Cancer is the second leading cause of mortality and morbidity among recipients of kidney transplants. The outcomes of patients with cancer and kidney transplants are substantially worse than patients with cancers but without kidney disease. Previous studies have shown at least a 2-fold increased risk of cancer-related mortality among transplant recipients compared to patients with cancer but without kidney disease.1-3 The heightened risk of cancer and cancer death after transplantation has prompted caution in accepting patients with end-stage kidney disease for transplantation, particularly for those with previous cancer. Patients with end-stage kidney disease and a cancer history in need of a transplant typically pose a greater challenge for transplant health professionals. Although a previous cancer history on dialysis is not an absolute contraindication for transplantation, waiting time between 2 and 5 years for most cancer types is recommended by clinical practice guidelines.4-6 This recommendation arises from several large registry analyses indicating that the risk of cancer recurrence was maximal within the first 5 years after kidney transplantation.7,8 In some circumstances, a second primary cancer may occur after transplantation. The second primary cancer may develop independent of the original primary cancer in patients exposed to exogenous carcinogens, such as immunosuppression and previous cancer treatment.
Once cancers recur or develop, the risks of cancer-related and other causes of death are unclear. In particular, there is a lack of information on the cancer-related and all-cause mortality among those who developed cancer recurrence and/ or a second primary cancer after transplantation. A recent UK study showed a 15-fold increase in cancer-specific mortality in those with previous cancer compared to recipients without previous cancer.9 However, data are lacking comparing outcomes of patients developing their first cancer after transplantation to those with a second primary malignancy and/or cancer recurrence after their first kidney transplants. In this study, we examined the prognosis of kidney transplant recipients who developed cancer and whether this varied with cancer type (first cancer, recurrence, and second primary cancer).
All recipients who received their first deceased or living donor kidney transplant in Australia and New Zealand and who developed a cancer after transplantation between 1965 and 2012 were included. Recipients receiving multiple organ grafts at any time and donor-transmitted cancers were excluded from the analyses. Recipients were stratified into 3 groups: recipients who developed their first cancer after kidney transplantation, recipients with recurrence of the same cancer after transplantation that they developed before their first transplant, and those who developed a second primary cancer after their first kidney transplantation.
Recorded baseline data included recipient characteristics (age, sex, ethnicity [indigenous and nonindigenous], cause of end-stage renal disease (categorized as diabetic nephropathy, glomerulonephritis, polycystic kidney disease, vascular/hypertensive disease, analgesic nephropathy, or other), dialysis duration before transplant (categorized as preemptive transplantation, less than 2 years, 2 to 4 years, longer than 4 years), comorbidities (diabetes, coronary artery disease, peripheral vascular disease, cerebrovascular disease, obstructive lung disease, and smoking history [categorized as nonsmoker or former/current smoker]), and transplant related factors such as the era of transplantation.
Ascertainment of Cancers
The ANZDATA registry records cancers of all kidney transplant recipients. Cancers reported to ANZDATA registry are coded for sites and cell type adapted from the International Classification of Disease for Oncology, first edition. The cancer records within ANZDATA registry are robust and accurate, and previous analyses showed a high concordance rate when comparing the records of incident cancer diagnoses in patients on renal replacement therapy to those reported to the New South Wales Cancer Registry (a mandatory reporting requirement for all hospitals and institutions that diagnosed or treated someone with cancers in New South Wales).10 We included all cancers except nonmelanocytic skin cancers and premalignant or in situ lesions.
Comparisons of baseline characteristics between recipients with and without previous cancer were made by the χ2 test and analysis of variance for categorical and continuous variables respectively, and the Mann-Whitney-Wilcoxon test for nonparametric variables.
Univariate and multivariate Cox proportional hazard models were used to assess the association between cancer groups, cancer-specific, and all-cause mortality. To be eligible for transplantation, all recipients were assumed to be cancer-free at the time of the transplant surgery. For cancer-specific and all-cause mortality, the time of exposure was considered from the time of cancer diagnoses after transplantation to death. The time of cancer diagnoses was chosen as the origin time of exposure because the risk of death (cancer and all-cause) commences at the time when transplant recipients developed cancers. For cancer-specific morality, recipients who were alive, lost to follow-up, or died from other causes were censored at the end of the follow-up period. For all-cause mortality, recipients who were alive or lost to follow-up were censored at the end of the follow-up period.
