American Journal of Transplantation 2014; XX: 1–8 Wiley Periodicals Inc.

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Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12969

Sirolimus Use and Cancer Incidence Among US Kidney Transplant Recipients E. L. Yanik1,*, S. K. Gustafson2, B. L. Kasiske2,3, A. K. Israni2,3, J. J. Snyder2,3, G. P. Hess4,5, y y E. A. Engels1, and D. L. Segev2,6,

Received 02 April 2014, revised and accepted for publication 04 August 2014

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Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 2 Scientific Registry of Transplant Recipients, Minneapolis Medical Research Foundation, Minneapolis, MN 3 Department of Medicine, University of Minnesota, Minneapolis, MN 4 Institute of Health Economics, University of Pennsylvania, Philadelphia, PA 5 Symphony Health Solutions, Horsham, PA 6 School of Medicine, Johns Hopkins University, Baltimore, MD  Corresponding author: Elizabeth L. Yanik, [email protected] y Both authors contributed equally. Sirolimus has anti-carcinogenic properties and can be included in maintenance immunosuppressive therapy following kidney transplantation. We investigated sirolimus effects on cancer incidence among kidney recipients. The US transplant registry was linked with 15 population-based cancer registries and national pharmacy claims. Recipients contributed sirolimusexposed time when sirolimus claims were filled, and unexposed time when other immunosuppressant claims were filled without sirolimus. Cox regression was used to estimate associations with overall and specific cancer incidence, excluding nonmelanoma skin cancers (not captured in cancer registries). We included 32 604 kidney transplants (5687 sirolimusexposed). Overall, cancer incidence was suggestively lower during sirolimus use (hazard ratio [HR] ¼ 0.88, 95% confidence interval [CI] ¼ 0.70–1.11). Prostate cancer incidence was higher during sirolimus use (HR ¼ 1.86, 95% CI ¼ 1.15–3.02). Incidence of other cancers was similar or lower with sirolimus use, with a 26% decrease overall (HR ¼ 0.74, 95% CI ¼ 0.57–0.96, excluding prostate cancer). Results were similar after adjustment for demographic and clinical characteristics. This modest association does not provide strong evidence that sirolimus prevents posttransplant cancer, but it may be advantageous among kidney recipients with high cancer risk. Increased prostate cancer diagnoses may result from sirolimus effects on screen detection. Abbreviations: HR, hazard ratio; mTOR, mammalian target of rapamycin; PSA, prostate-specific antigen; SRTR, Scientific Registry for Transplant Recipients

Introduction Kidney transplant recipients have higher cancer risk than the general population, largely due to pharmacologically induced immunosuppression administered to prevent graft rejection (1,2). However, different immunosuppressant medications may have varying effects on cancer risk following transplantation. In particular, mammalian target of rapamycin (mTOR) inhibitors, a class of immunosuppressants, have anti-carcinogenic properties (3,4). The mTOR is a protein that plays a key role in an important signaling pathway that controls cellular growth and proliferation (5). This pathway is often hyperactivated in malignant cells (5,6). Furthermore, mTOR signaling may be required for malignant transformation (7–9). Inhibition of this pathway thus could hinder one of the major mechanisms of continued tumor growth. Sirolimus, a medication approved by the US Food and Drug Administration in 1999, is the only mTOR inhibitor currently in wide use as a part of maintenance therapy in kidney transplantation (6,10). A number of clinical trials and epidemiologic studies have found the use of sirolimusbased immunosuppressant regimens to be associated with reduced incidence of nonmelanoma skin cancers, which are the most common malignancies following kidney transplantation (11–14). However, the effects of sirolimus on risk of other cancers are less well defined (15,16). The large US Scientific Registry for Transplant Recipients (SRTR) provides a resource for addressing this question, but an obstacle is that data on immunosuppressant medications are not reliably reported after the initial regimen. While associations between initial immunosuppressant regimens and cancer incidence have been considered (17), sirolimus is usually initiated after discharge from the hospitalization for the transplantation procedure, and so this method of classification may only capture atypical sirolimus users. In addition, the reliability and granularity of cancer data reported through the transplant registry are limited. To address these limitations, we investigated the effects of sirolimus exposure on subsequent cancer incidence among 1

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kidney recipients by linking the SRTR with a national pharmacy claims database and population-based cancer registries. The use of pharmacy claims allows for capture of immunosuppressant use for an extended time after transplantation. Cancer registries reliably ascertain cancer diagnoses and include information that is unavailable in the SRTR, such as cancer stage at diagnosis. As a result, these data linkages provide a unique opportunity to improve upon prior studies of the effect of sirolimus on cancer risk.

