therapeutic potential of these medications. Because immune checkpoint inhibitors are fairly new, further studies are needed to assess irAEs and the long-term impact in patients treated with immunomodulators.

The incidence of cutaneous melanoma (CM) has increased, warranting further study of new risk factors.^1,2 Hereditary risk factors for CM include light-colored eyes; fair skin; light brown, blonde, or red hair; tendency to burn; high density of freckles; history of other types of skin cancer; high number of common, atypical, and/or congenital nevi; and family history of skin cancer, as well as risks related to the presence of CDKN2A, BRAF, and MC1R gene mutations. Environmental risk factors include UV exposure from sunlight or tanning beds, among others.^3-5

Nutritional factors also have been suggested as possible modifiable risk factors for CM.⁶ Evidence from epidemiological studies show that diets rich in fruits and vegetables are associated with lower risks for several types of cancer.^7,8 A growing number of studies have assessed the effects of diet and the intake of nutrients on the prevention of cancer, specifically the use of dietary supplements to protect the skin from the adverse effects of UV light.⁶

Preformed vitamin A (ie, retinol) is necessary for the regulation of cell differentiation and also can reduce the incidence of skin tumors in animals exposed to UV light. Certain carotenoids such as α-carotene and β-carotene are metabolized to retinol. These retinol precursors, along with antioxidant nutrients, are important components of fruits and vegetables and may account for the observed anticancer effects of these foods.⁸

The aim of this study was to assess the relationship between dietary intake and the risk for CM.

Methods

Participants

A case-control study was carried out between 2012 and 2013 at 3 reference centers in Porto Alegre, Brazil—Universidade Federal de Ciências da Saúde de Porto Alegre, Pontifícia Universidade Católica do Rio Grande do Sul, and Hospital de Clínicas de Porto Alegre—for the treatment of patients with CM. Enrolled patients were 18 years and older with a diagnosis of primary CM confirmed by histology. Controls were selected from patients at the same centers, and they were enrolled and matched by institution. Controls were frequency matched to cases by sex and age (+/– 5 years). Exclusion criteria for controls were those presenting with suspicious lesions and those needing radiation therapy or chemotherapy due to other diseases. The study was approved by the ethics committees of the participating centers and informed consent was obtained from all participants. A total of 191 participants (95 cases; 96 controls) were enrolled in the study.

Data Collection

After informed consent was obtained, participants were interviewed and were clinically examined by an experienced dermatologist (C.B.H. and M.M.S.). The questionnaire included sociodemographic variables, medical history, phenotypic characteristics (ie, Fitzpatrick skin type, skin/hair/eye color), family history of skin cancer, history of sunlight exposure, history of sunburns, use of artificial tanning, sunscreen use, and detailed dietary intake. Physical examination included the assessment of several melanocytic lesions (nevi, freckles/ephelides, lentigines, and café au lait spots), actinic keratoses, solar elastosis, and nonmelanocytic tumors following the International Agency for Research on Cancer (IARC) protocol.⁹

Using a food frequency questionnaire, participants were asked to report their usual frequency of consumption of each food from a list of 36 foods. The frequency of intake of all groups of food and beverages was defined according to the following scale: never, rarely (less than once monthly), once or twice weekly, 3 to 4 times weekly, 5 to 7 times weekly, and more than 7 times weekly. Combination of categories was based on the overall distribution among controls. Therefore, for some items such as mussels and fresh herbs, only 2 categories were used.

Statistical Analysis

A descriptive statistical analysis of the results was performed using SPSS version 20.0 with absolute and relative frequencies for the categorical variables, and mean, SD, and median for the continuous variables. The symmetry of distributions was investigated using the Kolmogorov-Smirnov test.

A t test for independent groups was applied for the continuous variables, while the Pearson χ² test was used for the categorical variables. The Fisher exact test was used in situations in which at least 25% of the values of the cells presented an expected frequency of less than 5. Monte Carlo simulation was used when at least 1 variable had a polytomic characteristic. Odds ratio (OR) was used to estimate the strength of the association between exposures and outcome. An unconditional binary logistic regression was used to study the association between dietary variables and the risk for CM. To obtain unbiased estimates, multivariate analyses were performed controlling for 1 or more confounding variables. Using low exposure as a base category, the risks and 95% CIs were calculated for the high-exposure categories. Based on the results of bivariate analyses, variables with P≤.25 or lower were included in the models. The likelihood ratio test was used to decide which covariates should be maintained in the model. To test the goodness of fit of the models, the Hosmer-Lemeshow statistic was used.

Potential confounding factors considered in the logistic regression model were sex; age; education level; skin, hair, and eye color; Fitzpatrick skin type; presence of freckles, solar lentigines, and actinic keratosis; history of nonmelanoma skin cancer; number of melanocytic nevi; family history of skin cancer; sunburns in adulthood (≥6 episodes a year); occupational sun exposure; and history of sunscreen use in adulthood.

Results

A total of 191 participants were enrolled in the study (95 [49.7%] cases; 96 [50.3%] controls). Most participants were female (60.0% of cases; 59.4% of controls). The mean age (SD) of cases and controls was 56.8 (13.9) years and 56.5 (13.2) years, respectively. Mean body mass index (SD) did not differ between cases (27.2 [4.6]) and controls (28.2 [6.5]). Education levels of 8 years or less predominated in both groups (64.2% of cases; 57.3% of controls). No statistical difference was found for sex, age, education, or body mass index. The most frequent anatomic sites of CM were the trunk (54.7%) and arms (20.0%), and the most frequent histological type was superficial spreading (62.8%). The median Breslow thickness was 0.90 mm. Ulceration was observed in 20.9% of the cases, and 67% of participants with CM had a high mitotic rate (≥1 mitosis per square millimeter).

Phenotypic characteristics associated with an increased risk for melanoma were light brown hair (OR, 6.73; 95% CI, 3.30-14.2), blonde/red hair (OR, 21.7; 95% CI, 7.51-63.1), light-colored eyes (eg, blue, gray, green)(OR, 13.2; 95% CI, 6.13-28.7), light brown eyes (OR, 5.01; 95% CI, 2.24-11.5), and Fitzpatrick skin types I and II (OR, 7.37; 95% CI, 2.90-26.1). Family history of skin cancer was associated with an increased risk for CM (OR, 4.31; 95% CI, 1.86-10.7) as well as sunburns in adulthood (OR, 1.64; 95% CI, 1.17-1.99). Regular sunscreen use in adulthood had a 5-fold increased risk for CM compared to not using sunscreen regularly (OR, 5.6; 95% CI, 2.85-10.7). Regarding pigmented lesions, the presence of solar lentigines (OR, 4.8; 95% CI, 2.2-11.2), 60 or more nevi (OR, 5.4; 95% CI, 2.4-12.7), and freckles (OR, 3.7; 95% CI, 1.82-7.64) were all associated with an increased risk for CM. Solar elastosis (OR, 2.5; 95% CI, 1.08-5.85), actinic keratosis (OR, 9.1, 95% CI, 3.97-20.84), and occupational exposure to sun (OR, 2.57; 95% CI, 1.23-5.38) also were associated with an increased risk for melanoma.

