The use of potent immunosuppressive drugs such as the calcineurin inhibitors (CNIs) tacrolimus and cyclosporine A (CsA) in renal transplantation has reduced acute rejection rates and improved early graft survival (1). Prolonged immunosuppression, however, significantly increases the risk of malignancy (2–14), contributing to the overall morbidity and mortality of renal transplantation patients. The rate of developing a malignancy has been reported as high as 40% to 70% during a 20-year period of immunosuppression after transplantation (2, 3, 9–13). In renal transplant patients, malignancy rates over shorter posttransplant time periods are also noteworthy, with a cumulative de novo tumor incidence for all cancers of 10.6% at 5 years posttransplant (15). These posttransplant malignancies are generally nonmelanoma skin carcinomas (NMSCs), that is, basal cell and squamous cell carcinoma (SCC) (4, 5, 16), Kaposi's sarcoma (8), and non-Hodgkin lymphoma, and are not related to transplantation per se, because patients receiving immunosuppression for rheumatoid arthritis and systemic lupus erythematosus show similarly increased rates of such malignancies (12).
Despite this increased risk of malignancy, only recently has substantial attention been focused on examining potential differences in tumorigenic potential between immunosuppressive regimens (17–27). Recent studies have reported significantly fewer skin malignancies among renal transplant patients receiving sirolimus (SRL) versus other CNI regimens (18–21, 25).
The impact of maintenance therapy with mammalian target of rapamycin (mTOR) inhibitors on the incidence of posttransplant malignancies was evaluated in 33,249 first kidney transplant recipients from deceased donors reported to the Organ Procurement and Transplantation Network/United Network for Organ Sharing (23). Analysis showed that patients treated with mTOR inhibitors exhibited highly significant reductions in the risk of developing any de novo malignancy (60% reduction) or a nonskin de novo solid cancer (55% reduction) compared with those treated without mTOR inhibitors (23). The Rapamune Maintenance Regimen study compared kidney transplant patients using an SRL-based, CNI-free therapy after CsA withdrawal at 3 months with those continuing a regimen including CsA (18). Through 5 years posttransplantation, patients who received SRL-based, CNI-free therapy had prolonged median time to first skin carcinoma (491 vs. 1126 days; P=0.007) and reduced nonskin cancer (e.g., lung, larynx, kidney, prostate, breast) incidence (9.6% vs. 4.0%; P=0.032).
Because SRL has a different molecular mechanism of action than CNIs (28–30), it is plausible that regimens using one or another of these agents, generally in combination with corticosteroids and azathioprine (AZA) or mycophenolate mofetil (MMF) (31–33), could result in lower malignancy rates while maintaining an acceptable level of immunoprophylaxis of acute allograft rejection. Nonetheless, the optimal regimen necessary to achieve acceptable levels of immunosuppression while minimizing the risk of malignancy has yet to be identified (34). Accordingly, this study examined malignancy rates in renal allograft recipients at 2 years after conversion to a SRL-based, CNI-free regimen compared with rates in patients who continued to receive CNI-based immunosuppression.
A total of 830 patients were enrolled, 824 of whom received study medication. Baseline demographic characteristics, as previously reported, were similar between treatment groups (Table 1) (35). Adverse events were the most common reason for premature withdrawal from assigned therapy. The overall rate of withdrawal from assigned therapy was higher for patients in the SRL conversion than the CNI continuation groups, although differences in overall withdrawal rates did not reach statistical significance at 2 years (25.8% vs. 20.0%, respectively, P=0.070).
Patients Analyzed for Malignancies at 2 Years
The analysis of patients with and without malignancy-related adverse events at 2 years included 551 patients in the SRL conversion group and 273 patients in the CNI continuation group. An analysis was also performed using a subset of each group that excluded patients with a prior history of the same malignancy at baseline that subsequently recurred in that patient during the study (n=20); this subset included 542 (98.4%) and 262 patients (96.0%) in the SRL conversion and CNI continuation groups, respectively.