Methods Study population The study population was identified using data from the SRTR. The SRTR data system includes data on all donor, waitlisted candidates, and transplant recipients in the United States, submitted by the members of the Organ Procurement and Transplantation Network (OPTN), and has been described elsewhere (18,19). The Health Resources and Services Administration (HRSA), US Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors. For identification of cancer cases, the SRTR has been linked to 15 population-based cancer registries that cover over 40% of the US population, as described previously (1). The characteristics of transplant recipients linked to cancer registries are similar to those of transplant recipients who do not reside in cancer registry coverage areas (1). To identify use of immunosuppressant medications, particularly sirolimus, throughout time after transplantation, the SRTR was further linked to a national pharmacy claims database (IMS Health) that includes claims from more than 70% of kidney recipients transplanted between January 1, 1995 and December 31, 2009. Recipients whose kidney transplant was a part of a multiple organ transplant or who had a prior nonkidney transplant were excluded from all analyses. Only recipients who were living in a cancer registry area at the time of transplantation were included. We included recipients of a kidney transplant between January 1, 1995 and December 31, 2009 who had 1 pharmacy claim after kidney transplantation for an immunosuppressant, including calcineurin inhibitors (CNIs), mTOR inhibitors, azathioprine, mycophenolate or glucocorticoids (prednisone or prednisolone). Ethical approval or exemption from review was given by institutional review boards at the National Cancer Institute, HRSA, and, as required, each cancer registry.

Exposure and outcome definitions The primary exposure of interest was sirolimus use as compared to use of nonsirolimus-containing immunosuppressant regimens. Immunosuppressant medication use, including start and end dates for successive prescriptions, was ascertained using the pharmacy claims data. Sirolimus use was considered a time-varying exposure. Except for two modifications described below, after a first immunosuppressant claim, person-time was considered sirolimus-unexposed until a first sirolimus claim. At this point, recipients started to contribute sirolimus-exposed person-time, which extended for as long as continuous sirolimus claims indicated refills. We made the first modification to this exposure assignment because most recipients had some short interruptions in claims between the end of a prescription and the date of a refill. We therefore modified the windows when recipients were considered to receive medications by adding 60 days to the end date of each prescription as a grace period, so that recipients who picked up refills later than expected, due to doctor-recommended dose reductions or imperfect adherence, would not be erroneously censored or re-categorized as unexposed. We found that for gaps in claims of less than

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60 days, receipt of sirolimus was the same before and after the gap 95% of the time. If a subsequent sirolimus claim was not filled by 60 days after a sirolimus refill was due, but other immunosuppressant claims were filled, then recipients began contributing sirolimus-unexposed person-time until a new sirolimus claim was observed. As such, a recipient might experience multiple sirolimus-exposed and -unexposed periods after transplantation. In a second modification, exposure lags of 6 months were used, in which incidence estimates and measures of association were calculated for cancers that occurred 6 months after the use of sirolimus or other immunosuppressant medications. This approach requires a biologically plausible time window for immunosuppressant medications to affect cancer-related processes and reduces the likelihood of reverse causation bias in which a cancer diagnosis or related symptoms lead to a change in immunosuppressant regimen. As a result of this approach, at-risk time for cancer effectively started at 6 months after the first immunosuppressant claim was observed (and at the earliest, 6 months after transplantation). Correspondingly, at-risk time for cancer ended 6 months after the end of an immunosuppressant exposure period. The primary outcome of interest was diagnosis of any cancer, as recorded within the 15 population-based cancer registries; squamous and basal cell skin cancers were excluded, since these are not captured by US cancer registries. Other outcomes of interest were individual cancers types for which the expected number of cases in the sirolimus-exposed person-time was at least 10 under the null hypothesis (incidence rate ratio ¼ 1.0). We evaluated ‘‘all cancers other than prostate cancer’’ as an outcome because the association for prostate cancer appeared to differ from the associations for other cancers.

