Several studies explored the effect of PTM on site-specific posttransplant de novo malignancies. Pretransplant malignancies were significantly associated with an increased risk of posttransplant NMSC (pooled HR, 4.64; 95% CI, 2.54-8.49; I2, 74%; Figure 5). Sensitivity analysis using the leave-one-study-out technique revealed that the study by Modaresi Esfeh et al significantly changed the pooled estimate (data not shown). Excluding this study reduced the HR and heterogeneity (see Figure S6, SDC, http://links.lww.com/TP/B260). One study evaluated patients with pretransplant melanoma. Arron et al39 reported that 336 recipients with pretransplant melanoma had an increased incidence of melanoma after transplant (HR, 5.38; 95% CI, 2.9-9.8) compared with 191 471 subjects without PTM. The 5-year cumulative incidence of incident primary melanoma was 0.75% in patients with PTM compared with 0.14% in subjects without PTM, an absolute risk difference of 0.61%. Additionally, 1 study evaluated the effect of PTM on the incidence of posttransplant lymphoproliferative disorders (PTLD).53 Data from the United States Renal Data System (USRDS) were linked to health administrative databases to identify 25 127 kidney transplant recipients and their incidence of PTLD. In this study, PTM was an independent risk factor for the development of PTLD (adjusted HR, 3.54; 95% CI, 2.31-5.43), but not for death after PTLD (adjusted HR, 2.04; CI, 0.96-4.3).53
This systematic review reports on the risk of all-cause mortality, cancer-specific mortality, and transplant de novo malignancy in 10 856, 1544, and 4302 SOTR with PTM, respectively. Our analysis indicated that for patients who received SOTR, PTM is associated with increased risk of all cause-mortality, cancer-specific mortality and of developing de novo malignancies after transplantation, compared with those without PTM. The association of all-cause mortality and SOTR with PTM did not vary by the type of transplanted organ.
The critical shortage of suitable organs for transplantation means that clinicians and policy makers must ensure scarce deceased donor organs are allocated to the patients who would benefit from them the most. Although transplant recipients with PTM experience worse outcomes, increasing the current waiting times between successful cancer treatment and transplantation will probably not improve outcomes in this group of patients. Current recommendations for listing transplant candidates with PTM have been based on the high risk of cancer recurrence reported by the Israel Penn International Transplant Tumor Registry and the natural history of the malignancy.1,2,5,59 However, more contemporary population-based registries, such as the Australia and New Zealand Dialysis and Transplant Registry and the United Network for Organ Sharing in the United States have reported lower recurrence rates, similar to those observed in the general population.6,7
Prolonging the requirement for remission times may not improve overall survival. Solid organ transplant recipients with PTM are more likely to receive organs from expanded criteria donors and to have prolonged time on dialysis before transplantation, factors associated with increased risks of cardiovascular mortality and graft failure.60,61 Importantly, simply prolonging mandatory remission times before transplantation may not have an impact on survival outcomes in patients with PTM. In the study by Brattstrom et al,27 the lower cancer-specific mortality observed in SOTR with longer intervals between cancer and transplantation did not translate into a reduction in all-cause mortality, possibly because an increase in noncancer mortality. Lastly, although prolonging remission times may reduce the risk of cancer recurrence, patients with PTM will remain at increased risk for de novo malignancies.
Although there is solid evidence for the risk of posttransplant de novo malignancy and cancer mortality after transplantation,10,12,45,58,62 little is known about the outcomes of transplant recipients with PTM. This study provides a systematic evaluation of the literature, including large numbers of patients with PTM. The findings of this review highlight the need to better understand and mitigate the cancer risk in recipients with PTM and to improve their overall survival. Future research is needed to explore whether the association of all-cause mortality in SOTR with PTM is explained solely by the increased cancer mortality or by other factors, such as cardiovascular disease and graft failure. Other aspects worth investigating include effects of immunosuppression in cancer recurrence, identification of pretransplant factors associated with worse outcomes, the effectiveness of enhanced posttransplant screening strategies, and the use of alternative immunosuppressive regimens in this high-risk group.
As the mean age of transplant candidates rises, the number of SOTR with PTM is expected to increase. Although the proportion of patients with PTM ranges from 0.4% to 5.4% in population-based cohorts, these patients accounted for as many as 7.4% of the SOTR in Ontario in 2010.10 Our synthesis of the literature has important clinical implications as it provides prognostic information for SOTR with PTM and the knowledge base to improve the outcomes of these patients. Our finding of an increased risk of second malignancies in this group is also important because there are currently no specific recommendations on screening for second malignancies in transplant recipients with PTM. Although not evaluated in this study, modification of immunosuppression regimens may have an impact on cancer outcomes in this population. Our findings highlight the need for further studies in this high-risk population.
Some limitations must be considered when interpreting these findings. Our search strategy was limited to select languages, which may have resulted in a language or cultural bias. Nonetheless, our expansive search across several databases has incorporated numerous studies conducted outside of the English-speaking world.27-29,32,37,47,49,51,52 We also acknowledge the presence of heterogeneity between studies reporting all-cause and cancer-specific mortality. Statistical heterogeneity was high between studies examining all-cause mortality; however, we used a random effect model for all our meta-analyses and investigated potential sources of heterogeneity. We explored if the heterogeneity was due to variation in organ types transplanted, methodological quality, or study design (population-based vs. nonpopulation based). These factors did not explain the heterogeneity. The sources of the observed heterogeneity are likely multifactorial. For example, differences in selection of transplant candidates with PTM across jurisdictions (0.4% of kidney transplant recipients had a PTM in the United Kingdom vs 2.4% of in the United States),6,58 and large variations in the comprehensiveness of risk-adjustment across studies may explain some of the residual heterogeneity. Lastly, there is a possibility that smaller studies showing no association between PTM and all-cause mortality could have been missed. Despite these limitations, the vast majority of point estimates were associated with increased risks for all-cause mortality, cancer-specific mortality, and incidence of posttransplant de novo malignancies. These findings strengthen our conclusions.
In conclusion, our findings indicate that SOTR with PTM have worse outcomes in terms of cancer mortality, all-cause mortality, and posttransplant de novo malignancies than those without PTM. As a risk factor for long-term all-cause mortality, PTM confers a similar risk to that of pretransplant cardiac events in kidney and heart recipients.63,64 These results reaffirm the need for careful selection of transplant recipients with PTM, tailored screening and management strategies, and justify further research to explore risk factors for adverse outcomes in this population.
The authors would like to thank the Information Specialists, Teruko Kishibe and Christine Neilson, at the Scotia Bank Health Sciences Library, Li Ki Shing Knowledge Institute, St. Michael's Hospital for performing the search presented in this systematic review. We would also like to thank Dr. Sarah Arron (UCSF) for her help in providing data used in this article.
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