At 2 years, a total of 51 of 824 patients (6.2%) had developed malignancies: 21 patients (3.8%) in the SRL conversion group and 30 patients (11.0%) in the CNI continuation group. Table 2 lists the types of malignancies by treatment group. When analyzed by number per 100 person-years of exposure, the overall rate of malignancy was significantly lower in the SRL conversion group than in the CNI continuation group (2.1 vs. 6.0, respectively; P<0.001; Table 3, Fig. 1A). NMSCs accounted for the majority of malignancies, and the rates of these cancers were also significantly lower in the SRL conversion group (1.2 vs. 4.3, P<0.001; Table 3, Fig. 1A). Although the incidence of melanoma was low (3/273 [1.1%] in the CNI continuation group and 0/551 [0%] in the SRL conversion group), the difference between treatment groups was statistically significant (P=0.036, Fisher's exact test). There were no reported cases of posttransplant lymphoproliferative disease in the CNI continuation group, whereas four were reported in the SRL conversion group, a difference that was not significant (P=0.308, Fisher's exact test). The rate of all other malignancies (AOM; e.g., chronic leukemia, prostate, gastrointestinal, breast, lung, cervix, endometrial cancers) was numerically lower in the SRL conversion group (1.0 vs. 2.1, P=0.058).
Patients with a prior history of a malignancy that recurred during the study may have been at an increased risk of experiencing a recurrence or the occurrence of a similar malignancy after randomization. Twenty patients had a prior history of malignancy; 9 in the SRL conversion group and 11 in the CNI continuation group. Among those who received a diagnosis of NMSC after randomization, 75% (9 of 12) of the SRL conversion patients and 45.5% (10 of 22) of the CNI continuation patients had a prior history of NMSC. Of the three patients who developed melanoma after randomization, two had a prior history of NMSC, but none had a prior history of melanoma. One additional patient with a prior history of breast cancer 11 years before randomization developed recurrent, metastatic disease at 5 months after randomization to CNI continuation.
When all patients with a prior history of any malignancy were excluded, the numbers per 100 person-years of exposure of all malignancies (1.2 vs. 4.2, P=0.001) and of NMSCs (0.3 vs. 2.4, P=0.002) remained significantly lower at 2 years in the SRL conversion group compared with the CNI continuation group, respectively (Table 3, Fig. 1B). The rate of AOM in patients with no prior history was similar between treatment groups (1.0 SRL conversion and 1.9 CNI continuation; P=0.088).
An analysis of variance procedure was performed on time-normalized SRL trough concentrations (Cmin,TN, high-performance liquid chromatography methodology) for subjects with baseline glomerular filtration rate greater than 40 mL/min. No significant difference was detected in the Cmin,TN at any time between the patients who developed a malignancy and those who did not. During the 2-year period of follow-up, the mean Cmin,TN±standard deviation for the two groups over 2 years was 11.6±3.3 ng/mL (n=16) and 12.0±3.5 ng/mL (n=478), respectively. Logistic regression showed a decreased odds ratio for the development of malignancy when Cmin,TN was considered, but only for the values observed (n=18 malignancies/411 observations) over the interval of 1.4 to 2 years after randomization (P<0.0247). The odds ratio was 0.887 with a 95% confidence interval of 0.800 to 0.985. Logistic regression procedures, using data collected over other time intervals, did not show significant results.
Additional Post Hoc Analyses
Exposure to study medication, measured in days, was based on a window of 812 days for the 2-year study; therefore, exposure to drug could exceed 2 years. The median exposure to study medication was 2.1 years for both treatment groups; mean exposure was 1.8 years for patients receiving SRL and 2.0 years for patients receiving CNI (P<0.001). To address the apparent imbalance in mean total exposure between treatment groups, malignancy rates (number of malignancies/number of patients) were stratified into three groups by total exposure times: 2.2 years or more, at least 2 years but less than 2.2 years, and less than 2 years. The malignancy rates in all three exposure strata were consistently lower for SRL-treated patients (4.3%, 1.0%, and 4.7%, respectively) compared with CNI-treated patients (14.6%, 3.4%, and 11.0%, respectively, P<0.001, Cochran-Mantel-Haenszel test). The Breslow-Day test was not significant (P=0.800), indicating consistency of results across all strata.
