The Importance of Skin Cancer Prevention in Organ Transplant Patients
An Editorial to Paper by Salgo: ‘Switch to Sirolimus in Long‐Term Renal Transplant Recipients: Reduced Premalignancies and Nonmelanoma Skin Cancer in a Controlled, Prospective, Randomized, Blinded Study’

Abstract

The paper by Salgo et al. ‘Switch to Sirolimus in long‐term RTR: Reduced premalignancies and NMSC in a controlled, prospective, randomized, blinded study’ is the first such trial to show the effectiveness of sirolimus in reduction of skin cancer in transplant patients. This study addresses a very important point as many long‐term organ transplant recipients are severely affected by skin cancer which can negatively affect quality of life and longevity. It is not rare that patients severely affected by this iatrogenic condition state that they may have forgone the transplant had they known what would happen to their skin. Sirolimus has accumulated considerable anecdotal experience in reducing skin cancer rates, and this was also corroborated in several retrospective studies (1Kauffman HM Cherikh WS Cheng Y Hanto DW Kahan BD Maintenance immunosuppression with target‐of‐rapamycin inhibitors is associated with a reduced incidence of de novo malignancies.Transplantation. 2005; 80: 883-889Crossref PubMed Scopus (553) Google Scholar). M‐tor inhibitors, which are used in organ transplantation because of their antiproliferative effects have gained attention also in cancer research and earlier this year everolimus and analogue Sirolimus were approved for the treatment of renal cell cancer (2Motzer RJ Escudier B Oudard S et al.Efficacy of everolimus in advanced renal cell carcinoma: A double‐blind, randomized, placebo‐controlled, phase III trial.Lancet. 2008; 372: 449-456Abstract Full Text Full Text PDF PubMed Scopus (2651) Google Scholar). This particular trial supports retrospective data that suggests that sirolimus inhibits skin cancer in organ transplant patients. This is the first prospective trial to show the effectiveness of sirolimus at decreasing skin cancers in renal transplant patients. Strengths of this particular study include the prospective, randomized design. The study is strengthened by the use of one dermatologist to remove interobserver variation in examination findings. However, this study was small with only 44 patients enrolled. Also, a short observation period of only 12 months limited the study. The drop‐out rate of participants in the sirolimus arm was particularly high and concerning. This drop‐out rate was not surprising, as sirolimus has serious potential side effects such as pneumonitis, edema, apthous ulcers and protienuria. While this study addresses the serious problem of skin cancer in organ transplantation, it does not help delineate what role sirolimus will have in the prevention and treatment of skin cancer. Skin cancer is the most common cancer in organ transplant recipients. OTR are 65 times more likely to develop squamous cell carcinoma of the skin compared to the general population (3Jensen P Hansen S Møller B et al.Skin cancer in kidney and heart transplant recipients and different long‐term immunosuppressive therapy regimens.J Am Acad Dermatol. 1999; 40: 177-186Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar). Squamous cell carcinoma is the most prevalent skin cancer in this group of patients. Unfortunately, cutaneous squamous cell carcinoma can result in metastatic disease and even death. Basal cell carcinoma and melanoma are also more common in organ transplant recipients. Even rare cutaneous malignancies such as Merkel cell carcinoma and Kaposi's sarcoma are more common in this population. Sirolimus will not likely replace standard immunosuppressive regimens but may be used as an alternative to standard regimens for patients at high risk for skin cancer. In the general population, some of the risk factors for the development of NMSC include age, male sex and fair skin, previous history of NMSC, geographic location, smoking, ionizing radiation and ultraviolet radiation/sun exposure. In the organ transplant population, the major risk factors for development of NMSC include Type I‐III skin (fair skin), age and age at transplantation, cumulative ultraviolet exposure, type of immunosuppressive regimen (4Rubel JR Milford EL Abdi R Cutaneous neoplasms in renal transplant recipients.Eur J Dermatol. 2002; 12: 532-535PubMed Google Scholar). The risk of NMSC increases with the extent and duration of immunosuppression. Primary prevention emphasizes the reduction of ultraviolet exposure. This requires many patients to change their lifestyle and behavior. The organ transplant recipient must practice daily sun avoidance and apply broad spectrum sunscreen. Secondary prevention includes early detection of skin cancers. Potential OTR should be examined by a dermatologist as part of the pretransplant evaluation. Any preexisting skin cancer and actinic keratoses can be treated prior to transplantation and initiation of immunosuppression. Topical and oral retinoids can be used as effective chemoprevention in at risk patients (3Wright T, Spencer J, Flowers F. Chemoprevention of nonmelanoma skin cancer. J Am Acad Dermatol; 54: 933–946; quiz 947–950. Review.Google Scholar). Field cancerization may be treated with topical medications such as imiquimod, 5‐fluorouracil and other approaches include photodynamic therapy, and modification of immunosuppression. Another tertiary prevention of skin cancer includes advanced and expert surgical treatment of these patients to minimize deformity and loss of function. Once established with a dermatologist, an OTR should have regular follow‐up with full skin exams. Based on the retrospective data and the prospective data from this randomized trial, mTOR inhibitors will probably have an integral role in the prevention and treatment of skin cancer in organ transplant recipients. Now, that sirolimus is shown to be effective against skin cancer, more investigation is needed to determine the following: Which patient population should receive sirolimus? Can we predict which patients will respond well or poorly to sirolimus? When is the optimal time for patients to start sirolimus for the prevention of skin cancer? Should sirolimus be used indefinitely for these patients? How effective is sirolimus at preventing development of skin cancer when compared to regular dermatologic follow‐up and conventional treatment/preventative measures in patients on standard immunosuppressive regimens? Is sirolimus cost effective? What effect does sirolimus have on survival? How will sirolimus benefit these patients in the long‐term? Note: The author declares no conflicts of interest.