The intake of most of the foods and beverages included in the study showed no association with CM. High frequency of butter intake (more than daily) was a protective factor for CM (OR, 0.33; 95% CI, 0.16-0.70) compared to low-frequency consumption (daily and less than daily). Consumption of mussels (OR, 0.53; 95% CI, 0.29-0.97) and oregano (OR, 0.28; 95% CI, 0.12-0.66) also were shown to be protective against CM (OR, 0.53; 95% CI, 0.29-0.97). Regarding beverages, those in the highest categories of consumption—liquor (OR, 2.12; 95% CI, 1.09-4.12) and spirits (OR, 2.23; 95% CI, 1.16-4.68)—were associated with an increased risk for CM.

To identify the relationship between CM and the consumption of some foods that were relevant on bivariate analysis, we performed a multivariate model. When adjustments were made, the association remained for butter (OR, 0.141; 95% CI, 0.032-0.613) and oregano (OR, 0.176; 95% CI, 0.042-0.735), while the risk associated with the consumption of both liquor (OR, 1.511; 95% CI, 0.39-5.90) and spirits (OR, 0.755; 95% CI, 0.130-4.393) disappeared (Table).

Comment

Observational studies show that diets rich in fruits and vegetables are associated with a lower risk for different types of cancers.^7,8 According to some studies, more than 30% of cancers in adulthood could be prevented or delayed by appropriate dietary intake and physical activity.¹⁰ However, there are still limited data on some specific cancers such as CM.

Substantial differences in the incidence of CM among different populations have suggested that environmental factors may play an etiological role in the development of CM and diet could be one of the modifiable risk factors.^11-13

Initially, we assessed the already known risk factors for CM, and results showed a significantly increased risk for participants with light brown, blonde, or red hair (P<.0001); light-colored and light brown eyes (P<.0001); Fitzpatrick skin types I and II (P<.0001); positive family history of skin cancer (P=.001); the presence of solar lentigines (P<.001), freckles (P<.001), and actinic keratosis (P<.0001); and high number of nevi (P<.0001). Sunburns in adulthood (P<.001) were associated with an increased risk for CM, and our findings are in agreement with the literature.¹²

Besides confirming the well-known risk factors for CM, our study also showed that some foods (eg, butter, oregano) may act as important protective factors in CM. It could be argued that the increased risks associated with the well-known risk factors (eg, Fitzpatrick skin type, number of sunburns) might not be as strong and/or could be modulated by dietary factors. To further elucidate this critical issue, we analyzed our data by examining the joint relationship between dietary consumption, individual characteristics, sun exposure, and melanoma. We conducted a multivariable analysis controlling for the well-known risk factors and our findings suggest that both butter and oregano, foods that are rich in vitamins A and D, are independent and protective risk factors for melanoma.

Vitamin A (retinol) is a fat-soluble, organic compound that cannot be synthesized by humans but is necessary for normal physiological function and therefore is classified as an essential nutrient. The main source of vitamin A in the human diet is from retinyl esters, mostly from animal products such as dairy products (eg, butter) as well as from plant-based, provitamin A carotenoids (α-carotene, β-carotene) that can be converted to retinol in the intestines.¹⁴

Some case-control studies have investigated the association of vitamin A intake and CM risk, reporting mixed findings. Naldi et al¹⁵ found a notable inverse association between vitamin A intake and CM risk. Le Marchand et al¹⁶ found no inverse association for carotenoids or retinol. Kirkpatrick et al¹⁷ found no evidence of a protective effect for vitamin A or carotenoids on CM. However, the Nurses’ Health Study and the Nurses’ Health Study II reported inverse associations between CM and retinol from foods and dietary supplements.⁸

Dairy products such as butter contain several components considered to be potentially anticarcinogenic, such as calcium, vitamin D, butyric acid, conjugated linoleic acid, sphingolipids, and probiotic bacteria. Some studies found an inverted association between melanoma and high intake of dairy products or other dietary sources of vitamin D, while some investigators showed no association.^6,18

Fortes et al¹⁸ assessed the role of diet on CM and found no protective effects of butter intake against the development of melanoma; however, a protective effect was found for carrots, which are rich in provitamin A (β-carotene) and for the regular intake of herbs rich in polyphenols (eg, rosemary). In our study, we found a protective effect against CM for butter but not for other dairy products. These findings could be explained by the high content of vitamin A in butter in comparison to other dairy products. Habitual intake of oregano also was associated with a protective effect for CM. Oregano is rich in polyphenols such as carvacrol, thymol, and rosmarinic acid, which are known for their antioxidant capacities and the inhibition of cyclooxygenase.^19-21 At experimental levels, both carvacrol and thymol have been shown to inhibit the growth of melanoma cells.^19,20 Rosmarinic acid, contained by both rosemary and oregano, have been shown at experimental levels to have photoprotective effects against melanoma.²¹

The relationship between dietary and nutritional intake and CM has a great potential that should be further explored. Tong and Young²² showed that proanthocyanidins found in grape seeds, epigallocatechin-3-gallate, resveratrol, rosmarinic acid, lycopene, and fig latex have demonstrated clear anticancer effects toward melanoma.

The strength of this study is the high response rate of both cases and controls and the use of incidence melanoma cases that decrease recall bias. A limitation of our study is that food portions were based on average portion size for each food item and therefore it can capture habitual consumption but not calculate actual nutrient intake. Misclassification of dietary exposure also could be a problem. Part of this misclassification is a result of a food frequency questionnaire being an imperfect measure of dietary history; however, we evaluated the reproducibility of the food frequency questionnaire used in this case-control study. Overall, there was a fair to good reproducibility between answers in 2 different periods (12 months apart). For example, agreement for frequency of intake of fresh herbs, tomatoes, and butter were 90.8%, 83.1%, and 83.3%, respectively.

Our sample size had sufficient statistical power to detect the effects of diet on CM.

Conclusion

Our study indicates that butter and oregano intake seem to have a protective role against the development of CM. Further studies are needed to confirm these findings.

The incidence of cutaneous melanoma (CM) has increased, warranting further study of new risk factors.^1,2 Hereditary risk factors for CM include light-colored eyes; fair skin; light brown, blonde, or red hair; tendency to burn; high density of freckles; history of other types of skin cancer; high number of common, atypical, and/or congenital nevi; and family history of skin cancer, as well as risks related to the presence of CDKN2A, BRAF, and MC1R gene mutations. Environmental risk factors include UV exposure from sunlight or tanning beds, among others.^3-5

Nutritional factors also have been suggested as possible modifiable risk factors for CM.⁶ Evidence from epidemiological studies show that diets rich in fruits and vegetables are associated with lower risks for several types of cancer.^7,8 A growing number of studies have assessed the effects of diet and the intake of nutrients on the prevention of cancer, specifically the use of dietary supplements to protect the skin from the adverse effects of UV light.⁶

Preformed vitamin A (ie, retinol) is necessary for the regulation of cell differentiation and also can reduce the incidence of skin tumors in animals exposed to UV light. Certain carotenoids such as α-carotene and β-carotene are metabolized to retinol. These retinol precursors, along with antioxidant nutrients, are important components of fruits and vegetables and may account for the observed anticancer effects of these foods.⁸

The aim of this study was to assess the relationship between dietary intake and the risk for CM.

