2.2 Chemoprevention

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Background

The main classes of agents used in the chemoprevention of keratinocyte cancer (KC) for individuals at extreme skin cancer risk are synthetic retinoids and nicotinamide.

Whilst large numbers of skin cancers can occur in immune competent individuals, chronically immunosuppressed organ transplant recipients (including heart/lung, hepatic and renal transplant recipients) have a greatly increased risk of developing skin cancer and are a major target population for chemoprevention (see: Organ transplantation and immunosuppression). For example, 25% of Australian renal transplant recipients will develop a KC by 5 years post transplantation and 44% by 9 years.[1] The most dramatic increase in incidence is seen in cutaneous squamous cell carcinoma (cSCC), though there is also an increase in the incidences of basal cell carcinoma (BCC) and melanoma.[2] A greater proportion of the cSCCs and BCCs occurring in this context show aggressive growth patterns and poor prognostic features.[3][4][5][6] Aggressive cSCCs contribute to substantial numbers of deaths in the Australian organ transplant population.[7]

Other causes of chronic immune suppression, such as chronic leukaemias and lymphomas, are associated with increased risk and aggressiveness of skin cancer,[8][9] and chemoprevention may sometimes be needed in this context.

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Overview of evidence (non-systematic literature review)

Synthetic retinoids

Four studies of retinoid chemoprophylaxis of skin cancer have been undertaken in renal transplant recipients. All have shown a significant reduction in rates of cSCCs during treatment.[10][11][12][13] In one study,[10] suppression of the incidence of KC was not maintained following cessation of retinoid chemoprophylaxis, suggesting that these agents act at a late stage in tumour development.

Due to the need for long-term therapy, it is recommended that retinoid treatment be instituted for transplant recipients and also for severely affected immune competent patients only when patients begin to suffer from numbers of cSCCs that are causing significant morbidity or are life-threatening. The long-term benefits must be weighed against the short- and long-term adverse effects of retinoids. The major long-term adverse effects are calcification of tendons and ligaments and spinal hyperostoses.[14]

Xeroderma pigmentosuma rare hereditary disorder associated with multiple early-onset SCCs and increased risk of other cancers

A trial using high dose isotretinoin in seven patients showed a 63% reduction in KCs, compared with the 2-year period before treatment.[15]

Naevoid basal cell carcinoma syndrome

Small trials of retinoids have demonstrated effective chemoprophylaxis of BCC in patients with naevoid BCC syndrome (Gorlin's syndrome).[16][17][18]

Betacarotene supplementation

Trials of betacarotene in the chemoprevention of KC have failed to demonstrate a beneficial effect.[16][19][20][21]

Nicotinamide

Nicotinamide is an amide form of vitamin B3 which enhances DNA repair after ultraviolet (UV) irradiation, and reduces the immune suppressive effects of sunlight on the skin.[22]

Oral nicotinamide reduced numbers of actinic (solar) keratoses (AKs) in phase II studies[23] and has been shown in one phase III randomised trial to reduce the incidence of KC in high-risk immune-competent individuals with multiple previous skin cancers.[24] Nicotinamide 500mg twice daily over 12 months reduced numbers of new KCs by 23% compared with placebo, with similar magnitudes of reduction observed for BCC and cSCC.[24] The rate of AKs was also reduced by approximately 15%. The chemopreventive effect was lost during a 6-month post-intervention follow-up period, suggesting that nicotinamide’s mechanisms of action relate to the promotion rather than initiation stages of carcinogenesis.

Nicotinamide lacks the vasodilatory effects of nicotinic acid and was well tolerated. At very high doses (approximately 8g daily), nicotinamide has been associated with reversible liver function abnormalities. These side effects are not seen at lower doses. There is a potential drug interaction with carbamazepine.[24][25]

Small phase II studies suggest that nicotinamide may be useful for the chemoprevention of KC in organ transplant recipients,[26][27] but as yet there have been no large trials of its safety and efficacy in this population. Its effects on chemoprevention of melanoma are currently unknown.


Key point(s)

Nicotinamide may be a useful chemopreventive adjunct to sun protection and sunscreen use in high risk, immune-competent individuals with a history of multiple keratinocyte cancers. It should not be recommended for lower-risk individuals without a history of skin cancer.