Statistical analysis The unit of analysis was the kidney transplant, with some recipients undergoing more than one transplant. After transplantation, follow-up began at the start of cancer registry coverage or 6 months after the first immunosuppressant claim, whichever came later. In all analyses, recipients only contributed follow-up time during person-time covered by immunosuppressant claims. As the IMS Health pharmacy claims data began in 2001, recipients with a kidney transplant prior to 2001 were considered late entries and only contributed time to the analysis after 2001. Left truncation was used to account for recipients whose follow-up did not begin immediately after transplantation. All exposure time in our study came after the US Food and Drug Administration approval of the use of sirolimus for kidney transplant recipients in 1999. If interruptions in claims of more than 60 days were present, then recipients could have multiple periods of follow-up corresponding to the time periods covered by immunosuppressant claims. Follow-up permanently ended at the earliest of death, transplanted kidney failure, new transplant, loss-to-follow-up by the SRTR or last date of cancer registry data. For sirolimus-exposed and sirolimus-unexposed person-time, incidence rates were calculated as the number of cancer diagnoses divided by the total person-time. If a recipient experienced more than one cancer diagnosis, all events contributed to the incidence rate. Only females were considered for breast cancer, and only males were considered for prostate cancer. Cox regression was used to estimate hazard ratios (HRs) relating sirolimus use and cancer incidence, with time since transplantation as the time scale. For analyses of individual cancer types, recipients were followed until the first diagnosis of the cancer of interest without censoring for other cancer types. Multivariable Cox regression was used to adjust for possible confounders measured at the time of transplantation and recorded in the SRTR, specifically: age at transplantation, sex, race, calendar year of

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Sirolimus and Cancer in Kidney Recipients transplantation, kidney transplant count (first, second, etc.) and donor type (deceased or living). The proportional hazards assumption was confirmed through the evaluation of an interaction term between the log of time since transplantation and sirolimus use. Cumulative incidence curves were plotted using extended Kaplan–Meier estimates. All statistical analyses were conducted using SAS version 9.3 (The SAS Institute, Cary, NC).

Sensitivity analyses To explore the robustness of our results, four sensitivity analyses were conducted. First, we estimated associations after additionally adjusting for time-varying calcineurin inhibitor (CNI) use. Second, we included only recipients undergoing a first kidney transplant. Third, we evaluated only recipients without a history of cancer before transplantation. Fourth, we considered sirolimus use as a time-varying, single-switch exposure. In this analysis, which mirrors an intent-to-treat analysis in a trial, all person-time after a first sirolimus claim was considered sirolimus-exposed regardless of whether sirolimus use was observed in subsequent claims.

Results Demographic and clinical characteristics of kidney recipients The SRTR includes 232 635 kidney transplants. Of these, 4790 were excluded because they occurred after nonkidney transplants and 138 219 transplants were excluded

because the recipients did not reside in areas covered by cancer registries (Figure 1). Among the remaining 89 626 kidney transplants, 32 604 transplants had 1 pharmacy immunosuppressant claim during cancer registry coverage after kidney transplantation and were included in the final study population. Of these, 5687 (17.4%) had a sirolimus claim after transplantation, whereas 26 917 (82.6%) never had a sirolimus claim. Among included kidney transplants, 59% of recipients were male, 56% were white and 21% were black (Table 1). The median age at transplantation was 49 years (interquartile range [IQR]: 39–58), and the median year of transplantation was 2003 (IQR: 2000–2005). Ninety-seven percent of transplants were first transplants, and 58% of kidney transplants were received from a deceased donor. Less than 4% of transplants occurred after a prior cancer diagnosis. The distribution of all of these characteristics was similar between recipients with and without a sirolimus claim after transplantation (Table 1). A total of 68 996 person-years of follow-up were covered by immunosuppressant claims after kidney transplantation. The median time between kidney transplantation and first pharmacy immunosuppressant claim was 206 days (IQR:

232,635 kidney transplants in the US Scientific Registry of Transplant Recipients from 1995 to 2009 4,790 transplants that occurred after prior nonkidney transplants

227,845 transplants 138,219 transplants in recipients that did not reside in areas covered by the cancer registries

89,626 transplants 22,239 transplants in recipients with no IMS data

67,387 transplants 34,783 transplants in recipients who had no IMS immunosuppressant claims during cancer registry coverage after transplant 32,604 transplants included in analysis

Figure 1: Flow chart of inclusion and exclusion criteria used to define study population of kidney transplants from 1995 to 2009.