Table 4 summarizes the results of the post hoc analyses based on patient age and length of time from transplant to randomization (a measure of length of time of exposure to immunosuppressive medications). The adjusted mean ages were the same for both treatment groups (49.3 vs. 49.3 years, P=0.997). As expected, patients who developed malignancy were, on average, older than those who did not develop malignancy (56.7 vs. 42.0 years, respectively, P<0.001). The adjusted mean age of patients who developed malignancy in the SRL conversion and CNI continuation groups (55.4 vs. 58.0 years, respectively) was not significantly different (P=0.488). Among all randomized patients, the adjusted mean time from transplant to randomization was significantly longer in the SRL conversion group compared with the CNI continuation group (3.9 vs. 3.0 years, respectively, P=0.003). As expected, the mean time from transplant to randomization was significantly greater among those patients who developed malignancy compared with those with no malignancy (3.7 vs. 3.1 years, P=0.035). Among the patients who developed malignancy, the mean time from transplant to randomization was significantly greater for the SRL conversion group compared with the CNI continuation group (4.6 vs. 2.9 years, respectively, P=0.005).
This study demonstrated that SRL-based immunosuppression significantly reduced the rate of malignancy in renal allograft recipients at 2 years postconversion compared with continuation of CNI-based immunosuppression. Patients converted to SRL-based, CNI-free immunosuppression experienced significantly fewer overall malignancies and fewer NMSCs through 24 months after conversion. Importantly, when patients with a history of malignancy before randomization were excluded from the analyses, the rate of overall malignancy and of NMSC remained significantly lower among patients converted to SRL after CNI discontinuation.
Because older age and a longer duration of exposure to immunosuppressants could predispose patients to higher rates of malignancy, post hoc analyses were performed to assess these potential confounding factors. Based on these analyses, neither age nor time from transplant to randomization accounted for the significant differences in malignancy rates observed between treatment groups. Similarly, a stratified analysis of malignancy rates by total time of exposure to immunosuppression confirmed that the significant differences in malignancy rates were not because of the observed minor differences in total time of exposure between treatment groups. Thus, the favorable differences in rates of malignancy attributable to SRL cannot be explained by a significant difference in patient age, a difference in time from transplant to randomization, or a difference in mean exposure to study drug during the study period. Furthermore, the significantly longer time from transplantation to randomization observed among patients who developed malignancy in the SRL conversion group, versus that in the CNI continuation group, underscores the robustness of the findings.
Multiple factors could partly explain the lower malignancy rates observed in the patients converted to SRL after CNI discontinuation. CNIs may exert effects on normal surveillance mechanisms for elimination of cells undergoing neoplastic transformation that are independent of their immunosuppressive activity (36, 37). Such effects would become apparent by comparison with the comparably immunosuppressed population treated only with SRL. Second, it is possible that SRL has actions, such as its demonstrated antiproliferative effects (38, 39), that reduce the rate of malignancies in addition to its immunosuppressive actions. The antitumor effects of SRL seem to be mediated by both p53-dependent and p-53-independent proapoptotic mechanisms (40–42). Because CNI and SRL have different molecular mechanisms of action, which only recently have been clearly understood, either mechanism or both could serve to produce the lower malignancy rates observed here (43–47).
In this clinical trial (Clinical trials no.: NCT00038948), the overall level of immunosuppression could also have been greater in the CNI continuation group than in the SRL conversion group. It was not possible to establish the extent to which the overall exposure to immunosuppressive therapy and immunosuppressive potency of the treatment regimens used in the two cohorts may or may not have been similar for several reasons: (a) to allow for institutional and regional differences in the standards of care for immunosuppression, exposure to CNIs and to SRL were both concentration-controlled over a broad range of trough levels; (b) it was not possible to establish standards of equivalence among CsA, tacrolimus, and SRL for given levels and durations of exposure, nor do clinically applicable standards of this type currently exist elsewhere; and (c) the levels of exposure to the concomitant immunosuppressive agents administered including antimetabolites and corticosteroids were not determined. Thus, the results of these analyses must be viewed as exploratory in nature.