Methods

Participants

A case-control study was carried out between 2012 and 2013 at 3 reference centers in Porto Alegre, Brazil—Universidade Federal de Ciências da Saúde de Porto Alegre, Pontifícia Universidade Católica do Rio Grande do Sul, and Hospital de Clínicas de Porto Alegre—for the treatment of patients with CM. Enrolled patients were 18 years and older with a diagnosis of primary CM confirmed by histology. Controls were selected from patients at the same centers, and they were enrolled and matched by institution. Controls were frequency matched to cases by sex and age (+/– 5 years). Exclusion criteria for controls were those presenting with suspicious lesions and those needing radiation therapy or chemotherapy due to other diseases. The study was approved by the ethics committees of the participating centers and informed consent was obtained from all participants. A total of 191 participants (95 cases; 96 controls) were enrolled in the study.

Data Collection

After informed consent was obtained, participants were interviewed and were clinically examined by an experienced dermatologist (C.B.H. and M.M.S.). The questionnaire included sociodemographic variables, medical history, phenotypic characteristics (ie, Fitzpatrick skin type, skin/hair/eye color), family history of skin cancer, history of sunlight exposure, history of sunburns, use of artificial tanning, sunscreen use, and detailed dietary intake. Physical examination included the assessment of several melanocytic lesions (nevi, freckles/ephelides, lentigines, and café au lait spots), actinic keratoses, solar elastosis, and nonmelanocytic tumors following the International Agency for Research on Cancer (IARC) protocol.⁹

Using a food frequency questionnaire, participants were asked to report their usual frequency of consumption of each food from a list of 36 foods. The frequency of intake of all groups of food and beverages was defined according to the following scale: never, rarely (less than once monthly), once or twice weekly, 3 to 4 times weekly, 5 to 7 times weekly, and more than 7 times weekly. Combination of categories was based on the overall distribution among controls. Therefore, for some items such as mussels and fresh herbs, only 2 categories were used.

Statistical Analysis

A descriptive statistical analysis of the results was performed using SPSS version 20.0 with absolute and relative frequencies for the categorical variables, and mean, SD, and median for the continuous variables. The symmetry of distributions was investigated using the Kolmogorov-Smirnov test.

A t test for independent groups was applied for the continuous variables, while the Pearson χ² test was used for the categorical variables. The Fisher exact test was used in situations in which at least 25% of the values of the cells presented an expected frequency of less than 5. Monte Carlo simulation was used when at least 1 variable had a polytomic characteristic. Odds ratio (OR) was used to estimate the strength of the association between exposures and outcome. An unconditional binary logistic regression was used to study the association between dietary variables and the risk for CM. To obtain unbiased estimates, multivariate analyses were performed controlling for 1 or more confounding variables. Using low exposure as a base category, the risks and 95% CIs were calculated for the high-exposure categories. Based on the results of bivariate analyses, variables with P≤.25 or lower were included in the models. The likelihood ratio test was used to decide which covariates should be maintained in the model. To test the goodness of fit of the models, the Hosmer-Lemeshow statistic was used.

Potential confounding factors considered in the logistic regression model were sex; age; education level; skin, hair, and eye color; Fitzpatrick skin type; presence of freckles, solar lentigines, and actinic keratosis; history of nonmelanoma skin cancer; number of melanocytic nevi; family history of skin cancer; sunburns in adulthood (≥6 episodes a year); occupational sun exposure; and history of sunscreen use in adulthood.

Results

A total of 191 participants were enrolled in the study (95 [49.7%] cases; 96 [50.3%] controls). Most participants were female (60.0% of cases; 59.4% of controls). The mean age (SD) of cases and controls was 56.8 (13.9) years and 56.5 (13.2) years, respectively. Mean body mass index (SD) did not differ between cases (27.2 [4.6]) and controls (28.2 [6.5]). Education levels of 8 years or less predominated in both groups (64.2% of cases; 57.3% of controls). No statistical difference was found for sex, age, education, or body mass index. The most frequent anatomic sites of CM were the trunk (54.7%) and arms (20.0%), and the most frequent histological type was superficial spreading (62.8%). The median Breslow thickness was 0.90 mm. Ulceration was observed in 20.9% of the cases, and 67% of participants with CM had a high mitotic rate (≥1 mitosis per square millimeter).

Phenotypic characteristics associated with an increased risk for melanoma were light brown hair (OR, 6.73; 95% CI, 3.30-14.2), blonde/red hair (OR, 21.7; 95% CI, 7.51-63.1), light-colored eyes (eg, blue, gray, green)(OR, 13.2; 95% CI, 6.13-28.7), light brown eyes (OR, 5.01; 95% CI, 2.24-11.5), and Fitzpatrick skin types I and II (OR, 7.37; 95% CI, 2.90-26.1). Family history of skin cancer was associated with an increased risk for CM (OR, 4.31; 95% CI, 1.86-10.7) as well as sunburns in adulthood (OR, 1.64; 95% CI, 1.17-1.99). Regular sunscreen use in adulthood had a 5-fold increased risk for CM compared to not using sunscreen regularly (OR, 5.6; 95% CI, 2.85-10.7). Regarding pigmented lesions, the presence of solar lentigines (OR, 4.8; 95% CI, 2.2-11.2), 60 or more nevi (OR, 5.4; 95% CI, 2.4-12.7), and freckles (OR, 3.7; 95% CI, 1.82-7.64) were all associated with an increased risk for CM. Solar elastosis (OR, 2.5; 95% CI, 1.08-5.85), actinic keratosis (OR, 9.1, 95% CI, 3.97-20.84), and occupational exposure to sun (OR, 2.57; 95% CI, 1.23-5.38) also were associated with an increased risk for melanoma.

The intake of most of the foods and beverages included in the study showed no association with CM. High frequency of butter intake (more than daily) was a protective factor for CM (OR, 0.33; 95% CI, 0.16-0.70) compared to low-frequency consumption (daily and less than daily). Consumption of mussels (OR, 0.53; 95% CI, 0.29-0.97) and oregano (OR, 0.28; 95% CI, 0.12-0.66) also were shown to be protective against CM (OR, 0.53; 95% CI, 0.29-0.97). Regarding beverages, those in the highest categories of consumption—liquor (OR, 2.12; 95% CI, 1.09-4.12) and spirits (OR, 2.23; 95% CI, 1.16-4.68)—were associated with an increased risk for CM.

To identify the relationship between CM and the consumption of some foods that were relevant on bivariate analysis, we performed a multivariate model. When adjustments were made, the association remained for butter (OR, 0.141; 95% CI, 0.032-0.613) and oregano (OR, 0.176; 95% CI, 0.042-0.735), while the risk associated with the consumption of both liquor (OR, 1.511; 95% CI, 0.39-5.90) and spirits (OR, 0.755; 95% CI, 0.130-4.393) disappeared (Table).

Comment

Observational studies show that diets rich in fruits and vegetables are associated with a lower risk for different types of cancers.^7,8 According to some studies, more than 30% of cancers in adulthood could be prevented or delayed by appropriate dietary intake and physical activity.¹⁰ However, there are still limited data on some specific cancers such as CM.

