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Nicotinamide for Chemoprevention of Cutaneous Squamous Cell Carcinoma in Solid Organ Transplant Recipients


Joyce Y. Cheng, BS
Oscar R. Colegio, MD, PhD

Oscar.colegio@yale.edu
Yale-New Haven Transplantation Center
New Haven, CT, USA



Immunosuppressed solid organ transplant recipients have a ~100-fold increased risk of cutaneous squamous cell carcinoma compared with the general population. Given that deaths from cutaneous squamous cell carcinoma in the United States white population were estimated to approximate the deaths from malignant melanoma in 2012 [1], it follows that mortality due to cutaneous squamous cell carcinoma would have been even greater among solid organ transplant recipients. A recent large population-based study of cancer mortality in solid organ transplant recipients in Ontario, Canada, found that, of all cancers, skin cancer was responsible for the highest incremental risk of death in solid organ transplant recipients, with a standardized mortality ratio of 29.82 (95% confidence interval, 18.23-46.10)[2].

An exciting advance in the fight against skin cancer was recently published in the New England Journal of Medicine [3]. After showing promise in Phase 2 trials at reducing the number of pre-skin cancers in Australians with sun-damaged skin, oral nicotinamide was found in the Phase 3 trial to be a safe and effective means of reducing rates of developing new pre-skin cancers and non-melanoma skin cancers in a cohort of 386 "high-risk" adult subjects with 2 or more confirmed non-melanoma skin cancers in the previous 5 years [3]. Subjects on oral nicotinamide had a 30% decrease in new cutaneous squamous cell carcinomas compared with those on placebo (p=0.05). Nicotinamide, the amide form of vitamin B3, is a precursor to NAD+ (a co-factor for ATP production) and is hypothesized to exert its anti-carcinogenic effects by increasing cellular energy available for DNA repair, thus mitigating UV-induced ATP depletion and glycolytic blockade.

Although these findings are significant, it should be noted that immunocompromised subjects-including the immunosuppressed solid organ transplant recipient patient population for which we care-were excluded from participating in this trial. Therefore, we must temper any potential excitement about these findings, as it remains undetermined whether they can be generalized to our immunosuppressed patients. Vigorous counsel for sun avoidance and annual total body skin exams remain tried-and-true methods for skin cancer prevention in solid organ transplant recipients.

Future trials that include immunosuppressed subjects are needed to determine whether oral nicotinamide will deserve a place among established skin cancer chemopreventative agents currently available to solid organ transplant recipients-acitretin, sirolimus, capecitabine, and 5-aminolevulinic acid-photodynamic therapy. Acitretin, a retinoid (vitamin A analog), exerts its physiologic effects by binding to a number of specific nuclear receptors; its mechanism in the chemoprophylaxis of skin cancer is largely unknown but may include effects on immunomodulation, induction of apoptosis, cell cycle control, inhibition of ornithine decarboxylase, inhibition of cellular proliferation and keratinization, and promotion of cellular differentiation [4]. An inhibitor of the mechanistic target of rapamycin (mTOR) pathway, sirolimus can have a secondary protective effect against the development of new cutaneous squamous cell carcinomas when substituted for a calcineurin inhibitor in solid organ transplant recipients' immunosuppressive regimens [5]. Capecitabine, an oral prodrug of the chemotherapeutic agent 5-fluorouracil, is an antimetabolite that targets rapidly dividing cells [6]. Widely used in the treatment of premalignant skin cancers, 5-aminolevulinic acid-photodynamic therapy utilizes a photosensitizing agent such as 5-aminolevulinic acid that preferentially accumulates in diseased cells and is then activated by light to produce destructive reactive oxygen species selective to the target diseased tissue [7].

Adverse effects of chemopreventative agents can limit their use in solid organ transplant recipients. Long-term high-dose nicotinamide intake has been associated as a risk factor for obesity and type 2 diabetes [8]. Acitretin can cause mucocutaneous dryness, hair loss, musculoskeletal pain, and increased triglyceride levels [9]. Many solid organ transplant recipients have to discontinue sirolimus due to side effects including edema, acneiform eruption, aphthous ulcers, and proteinuria.5 Tolerability of oral capecitabine is limited by fatigue, hand-foot syndrome, diarrhea, and, rarely, neutropenia [6]. 5-aminolevulinic acid-photodynamic therapy shows great promise as an noninvasive means of reversing actinic skin damage in solid organ transplant recipients but can cause pain upon illumination, allergic contact dermatitis, and, occasionally, intensive phototoxic reactions [10].

One final consideration in prescribing oral nicotinamide, the amide form of vitamin B3, as a chemopreventative agent against cutaneous squamous cell carcinoma is that it is presently only available-and regulated by the United States Food and Drug Administration-as a dietary supplement, not as a drug. In other words, unlike drugs, which must be demonstrated to be safe and effective for their stated uses prior to marketing, dietary supplements are neither formally inspected nor approved by the Food and Drug Administration for safety or effectiveness prior to marketing (Dietary Supplement Health and Education Act of 1994, www.fda.gov/Food/DietarySupplements). Therefore, it may currently be impossible to predict the relative efficacy of nicotinamide for skin cancer chemoprevention between different formulations unless it becomes regulated as a drug. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


References:

  1. Karia PS, Han J , Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. Journal of the American Academy of Dermatology 2013;68:957-66.
  2. Acuna SA, Fernandes KA, Daly C , et al. CAncer mortality among recipients of solid-organ transplantation in ontario, canada. JAMA Oncology 2016:1-8.
  3. Chen AC, Martin AJ, Choy B, Fernandez-Penas P, Dalziell RA, McKenzie CA et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. The New England journal of medicine 2015;373:1618-26.
  4. Lens M , Medenica L. Systemic retinoids in chemoprevention of non-melanoma skin cancer. Expert Opin Pharmacother 2008;9:1363-74.
  5. Euvrard S, Morelon E, Rostaing L, Goffin E, Brocard A, Tromme I et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. The New England journal of medicine 2012;367:329-39.
  6. Jirakulaporn T, Endrizzi B, Lindgren B, Mathew J, Lee PK , Dudek AZ. Capecitabine for skin cancer prevention in solid organ transplant recipients. Clinical transplantation 2011;25:541-8.
  7. Zhao B , He YY. Recent advances in the prevention and treatment of skin cancer using photodynamic therapy. Expert Rev Anticancer Ther 2010;10:1797-809.
  8. Li D, Tian YJ, Guo J, Sun WP, Lun YZ, Guo M et al. Nicotinamide supplementation induces detrimental metabolic and epigenetic changes in developing rats. The British journal of nutrition 2013;110:2156-64.
  9. Chen K, Craig JC , Shumack S. Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials. The British journal of dermatology 2005;152:518-23.
  10. Togsverd-Bo K, Omland SH, Wulf HC, Sorensen SS , Haedersdal M. Primary prevention of skin dysplasia in renal transplant recipients with photodynamic therapy: a randomized controlled trial. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2015;15:2986-90.



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