Tools
Mohs Micrographic Surgery Chemoprophylaxis Options for Nicotinamide and Oral Retinoids
Introduction
The Mohs surgeon should be familiar with nonsurgical options for treating nonmelanoma skin cancers (NMSCs) and medical options for preventing new skin cancer formation. Patients not well-suited for cutaneous surgery due to their overall clinical health can be offered alternative treatment modalities such as topical or systemic chemotherapy or radiation. Other patients with extensive sun exposure over the years, certain genodermatoses, chronic radiation exposure, and immunosuppression are at greater risk of developing NMSCs than patients without these risk factors.[1] In patients with increased risk factors, chemoprophylaxis, or agents used to slow the growth of NMSCs, can be utilized to prevent the formation of NMSCs and, subsequently, the associated morbidity and mortality.[1]
Basal cell carcinoma (BCC) is the most prevalent NMSC in the United States, with an annual incidence of approximately 2 million.[2] Although death from BCC is rare, the tumors can be associated with significant morbidity and cost. The second most common NMSC, squamous cell carcinoma (SCC), has an annual incidence of approximately 700,000 cases in the United States, of which approximately 2% result in death.[3] In addition to preventing the morbidity and mortality associated with these NMSCs, there is evidence that preventative measures such as chemoprophylaxis save the healthcare system money. A study from 2015 analyzed the economic burden of skin cancer treatments and found the average annual cost of skin cancer treatments increased from 2002-2006 to 2007-2011 from $3.6 billion to $8.1 billion.[4] Preventing new NMSC formation can reduce healthcare spending and patient morbidity and mortality.
Nicotinamide and oral retinoids are 2 systemic chemoprophylactic medications used in populations at high risk of developing NMSCs. A survey sent to the American College of Mohs Surgeons found that 76.9% of the respondents recommend nicotinamide to their patients for NMSC prevention.[5] These 2 medications are essential tools the Mohs surgeon can utilize to decrease morbidity and mortality in patients with multiple NMSCs.
Function
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Function
Nicotinamide is a form of water-soluble vitamin B3 available in both oral and topical formulations; the oral formulation has been demonstrated to decrease the rate of NMSC formation.[6]
Nicotinamide plays an essential role in glycolysis by generating the NAD+ needed for ATP production and therefore is critical for generating cellular energy and influencing cellular metabolism.[7] By preventing cellular energy depletion, nicotinamide increases excisional DNA repair and prevents immunosuppression due to ultraviolet radiation (UVR).[1]
Recommendations have been published in the Journal of the American Academy of Dermatology (JAAD) that support using nicotinamide 500 mg twice daily in patients with field cancerization or a history of more than one SCC.[8][9] These recommendations are based on a randomized controlled trial in Australia that enrolled immunocompetent patients with more than two NMSCs into a nicotinamide arm and a placebo arm. This trial found a 23% decrease in SCCs and a 13% reduction in actinic keratoses (AKs) in patients taking nicotinamide 500 mg twice daily, followed over 1 year, compared to the patients taking a placebo.[10] This study did not find a significant decrease in new BCC formation in the nicotinamide group compared to the placebo group.[10]
The same research group studied the use of nicotinamide in renal transplant recipients; however, this study was underpowered to assess the rate of SCC formation in this patient population.[11] A different research group published a randomized placebo-controlled trial in March 2023 that found that oral nicotinamide therapy over 1 year did not decrease NMSCs or AKs in immunosuppressed solid-organ transplant recipients.[12] Furthermore, a systematic review and meta-analysis were performed to analyze the effect of nicotinamide on skin cancer prophylaxis regardless of immunosuppression status. This analysis found moderate-quality evidence to support nicotinamide use for SCC prevention and low-quality evidence to support nicotinamide use for BCC prevention in general and organ-transplant-recipient populations.[13]
Retinoids comprise natural and synthetic vitamin A analogs with multiple therapeutic uses in dermatology, including acne, psoriasis, and cutaneous T-cell lymphoma. Numerous topical and oral formulations of retinoids target retinoid nuclear receptors to exert their effects. The mechanism of action regarding retinoid chemoprophylaxis is poorly understood but likely represents a combination of factors, including immunomodulation, inhibition of cellular proliferation and keratinization, and induction of apoptosis.[14]
The third-generation oral retinoid, acitretin, is well-established in the literature to prevent skin cancer formation in solid-organ transplant recipients and patients with diseases predisposing to UVR damage, like xeroderma pigmentosum. Isotretinoin, a first-generation oral retinoid, has a single documented case of its use in a kidney-transplant recipient. This patient was treated with 0.5 mg to 1.0 mg/kg/day with a subsequent reduction of new NMSCs by half over 2 months.[15] Although the use of isotretinoin in the transplant population is not well studied, it may be considered an alternative in patients who cannot tolerate acitretin due to renal insufficiency.[16] Isotretinoin has also been shown to decrease the incidence of NMSC in patients with xeroderma pigmentosum. Treatment with isotretinoin 2 mg/kg/day in these patients over 2 years resulted in a 63% decrease in NMSC formation in 5 of 7 patients.[17][18]