Substantial differences in the incidence of CM among different populations have suggested that environmental factors may play an etiological role in the development of CM and diet could be one of the modifiable risk factors.^11-13

Initially, we assessed the already known risk factors for CM, and results showed a significantly increased risk for participants with light brown, blonde, or red hair (P<.0001); light-colored and light brown eyes (P<.0001); Fitzpatrick skin types I and II (P<.0001); positive family history of skin cancer (P=.001); the presence of solar lentigines (P<.001), freckles (P<.001), and actinic keratosis (P<.0001); and high number of nevi (P<.0001). Sunburns in adulthood (P<.001) were associated with an increased risk for CM, and our findings are in agreement with the literature.¹²

Besides confirming the well-known risk factors for CM, our study also showed that some foods (eg, butter, oregano) may act as important protective factors in CM. It could be argued that the increased risks associated with the well-known risk factors (eg, Fitzpatrick skin type, number of sunburns) might not be as strong and/or could be modulated by dietary factors. To further elucidate this critical issue, we analyzed our data by examining the joint relationship between dietary consumption, individual characteristics, sun exposure, and melanoma. We conducted a multivariable analysis controlling for the well-known risk factors and our findings suggest that both butter and oregano, foods that are rich in vitamins A and D, are independent and protective risk factors for melanoma.

Vitamin A (retinol) is a fat-soluble, organic compound that cannot be synthesized by humans but is necessary for normal physiological function and therefore is classified as an essential nutrient. The main source of vitamin A in the human diet is from retinyl esters, mostly from animal products such as dairy products (eg, butter) as well as from plant-based, provitamin A carotenoids (α-carotene, β-carotene) that can be converted to retinol in the intestines.¹⁴

Some case-control studies have investigated the association of vitamin A intake and CM risk, reporting mixed findings. Naldi et al¹⁵ found a notable inverse association between vitamin A intake and CM risk. Le Marchand et al¹⁶ found no inverse association for carotenoids or retinol. Kirkpatrick et al¹⁷ found no evidence of a protective effect for vitamin A or carotenoids on CM. However, the Nurses’ Health Study and the Nurses’ Health Study II reported inverse associations between CM and retinol from foods and dietary supplements.⁸

Dairy products such as butter contain several components considered to be potentially anticarcinogenic, such as calcium, vitamin D, butyric acid, conjugated linoleic acid, sphingolipids, and probiotic bacteria. Some studies found an inverted association between melanoma and high intake of dairy products or other dietary sources of vitamin D, while some investigators showed no association.^6,18

Fortes et al¹⁸ assessed the role of diet on CM and found no protective effects of butter intake against the development of melanoma; however, a protective effect was found for carrots, which are rich in provitamin A (β-carotene) and for the regular intake of herbs rich in polyphenols (eg, rosemary). In our study, we found a protective effect against CM for butter but not for other dairy products. These findings could be explained by the high content of vitamin A in butter in comparison to other dairy products. Habitual intake of oregano also was associated with a protective effect for CM. Oregano is rich in polyphenols such as carvacrol, thymol, and rosmarinic acid, which are known for their antioxidant capacities and the inhibition of cyclooxygenase.^19-21 At experimental levels, both carvacrol and thymol have been shown to inhibit the growth of melanoma cells.^19,20 Rosmarinic acid, contained by both rosemary and oregano, have been shown at experimental levels to have photoprotective effects against melanoma.²¹

The relationship between dietary and nutritional intake and CM has a great potential that should be further explored. Tong and Young²² showed that proanthocyanidins found in grape seeds, epigallocatechin-3-gallate, resveratrol, rosmarinic acid, lycopene, and fig latex have demonstrated clear anticancer effects toward melanoma.

The strength of this study is the high response rate of both cases and controls and the use of incidence melanoma cases that decrease recall bias. A limitation of our study is that food portions were based on average portion size for each food item and therefore it can capture habitual consumption but not calculate actual nutrient intake. Misclassification of dietary exposure also could be a problem. Part of this misclassification is a result of a food frequency questionnaire being an imperfect measure of dietary history; however, we evaluated the reproducibility of the food frequency questionnaire used in this case-control study. Overall, there was a fair to good reproducibility between answers in 2 different periods (12 months apart). For example, agreement for frequency of intake of fresh herbs, tomatoes, and butter were 90.8%, 83.1%, and 83.3%, respectively.

Our sample size had sufficient statistical power to detect the effects of diet on CM.

Conclusion

Our study indicates that butter and oregano intake seem to have a protective role against the development of CM. Further studies are needed to confirm these findings.

The incidence of cutaneous melanoma (CM) has increased, warranting further study of new risk factors.^1,2 Hereditary risk factors for CM include light-colored eyes; fair skin; light brown, blonde, or red hair; tendency to burn; high density of freckles; history of other types of skin cancer; high number of common, atypical, and/or congenital nevi; and family history of skin cancer, as well as risks related to the presence of CDKN2A, BRAF, and MC1R gene mutations. Environmental risk factors include UV exposure from sunlight or tanning beds, among others.^3-5

Nutritional factors also have been suggested as possible modifiable risk factors for CM.⁶ Evidence from epidemiological studies show that diets rich in fruits and vegetables are associated with lower risks for several types of cancer.^7,8 A growing number of studies have assessed the effects of diet and the intake of nutrients on the prevention of cancer, specifically the use of dietary supplements to protect the skin from the adverse effects of UV light.⁶

Preformed vitamin A (ie, retinol) is necessary for the regulation of cell differentiation and also can reduce the incidence of skin tumors in animals exposed to UV light. Certain carotenoids such as α-carotene and β-carotene are metabolized to retinol. These retinol precursors, along with antioxidant nutrients, are important components of fruits and vegetables and may account for the observed anticancer effects of these foods.⁸

The aim of this study was to assess the relationship between dietary intake and the risk for CM.

Methods

Participants

A case-control study was carried out between 2012 and 2013 at 3 reference centers in Porto Alegre, Brazil—Universidade Federal de Ciências da Saúde de Porto Alegre, Pontifícia Universidade Católica do Rio Grande do Sul, and Hospital de Clínicas de Porto Alegre—for the treatment of patients with CM. Enrolled patients were 18 years and older with a diagnosis of primary CM confirmed by histology. Controls were selected from patients at the same centers, and they were enrolled and matched by institution. Controls were frequency matched to cases by sex and age (+/– 5 years). Exclusion criteria for controls were those presenting with suspicious lesions and those needing radiation therapy or chemotherapy due to other diseases. The study was approved by the ethics committees of the participating centers and informed consent was obtained from all participants. A total of 191 participants (95 cases; 96 controls) were enrolled in the study.

Data Collection

After informed consent was obtained, participants were interviewed and were clinically examined by an experienced dermatologist (C.B.H. and M.M.S.). The questionnaire included sociodemographic variables, medical history, phenotypic characteristics (ie, Fitzpatrick skin type, skin/hair/eye color), family history of skin cancer, history of sunlight exposure, history of sunburns, use of artificial tanning, sunscreen use, and detailed dietary intake. Physical examination included the assessment of several melanocytic lesions (nevi, freckles/ephelides, lentigines, and café au lait spots), actinic keratoses, solar elastosis, and nonmelanocytic tumors following the International Agency for Research on Cancer (IARC) protocol.⁹

Using a food frequency questionnaire, participants were asked to report their usual frequency of consumption of each food from a list of 36 foods. The frequency of intake of all groups of food and beverages was defined according to the following scale: never, rarely (less than once monthly), once or twice weekly, 3 to 4 times weekly, 5 to 7 times weekly, and more than 7 times weekly. Combination of categories was based on the overall distribution among controls. Therefore, for some items such as mussels and fresh herbs, only 2 categories were used.

