Guarding against nonmelanoma skin cancer in solid organ transplant recipients

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doi:10.12788/jfp.0172

Applied Evidence

Guarding against nonmelanoma skin cancer in solid organ transplant recipients

J Fam Pract. 2021 April;70(3):121-130 | 10.12788/jfp.0172

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References

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19. Blomberg M, He SY, Harwood C, et al; NCI Keratinocyte Carcinoma Consortium. Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients. Br J Dermatol. 2017;177:1225-1233. doi: 10.1111/bjd.15950

20. Urwin HR, Jones PW, Harden PN, et al. Predicting risk of nonmelanoma skin cancer and premalignant skin lesions in renal transplant recipients. Transplantation. 2009;87:1667-1671. doi: 10.1097/TP.0b013e3181a5ce2e

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25. Puza CJ, Myers SA, Cardones AR, et al. The impact of transplant rejection on cutaneous squamous cell carcinoma in renal transplant recipients. Clin Exp Dermatol. 2018;44:265-269. doi: 10.1111/ced.13699

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28. Askew DA, Mickan SM, Soyer HP, et al. Effectiveness of 5-fluorouracil treatment for actinic keratosis—a systematic review of randomized controlled trials. Int J Dermatol. 2009;48:453-463. doi: 10.1111/j.1365-4632.2009.04045.x

29. Salim A, Leman JA, McColl JH, et al. Randomized comparison of photodynamic therapy with topical 5-fluorouracil in Bowen‘s disease. Br J Dermatol. 2003;148:539-543. doi: 10.1046/j.1365-2133.2003.05033.x

30. Morton CA. A synthesis of the world‘s guidelines on photodynamic therapy for non-melanoma skin cancer. G Ital Dermatol Venereol. 2018;153:783-792. doi: 10.23736/S0392-0488.18.05896-0

31. Joly F, Deret S, Gamboa B, et al. Photodynamic therapy corrects abnormal cancer-associated gene expression observed in actinic keratosis lesions and induces a remodeling effect in photodamaged skin. J Dermatol Sci. 2018;S0923-1811(17)30775-2. doi: 10.1016/j.jdermsci.2018.05.002

32. Patel GK, Goodwin R, Chawla M, et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen‘s disease): a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2006;54:1025-1032. doi: 10.1016/j.jaad.2006.01.055

33. Imiquimod. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed August 6, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7077?cesid=aRo1Yh9sd0Q&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dimiquimod%26t%3Dname%26va%3Dimiquimod

34. Diclofenac. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed August 6th, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/1772965?cesid=5vTk7J3Vmvc&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Ddiclofenac%26t%3Dname%26va%3Ddiclofenac

35. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618-1626. doi: 10.1056/NEJMoa1506197

36. Yiasemides E, Sivapirabu G, Halliday GM, et al. Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis. 2009;30:101-105. doi: 10.1093/carcin/bgn248

37. Otley CC, Stasko T, Tope WD, et al. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006;32:562-568. doi: 10.1111/j.1524-4725.2006.32115.x

38. McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol. 1999;140:656-660. doi: 10.1046/j.1365-2133.1999.02765.x

39. Capecitabine. Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed February 13, 2019. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6519?cesid=7WMsK72X7T7&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dcapecitabine%26t%3Dname%26va%3Dcapecitabine

40. Wollina U, Hansel G, Koch A, et al. Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin. J Cancer Res Clin Oncol. 2005;131:300-304. doi: 10.1007/s00432-004-0656-6

41. Zavattaro E, Veronese F, Landucci G, et al. Efficacy of topical imiquimod 3.75% in the treatment of actinic keratosis of the scalp in immunosuppressed patients: our case series. J Dermatol Treat. 2020;31:285-289. doi: 10.1080/09546634.2019.1590524

42. Neugebauer R, Su KA, Zhu Z, et al. Comparative effectiveness of treatment of actinic keratosis with topical fluorouracil and imiquimod in the prevention of keratinocyte carcinoma: a cohort study. J Am Acad Dermatol. 2019;80:998-1005. doi: 10.1016/j.jaad.2018.11.024

43. Gupta AK, Paquet M. Network meta-analysis of the outcome ‚participant complete clearance in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol. 2013;169:250-259. doi: 10.1111/bjd.12343

44. Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med. 2019;380:935-946. doi: 10.1056/NEJMoa1811850

