Guarding against nonmelanoma skin cancer in solid organ transplant recipients

,; ,; ,

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

PDF Download

References

1. Bhat M, Mara K, Dierkhising R, et al. Immunosuppression, race, and donor-related risk factors affect de novo cancer incidence across solid organ transplant recipients. Mayo Clin Proc. 2018;93:1236-1246. doi: 10.1016/j.mayocp.2018.04.025

2. Togsverd-Bo K, Philipsen PA, Haedersdal M, et al. Organ transplant recipients express enhanced skin autofluorescence and pigmentation at skin cancer sites. J Photochem Photobiol B. 2018;188:1-5. doi: 10.1016/j.jphotobiol.2018.08.008

3. Kearney L, Hogan D, Conlon P, et al. High-risk cutaneous malignancies and immunosuppression: challenges for the reconstructive surgeon in the renal transplant population. J Plast Reconstr Aesthet Surg. 2017;70:922-930. doi: 10.1016/j.bjps.2017.03.005

4. Borgogna C, Olivero C, Lanfredini S, et al. β-HPV infection correlates with early stages of carcinogenesis in skin tumors and patient-derived xenografts from a kidney transplant recipient cohort. Front Microbiol. 2018;9:117. doi: 10.3389/fmicb.2018.00117

5. Nunes EM, Talpe-Nunes V, Sichero L. Epidemiology and biology of cutaneous human papillomavirus. Clinics (Sao Paulo). 2018;73(suppl 1):e489s. doi: 10.6061/clinics/2018/e489s

6. Pini AM, Koch S, Schärer L, et al. Eruptive keratoacanthoma following topical imiquimod for in situ squamous cell carcinoma of the skin in a renal transplant recipient. J Am Acad Dermatol. 2008;59(suppl 5):S116-S117. doi: 10.1016/j.jaad.2008.06.018

7. Ilyas M, Zhang N, Sharma A. Residual squamous cell carcinoma after shave biopsy in solid organ transplant recipients. Dermatol Surg. 2018;44:370-374. doi: 10.1097/DSS.0000000000001340

8. Brunner M, Veness MJ, Ch‘ng S, et al. Distant metastases from cutaneous squamous cell carcinoma—analysis of AJCC stage IV. Head Neck. 2013;35:72-75. doi: 10.1002/hed.22913

9. Hartman RI, Green AC, Gordon LG; Skin Tumours and Allograft Recipients (STAR) Study. Sun protection among organ transplant recipients after participation in a skin cancer research study. JAMA Dermatol. 2018;154:842-844. doi: 10.1001/jamadermatol.2018.1164

10. Chan A-W, Fung K, Austin PC, et al. Improved keratinocyte carcinoma outcomes with annual dermatology assessment after solid organ transplantation: population-based cohort study. Am J Transplant. 2018;19:522-531. doi: 10.1111/ajt.14966

11. Hofbauer GF, Anliker M, Arnold A, et al. Swiss clinical practice guidelines for skin cancer in organ transplant recipients. Swiss Med Wkly. 2009;139:407-415. doi: https://doi.org/10.4414/smw.2014.14026

12. Ulrich C, Kanitakis J, Stockfleth E, et al. Skin cancer in organ transplant recipients—where do we stand today? Am J Transplant. 2008;8:2192-2198. doi: 10.1111/j.1600-6143.2008.02386.x

13. Chen SC, Pennie ML, Kolm P, et al. Diagnosing and managing cutaneous pigmented lesions: primary care physicians versus dermatologists. J Gen Intern Med. 2006;21:678-682. doi: 10.1111/j.1525-1497.2006.00462.x

14. Ismail F, Mitchell L, Casabonne D, et al. Specialist dermatology clinics for organ transplant recipients significantly improve compliance with photoprotection and levels of skin cancer awareness. Br J Dermatol. 2006;155:916-925. doi: 10.1111/j.1365-2133.2006.07454.x

15. O‘Reilly Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part II. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011;65:263-279. doi: 10.1016/j.jaad.2010.11.063

16. Tunçer Vural A, Karataş Toğral A, Kirnap M, et al. Skin cancer risk awareness and sun-protective behavior among solid-organ transplant recipients. Exp Clin Transplant. 2018;16(suppl 1):203-207. doi: 10.6002/ect.TOND-TDTD2017.P65

17. Papier K, Gordon LG, Khosrotehrani K, et al. Increase in preventive behaviour by organ transplant recipients after sun protection information in a skin cancer surveillance clinic. Br J Dermatol. 2018;179:1195-1196. doi: 10.1111/bjd.16836

18. Wu SZ, Jiang P, DeCaro JE, et al. A qualitative systematic review of the efficacy of sun protection education in organ transplant recipients. J Am Acad Dermatol. 2016;75:1238-1244.e5. doi: 10.1016/j.jaad.2016.06.031

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

21. Infusino SD, Loi C, Ravaioli GM, et al. Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience. G Ital Dermatol Venereol. 2020;155:662-668. doi: 10.23736/S0392-0488.18.06091-1

22. Naldi L, Venturuzzo A, Invernizzi P. Dermatological complications after solid organ transplantation. Clin Rev Allergy Immunol. 2018;54:185-212. doi: 10.1007/s12016-017-8657-9

23. Sunscreen FAQs. American Academy of Dermatology Web site. Accessed February 25, 2021. www.aad.org/media/stats/prevention-and-care/sunscreen-faqs

24. Vos M, Plasmeijer EI, van Bemmel BC, et al. Azathioprine to mycophenolate mofetil transition and risk of squamous cell carcinoma after lung transplantation. J Heart Lung Transplant. 2018;37:853-859. doi: 10.1016/j.healun.2018.03.012

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

26. Abikhair Burgo M, Roudiani N, Chen J, et al. Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma. JCI Insight. 2018;3:e120750. doi: 10.1172/jci.insight.120750

27. Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: management of advanced and high-stage tumors. J Am Acad Dermatol. 2018;78:249-261. doi: 10.1016/j.jaad.2017.08.058

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

Topical chemoprophylaxis

Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.²⁷ (See TABLE 2.^27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.²⁷ Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.²⁷

5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.^27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.²⁷

PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.^30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.³⁰ A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.²⁷

Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-specific apoptosis coordinated by type 1 T-helper lymphocytes.³² Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.^33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.^42-44

The tolerability of field treatment with imiquimod has been called into question.²⁷ However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.⁴⁴

Continue to: Diclofenac