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Yanik et al Table 1: Baseline demographic and clinical characteristics of US kidney transplants linked to pharmacy claims and cancer registry data, by sirolimus exposure status Characteristic

Total

Total Sex Male Female Age at transplant, years Recipient race White, non-Hispanic Black, non-Hispanic Hispanic Asian/Pacific Islander Other Kidney transplant count First Second Third Donor type Deceased Living Kidney transplant year Cancer diagnosis prior to transplant

Ever sirolimus-exposed

Never sirolimus-exposed

32 604 (100)

5 687 (100)

26 917 (100)

19 319 (59.3) 13 285 (40.7) 49 (39–58)

3 492 (61.4) 2 195 (38.6) 48 (38–56)

15 827 (58.8) 11 090 (41.2) 49 (39–58)

18 396 6 819 5 009 2 190 190

3 189 1 359 835 280 24

15 207 5 460 4 174 1 910 166

(56.4) (20.9) (15.4) (6.7) (0.6)

(56.1) (23.9) (14.7) (4.9) (0.4)

(56.5) (20.3) (15.5) (7.1) (0.6)

31 613 (97.0) 975 (3.0) 16 (0.05)

5 502 (96.7) 184 (3.2) 1 (0.02)

26 111 (97.0) 791 (2.9) 15 (0.06)

18 978 13 626 2003 1 197

3 238 2 449 2002 234

15 740 11 177 2002 963

(58.2) (41.8) (2000–2005) (3.7)

(56.9) (43.1) (2000–2004) (4.1)

(58.5) (41.5) (1999–2005) (3.6)

Numbers represent N (%) for categorical variables, and median (interquartile range) for continuous variables. Total follow-up was 68 996 person-years, with 8147 person-years of sirolimus-exposed time.

The most frequently diagnosed were kidney cancer (N ¼ 122) and prostate cancer (N ¼ 108).

7–1055). Among sirolimus users, 38% had an interruption or discontinuation of sirolimus use of greater than 60 days. CNIs were used during 72% of sirolimus-exposed time, compared to 89% of sirolimus-unexposed time.

In unadjusted analyses, total cancer incidence appeared lower during sirolimus-exposed time compared to sirolimus-unexposed time, although this difference was not significant (HR: 0.88, 95% confidence interval [CI]: 0.70– 1.11) (Table 2). Estimated incidence rates during sirolimusexposed time appeared lower than during unexposed time for almost all individual cancer types, particularly for lung cancer, kidney cancer and breast cancer, but none of these

Sirolimus and cancer incidence During 60 849 person-years of sirolimus-unexposed time, 787 cancers were diagnosed (incidence: 1293 cases per 100 000 person-years; Table 2). During the 8147 personyears of sirolimus-exposed time, 85 cancers were diagnosed (incidence: 1043 cases per 100 000 person-years). Table 2: Cancer incidence associated with sirolimus exposure Sirolimus-exposed person-time Cancer Kidney Prostate3 Lung Non-Hodgkin lymphoma Breast3 Colorectum Other cancers Total Total (excluding prostate)

Sirolimus-unexposed person-time

Cases

Incidence1

Cases

Incidence1

9 21 4 7 3 3 36 85 64

110 413 49 86 98 37 442 1043 786

113 87 80 73 61 46 320 787 700

186 246 131 120 239 76 526 1293 1150

Hazard ratio (95% confidence interval) Unadjusted 0.52 1.70 0.38 0.77 0.43 0.61 0.88 0.88 0.74

(0.24, (1.05, (0.14, (0.35, (0.13, (0.19, (0.62, (0.70, (0.57,

1.13) 2.74) 1.05) 1.67) 1.36) 1.97) 1.24) 1.11) 0.96)

Adjusted2 0.50 1.86 0.46 0.79 0.46 0.62 0.93 0.94 0.78

(0.23, (1.15, (0.17, (0.36, (0.14, (0.19, (0.65, (0.74, (0.60,

1.09) 3.02) 1.27) 1.73) 1.47) 2.02) 1.32) 1.18) 1.02)

There were 8147 sirolimus-exposed person-years and 60 849 unexposed person-years. Among males, there were 5089 sirolimus-exposed person-years and 35 337 unexposed person-years. Among females, there were 3058 sirolimus-exposed person-years and 25 512 unexposed person-years. 1 All incidence rates are expressed per 100 000 person-years. 2 Analyses are adjusted for age at transplant, sex, race, calendar year of transplant, kidney transplant count and donor type (living vs. deceased). 3 Prostate cancer incidence was calculated only among men. Breast cancer incidence was calculated only among women.

