Using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry, kidney failure patients who have received a first deceased and living donor kidney transplant in Australia and New Zealand between 1980 and 2016 and had developed “de novo” cancer after transplantation were included in the analyses. Recipients with a prior history of cancer (other than a history of non-melanoma skin cancer- NMSC) and known “donor-transmitted” and “donor-derived” cancers were excluded (Figure 1). De novo cancer was defined as a cancer that occurred in a kidney transplant recipient with no prior history of cancer before transplantation and included all cancer types except NMSC. Donor-transmitted cancers are those cancers which are present in the donated organ and tissue at transplantation, whereas donor-derived cancers are those that are of donor origin but developed de novo in the allograft after transplantation. Details of both donor-derived and donor-transmitted cancers are provided to the ANZDATA registry by the individual units. However, the ANZDATA registry does not verify whether the cancer cells were of donor origin.

The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism.” Ethics approval was obtained from the Human Research Ethics Committee of Western Australia, Australia. Written informed consents were sought from patients with kidney failure at time of entry into the registry, including the utilization of aggregate data for future research.

Recipients were categorized according to whether they had developed early cancer or late cancer post kidney transplant. Early-onset cancers were defined as those cancers occurring within the first 12-months post transplantation, whereas late-onset cancers were defined as those occurring 12-months after transplantation.

Baseline characteristics recorded by the ANZDATA registry included donor factors of age, type and sex; recipient characteristics of age, sex, ethnicity, body mass index, waiting time prior to transplantation, comorbid conditions at time of transplantation (presence or absence of diabetes, coronary artery disease, cerebrovascular disease and peripheral vascular disease), primary causes of kidney failure; and transplant-related factors including the number of human leukocyte antigen (HLA) mismatches, total ischemic time (in hours), induction (none, interleukin-2 receptor therapy and T-cell depleting therapy) and initial immunosuppressive therapies (prednisolone, calcineurin-inhibitor and anti-metabolite therapies) and transplant era (categorized into 1980–1989, 1990–1999 and 2000–2016 transplant periods).

De novo cancers occurring post-kidney transplantation were reported to the ANZDATA registry. The registry does not verify the histology of the de novo cancers, but the cancer records within the ANZDATA registry are accurate with a high concordance rate compared to those reported to the New South Wales Cancer Registry (9), a mandatory requirement for cancer reporting in New South Wales. De novo cancers are recorded according to cancer sites and cell types according to the International Classification of Disease for Oncology, edition 3, first revision (ICD-O-3.1) (10).

The primary outcomes included the frequency, types, sites, stage (including presence of lymph node involvement and distant metastatic disease) and occurrence of cancer recurrence. Other outcomes included treatment of the de novo cancers in recipients with early cancers and comparison of the risk of cancer-related and all-cause death between recipients with early cancer and those with late cancer. We also defined the risk factors for all-cause deaths in recipients with early cancers.

Data were expressed as number (proportion), mean and standard deviation (SD) and median and interquartile range (IQR) where appropriate, with comparisons between groups by chi-square test, analysis of variance (ANOVA) and Kruskal–Wallis test, respectively. We compared the frequency, cancer types, stage and outcomes of patients who developed early cancers with those who developed cancers 12 months after transplantation. The treatment patterns, responses to treatment and outcome of early-onset cancers were also described. Kaplan Meier survival curves were constructed for all-cause and cancer-specific mortality in recipients with early cancers and stratified by site-specific cancer types. The log-rank test was used to test the trend of all-cause and cancer-specific survival functions across the cancer types. Survival time was censored at the date of the clinical outcome or on 31 December 2017. The cumulative survivals (and 95%CI) from the time of cancer diagnosis till the time of death were calculated for patients with early and late-onset cancers. Adjusted multivariable cox regression models were used to evaluate the risk factors for all-cause mortality in patients with early-onset cancers. Covariates with p-values of <0.25 in the unadjusted association for all-cause mortality were included in the multivariable analyses. Proportional hazard assumptions were checked, and two-way interactions were tested. The final model retained the covariates that remained significant after adjustment using a backward stepwise strategy. Variables included in the final multi-variable model included donor age, recipient age (stratified as <35, 35–55 and over 55 years), sex, race (Indigenous Australians, Maori and other), smoking status (stratified as current smoker, ex-smoker or non-smoker), induction immunosuppression, initial anti-metabolite therapy (none, azathioprine and mycophenolic acid) and transplant era.