All explanatory variables that had an association with death at P less than 0.25 in the unadjusted analyses were included in the multivariable-adjusted analyses. Using a stepwise backward elimination process, the least significant variables were then removed from the base model. In all models, however, we adjusted for age, sex, and smoking. Potential effect modification between the study factor (cancer groups) and other covariates was examined using 2-way interaction terms. A P value less than 0.05 was considered as statistically significant. The proportional hazards assumptions of all Cox models was assessed by fitting log(time)-dependent covariates in the multivariate models and by plotting the Schoenfeld residuals, but no variables showed evidence of departure from the proportional hazards assumption. Results are expressed as hazard ratio (HR) with 95% confidence interval (95% CI). Site-specific analyses were performed to assess the relationship between previous cancer types and second primary cancers. All analyses were undertaken with SAS statistical software 9.4.
A total of 21,415 patients were transplanted in Australia and New Zealand between 1965 and 2012, of whom 651 recipients (3%) developed cancer before receiving their first kidney transplants. A total of 2840 recipients developed cancer after the first kidney transplantation. The overall cancer incidence rate was 10.4 per 1000 patient years.
Baseline Characteristics of the Study Participants
Of the 2840 recipients diagnosed with cancer after their first kidney transplantation, 2760 (97.2%) developed their first cancers after transplantation, 23 (0.8%) experienced cancer recurrences, and 57 (2 %) developed second primary cancers. All 2840 recipients were followed and included in the final analyses until death or the end of follow-up period (December 31, 2012). The overall median follow-up time (from the time of transplantation) was 8.4 years for recipients who developed the first cancers after transplantation (interquartile range [IQR], 4.8-10.1 years), 11.2 years for those with cancer recurrence (IQR, 3.6-18.9 years), and 8.3 years for those who developed a second primary cancer (IQR, 4.8–10.9 years) (Table 1).
Compared to recipients with no previous cancer developing their first cancer after transplantation, recipients with a second primary cancer were older at time of transplantation (mean [SD] 53.9 ± 12 years vs 43.9 ± 14.2 years; P < 0.001) and had spent more time on dialysis (mean [SD] 3.34 ± 2.43 years vs 1.93 ± 2.1 years, P < 0.001). Among those with a previous cancer history, the time from transplantation to cancer diagnosis was significantly shorter compared to those without cancer before transplantation (6.8 ± 5.0 years to cancer recurrence and 6.6 ± 5.6 years to second primary cancer compared to 9.9 ± 7.6 years to first cancer, P = 0.01).
Frequency and Incidence of Cancer by Site and Cancer History
Table 2 shows the frequency and incidence of site-specific cancer for the 3 groups of transplant recipients with cancers. Among recipients who developed their first cancer after transplantation, cancer of the digestive tract was the most common (n = 509, 18.4%), followed by urinary tract cancer (n = 370, 13.4%), melanoma (n = 295, 10.7%), cancer of the female genital tract (n = 288, 10.4%), cancer of the respiratory tract (n=218, 7.9%), hematological malignancy (n = 217, 7.9%), prostate (n = 167, 6.1%), and breast cancer (n = 150, 5.1%). Cancer recurrence was observed among those with a history of urinary tract cancer (n = 8, 30.4%), breast cancer (n = 6, 26.1%), melanoma (n = 3, 13%), female genital tract cancer (n = 3, 13%), hematological malignancy (n = 2, 8.7%), prostate (n = 1, 4.4%), and oral cancer (n = 1, 4.4%). Regardless of the previous cancer type, cancer of the respiratory tract was the most frequently occurring second primary cancer (n = 13, 13.2%), followed by cancer of the digestive tract (n = 8, 14.2%), melanoma (n = 8, 14.2%), and urinary tract cancer (n = 7, 12.5%) (Table 3).
Frequency and Incidence of Cancer Death by Site and Cancer History
There were a total of 1175 cancer and 624 noncancer deaths within the study cohort. Of those who developed their first cancer after transplantation, 1139 of 2760 (41.3%) died from cancer. Among recipients with cancer recurrence and second primary cancers, 8 of 23 (34.8%) and 28 of 57 (49.1%) died from cancer, respectively. In recipients whose first cancer was after transplantation, cancer of the digestive system was the leading cause of cancer death, followed by death from respiratory and urinary tract cancers. Among those with cancer recurrence, urinary tract malignancy was the most frequent cause of cancer death (3 of 8, 37.5%). For recipients with recurrent melanoma, 1 of 3 died within 10 years of cancer diagnosis. The single recipient with recurrent oral cancer died within 12 months of recurrence. In patients who developed a second primary malignancy, cancer of the digestive system was the most common cause of cancer death (8 of 28, 28.6%), followed by cancer of the respiratory system (6 of 28, 21.4%), melanoma (5 of 28, 17.9%), and urinary tract cancer (3 of 28, 10.7%) (Table 4).