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associations was statistically significant (Table 2). The notable exception was prostate cancer, where incidence was 70% higher during sirolimus-exposed time (HR: 1.70, 95% CI: 1.05–2.74). After excluding prostate cancer, incidence of other cancers was 26% lower during sirolimus-exposed time (HR: 0.74, 95% CI: 0.57–0.96) (Table 2). Results were similar after adjustment for demographic and clinical characteristics (Table 2). For instance, in multivariable analysis, incidence of cancers, excluding prostate, was 22% lower during sirolimus-exposed time (HR: 0.78, 95% CI: 0.60–1.02). Prostate cancer incidence remained statistically significantly higher during sirolimus-exposed time compared to sirolimus-unexposed time in multivariable analysis (HR: 1.86, 95% CI: 1.15–3.02). No associations were found to violate the proportional hazards assumption (all p-values > 0.10). However, upon visual inspection, the reduced incidence of nonprostate cancer during sirolimus-exposed time did not become apparent until 3 years posttransplant (Figure 2). By contrast, differences in the incidence of prostate cancer between sirolimus-exposed and sirolimus-unexposed recipients were apparent 2 years posttransplant. Sensitivity analyses In sensitivity analyses, results were similar after adjusting for CNI use. Overall cancer incidence, excluding prostate cancer, was 22% lower during sirolimus-exposed time in adjusted analyses (HR: 0.78, 95% CI: 0.60–1.02), while nonprostate cancer incidence was not associated with CNI use (HR: 1.01, 95% CI: 0.81–1.27) (Table S1). Sirolimus also

remained associated with prostate cancer incidence after adjustment for CNI use (HR: 1.71, 95% CI: 1.04–2.80). When considering different inclusion criteria, results were similar to the primary analysis, though associations with nonprostate cancer incidence were no longer statistically significant. Among the 31 613 recipients receiving their first kidney transplant, overall cancer incidence, excluding prostate cancer, was estimated to be 18% lower during sirolimusexposed time compared to sirolimus-unexposed time (adjusted HR: 0.82, 95% CI: 0.65–1.03) (Table S2). Similarly, among 31 407 kidney transplants among recipients with no cancer diagnosis prior to transplantation, overall nonprostate cancer incidence was estimated to be 16% lower during sirolimus-exposed time compared to unexposed time (adjusted HR: 0.84, 95% CI: 0.67–1.06) (Table S3). Results also did not notably vary when sirolimus exposure was defined as a time-varying, single-switch variable. The associations of sirolimus with reduced incidence of individual cancers and all nonprostate cancers together were slightly weaker (unadjusted HR: 0.79, 95% CI: 0.63– 1.00; adjusted HR: 0.83, 95% CI: 0.65–1.05: Table S4). In contrast, the association between sirolimus use and higher prostate cancer incidence was slightly stronger (unadjusted HR: 1.76, 95% CI: 1.13–2.76; adjusted HR: 1.97, 95% CI: 1.24–3.12).

Discussion In this large sample of 32 604 US kidney transplants, sirolimus use was associated with a suggestive decrease in

Figure 2: Cumulative incidence of cancer after kidney transplantation during sirolimus-exposed and sirolimus-unexposed time. The solid lines represent the cumulative cancer incidence for sirolimus-exposed recipients, whereas the dotted line represents cumulative cancer incidence among the sirolimus-unexposed. Below the x-axis of each graph panel are listed the number of sirolimus-exposed and sirolimus-unexposed recipients who were in follow-up at 2-year intervals after kidney transplant. Prostate cancer incidence was calculated only among males.