The length of time and levels of exposure to overall immunosuppression notwithstanding, the observed rates of biopsy-confirmed acute rejection were only slightly higher in the SRL conversion group compared with the CNI continuation group—differences that were not significant at 12 or 24 months after SRL conversion (35). At 24 months, SRL conversion in patients with a baseline glomerular filtration rate greater than 40 mL/min was associated with excellent graft survival. No significant differences in graft survival were observed between the treatment groups at 12 and 24 months (35). In addition, acute rejection was not reported to be an important reason for premature discontinuation from assigned therapy in the SRL conversion group. Finally, the rates of treatment-emergent adverse events reported for SRL conversion patients in this clinical trial were comparable with or higher than those previously reported in patients treated with SRL after CsA withdrawal, and targeted trough levels at or greater than those specified in the protocol for this clinical trial (35, 48).
The aforementioned observations are consistent with the conclusions that whether the overall degree of immunosuppression among SRL conversion patients was comparable with or somewhat lower than that among CNI continuation patients in this clinical trial, it was sufficient to be associated with clinically acceptable rates of biopsy-confirmed acute rejection and lower rates of overall and cutaneous treatment-emergent malignancy during the 2-year period of follow-up. Likewise, SRL concentrations were similar throughout the study for those who developed malignancies and those who did not. Nonetheless, at exposures corresponding to the SRL concentrations observed, therapy targeted to these concentrations was associated with a decreased odds ratio of developing a treatment-emergent malignancy, when the SRL Cmin,TN were considered over the second year of the study. The results from this study suggest that substantial benefit in reduction in the rate of malignancies over time in immunosuppressed renal transplant patients may be obtained from therapies based on SRL that do not include the use of CNIs.
MATERIALS AND METHODS
This open-label, randomized, comparative study was conducted at 111 centers worldwide. The detailed methodology and primary results have been reported previously (34). Briefly, patients at least 13 years of age who were recipients of renal allografts obtained from living or deceased donors within 6 to 120 months before randomization were eligible for inclusion. All patients must have been receiving corticosteroids plus a CNI (CsA or tacrolimus) beginning within 2 weeks after transplantation, plus AZA (≥50 mg/day) or MMF (≥500 mg/day) for at least 12 weeks before randomization. Patients with any history of posttransplant lymphoproliferative disease or with known or suspected malignancy within 5 years before screening (with the exception of adequately treated basal cell or SCC of the skin) were excluded from the study.
Patients were randomly assigned (2:1) to SRL conversion or CNI continuation. Those assigned to SRL conversion received a single loading dose (12–20 mg) given 4 to 24 hr after their last dose of CNI. Subsequently, SRL (4–8 mg) was given daily with dosage adjusted to maintain trough concentration blood levels ranging from 8 to 20 ng/mL. Thereafter, maximum allowable doses of MMF or AZA were reduced to 1.5 g/day or 75 mg/day, respectively. Once SRL trough levels were within target range, MMF or AZA could be discontinued or patients could be switched from one to the other, at the discretion of the investigator. Corticosteroids, corresponding to prednisone dosage of 2.5 to 15 mg/day or the every-other-day equivalent, were continued. Patients assigned to CNI continuation received CsA concentration-controlled to 12-hr trough levels of 50 to 250 ng/mL or tacrolimus to 12-hr trough levels of 4 to 10 ng/mL. Corticosteroids were continued, whereas MMF or AZA could be continued or stopped, as specified earlier.
The primary efficacy and safety endpoints of the study have been reported elsewhere (34). Malignancy rates at 2 years were determined for the safety population of patients who received at least one dose of study drug (n=824) and were based on investigator-reported adverse events. These adverse events were collected for all patients, whether or not they continued to receive assigned therapy, for the duration of the protocol-mandated follow-up period, through 24 months after randomization. Data on adverse events were collected on three distinct case report forms (CRFs): one for malignancies; a second for infections; and a third for nonmalignancy, noninfection-related adverse events. When infections or malignancies were mistakenly recorded on the incorrect CRF, the site was queried to have the event transferred to an appropriate CRF. All events were coded to COSTART preferred terms.