There is little evidence for using other oral retinoids in the chemoprevention of NMSCs. Oral alitretinoin is unavailable commercially in the United States and is primarily used for chronic eczema in Europe.[19] Bexarotene is primarily used for treating cutaneous T-cell lymphoma and has been used for lymphoproliferative disorders in organ-transplant recipients.[20][21]
A 2018 study recommends starting a patient on prophylactic acitretin if a patient has developed more than 5 SCCs over 2 to 3 years, the formation of at least 1 SCC of stage T2b/T3 or higher in combination with field photodamage, or field photodamage that is nonresponsive to 5-fluorouracil or photodynamic therapy.[9] In these patient populations, the authors recommend starting oral acitretin at 10 mg every other day with gradual dose increases as tolerated over a month until a final dose of 20 mg daily is reached.[9]
Issues of Concern
The adverse effects of the chemoprophylactic agents should be weighed against their potential benefit to patients. Nicotinamide is a relatively safe medication since it is a form of water-soluble vitamin B3; excess nicotinamide is excreted from the body. However, patients should be counseled to avoid the readily available over-the-counter formulation of niacin, which can produce flushing.[22] There are over-the-counter formulations of nicotinamide available that avoid this effect. Additionally, nicotinamide can result in liver failure at doses greater than 3 g daily.[23]
Topical retinoids primarily have localized adverse effects, including redness, dryness, pruritis, and peeling of the skin.[24] The adverse effects of oral retinoids are more systemic and potentially more severe when compared to topical retinoids. Oral retinoid therapy is teratogenic, affecting the developing fetal central nervous system, cardiovascular system, thymus, and face.[24] Although topical retinoid formulations do not appear to concentrate in plasma, even in applications beyond the recommended dose, many practitioners avoid topical retinoids during pregnancy.[25] The potential teratogenic effects of retinoids used as chemoprophylaxis may be a lesser concern overall, as most patients requiring chemoprophylaxis are beyond childbearing. However, it could still be relevant for a small subset of patients.
Other effects of oral retinoids include dryness of mucous membranes, arthralgias, myalgias, bone pain, headaches, and night blindness.[24] Dryness of mucous membranes, especially cheilitis, is common and treated symptomatically. Evidence shows that retinoids affect bone metabolism, but studies conflict with whether the drugs decrease bone mineral density over time. However, skeletal hyperostosis and extraspinal calcification of ligaments and tendons can occur with oral retinoids.[26] Headaches associated with oral retinoids tend to be mild, but a high index of suspicion is warranted for pseudotumor cerebri if the headaches are severe and associated with visual symptoms. Additionally, concurrent use of retinoids and tetracyclines should be avoided since this class of drugs is also associated with pseudotumor cerebri.[27]
Oral retinoids are also associated with elevated cholesterol, triglycerides, and liver enzymes.[24] The liver enzyme elevations typically peak between 2 and 8 weeks of therapy and then return to baseline. Current laboratory screening recommendations include baseline screening of complete blood count, creatinine, lipid panel, and liver enzymes. A lipid panel and liver enzymes should then be checked monthly for 1 to 2 months as the dose is escalated after therapy initiation and every 3 months once the patient has reached a stable dose.[24][9] A meta-analysis found that isotretinoin causes an increase in both lipids and liver enzymes, but the mean changes were not high-risk.[28] If liver enzymes increase more than 3-fold of the upper limit of normal, it is advisable to discontinue the oral retinoid.[29] Alcohol use should be strongly discouraged in patients taking oral retinoids; it is associated with increased retinoid metabolism and subsequent hepatic toxicity and fibrosis.[30]
Depression is an effect of oral retinoids that remains debated. Some literature suggests an association between oral retinoids and mood disorders; other sources indicate improved mood while on the medication, possibly due to improvement in the underlying cutaneous condition.[31] Patients undergoing oral retinoid therapy should be screened for depression and mood disorders and counseled about the possible association; the medication should be discontinued if symptoms arise during oral retinoid therapy.[24]
Acitretin has been associated with poor wound healing, characterized by excessive granulation tissue formation and hypertrophic scarring. A study published in 2004 evaluating the surgical outcomes of solid-organ transplant patients taking acitretin did not find a significant difference in wound healing complications when compared to patients not taking the medication.[32]
Clinical Significance
The patients most likely to need chemoprophylaxis for NMSCs are transplant recipients on immunosuppressive medications, people with certain genodermatoses, and patients with significant sun exposure over their lifetime. Since Mohs surgeons are likely to encounter more aggressive NMSCs in practice, they should be familiar with the risks unique to each of these populations and the appropriate management of NMSC chemoprophylaxis.