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cancer incidence. Incidence appeared lower for a number of individual cancer types, though these associations were not statistically significant. The one exception was prostate cancer, for which incidence was observed to be 70% higher during sirolimus-exposed time. Both the association with higher prostate cancer incidence and the modest decrease in incidence for all other cancers were shown to be robust to adjustment for other variables, changes in the inclusion criteria for the study population, and changes in the definition of the sirolimus exposure. An association between sirolimus and reduced cancer incidence is supported by prior biological evidence. Sirolimus has been shown in vivo to block mTOR kinase binding activity, which is a key step in the PI3K/Akt/mTOR pathway that regulates cell growth and proliferation (20). Overactivation of this pathway is frequently observed in malignant cells and is associated with poor prognosis after a cancer diagnosis (21–23). As such, a number of cancer treatments target the PI3K/Akt/mTOR pathway (24). In phase 1 trials evaluating mTOR inhibitors as a cancer treatment option, partial responses have been observed for kidney, lung and breast cancers (25,26). Temsirolimus, a derivative of sirolimus, is approved as a treatment for renal cell carcinoma and has been shown to improve overall survival in advanced metastatic cases (27). Corresponding with these findings, incidence rates of kidney cancer, lung cancer and breast cancer were lower in association with sirolimus use, but none of these associations with specific cancer types was significant. The cancer preventive potential of sirolimus has been of great interest for kidney recipient populations, as sirolimus can also serve as a component of maintenance immunosuppressant treatment following transplantation. Most prior studies, including randomized clinical trials, have centered around prevention and treatment of nonmelanoma skin cancers, as these are a common malignant complication following a kidney transplant (12–14). While some studies have indicated possible reductions in nonskin cancers with sirolimus use, few have been large enough to provide precise incidence rate comparisons (15,16,28,29). The largest prior study considering differences in the incidence rates of nonskin malignancies by sirolimus exposure was conducted using US OPTN data, the same database from which our transplant recipients were selected (17). This previous study defined sirolimus exposure based on the discharge immunosuppressant regimen after transplantation and also observed lower cancer incidence rates in recipients using sirolimus (17). However, few recipients are prescribed sirolimus at hospital discharge due to sirolimus’ effects on impaired wound healing (10). Instead, most recipients initiate sirolimus later in their posttransplant clinical care. This is evinced by the fact that only 8% of kidney transplant recipients were considered sirolimus-exposed based on discharge immunosuppressant medications (17), while 6

17% of kidney recipients in our study were identified as initiating sirolimus. Furthermore, this prior study used cancer diagnoses reported at follow-up visits to transplant centers, but only examined cancer risk overall and lacked the reliable data from cancer registries that were used in our study. The association we found between sirolimus use and increased diagnosis of prostate cancer is novel, and a known biological mechanism to explain an increase in risk is not readily available. Of note, the increased risk was primarily driven by an increase in diagnosis of localized prostate cancers (HR for localized prostate: 1.74, 95% CI: 1.05–2.88), while the five prostate cancers diagnosed beyond localized stage were detected during sirolimusunexposed time. This may indicate that the association we observed is the result of a detection bias, or screening effect, as localized prostate cancer is frequently detected through prostate-specific antigen (PSA) screening. While sirolimus has not been demonstrated to directly affect the detection of PSA among cancer-free individuals (30), it may directly or indirectly affect PSA levels among those with indolent tumors. Since monitoring of PSA levels is often the major component of prostate cancer screening, differential levels could affect prostate cancer diagnosis rates in sirolimus users. In this study, we were able to benefit from a wellenumerated transplant population that represents a large proportion of the total US transplant population. This large population allowed us to evaluate associations with cancer types that prior studies had not considered individually. In addition, we were able to improve upon previous studies by using more reliable data for cancer diagnoses through linkage to the cancer registries. Cancer registries are generally considered the gold standard for ascertainment of cancer diagnoses due to the completeness of ascertainment and the quality control measures taken to confirm diagnoses. We also used data for sirolimus use obtained through linkage to pharmacy claims, which allowed assessment of changes in sirolimus use across time after transplant. This is particularly important as we found that many recipients had interruptions or discontinuations in sirolimus use after sirolimus initiation. While we were able to improve on the validity and reliability of previous data used to examine the association between sirolimus use and cancer incidence, a number of unavoidable limitations remain. Although our sample size was large, we still had limited ability to make inferences for some individual cancer types due to a small number of cases. We were not able to include squamous or basal cell skin cancers, as these are not captured by US cancer registries. Additionally, as previous evidence has suggested that mTOR inhibitors have anti-carcinogenic effects, clinicians may have preferentially prescribed sirolimus for recipients whom they perceived to have heightened cancer risk. While excluding recipients with prior cancer diagnoses American Journal of Transplantation 2014; XX: 1–8