Post hoc analyses included calculation of malignancy rates based on time of exposure to study drug (i.e., the number of events [malignancies] per 100 person-years of follow-up). Malignancies were divided into two categories: the first consisted of NMSCs, including basal cell carcinoma, SCC, and three cases of skin carcinoma/skin lesion recorded in the malignancy CRF and not otherwise specified; the second category consisted of AOM, which included all other solid organ and hematologic malignancies and melanoma. Note that patients with more than one malignancy were counted only once in each category, although a patient could contribute to both NMSC and AOM categories. Malignancy rates were also analyzed in the population of patients without a prior history of the same malignancy that they developed during the study. Additional post hoc analyses were performed to assess the impact, if any, of potential differences in patient age and time from transplant to randomization with respect to treatment, presence of malignancy, and the combination of treatment and presence of malignancy.
The incidence of malignancies for both treatment groups was calculated as the number of events per 100 person-years of follow-up, specifically the number of patients with at least one event divided by total exposure, the latter calculated as the sum of study drug exposures for patients with events plus those without events. A patient's exposure to study medication was calculated as the number of years of exposure to study medication, from the date of the first dose to the date of the last dose. For a patient with an event, exposure was measured from the start of study drug to the date of the diagnosis of the malignancy. For patients who did not have events, exposure was calculated as the time from the first dose to the last dose of study medication. The estimate of the difference in rates between treatment groups was reported along with the 95% confidence intervals of the difference in rates (Wald method) (49). Statistical significance was assessed by associated z-score; P values less than 0.05 were considered as significant (one-tailed test). To assess possible confounding effects of age and time from transplant on the incidence of malignancy, linear models (analysis of variance) with treatment, malignancy status, and an interaction term for malignancy status and treatment were fit separately to these dependent variables. Least squares means and P values were obtained for each factor.
The Sirolimus CONVERT Trial Study Group
The following principal investigators, listed alphabetically, comprised the Sirolimus CONVERT Trial Study Group: J. Alberú, Instituto Nacional de Ciencias, Mexico City, Mexico; R.R. Alloway, University Hospital, Cincinnati, OH; E. Ancona, Clinica Chirurgica General III, University of Padua, Padua, Italy; M. Arias, Hospital Marques de Valdecilla, Santander, Spain; P. Bachleda, Fakultni Nemocnice, Olomouc, Czech Republic; J.A. Bertolatus, University of Iowa Hospitals and Clinics, Iowa City, IA; J.L. Bosmans, University Hospital Antwerpen, Edegem, Belgium; B. Bourbigot, CHU La Cavale Blanche, Brest, France; D.C. Brennan, Washington University School of Medicine, St. Louis, MO; K. Brinker (deceased), Dallas Transplant Institute, Dallas, TX; S. Campbell, Princess Alexandra Hospital, Wooloongabba, Australia; J.M. Campistol, Hospital Clinic i Provincial, Barcelona, Spain; D.B. Monteiro de Carvalho, Hospital Geral de Bonsucesso, Rio de Janeiro, Brazil; J.A. Castillo-Lugo, Dallas Transplant Institute, Dallas, TX; S. Cho, Boston Medical Center, Boston, MA; S. Cockfield, University of Alberta Hospitals, Edmonton, AB, Canada; D.J. Cohen, Columbia University