Statistical Analysis

A descriptive statistical analysis of the results was performed using SPSS version 20.0 with absolute and relative frequencies for the categorical variables, and mean, SD, and median for the continuous variables. The symmetry of distributions was investigated using the Kolmogorov-Smirnov test.

A t test for independent groups was applied for the continuous variables, while the Pearson χ² test was used for the categorical variables. The Fisher exact test was used in situations in which at least 25% of the values of the cells presented an expected frequency of less than 5. Monte Carlo simulation was used when at least 1 variable had a polytomic characteristic. Odds ratio (OR) was used to estimate the strength of the association between exposures and outcome. An unconditional binary logistic regression was used to study the association between dietary variables and the risk for CM. To obtain unbiased estimates, multivariate analyses were performed controlling for 1 or more confounding variables. Using low exposure as a base category, the risks and 95% CIs were calculated for the high-exposure categories. Based on the results of bivariate analyses, variables with P≤.25 or lower were included in the models. The likelihood ratio test was used to decide which covariates should be maintained in the model. To test the goodness of fit of the models, the Hosmer-Lemeshow statistic was used.

Potential confounding factors considered in the logistic regression model were sex; age; education level; skin, hair, and eye color; Fitzpatrick skin type; presence of freckles, solar lentigines, and actinic keratosis; history of nonmelanoma skin cancer; number of melanocytic nevi; family history of skin cancer; sunburns in adulthood (≥6 episodes a year); occupational sun exposure; and history of sunscreen use in adulthood.

Results

A total of 191 participants were enrolled in the study (95 [49.7%] cases; 96 [50.3%] controls). Most participants were female (60.0% of cases; 59.4% of controls). The mean age (SD) of cases and controls was 56.8 (13.9) years and 56.5 (13.2) years, respectively. Mean body mass index (SD) did not differ between cases (27.2 [4.6]) and controls (28.2 [6.5]). Education levels of 8 years or less predominated in both groups (64.2% of cases; 57.3% of controls). No statistical difference was found for sex, age, education, or body mass index. The most frequent anatomic sites of CM were the trunk (54.7%) and arms (20.0%), and the most frequent histological type was superficial spreading (62.8%). The median Breslow thickness was 0.90 mm. Ulceration was observed in 20.9% of the cases, and 67% of participants with CM had a high mitotic rate (≥1 mitosis per square millimeter).

Phenotypic characteristics associated with an increased risk for melanoma were light brown hair (OR, 6.73; 95% CI, 3.30-14.2), blonde/red hair (OR, 21.7; 95% CI, 7.51-63.1), light-colored eyes (eg, blue, gray, green)(OR, 13.2; 95% CI, 6.13-28.7), light brown eyes (OR, 5.01; 95% CI, 2.24-11.5), and Fitzpatrick skin types I and II (OR, 7.37; 95% CI, 2.90-26.1). Family history of skin cancer was associated with an increased risk for CM (OR, 4.31; 95% CI, 1.86-10.7) as well as sunburns in adulthood (OR, 1.64; 95% CI, 1.17-1.99). Regular sunscreen use in adulthood had a 5-fold increased risk for CM compared to not using sunscreen regularly (OR, 5.6; 95% CI, 2.85-10.7). Regarding pigmented lesions, the presence of solar lentigines (OR, 4.8; 95% CI, 2.2-11.2), 60 or more nevi (OR, 5.4; 95% CI, 2.4-12.7), and freckles (OR, 3.7; 95% CI, 1.82-7.64) were all associated with an increased risk for CM. Solar elastosis (OR, 2.5; 95% CI, 1.08-5.85), actinic keratosis (OR, 9.1, 95% CI, 3.97-20.84), and occupational exposure to sun (OR, 2.57; 95% CI, 1.23-5.38) also were associated with an increased risk for melanoma.

The intake of most of the foods and beverages included in the study showed no association with CM. High frequency of butter intake (more than daily) was a protective factor for CM (OR, 0.33; 95% CI, 0.16-0.70) compared to low-frequency consumption (daily and less than daily). Consumption of mussels (OR, 0.53; 95% CI, 0.29-0.97) and oregano (OR, 0.28; 95% CI, 0.12-0.66) also were shown to be protective against CM (OR, 0.53; 95% CI, 0.29-0.97). Regarding beverages, those in the highest categories of consumption—liquor (OR, 2.12; 95% CI, 1.09-4.12) and spirits (OR, 2.23; 95% CI, 1.16-4.68)—were associated with an increased risk for CM.

To identify the relationship between CM and the consumption of some foods that were relevant on bivariate analysis, we performed a multivariate model. When adjustments were made, the association remained for butter (OR, 0.141; 95% CI, 0.032-0.613) and oregano (OR, 0.176; 95% CI, 0.042-0.735), while the risk associated with the consumption of both liquor (OR, 1.511; 95% CI, 0.39-5.90) and spirits (OR, 0.755; 95% CI, 0.130-4.393) disappeared (Table).

Comment

Observational studies show that diets rich in fruits and vegetables are associated with a lower risk for different types of cancers.^7,8 According to some studies, more than 30% of cancers in adulthood could be prevented or delayed by appropriate dietary intake and physical activity.¹⁰ However, there are still limited data on some specific cancers such as CM.

Substantial differences in the incidence of CM among different populations have suggested that environmental factors may play an etiological role in the development of CM and diet could be one of the modifiable risk factors.^11-13

Initially, we assessed the already known risk factors for CM, and results showed a significantly increased risk for participants with light brown, blonde, or red hair (P<.0001); light-colored and light brown eyes (P<.0001); Fitzpatrick skin types I and II (P<.0001); positive family history of skin cancer (P=.001); the presence of solar lentigines (P<.001), freckles (P<.001), and actinic keratosis (P<.0001); and high number of nevi (P<.0001). Sunburns in adulthood (P<.001) were associated with an increased risk for CM, and our findings are in agreement with the literature.¹²

Besides confirming the well-known risk factors for CM, our study also showed that some foods (eg, butter, oregano) may act as important protective factors in CM. It could be argued that the increased risks associated with the well-known risk factors (eg, Fitzpatrick skin type, number of sunburns) might not be as strong and/or could be modulated by dietary factors. To further elucidate this critical issue, we analyzed our data by examining the joint relationship between dietary consumption, individual characteristics, sun exposure, and melanoma. We conducted a multivariable analysis controlling for the well-known risk factors and our findings suggest that both butter and oregano, foods that are rich in vitamins A and D, are independent and protective risk factors for melanoma.