Kaplan Meier Survival Estimates for Recipients With and Without a Previous Cancer
Figure 1 shows the cumulative cancer-specific survival for recipients with cancer recurrences, second primary cancers, and recipients developing their first cancer after transplantation. The time of exposure was considered from the time of cancer diagnoses after transplantation. Transplant recipients who developed cancer after transplantation experienced poor cancer-specific and overall survivals. The cumulative 5- and 10-year cancer-specific survivals were 66.3% and 49.7%, respectively, for recipients with cancer recurrence, 47.4% and 43.8%, respectively, for those developing second primary cancers and 53.% and 50.3%, respectively, for those with first primary cancer after transplantation. There was no significant difference in cancer-specific survival between the 3 groups of transplanted patients (P = 0.28). Figure 2 shows the cumulative all-cause survival at 5 and 10 years for recipients with cancer recurrence (53.3% and 20.0%; respectively), second primary cancer (36.0% and 13.6%, respectively) and first cancer after transplantation (43.0% and 31.6%, respectively). There were no significant differences in the overall-survivals between the 3 groups of transplanted patients with cancers (P = 0.83).
Effects of Previous Cancer, Cancer-Specific, and All-Cause Mortality
The adjusted hazard ratios (HRs) for cancer-specific and all-cause mortality in recipients by cancer types are shown in Figures 2 and 3. Compared to recipients without previous cancer history developing new primary cancers after transplantation, the adjusted HRs for cancer mortality among recipients with cancer recurrences and second primary cancers were 0.79 (95% CI, 0.38-1.67; P = 0.54) and 1.01 (95%CI, 0.63-1.62; P = 0.95), respectively, after adjusting for age, sex, body mass index, smoking status, time on dialysis, era of transplantation, history of diabetes mellitus, and chronic obstructive pulmonary disease. Compared to recipients who developed de novo cancers after transplantation, the adjusted HRs for all-cause mortality among recipients with cancer recurrence and second primary cancers were 0.86 (95% CI, 0.45-1.66; P = 0.66) and 1.16 (95% CI, 0.79-1.69; P = 0.45), respectively, after adjusting for age, gender, smoking status, history of diabetes, peripheral vascular disease, chronic obstructive pulmonary disease, era of transplantation, and time on dialysis.
Our study suggests that cancer recurrence and a second primary cancer are uncommon after renal transplantation, occurring in less than 10% of recipients with previous cancer history. Regardless of previous cancer history, the overall survival for recipients who developed cancer after transplantation was generally poor, with less than 50% surviving 5 years after cancer diagnosis. For those who did not die from cancer, less than 20% survived more than 10 years after cancer diagnosis. Cancer of the digestive, respiratory, and urinary tract systems were the 3 most common causes of cancer death regardless of cancer types (first cancer, recurrence, and second primary). There were no significant differences in the risk of cancer-specific and all-cause mortality between patients who developed their first cancer after transplantation, those with cancer recurrence, and those with second primary cancers. For recipients with second primary cancers and/or cancer recurrence, outcomes were no worse than those of patients whose posttransplant malignancy was their first cancer.
In our study, only 3.5% (n = 23) and 8.8% (n = 57) of recipients with previous cancer (n = 651) developed a recurrent or second primary cancer, respectively. This is in contrast to data from the United States registry analysis by Israel Penn which reported an average cancer recurrence rate of 21%.11 This discrepancy is likely explained by differences in reporting, selection bias of recipients, ascertainment bias of cancer diagnosis, and unadjusted residual confounders.
The lack of observed differences in outcomes between cancer types was unexpected. Studies in the general population have shown that recurrent cancer and second primary cancers are inherently more aggressive than primary cancers. These cancers are the leading cause of death among several populations of long-term cancer survivors, such as those with Hodgkin lymphoma and lung cancers.12,13 In the transplant population, we had expected that recipients with cancer recurrence and/or second primary cancers experienced worse cancer prognoses than patients with primary cancers. Patients with second primary cancers and/ or recurrences may have acquired resistance to chemotherapy therapy and have limited options for the second treatment or diminished reserves to tolerate intensive treatment in the context of long-term immunosuppression. In addition, transplant recipients with a history of cancer may have a different tumor biology, genetic predisposition, and immunological factors that make them more susceptible to transplant-related complications including death from other causes, which may not be observed in recipients without a previous cancer history.
A single study has examined the impact of a pre-transplant malignancy on overall mortality among renal transplant recipients in a recent linked data analysis between the UK national transplant database and the Office for the National Statistics with over 100000 person-years of follow-up.9 A total of 376 cancer deaths were recorded, with the commonest cancer types being lymphoproliferative disease, followed by lung and kidney cancers. The risk of cancer death was at least 15-fold greater in patients with a previous history of cancer compared to those without a previous cancer history.