Analyses were undertaken using SPSS V10 statistical software program (SPSS Inc., North Sydney, Australia), R (version 3.6) and STATA (version 11 StataCorp LP, College Station, TX). P-values of <0.05 were considered statistically significant.

Between 1980 and 2016, a total of 21,844 patients received a first kidney transplant. Of these, 2,871 kidney transplant recipients developed cancer(s) post-transplantation, with 2,759 (96.1%) recipients developing de novo cancers post-transplant and 112 (3.9%) with either pre-transplant or donor derived cancers, respectively. Of the 2,759 recipients with de novo cancers, 243 (8.8%) developed de novo cancers within the first 12 months post-transplantation (Figure 1). The median (IQR) patient-follow up time for all recipients was 13.4 years (7.84–20.44) resulting in 40,006 patient-years of follow up with shorter median (IQR) follow-up periods for those who developed early cancer (4.8 [1.6–10.9]) years with 1,699 patient-years of follow-up.

Baseline characteristics of the study population with early and late onset de novo cancers are shown in Table 1. Recipients who developed early cancer were older (mean [SD] age: 50.8 [15.4] vs. 45.3 [14.2] years, p < 0.001), more likely to have pre-transplant diabetes (16.5% vs. 10.5%, p = 0.002) and coronary artery disease (12.3% vs. 6%, p < 0.001) and received kidneys from older donors (mean [SD] age: 42.3 [17.1] vs. 35.7 [18.6] years, p < 0.001) compared to those who developed late cancers. Additionally, a higher proportion of early de novo cancers developed in later transplant era (after the year 2000) [63.8% vs. 33.8%, p < 0.001]. The incidence rate of early onset cancer was 0.01 (95%CI: 0.007, 0.013) per 1000-person-days between 1980–1989, 0.02 (95%CI: 0.013, 0.022) per 1000-person-days between 1990–1999 and 0.09 (95%CI: 0.08, 0.10) per 1000-person-days after the year 2000.

Recipients who developed early cancer in the latter era (after 2000) were older compared to those who developed cancer in the earlier eras (p ≤ 0.01, Supplementary Table S1). The proportion of incident kidney transplant recipients with early-onset cancers was similar across the three eras of 1980-1989 (0.8%), 1990–1999 (1.2%) and 2000–2016 (1.2%) (p = 0.36, Supplementary Figure S1).

The median (IQR) time to cancer onset was 205 days (107–298) in those with early-onset cancer compared to 2,083 days (1,675–4,914) in those with late-onset cancer. The three most common types of cancers in those who developed early de novo cancers were PTLD (25%), urinary tract cancers (18%) and malignant melanoma (12%). For late-onset cancers, the three most common types of de novo cancers were PTLD (14%), urinary tract cancers (13.6%) and melanomas (10.6%) (Table 2). Supplementary Table S2 demonstrates differences between recipients of living and deceased donor kidneys who developed early cancers. The distribution of the three most frequently occurring cancers (PTLD, urinary cancers and melanomas) were similar between the two groups.

Of recipients who had early-onset cancers, 25% (n = 61) developed or presented with advanced stage disease (lymph node involvement or distant metastases). At the time of presentation, 50% of lung, 42% of colorectal and 17% of breast cancers had evidence of advanced disease (Figure 2A). For late-onset cancers, 45% of lung, 41% of colorectal and 26% of breast cancers had evidence of advanced disease at the time of diagnosis. In contrast, 9% and 14% of early kidney cancers and melanomas and 16% and 6% of these late cancers respectively, presented with evidence of advanced disease. Kaplan-Meier survival curves for all-cause mortality and cancer mortality according to the most common site-specific cancer types are shown in Figure 2B.