Vitamin A (retinol) is a fat-soluble, organic compound that cannot be synthesized by humans but is necessary for normal physiological function and therefore is classified as an essential nutrient. The main source of vitamin A in the human diet is from retinyl esters, mostly from animal products such as dairy products (eg, butter) as well as from plant-based, provitamin A carotenoids (α-carotene, β-carotene) that can be converted to retinol in the intestines.¹⁴

Some case-control studies have investigated the association of vitamin A intake and CM risk, reporting mixed findings. Naldi et al¹⁵ found a notable inverse association between vitamin A intake and CM risk. Le Marchand et al¹⁶ found no inverse association for carotenoids or retinol. Kirkpatrick et al¹⁷ found no evidence of a protective effect for vitamin A or carotenoids on CM. However, the Nurses’ Health Study and the Nurses’ Health Study II reported inverse associations between CM and retinol from foods and dietary supplements.⁸

Dairy products such as butter contain several components considered to be potentially anticarcinogenic, such as calcium, vitamin D, butyric acid, conjugated linoleic acid, sphingolipids, and probiotic bacteria. Some studies found an inverted association between melanoma and high intake of dairy products or other dietary sources of vitamin D, while some investigators showed no association.^6,18

Fortes et al¹⁸ assessed the role of diet on CM and found no protective effects of butter intake against the development of melanoma; however, a protective effect was found for carrots, which are rich in provitamin A (β-carotene) and for the regular intake of herbs rich in polyphenols (eg, rosemary). In our study, we found a protective effect against CM for butter but not for other dairy products. These findings could be explained by the high content of vitamin A in butter in comparison to other dairy products. Habitual intake of oregano also was associated with a protective effect for CM. Oregano is rich in polyphenols such as carvacrol, thymol, and rosmarinic acid, which are known for their antioxidant capacities and the inhibition of cyclooxygenase.^19-21 At experimental levels, both carvacrol and thymol have been shown to inhibit the growth of melanoma cells.^19,20 Rosmarinic acid, contained by both rosemary and oregano, have been shown at experimental levels to have photoprotective effects against melanoma.²¹

The relationship between dietary and nutritional intake and CM has a great potential that should be further explored. Tong and Young²² showed that proanthocyanidins found in grape seeds, epigallocatechin-3-gallate, resveratrol, rosmarinic acid, lycopene, and fig latex have demonstrated clear anticancer effects toward melanoma.

The strength of this study is the high response rate of both cases and controls and the use of incidence melanoma cases that decrease recall bias. A limitation of our study is that food portions were based on average portion size for each food item and therefore it can capture habitual consumption but not calculate actual nutrient intake. Misclassification of dietary exposure also could be a problem. Part of this misclassification is a result of a food frequency questionnaire being an imperfect measure of dietary history; however, we evaluated the reproducibility of the food frequency questionnaire used in this case-control study. Overall, there was a fair to good reproducibility between answers in 2 different periods (12 months apart). For example, agreement for frequency of intake of fresh herbs, tomatoes, and butter were 90.8%, 83.1%, and 83.3%, respectively.

Our sample size had sufficient statistical power to detect the effects of diet on CM.

Conclusion

Our study indicates that butter and oregano intake seem to have a protective role against the development of CM. Further studies are needed to confirm these findings.

ORLANDO – Assessment, education, and a judicious dose of medication can make a big difference to patients who are feeling anxious about undergoing Mohs surgery.

No studies or guidelines lay out a step-by-step management plan for anxious patients. But a little bit of common sense and empathy go a long way in easing the feeling, according to presenters at the annual meeting of the American College of Mohs Surgery.

?

“We don’t have an algorithm for reducing anxiety,” said Dr. Joseph Sobanko of the University of Pennsylvania, Philadelphia. “But we do have a lot of studies showing that better psychosocial health is related to better surgical outcomes.”

The lack of definitive guidance means that anxious patients might be identified and assessed by gut instinct, he continued. “Those of you who see patients probably have a gestalt technique of identifying the anxious ones. I would suggest this might not be the best way.”

Instead of guessing, he recommends assessing all patients with a validated screening tool, and dealing with anxiety proactively.

Assessing anxiety

Although anxiety assessment may not be part of a typical Mohs surgery intake, it probably should be, Dr. Sobanko said. There are a number of excellent, well-validated tools, and none of them require expertise in psychology to administer.

The Beck Anxiety Inventory is a 21-question index that takes about 10 minutes to complete. It assesses subjective, somatic, and panic-related symptoms of anxiety, and has been validated in a variety of clinical settings. It focuses quite a bit on strong physical symptoms, however, which Dr. Sobanko feels “may not be as relevant for our patients.”

The State-Trait Anxiety Inventory consists of 40 questions and takes about 15 minutes to complete. “I like it because it not only assesses how they generally feel, but how they feel at the moment,” he said. “We think it’s good and we do use it, but it takes a while to complete.”

The Hospital Anxiety and Depression Scale is short, with only 14 questions, and takes only about 5 minutes to complete. “It’s validated for hospital patients, but we are often working with patients who are less sick than that,” Dr. Sobanko said.

The Skin Cancer Index is his go-to anxiety screen for Mohs patients. It includes 15 questions that “really get to the heart of things that matter to our patients: emotional, social, and appearance issues,” he noted. Created in 2006, it was validated in a large cohort of Mohs surgery patients (Arch Facial Plast Surg. 2006;8[5]:314-318). The questions probe patients’ feelings about the seriousness of their skin cancer, its long-term health effect, and the impact the lesion – and its treatment – will have on appearance.

Tackling anxiety

Dr. Sobanko described his own, soon-to-be-published study of 104 Mohs surgery patients, who were randomized to receive a presurgical phone call to discuss anxiety, or the usual presurgical consultation. It was easy to implement the call, he said, noting that 70% were reached on the first try, and the interaction only took about 7 minutes.

Anxiety was common, with 43% reporting being anxious about the procedure. A frequent worry (25%) was whether their skin cancer would threaten their health over the long term. But both groups reported about the same reduction in anxiety after their discussion with the provider, whether it occurred over the phone or in person. After surgery, they expressed similar levels of satisfaction with the experience.

Clearly, the most effective method of dealing with patient anxiety has yet to be identified, Dr. Sobanko noted. Others are being explored, including music and educational videos.

In 2013, he and colleagues published a small study showing that music significantly reduced anxiety during Mohs surgery (Dermatol Surg. 2013 Feb;39[2]:298-305). It randomized 100 patients to surgery without music, or to listening to a playlist they had selected for themselves. Anxiety was measured using the State-Trait Anxiety Inventory and on a visual analog scale. Subjects in the music group experienced statistically significantly lower scores on both measures, Dr. Sobanko said.

A study presented at the meeting found that a preoperative education video helped as well. Dr. Sidney Smith of the Georgia Skin and Cancer Clinic, Savannah, examined the benefit of a 9-minute video created by the American College of Mohs Surgery. The video interviews patients about their experiences, describes the surgery and overall cure rates, and touches on reconstruction and follow-up.

The study comprised 200 patients; 100 saw the movie, and then completed a 24 question survey about their perception of the procedure. Almost all (94%) of those who viewed it said the video answered their questions; 85% said it relieved their fear about undergoing the surgery.

Treating anxiety

Anxiolytics can be easily employed to help ease day-of-surgery anxiety, Dr. Jerry Brewer said at the meeting. Generally speaking, the medications are safe, well-tolerated, and very effective.

“One thing we should remember, however, is that anxiolytics do not affect pain. They have no effect on pain receptors, although they may affect a patient’s memory of pain. For people who are anxious, though, this can be a really great help,” said Dr. Brewer of the Mayo Clinic, Rochester, Minn.

He favors the short-acting benzodiazepines, particularly midazolam. It has a peak concentration of 17-55 minutes, so it’s particularly well suited for shorter cases. It also has a very rapid metabolization profile, with an elimination half life of 3-7 hours.

Since midazolam has twice the affinity for the benzodiazepine receptors as does diazepam, it can be effective in relatively small doses – usually about 0.25 mg/kg. The dose should be reduced by half for elderly patients and for those with renal or hepatic failure. In those patients, the elimination half-life can be increased up to 13 hours.