According to the United Network for Organ Sharing, more than 42,800 organ transplants were performed in 2022. Solid-organ transplant recipients are estimated to have between 60 and 250 times the risk of developing an SCC and 10 to 40 times the risk of developing a BCC above the general population.[33] It is estimated that NMSCs cause approximately 3% of cancer-related deaths in the transplant population.[34] Most skin cancers will begin to develop within 8 years of transplant in younger patients but as early as 3 years in patients who undergo transplant after age 60.[35][36] Furthermore, the time interval between the formation of new skin cancers reduces with each subsequent occurrence following the appearance of the initial skin cancer. Additionally, the severity of the tumors correlates with the total number of skin cancers the patient has experienced.[37] SCCs also tend to be more aggressive in transplant recipients, with a recurrence rate of 13.4%.[38]
The most important factor in NMSC development in this patient population is high UVR exposure before and after the transplant.[39][33] Other predisposing factors to NMSC development include fair skin, aging, tobacco use, and infection with the Human papillomavirus.[33] These factors must be considered when evaluating the risk of NMSC in solid-organ transplant patients and the timing of the initiation of chemoprophylaxis therapy.
Other Issues
Patients should be educated that discontinuing acitretin will rapidly return the rate of SCC formation to baseline.[40] Other potential chemoprophylaxis measures can be considered if acitretin is contraindicated or poorly tolerated. Other chemoprophylactic options include photodynamic therapy or topical chemoprophylaxis with retinoids, 5-fluorouracil, imiquimod, ingenol mebutate, or diclofenac. Of these options, 5-fluorouracil and imiquimod have the strongest level of evidence for use.[9]
The role of nicotinamide as chemoprophylaxis for melanocytic tumors seems plausible based on its mechanism of action but has not been confirmed in clinical trials.[41] However, there is some evidence that administration of N-acetylcysteine may reduce ultraviolet-induced oxidative stress in melanocytic nevi and thereby reduce long-term melanoma risk.[42]
It is also well established that switching from a calcineurin inhibitor to a mechanistic target of rapamycin (mTOR) inhibitor reduces the number of NMSCs seen in both kidney and liver transplant recipients.[43] Communicating with the transplant physician and making appropriate drug regimen modification recommendations is important, especially if the patient has experienced multiple or high-risk NMSCs.
Enhancing Healthcare Team Outcomes
Although some Mohs surgeons will not medically manage high-risk patients, they must understand which patients may benefit from chemoprophylaxis and work with the primary dermatologist to ensure they receive comprehensive care. Additionally, if the Mohs surgeon does manage high-risk patients with chemoprophylaxis, they should work alongside the transplant physician to ensure their medication regimen balances the role of organ anti-rejection and the development of malignancies. Many prospective randomized controlled trials have demonstrated that mTOR inhibitors like sirolimus reduce the incidence of SCCs in the organ transplant population.[44][45][46]
Collaboration among healthcare professionals involved in the care of solid-organ transplant recipients should also include nurses and pharmacists. An interdisciplinary approach ensures comprehensive care, sharing of expertise, and better management of potential complications. By implementing these strategies, the healthcare team can help reduce the risk of developing skin cancer in patients who have undergone solid-organ transplantation. Early detection, sun protection, regular monitoring, and comprehensive care are key to promoting the best possible outcomes and overall well-being for these patients.
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