Among recipients who developed de novo early-onset cancers, 77 (32%) died with 70 (91%) deaths attributed to cancer related deaths (Table 3). The median (IQR) time from cancer diagnosis to cancer-specific and all-cause deaths was 145 days (IQR: 20–464) and 144 days (20–505), respectively. For recipients with late-onset cancers, 1,473 (59%) recipients died with 977 (39%) attributed to cancer-related deaths. The median time from cancer diagnosis to cancer-specific and all-cause deaths were 229 days (53–781) and 427 days (80–1,623), respectively. Figures 3, 4 shows the Kaplan Meier curves of cancer-related deaths and all-cause deaths for recipients with early and late-onset de novo cancer; both from time of transplant and from time of cancer diagnosis, with majority of deaths being related to cancer in those who developed early de novo cancer.

Following cancer diagnosis, the overall patient survivals at 1, 5 and 10 years for recipients who developed early de novo cancer were 77% (95%CI: 70.7, 81.4), 46% (95%CI: 39.7, 52.2) and 25% (95%CI: 19.8, 30.7). In recipients who developed late de novo cancers, the overall patient survivals at 1, 5 and 10 years were 73% (95%CI: 70.7, 74.2), 41% (95%CI: 38.6, 42.3) and 20% (95%CI: 18.2, 21.3) (Supplementary Figure S1).

Most of the early cancer related deaths were associated with lung (75%) and colorectal (58.3%) cancers (Table 3).

Of those who developed lung cancer, 75% (n = 6) died, with the median (IQR) time to death of 142 days (6–236). The median (IQR) age at diagnosis was 56 years (50–62) with 50% being males. 50% (n = 3) of the patients presented with advanced stage disease at the time of presentation.

Of those who developed early colorectal cancer, 58% (n = 7) died, with the median (IQR) time to death of 651 days (96–924). The median (IQR) age at diagnosis was 59 years (49–69) with 57% being males. 57% (n = 4) of the recipients presented with advanced stage disease at the time of presentation.

Of the more common cancer types, 25 (40%) recipients died from PTLD (median [IQR] age at diagnosis was 48 [28–56] years) while 7 (16%) died from urinary tract cancers (median [IQR] age at diagnosis was 56 [49–60] years), with nearly 50% of those dying from the latter presenting with advanced stage disease. A detailed description of all the early onset de novo cancers that had contributed to premature mortality is shown in Table 3.

Of all recipients with early-onset cancers (n = 243), onset of a second (new) cancer or recurrence of de novo cancer occurred in 39 recipients (16%), with a median (IQR) time to cancer occurrence of 1,165 (71–2,309) days. The most common cancers were those that involved the urinary tract, lung and the gastrointestinal tracts (15% each). Seven (18%) of these second cancers occurred within 1 year of the primary malignancy.

In this cohort, 77% (n = 33) recipients developed a second new malignancy at a different site within a median (IQR) of 1,414 (435–2,423) days, of which, the most common cancer sites were lung cancer (n = 6, 18%) closely followed by cancer of the urinary tract (n = 5, 15%). Additionally, 15% (n = 6) recipients had recurrence of the de novo primary malignancy within a median (IQR) of 5 (0–159) days, of which 33% (n = 2) had recurrence of melanomas and 33% (n = 2) had recurrence of transitional cell cancer of the urinary tract.

Treatments of cancers that resulted in death were diverse and included various combinations of surgical resection, chemotherapy, radiotherapy and reduction of immunosuppressive medications (Table 4).

Risk factors associated with all-cause death among those with early cancers were older recipient age [>55 years: 2.42 (1.49–3.94), ref: 35-55 years] and older donor age [1.18 (1.03–1.36), per 10-years].