45. Bangash HK, Colegio OR. Management of non-melanoma skin cancer in immunocompromised solid organ transplant recipients. Curr Treat Options Oncol. 2012;13:354-376. doi: 10.1007/s11864-012-0195-3

46. Ulrich C, Johannsen A, Röwert-Huber J, et al. Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses. Eur J Dermatol. 2010;20:482-488. doi: 10.1684/ejd.2010.1010

47. Ulrich C, Hackethal M, Ulrich M, et al. Treatment of multiple actinic keratoses with topical diclofenac 3% gel in organ transplant recipients: a series of six cases. Br J Dermatol. 2007;156(suppl 3):40-42. doi: 10.1111/j.1365-2133.2007.07864.x

48. Wu Y, Tang N, Cai L, et al. Relative efficacy of 5-fluorouracil compared with other treatments among patients with actinic keratosis: a network meta-analysis. Dermatol Ther. 2019;32:e12822. doi: 10.1111/dth.12822

49. Stockfleth E, Kerl H, Zwingers T, et al. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol. 2011;165:1101-1108. doi: 10.1111/j.1365-2133.2011.10387.x

50. Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatment of actinic keratoses of the face and scalp. J Drug Dermatol. 2006;5:156-159.

51. Nichols AJ, Allen AH, Shareef S, et al. Association of human papillomavirus vaccine with the development of keratinocyte carcinomas. JAMA Dermatol. 2017;153:571-574. doi: 10.1001/jamadermatol.2016.5703

52. Nichols AJ, Gonzalez A, Clark ES, et al. Combined systemic and intratumoral administration of human papillomavirus vaccine to treat multiple cutaneous basaloid squamous cell carcinomas. JAMA Dermatol. 2018;154:927-930. doi: 10.1001/jamadermatol.2018.1748

53. Rousseau B, Guillemin A, Duvoux C, et al. Optimal oncologic management and mTOR inhibitor introduction are safe and improve survival in kidney and liver allograft recipients with de novo carcinoma. Int J Cancer. 2019;144:886-896. doi: 10.1002/ijc.31769

54. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 2004;18:446-449. doi: 10.1111/j.1399-0012.2004.00188.x

55. Euvrard S, Morelon E, Rostaing L, et al; TUMORAPA Study Group. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. 2012;367:329-339. doi: 10.1056/NEJMoa1204166

56. Hoogendijk-van den Akker JM, Harden PN, Hoitsma AJ, et al. Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. J Clin Oncol. 2013;31:1317-1323. doi: 10.1200/JCO.2012.45.6376

57. Karia PS, Azzi JR, Heher EC, et al. Association of sirolimus use with risk for skin cancer in a mixed-organ cohort of solid-organ transplant recipients with a history of cancer. JAMA Dermatol. 2016;152:533-540. doi: 10.1001/jamadermatol.2015.5548

58. Stratigos A, Garbe C, Lebbe C, et al; European Dermatology Forum (EDF); European Association of Dermato-Oncology (EADO); European Organization for Research and Treatment of Cancer (EORTC). Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer. 2015;51:1989-2007. doi: 10.1016/j.ejca.2015.06.110

59. Goldman G. The current status of curettage and electrodesiccation. Dermatol Clin. 2002;20:569-578, ix. doi: 10.1016/s0733-8635(02)00022-0

60. Stasko T, Brown MD, Carucci JA, et al; International Transplant-Skin Cancer Collaborative; European Skin Care in Organ Transplant Patients Network. Guidelines for the management of squamous cell carcinoma in organ transplant recipients. Derm Surg. 2004;30:642-650. doi: 10.1111/j.1524-4725.2004.30150.x

61. Telfer NR, Colver GB, Morton CA; British Association of Dermatologists. Guidelines for the management of basal cell carcinoma. Br J Dermatol. 2008;159:35-48. doi: 10.1111/j.1365-2133.2008.08666.x

Diclofenac is a nonsteroidal anti-inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.^34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.³⁴ Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population^46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.^43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.^43,48,50

Systemic chemoprophylaxis

Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.^27-40)

Nicotinamide, the amide form of vitamin B₃, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.²⁷ Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.^27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.^27,36

Because the intensity of immunosuppression and the individual immunosuppressants used affect the risk of nonmelanoma skin cancer, conduct a thorough medication review at all visits.

There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.^27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.²⁷

Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.^27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.²⁷

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