The observed differences between our study findings and other published literature may be explained by potential variations between countries and units in host characteristics, etiological factors shared with the initial malignancy, previous cancer treatment, and environmental exposure such as immunosuppression after transplantation. Alternately, it may be explained by disparities in the selection process for transplant listing/acceptance between countries. Our process may be discriminatory and limited to those with potentially favorable prognostic factors. Also, given the small numbers of patients in individual cancer subgroups in this study, it may lack the statistical power to detect a significant difference in the cancer-specific and all-cause mortality by cancer types.
Melanoma was the third most common cancer in all 3 cancer groups. The recurrence rate of melanoma was lower (13%) than that reported by Israel Penn (30%, n = 6).7 This may be explained by the shorter waiting period for transplant listing in the Penn cohort; as half of the recurrences occurred in transplant recipients who waited less than 2 years from cancer remission to transplantation, and another third waited between 2 and 5 years. The current Australasian guidelines suggest in general a waiting period of at least 5 years for potential recipients with a history of melanoma.14
Strengths and Limitations
To our knowledge, this is the first study that has explored the difference in cancer-specific and all-cause mortality between recipients with and without a previous cancer who develop cancer after transplantation in a large cohort of kidney transplant recipients. The relatively high accuracy and robustness of cancer records within the ANZDATA registry has been previously demonstrated and coding errors should therefore be minimal. In addition, cancer-related and all cause mortalities were calculated from the time of cancer diagnosis as opposed to the time of transplantation, a method that correctly addresses the question of how the cancers developed after transplant affect the overall patient outcomes. Although adjustment was made for multiple confounding factors, there may be unmeasured residual confounders, such as type and intensity of maintenance immunosuppression, use of immunosuppression for the original kidney disease before renal replacement therapy, the severity of comorbidities accounted for, and remaining comorbidities that were not reported in the ANZDATA registry, graft function, and rejection which may all potentially impact on mortality outcomes. The ANZDATA registry does not provide detailed information on the dosing of the various types of immunosuppression but the majority of transplant recipients were initiated on a combination of prednisolone, cyclosporine and azathioprine before 2005, whereas since 2005, there was a paradigm shift to using prednisolone, tacrolimus, and mycophenolate as the choice of initial immunosuppression. Over the past decade, there had been no substantial change in the proportion of recipients receiving mechanistic target of rapamycin inhibitors (maintained between 4% and 5%). Cancer screening practices are also likely to be different by transplant era and may have influenced the overall cancer outcomes because screened detected early stage cancers often have better prognoses compared to those with advanced stage disease. Reporting bias, such as underreporting and selective reporting, may exist.
Implications for Future Research
One of the most significant complications for cancer survivors is the occurrence of new cancer, which may be even greater for patients on dialysis who have undergone transplantation. Future research could evaluate the role of genetic markers in identifying subgroups of patients at heightened susceptibility of therapy-associated second primary cancers and recurrence, or those sharing similar etiological factors.
The relatively low risk of disease recurrence and subsequent cancer development observed in the current study suggests that the current selection criteria and exclusionary interval between successful cancer treatment/remission and transplantation are appropriate, and that a sensible degree of caution is being exercised in selecting patients for transplantation. However, this study is unable to ascertain whether the criteria are overly strict, preventing otherwise suitable patients from accessing transplantation. Understanding an individual's cancer risk is important in future clinical management and cancer screening/prevention strategies. The emerging ability to assess each individual's genetic profile may improve assessment of predisposition to specific cancer types and their interaction with previous cancer therapy and immunosuppression.
Our study adds to the existing knowledge by showing kidney transplant recipients with second primary or cancer recurrence after transplantation may not be at a greater risk of death in comparison to those without previous cancer who develop a malignancy after transplantation, while confirming the dismal survival of renal transplant recipients with cancer. The relatively low rate of disease recurrence and subsequent cancer development observed in Australia and New Zealand suggests that the current selection criteria and recommended waiting period between successful cancer treatment and transplantation are sensible and may account for the lack of additional survival disadvantage compared to cancer patients without malignancy before transplantation.
The authors would like to thank the substantial contributions of the entire Australian and New Zealand nephrology community (physicians, surgeons, database managers, nurses, renal operators and patients) that provide information to, and maintain, the ANZDATA Registry database. The data reported here have been supplied by the Australia and New Zealand Dialysis and Transplant Registry. The interpretation and reporting of these data are the responsibility of the Editors and in no way should be seen as an official policy or interpretation of the Australia and New Zealand Dialysis and Transplant Registry.
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