Cancer after solid organ transplantation : incidence, risk factors, and survival

Background: Solid organ transplant recipients (OTRs) are at increased risk of cancer compared with the general population, mainly due to post-transplant immunosuppressive treatment. Furthermore, once diagnosed with cancer, OTRs might experience worse cancer-specific and overall survival than non-transplanted cancer patients. Colorectal cancer (CRC), one of the most commonly occurring cancers in the general population, has often been associated with an even higher incidence after organ transplantation. Its relatively high posttransplantation frequency enables epidemiological research with comparatively high statistical power on e.g. differences in cancer characteristics and treatment associated with transplantation. The aims of the present thesis were to estimate relative and absolute (including excess) risks of a wide range of cancers among Nordic kidney transplant recipients (KTRs), compared with the general population (Study I); to investigate differences in cancerspecific survival among OTRs with cancer, compared with non-transplanted cancer patients, for different types of cancer (Study II); and to establish the influence of organ transplantation on various cancer characteristics, as well as on cancer treatment and outcomes, among Swedish CRC patients (Study III).

Materials and methods: In Study I, Nordic national patient, cancer, cause of death, kidney, and transplantation registers were used to identify all recipients of a kidney transplant during 1995 through 2011, as well as corresponding patient and donor characteristics possibly associated with cancer risk. Standardized incidence ratios (SIR), cumulative incidence in the presence of competing events, and absolute excess risks of cancer were calculated. Risk factors for cancer were studied using Cox regression. In Study II, the Swedish national cancer register was used to identify all Swedish cancer patients with a first cancer diagnosis during 1992 through 2013. Data on patient, cancer, and cause of death characteristics were obtained through linkage with the national cancer and cause of death registers. Cox regression was used to estimate hazard ratios for cancer-specific and all-cause death, comparing cancer patients with a history of solid organ transplantation to those without. In Study III, the Swedish register linkage database CRCBaSe was used to identify all Swedish CRC patients with a history of solid organ transplantation prior to first CRC. Five non-transplanted CRC patients were matched to each OTR. Logistic and multinomial regression was used to evaluate the impact of transplantation on cancer characteristics and treatment, and Cox regression was used to estimate rates of cancer-specific and all-cause death depending on previous organ transplantation.

Results: Among 12,984 Nordic KTRs included in Study I, increased incidence rates (compared with the general population) were found for a wide range of cancers, especially infection-related cancer types such as non-melanoma skin cancer (NMSC), lip, oral and nasal cancers, male and female external genital cancer, and non-Hodgkin lymphoma. However, excluding NMSC, absolute risks were generally higher for non-infection-related cancers (which were often associated with moderately increased rates), such as lung and kidney cancer. Accounting for the competing event of death, the five-year cumulative incidence of cancer was 8%. In Study II, the rate of cancer-specific death was 1.35-fold increased among 2,143 cancer patients with a history of organ transplantation, compared with 946,089 nontransplanted cancer patients. Specifically, lymphoma, malignant melanoma, and urothelial, breast, head/neck, and colorectal cancers were associated with increased cancer-specific death rates among OTRs, compared with non-OTRs. Study III included 99 OTRs and 491 matched non-OTR comparators with CRC. Transplantation history was associated with lower odds of receiving treatment with abdominal surgery, neoadjuvant radiation for rectal cancer, and adjuvant therapy for colon cancer. Cancer-specific and overall survival, as well as disease-free survival, was lower among the OTRs than among the non-OTRs.

Conclusions: Nordic KTRs are at increased risk of developing a wide range of cancers posttransplant, both in relative and absolute terms. Once diagnosed with cancer, OTRs with cancer had worse cancer-specific prognosis, both overall and for several specific cancer types, than non-transplanted cancer patients. Among CRC patients, previous transplantation was associated with differences in both treatment and outcomes. These findings should be considered when evaluating Nordic post-transplant cancer screening protocols, and support holding multidisciplinary team conferences, including organ transplant specialists, for posttransplantation cancer care.

List of scientific papers

I. Benoni H, Eloranta S, Dahle DO, Svensson MHS, Nordin A, Carstens J, Mjøen G, Helanterä I, Hellström V, Enblad G, Pukkala E, Sørensen SS, Lempinen M, Smedby KE. Relative and absolute cancer risks among Nordic kidney transplant recipients – a population-based study. Transplant International. 2020 Dec; 33(12): 1700-1710.
https://doi.org/10.1111/tri.13734

II. Benoni H, Eloranta S, Ekbom A, Wilczek H, Smedby KE. Survival among solid organ transplant recipients diagnosed with cancer compared to nontransplanted cancer patients – a nationwide study. International Journal of Cancer. 2020 Feb; 146(3): 682-691.
https://doi.org/10.1002/ijc.32299

III. Benoni H, Nordenvall C, Hellström V, Weibull CE, Martling A, Smedby KE, Eloranta S. Colorectal cancer patients with a history of solid organ transplantation receive less intense cancer treatment than non-transplant recipients. [Manuscript]