The typical dose for both adults and children is 10-20 mg. “We should remember that patients who take narcotics and those who take a benzodiazepine as a sleep aide may be quite tolerant and need a higher dose,” Dr. Brewer said.

Diazepam has a peak concentration of about 2 hours, but a much longer elimination half-life – up to 48 hours in a healthy adult and up to 80 hours in an elderly person. “It’s important that patients know they’re going to have this drug in their system for a couple days. This should be part of the consenting process,” Dr. Brewer pointed out.

Lorazepam has a peak concentration of about 2 hours as well, but a shorter half-life of 12-18 hours. That can be prolonged by 75% in patients with renal problems.

With the right clinical supervision, these medications are very safe, he said. “We treat about 800 patients per year with these and have data on about 12,000. Of those, we have had very few problems. Two have fallen out of bed. One patient wrote and said he was discharged too early, as he was very tired. One person fell and hit his head in the bathroom. One was sedated enough to need a sternal rub to improve responsiveness. And one gentleman enjoyed the medication so much that when the nurse left the room for a moment he grabbed the rest of the dose and drank it.”

Safe discharge is crucial when using anxiolytics, he added. “They absolutely cannot drive themselves home and they cannot go back to work. We make sure there is a reliable person to stay with the patient for at least 4 hours after discharge.”

Dr. Brewer does not discharge any patient until that person displays a zero rating on the Richmond Agitation-Sedation Scale (RASS) sedation scale. “That means he is awake, alert, and calmly interacting with you.”

Neither Dr. Sobanko nor Dr. Brewer had any financial declarations.

msullivan@frontlinemedcom.com

ORLANDO – Assessment, education, and a judicious dose of medication can make a big difference to patients who are feeling anxious about undergoing Mohs surgery.

No studies or guidelines lay out a step-by-step management plan for anxious patients. But a little bit of common sense and empathy go a long way in easing the feeling, according to presenters at the annual meeting of the American College of Mohs Surgery.

?

“We don’t have an algorithm for reducing anxiety,” said Dr. Joseph Sobanko of the University of Pennsylvania, Philadelphia. “But we do have a lot of studies showing that better psychosocial health is related to better surgical outcomes.”

The lack of definitive guidance means that anxious patients might be identified and assessed by gut instinct, he continued. “Those of you who see patients probably have a gestalt technique of identifying the anxious ones. I would suggest this might not be the best way.”

Instead of guessing, he recommends assessing all patients with a validated screening tool, and dealing with anxiety proactively.

Assessing anxiety

Although anxiety assessment may not be part of a typical Mohs surgery intake, it probably should be, Dr. Sobanko said. There are a number of excellent, well-validated tools, and none of them require expertise in psychology to administer.

The Beck Anxiety Inventory is a 21-question index that takes about 10 minutes to complete. It assesses subjective, somatic, and panic-related symptoms of anxiety, and has been validated in a variety of clinical settings. It focuses quite a bit on strong physical symptoms, however, which Dr. Sobanko feels “may not be as relevant for our patients.”

The State-Trait Anxiety Inventory consists of 40 questions and takes about 15 minutes to complete. “I like it because it not only assesses how they generally feel, but how they feel at the moment,” he said. “We think it’s good and we do use it, but it takes a while to complete.”

The Hospital Anxiety and Depression Scale is short, with only 14 questions, and takes only about 5 minutes to complete. “It’s validated for hospital patients, but we are often working with patients who are less sick than that,” Dr. Sobanko said.

The Skin Cancer Index is his go-to anxiety screen for Mohs patients. It includes 15 questions that “really get to the heart of things that matter to our patients: emotional, social, and appearance issues,” he noted. Created in 2006, it was validated in a large cohort of Mohs surgery patients (Arch Facial Plast Surg. 2006;8[5]:314-318). The questions probe patients’ feelings about the seriousness of their skin cancer, its long-term health effect, and the impact the lesion – and its treatment – will have on appearance.

Tackling anxiety

Dr. Sobanko described his own, soon-to-be-published study of 104 Mohs surgery patients, who were randomized to receive a presurgical phone call to discuss anxiety, or the usual presurgical consultation. It was easy to implement the call, he said, noting that 70% were reached on the first try, and the interaction only took about 7 minutes.

Anxiety was common, with 43% reporting being anxious about the procedure. A frequent worry (25%) was whether their skin cancer would threaten their health over the long term. But both groups reported about the same reduction in anxiety after their discussion with the provider, whether it occurred over the phone or in person. After surgery, they expressed similar levels of satisfaction with the experience.

Clearly, the most effective method of dealing with patient anxiety has yet to be identified, Dr. Sobanko noted. Others are being explored, including music and educational videos.

In 2013, he and colleagues published a small study showing that music significantly reduced anxiety during Mohs surgery (Dermatol Surg. 2013 Feb;39[2]:298-305). It randomized 100 patients to surgery without music, or to listening to a playlist they had selected for themselves. Anxiety was measured using the State-Trait Anxiety Inventory and on a visual analog scale. Subjects in the music group experienced statistically significantly lower scores on both measures, Dr. Sobanko said.

A study presented at the meeting found that a preoperative education video helped as well. Dr. Sidney Smith of the Georgia Skin and Cancer Clinic, Savannah, examined the benefit of a 9-minute video created by the American College of Mohs Surgery. The video interviews patients about their experiences, describes the surgery and overall cure rates, and touches on reconstruction and follow-up.

The study comprised 200 patients; 100 saw the movie, and then completed a 24 question survey about their perception of the procedure. Almost all (94%) of those who viewed it said the video answered their questions; 85% said it relieved their fear about undergoing the surgery.

Treating anxiety

Anxiolytics can be easily employed to help ease day-of-surgery anxiety, Dr. Jerry Brewer said at the meeting. Generally speaking, the medications are safe, well-tolerated, and very effective.

“One thing we should remember, however, is that anxiolytics do not affect pain. They have no effect on pain receptors, although they may affect a patient’s memory of pain. For people who are anxious, though, this can be a really great help,” said Dr. Brewer of the Mayo Clinic, Rochester, Minn.

He favors the short-acting benzodiazepines, particularly midazolam. It has a peak concentration of 17-55 minutes, so it’s particularly well suited for shorter cases. It also has a very rapid metabolization profile, with an elimination half life of 3-7 hours.

Since midazolam has twice the affinity for the benzodiazepine receptors as does diazepam, it can be effective in relatively small doses – usually about 0.25 mg/kg. The dose should be reduced by half for elderly patients and for those with renal or hepatic failure. In those patients, the elimination half-life can be increased up to 13 hours.

The typical dose for both adults and children is 10-20 mg. “We should remember that patients who take narcotics and those who take a benzodiazepine as a sleep aide may be quite tolerant and need a higher dose,” Dr. Brewer said.

Diazepam has a peak concentration of about 2 hours, but a much longer elimination half-life – up to 48 hours in a healthy adult and up to 80 hours in an elderly person. “It’s important that patients know they’re going to have this drug in their system for a couple days. This should be part of the consenting process,” Dr. Brewer pointed out.

Lorazepam has a peak concentration of about 2 hours as well, but a shorter half-life of 12-18 hours. That can be prolonged by 75% in patients with renal problems.

