In this cohort of 1776 renal transplants, sirolimus user was associated with a decreased cancer incidence. Cancer incidence appeared lower for a number of specific cancer types, though these associations were not absolute statistically significant except hepatoma and urothelial cancer. Even though we adjusted confounding factors, the trend of lowering incidence of hepatoma and urothelial cancer still existed. The reduced cancer incidence in our study might both result from the
antineoplastic effect of sirolimus and the result of reducing CNIs. Furthermore, not only the benefit of decreased cancer incidence, but the trend of decreased mortality incidence in sirolimus user in our study. We also observed the dose-response effect between sirolimus dosage and survival rate which was never mentioned in previous studies.
Renal transplantation was associated with a marked increase in cancer risk at a wide variety of sites, and this phenomenon was mainly due to immunosuppressive agent (10). Nevertheless, an increased cancer incidence turned into insignificant with the use of mTOR inhibitors in a recent decade according to our results (Table 2). We supposed the possible reason may be due to mTOR inhibitors which had antineoplastic effect was used extensively from 2000. Our results of this large
population-based study indicated that the use of sirolimus may be associated with decreased risks of cancer and mortality in patients post renal transplantation. The majority of the published preclinical studies have suggested that mTOR inhibitors have antineoplastic effects (11). The possible
mechanism by which mTOR inhibitors cause cell differentiation and induce cancer cell apoptosis has been demonstrated in prior studies (12,13). Besides, in vivo study, it showed that VEGF, CXCR3 and CXCR3-binding ligands (CXCL10 and CXCL11) are overexpressed in
post-transplantation renal cancer tissues following CNI (CsA) treatment and mTOR inhibitors could inhibite CNI-induced over-expression of the angiogenic cytokine VEGF, and the chemokine
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receptor CXCR3 and its ligands in post-transplantation tumor tissues (13). Our results are consistent with prior in vitro studies and provide clinical evidence for a decreased risk of cancer that is
associated with the use of mTOR inhibitors in patients post renal transplantation.
Previous studies have been conducted to investigate the association between the use of mTOR inhibitors and the risk of developing cancer, but only few clinical studies focused on the relationship between mTOR inhibitors and specific cancer types (11). Yanik et al. (14) conducted a retrospective analysis in a population from SRTR in the U.S. to assess the influence of sirolimus on the risk of specific cancer types. A reduction of risk for specific cancer types in patients treated with sirolimus was observed except prostate cancer (unadjusted HR 1.70 [95% CI 1.05–2.74], adjusted HR 1.86 [95% CI 1.15–3.02]). However, the reduction of risk for each cancer type did not attain statistical significance. Most previous studies mentioned about nonmelanoma skin cancers, because these are a common malignant complication following a kidney transplant in western countries, not in Asia countries (15). But we observed different significance of specific cancer types compared to the results of SRTR. Our results revealed the reduction of risks of urothelial cancer and hepatoma were significant, and these results had been proved in previous studies (16) (17). Incidence of colorectal cancer incidence increased insignificantly. Similar result was mentioned in previous study in 2005, which showed one de novo colorectal cancer in eleven patients with solid tumors in the
sirolimus/everolimus alone group (18). However, in vitro study showed that mTOR is commonly activated in colon cancer. mTOR complex 1 (mTORC1) is a major downstream target of the
PI3K/ATK pathway and activates protein synthesis by phosphorylating key regulators of messenger RNA translation and ribosome synthesis. Rapamycin analogs are non-ATP-competitive mTORC1 inhibitors, and suppress proliferation and tumor angiogenesis and invasion (19). It needed further study to identify the difference between in vivo and in vitro.
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Calcineurin inhibitors were widely recommended for the primary prevention of graft rejection in patients post renal transplantation, and it has been proved to increase cancer incidence (20). The regimen consisting of cyclosporine, azathioprine with prednisolone could be distinguished by the highest risk of malignancy occurrence (5.2%) (20). Therefore, increased cancer incidence post renal transplantation is considered as calcineurin inhibitors neoplastic effect. Comparison sirolimus users alone with other immunosuppressive agent users was difficult to practice in our study, because the sample size was too small and there were only 21 subjects in sirolimus alone group. According to our analysis, sirolimus supplied anti-neoplastic effect to renal transplantation subjects whether calcineurin inhibitors exposure or not. In addition, sirolimus might neutralize neoplastic effect of calcineurin inhibitors. As concern about steroid, azathioprine and mycophenolate might be major confounders in our study, we conducted an additional sensitivity analysis to investigate the effect of concomitant use of sirolimus and steroid, azathioprine or mycophenolate. In our additional
sensitivity analysis, the use of sirolimus showed a significant decrease in the risk of cancer within the groups that concomitantly used steroid, azathioprine or mycophenolate (p=0.01).
A potential bias that may result from confounding indications is the association between end-stage kidney disease and cancer risk. End-stage kidney disease and cancer have many mutual risk factors, and end-stage kidney disease is suggested to be associated with an increased risk of certain cancers.
A recent study also indicated that the longer dialysis duration was related to the risk of cancer and certain other cancer-related causes of death (21). The potential causality or association between end-stage kidney disease and cancer has not been clearly established, and it remains unclear whether the association between these two diseases is direct or indirect, and whether the cancer risk would be influenced by the dialysis induced anuria. There are limitations of our database in that the
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NHIRD did not include detailed results from laboratory tests; thus, we were unable to provide exact measurements of uremic toxin level or urine amount status.
Except cancer incidence, we also focused on mortality rate between sirolimus-exposed subjects and sirolimus-unexposed subjects. We searched the PubMed database for articles published up to April 2016 and identified four original clinical studies focusing on the assessment of survival rate in patients exposed to sirolimus. Most results of previous clinical studies appeared to be neutral in regard to survival rate. After renal transplantation, few studies showed good survival rate in sirolimus-unexposed subjects (22). On the contrary, some studies supported that an increased survival rate came with an increased dosage of sirolimus (23). In our study, sirolimus-exposed subjects had insignificant lower mortality rate compared to sirolimus-unexposed subjects (p=0.39).
The survival curve of sirolimus-exposed subjects seemed to be better than the curve of
sirolimus-unexposed subjects (p=0.11). Base on the result, we analyzed the relationship between sirolimus cumulative defined daily dose and mortality rate further. It seemed to be a trend that as the sirolimus cddd increased, the mortality rate decreased, although the result was insignificant. This finding had never been mentioned in previous clinical studies. It was a future work that whether there was a threshold of effective sirolimus cddd in survival rate prolongation or not, but the dose-response effect between sirolimus and survival rate gave us a guild to follow it.
We also had incomplete data on several variables known to be associated with cancer, such as unhealthy life habit, obesity, a family history of cancer, recurrent or de novo cancer, smoking or alcohol consumption. Furthermore, a detection bias could occur in our study in those patients receiving renal transplantation might have access to a better economic status and an increased opportunity to receive cancer screening, which would result in higher cancer detection rates and
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would also decrease subsequent cancer rates. Some confounders about mortality, such as accident, could not be corrected in our database, which might relate to detection bias.
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