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References

  1. Leigh IM, Glover MT. Cutaneous warts and tumours in immunosuppressed patients. J R Soc Med 1995 Feb;88(2):61-2 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7769594.
  2. Barr BB, Benton EC, McLaren K, Bunney MH, Smith IW, Blessing K, et al. Human papilloma virus infection and skin cancer in renal allograft recipients. Lancet 1989 Jan 21;1(8630):124-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2563048.
  3. Funk-Debleds P, Ducroux E, Guillaud O, Ursic-Bedoya J, Decullier E, Vallin M, et al. Subsequent nonmelanoma skin cancers and impact of immunosuppression in liver transplant recipients. J Am Acad Dermatol 2018 Jul;79(1):84-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/29307647.
  4. Krynitz B, Edgren G, Lindelöf B, Baecklund E, Brattström C, Wilczek H, et al. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008--a Swedish population-based study. Int J Cancer 2013 Mar 15;132(6):1429-38 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22886725.
  5. Sheil AG, Disney AP, Mathew TH, Amiss N. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc 1993 Feb;25(1 Pt 2):1383-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8442150.
  6. Veness MJ, Quinn DI, Ong CS, Keogh AM, Macdonald PS, Cooper SG, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer 1999 Apr 15;85(8):1758-64 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10223570.
  7. Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol 1999 Jan;40(1):27-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9922009.
  8. Mehrany K, Weenig RH, Lee KK, Pittelkow MR, Otley CC. Increased metastasis and mortality from cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia. J Am Acad Dermatol 2005 Dec;53(6):1067-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16310071.
  9. Otley CC. Non-Hodgkin lymphoma and skin cancer: A dangerous combination. Australas J Dermatol 2006 Nov;47(4):231-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17034463.
  10. 10.010.1 Bavinck JN, Tieben LM, Van der Woude FJ, Tegzess AM, Hermans J, ter Schegget J, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol 1995 Aug;13(8):1933-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7636533.
  11. Gibson GE, O'Grady A, Kay EW, Murphy GM. Low-dose retinoid therapy for chemoprophylaxis of skin cancer in renal transplant recipients. J Eur Acad Dermatol Venereol 1998 Jan;10(1):42-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9552756.
  12. Kelly JW, Sabto J, Gurr FW, Bruce F. Retinoids to prevent skin cancer in organ transplant recipients. Lancet 1991 Nov 30;338(8779):1407 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1682775.
  13. Rook AH, Jaworsky C, Nguyen T, Grossman RA, Wolfe JT, Witmer WK, et al. Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation 1995 Mar 15;59(5):714-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7886798.
  14. Gerber LH, Helfgott RK, Gross EG, Hicks JE, Ellenberg SS, Peck GL. Vertebral abnormalities associated with synthetic retinoid use. J Am Acad Dermatol 1984 May;10(5 Pt 1):817-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6586753.
  15. Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 1988 Jun 23;318(25):1633-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3287161.
  16. 16.016.1 Goldberg LH, Hsu SH, Alcalay J. Effectiveness of isotretinoin in preventing the appearance of basal cell carcinomas in basal cell nevus syndrome. J Am Acad Dermatol 1989 Jul;21(1):144-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2745766.
  17. Hodak E, Ginzburg A, David M, Sandbank M. Etretinate treatment of the nevoid basal cell carcinoma syndrome. Therapeutic and chemopreventive effect. Int J Dermatol 1987 Nov;26(9):606-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3443534.
  18. Peck GL, DiGiovanna JJ, Sarnoff DS, Gross EG, Butkus D, Olsen TG, et al. Treatment and prevention of basal cell carcinoma with oral isotretinoin. J Am Acad Dermatol 1988 Jul;19(1 Pt 2):176-85 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3165982.
  19. Green A, Williams G, Neale R, Hart V, Leslie D, Parsons P, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999 Aug 28;354(9180):723-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10475183.
  20. Frieling UM, Schaumberg DA, Kupper TS, Muntwyler J, Hennekens CH. A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physician's health study. Arch Dermatol 2000 Feb;136(2):179-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10677093.
  21. Greenberg ER, Baron JA, Stukel TA, Stevens MM, Mandel JS, Spencer SK, et al. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. The Skin Cancer Prevention Study Group. N Engl J Med 1990 Sep 20;323(12):789-95 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2202901.
  22. Yiasemides E, Sivapirabu G, Halliday GM, Park J, Damian DL. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis 2009 Jan;30(1):101-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19028705.
  23. Surjana D, Halliday GM, Martin AJ, Moloney FJ, Damian DL. Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials. J Invest Dermatol 2012 May;132(5):1497-500 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22297641.
  24. 24.024.124.2 Chen AC, Martin AJ, Choy B, Fernández-Peñas P, Dalziell RA, McKenzie CA, et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. N Engl J Med 2015 Oct 22;373(17):1618-26 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26488693.
  25. Damian DL. Nicotinamide for skin cancer chemoprevention. Australas J Dermatol 2017 Aug;58(3):174-180 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28321860.
  26. Chen AC, Martin AJ, Dalziell RA, McKenzie CA, Lowe PM, Eris JM, et al. A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients. Br J Dermatol 2016 Nov;175(5):1073-1075 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27061568.
  27. Drago F, Ciccarese G, Parodi A. Nicotinamide for Skin-Cancer Chemoprevention. N Engl J Med 2016 Feb 25;374(8):789-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26933858.

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