With the right clinical supervision, these medications are very safe, he said. “We treat about 800 patients per year with these and have data on about 12,000. Of those, we have had very few problems. Two have fallen out of bed. One patient wrote and said he was discharged too early, as he was very tired. One person fell and hit his head in the bathroom. One was sedated enough to need a sternal rub to improve responsiveness. And one gentleman enjoyed the medication so much that when the nurse left the room for a moment he grabbed the rest of the dose and drank it.”

Safe discharge is crucial when using anxiolytics, he added. “They absolutely cannot drive themselves home and they cannot go back to work. We make sure there is a reliable person to stay with the patient for at least 4 hours after discharge.”

Dr. Brewer does not discharge any patient until that person displays a zero rating on the Richmond Agitation-Sedation Scale (RASS) sedation scale. “That means he is awake, alert, and calmly interacting with you.”

Neither Dr. Sobanko nor Dr. Brewer had any financial declarations.

msullivan@frontlinemedcom.com

ORLANDO – Assessment, education, and a judicious dose of medication can make a big difference to patients who are feeling anxious about undergoing Mohs surgery.

No studies or guidelines lay out a step-by-step management plan for anxious patients. But a little bit of common sense and empathy go a long way in easing the feeling, according to presenters at the annual meeting of the American College of Mohs Surgery.

?

“We don’t have an algorithm for reducing anxiety,” said Dr. Joseph Sobanko of the University of Pennsylvania, Philadelphia. “But we do have a lot of studies showing that better psychosocial health is related to better surgical outcomes.”

The lack of definitive guidance means that anxious patients might be identified and assessed by gut instinct, he continued. “Those of you who see patients probably have a gestalt technique of identifying the anxious ones. I would suggest this might not be the best way.”

Instead of guessing, he recommends assessing all patients with a validated screening tool, and dealing with anxiety proactively.

Assessing anxiety

Although anxiety assessment may not be part of a typical Mohs surgery intake, it probably should be, Dr. Sobanko said. There are a number of excellent, well-validated tools, and none of them require expertise in psychology to administer.

The Beck Anxiety Inventory is a 21-question index that takes about 10 minutes to complete. It assesses subjective, somatic, and panic-related symptoms of anxiety, and has been validated in a variety of clinical settings. It focuses quite a bit on strong physical symptoms, however, which Dr. Sobanko feels “may not be as relevant for our patients.”

The State-Trait Anxiety Inventory consists of 40 questions and takes about 15 minutes to complete. “I like it because it not only assesses how they generally feel, but how they feel at the moment,” he said. “We think it’s good and we do use it, but it takes a while to complete.”

The Hospital Anxiety and Depression Scale is short, with only 14 questions, and takes only about 5 minutes to complete. “It’s validated for hospital patients, but we are often working with patients who are less sick than that,” Dr. Sobanko said.

The Skin Cancer Index is his go-to anxiety screen for Mohs patients. It includes 15 questions that “really get to the heart of things that matter to our patients: emotional, social, and appearance issues,” he noted. Created in 2006, it was validated in a large cohort of Mohs surgery patients (Arch Facial Plast Surg. 2006;8[5]:314-318). The questions probe patients’ feelings about the seriousness of their skin cancer, its long-term health effect, and the impact the lesion – and its treatment – will have on appearance.

Tackling anxiety

Dr. Sobanko described his own, soon-to-be-published study of 104 Mohs surgery patients, who were randomized to receive a presurgical phone call to discuss anxiety, or the usual presurgical consultation. It was easy to implement the call, he said, noting that 70% were reached on the first try, and the interaction only took about 7 minutes.

Anxiety was common, with 43% reporting being anxious about the procedure. A frequent worry (25%) was whether their skin cancer would threaten their health over the long term. But both groups reported about the same reduction in anxiety after their discussion with the provider, whether it occurred over the phone or in person. After surgery, they expressed similar levels of satisfaction with the experience.

Clearly, the most effective method of dealing with patient anxiety has yet to be identified, Dr. Sobanko noted. Others are being explored, including music and educational videos.

In 2013, he and colleagues published a small study showing that music significantly reduced anxiety during Mohs surgery (Dermatol Surg. 2013 Feb;39[2]:298-305). It randomized 100 patients to surgery without music, or to listening to a playlist they had selected for themselves. Anxiety was measured using the State-Trait Anxiety Inventory and on a visual analog scale. Subjects in the music group experienced statistically significantly lower scores on both measures, Dr. Sobanko said.

A study presented at the meeting found that a preoperative education video helped as well. Dr. Sidney Smith of the Georgia Skin and Cancer Clinic, Savannah, examined the benefit of a 9-minute video created by the American College of Mohs Surgery. The video interviews patients about their experiences, describes the surgery and overall cure rates, and touches on reconstruction and follow-up.

The study comprised 200 patients; 100 saw the movie, and then completed a 24 question survey about their perception of the procedure. Almost all (94%) of those who viewed it said the video answered their questions; 85% said it relieved their fear about undergoing the surgery.

Treating anxiety

Anxiolytics can be easily employed to help ease day-of-surgery anxiety, Dr. Jerry Brewer said at the meeting. Generally speaking, the medications are safe, well-tolerated, and very effective.

“One thing we should remember, however, is that anxiolytics do not affect pain. They have no effect on pain receptors, although they may affect a patient’s memory of pain. For people who are anxious, though, this can be a really great help,” said Dr. Brewer of the Mayo Clinic, Rochester, Minn.

He favors the short-acting benzodiazepines, particularly midazolam. It has a peak concentration of 17-55 minutes, so it’s particularly well suited for shorter cases. It also has a very rapid metabolization profile, with an elimination half life of 3-7 hours.

Since midazolam has twice the affinity for the benzodiazepine receptors as does diazepam, it can be effective in relatively small doses – usually about 0.25 mg/kg. The dose should be reduced by half for elderly patients and for those with renal or hepatic failure. In those patients, the elimination half-life can be increased up to 13 hours.

The typical dose for both adults and children is 10-20 mg. “We should remember that patients who take narcotics and those who take a benzodiazepine as a sleep aide may be quite tolerant and need a higher dose,” Dr. Brewer said.

Diazepam has a peak concentration of about 2 hours, but a much longer elimination half-life – up to 48 hours in a healthy adult and up to 80 hours in an elderly person. “It’s important that patients know they’re going to have this drug in their system for a couple days. This should be part of the consenting process,” Dr. Brewer pointed out.

Lorazepam has a peak concentration of about 2 hours as well, but a shorter half-life of 12-18 hours. That can be prolonged by 75% in patients with renal problems.

With the right clinical supervision, these medications are very safe, he said. “We treat about 800 patients per year with these and have data on about 12,000. Of those, we have had very few problems. Two have fallen out of bed. One patient wrote and said he was discharged too early, as he was very tired. One person fell and hit his head in the bathroom. One was sedated enough to need a sternal rub to improve responsiveness. And one gentleman enjoyed the medication so much that when the nurse left the room for a moment he grabbed the rest of the dose and drank it.”

Safe discharge is crucial when using anxiolytics, he added. “They absolutely cannot drive themselves home and they cannot go back to work. We make sure there is a reliable person to stay with the patient for at least 4 hours after discharge.”

Dr. Brewer does not discharge any patient until that person displays a zero rating on the Richmond Agitation-Sedation Scale (RASS) sedation scale. “That means he is awake, alert, and calmly interacting with you.”

Neither Dr. Sobanko nor Dr. Brewer had any financial declarations.

msullivan@frontlinemedcom.com