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did not noticeably change our results, we did not have information on some important indicators of cancer risk, such as tobacco use or a family history of cancer. If sirolimus was disproportionately prescribed to recipients with higher cancer risk, then our results would be expected to underestimate the protective effect of sirolimus. However, many of the determinants of sirolimus use not examined in this study, such as clinicians’ concerns about kidney damage, may have no relation to cancer risk and thus would not be expected to bias our results. The sirolimus associations observed in our study may also be due in part to co-interventions, such as changes in the use of other immunosuppressants. Our results did not change notably after accounting for CNI use, but sirolimus users may have had lower levels of CNIs than sirolimus users. While dose information is available through pharmaceutical claims, this is a poor surrogate for drug levels, particularly because comprehensive data were not available on weight, height, liver function and other relevant factors. Additionally, we could not assess differing effects by cumulative sirolimus exposure because we did not have complete claims coverage over time after transplantation for many recipients. A third of recipients had transplants before 2001, when our prescription claims records started. After 2001, we only had complete pharmacy fill data from IMS-covered pharmacies. Everolimus, another mTOR inhibitor, may have effects on cancer that differ from those observed for sirolimus, but we could not evaluate it, as it was only used in our study population after the end of cancer registry follow-up in 2009. In conclusion, our study suggests that sirolimus use may be responsible for a modest reduction in nonprostate cancer incidence after kidney transplantation. Of course, clinical decisions regarding type of immunosuppressant regimen must take into consideration a number of risks following transplantation, including graft rejection and kidney damage. Given the modest association identified, our study does not provide strong evidence that sirolimus should be used to prevent cancer following kidney transplantation. However, sirolimus-based regimens may be of benefit among transplant recipients with a past history of cancer or known cancer risk factors. In the future, studies more narrowly targeted among transplant recipients with high cancer risk may be able to identify whether sirolimus-based immunosuppressant regimens result in better overall survival in these groups.

Acknowledgments The authors gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (Monica Lin), the SRTR (Paul Newkirk) and the following cancer registries: the states of California (Tina Clarke), Colorado (Jack Finch), Connecticut (Lou Gonsalves), Georgia (Rana Bayakly), Hawaii (Brenda Hernandez), Iowa (Charles Lynch), Illinois (Lori Koch), Michigan (Glenn Copeland), New Jersey (Xiaoling Niu,

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Sumathy Vasanthan), New York (Amy Kahn), North Carolina (Chandrika Rao), Texas (Melanie Williams) and Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank analysts at Information Management Services for programming support (David Castenson, Matthew Chaloux, Michael Curry and Ruth Parsons). The views expressed in this paper are those of the authors and should not be interpreted to reflect the views or policies of the National Cancer Institute, Health Resources and Services Administration, SRTR, cancer registries or their contractors. This research was supported in part by the Intramural Research Program of the National Cancer Institute. Research support for this study was also provided by Pfizer. During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI (contract HHSH234200537009C); beginning in September 2010, the SRTR was managed by Minneapolis Medical Research Foundation in Minneapolis, MN (HHSH250201000018C). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807–01), Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Illinois (5658DP000805-04), Michigan (5U58DP000812-03), New Jersey (5U58DP003931-02), New York (U58DP003879), North Carolina (U58DP000832) and Texas (5U58DP00082404). The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C and HHSN261201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201000037C, N01-PC-35137 and N01-PC-35139), Iowa (HSN261201000032C and N01-PC-35143), New Jersey (HHSN 261201300021I and N01PC-2013-00021), Seattle-Puget Sound (N01-PC-35142) and Utah (HHSN261201000026C). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, New Jersey, New York (Cancer Surveillance Improvement Initiative 142491), Texas and Washington, as well as the Fred Hutchinson Cancer Research Center in Seattle, WA.

Disclosure The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Research support for this study was provided by Pfizer. Pfizer played no role in the data analysis, interpretation of results or preparation of the manuscript. The data reported here have been supplied by the Minneapolis Medical Research Foundation (MMRF) as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy of or interpretation by the SRTR or the US Government.

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Supporting Information Additional Supporting Information may be found in the online version of this article. Table S1: Cancer incidence associated with sirolimus and CNI exposure in a multivariable model with time-varying exposures. Table S2: Cancer incidence associated with sirolimus exposure in first transplants. Table S3: Cancer incidence associated with sirolimus exposure in recipients with no registry cancer prior to transplant. Table S4: Cancer incidence associated with sirolimus exposure in single-switch analysis.

American Journal of Transplantation 2014; XX: 1–8

Sirolimus use and cancer incidence among US kidney transplant recipients.

Sirolimus has anti-carcinogenic properties and can be included in maintenance immunosuppressive therapy following kidney transplantation. We investiga...
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