Medical Center, New York, NY; D.J. Conti, Albany Medical Center, Albany, NY; F.L. de Carvalho Contieri, Hospital Universitario Evangelico de Curitiba, Curitiba, Brazil; F.G. Cosio, Rochester Methodist Hospital, Rochester, MN; P. Daloze, Hopital Notre Dame, Montreal, QB, Canada; M. Davalos Michel, CEMIC, Buenos Aires, Argentina; C.L. Davis, University of Washington Medical Center, Seattle, WA; D. del Castillo, Hospital Universitario Reina Sofia, Cordoba, Spain; M. del Carmen Rial, Instituto de Nefrologia, Buenos Aires, Argentina; H. Diliz, Centro Medico Nacional 20 de Noviembre, Colonia del Valle, Mexico; J. Dominguez, Hospital Dr. Sotero del Rio, Santiago, Chile; D. Durand, Hopital Rangueil, Toulouse, France; F. Egidi, Methodist University Hospital, Memphis, TN; J. Eris, Royal Prince Alfred Hospital, Camperdown, Australia; B. Fellstrom, Njurmedicinska Kliniken, Uppsala, Sweden; A. Flores, Hospital de Especialidades Num. 1 Leon, Guanajuato, Mexico; L. Gaite, Clinica de Nefrologia y Urologia y Sante Fe, Argentina; V.D. Garcia, Santa Casa de Porto Alegre, Porto Alegre, Brazil; M. Glyda, Szpital Wojewodzki w Poznaniu, Poznan, Poland; I. Gonzalez, Hospital Fray Junipero Serra ISSSTE de Tijuana, Tijuana Baja California, Mexico; J.M. Gonzalez Posada, Hospital Universitario de Canarias-La Laguna, Sta. Cruz de Tenerife, Spain; P.F. Gores, Carolinas Medical Center, Charlotte, NC; M.V. Govani, Clarian Health Partners, Indiana University School of Medicine, Indianapolis, IN; C. Gracida, Hospital de Especialidades Centro Medico Nacional Siglo XXI, Mexico; J.M. Grinyo, C.S.U. Bellvitge, Barcelona, Spain; G.C. Groggel, University of Nebraska Medical Center, Omaha, NE; J. Halkett, Groote Schuur Hospital, Cape Town, South Africa; K. Hamawi, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; A. Holm, Hospital General Centro Medico Nacional La Raza, Mexico; I. Houde, Centre Hospitalier Univerisitaire de Quebec, QB, Canada; D.E. Hricik, University Hospitals of Cleveland, Cleveland, OH; B. Hutchison, Sir Charles Gairdner Hospital, Nedlands, Australia; R. Jaramillo, Hospital Regional 1 de Octubre, Mexico; T.D. Johnston, University of Kentucky, Lexington, KY; J.F Juarez, Hospital de Especialidades 71 IMSS, Torreón Coahuila, Mexico; J. Kanellis, Monash Medicla Centre, Clayton, Australia; M. Klinger, Akademia Medyczna we Wroclawiu, Wroclaw, Poland; G. Knoll, Ottawa Hospital, Ottawa, ON, Canada; B. Kraemer, Klinikum der Universitat Regensburg, Regensburg, Germany; H. Kreis, Hopital Necker, Paris, France; M.R. Laftavi, Buffalo General Hospital, Buffalo, NY; D. Landsberg, St. Paul's Hospital, Vancouver, BC, Canada; C. Legendre, Hopital Saint-Louis, Paris, France; M. Lorber, Yale-New Haven Hospital, New Haven, CT; F.-L. Luan, University of Michigan Hospital, Ann Arbor, MI; D. Ludwin, St. Joseph's Healthcare, Hamilton, ON, Canada; E.C. Maggiora, Sanatorio de la Trinidad Mitre, Buenos Aires, Argentina; E. Mancilla, Instituto Nacional de Cardiologia, Tlalpan, Mexico; R. Manfro, Hospital das Clinicas de Porto Alegre, Porto Alegre, Brazil; R. Mann, UMDNJ/Robert Wood Johnson University Hospital, New Brunswick, NJ; P.U. Massari, Hospital Privado-Centro Medico de Cordoba, Cordoba, Argentina; A.J. Matas, Fairview University Medical Center, Minneapolis, MN; G. Mayer, Universitatsklinik fur Innere Medizin, Innsbruck, Austria; J. Morales, Clinica Las Condes, Santiago, Chile; J.M. Morales, Hospital 12 de Octubre, Madrid, Spain; A. Mota, Hospitais da Univerisdade de Coimbra, Coimbra, Portugal; N. Muirhead, London Health Sciences Centre, London, ON, Canada; S. Naicker, Johannesburg Hospital, Parktown, South Africa; G. Nanni, Cattedra di Chirurgia Sostitutiva e dei Trapianti, Rome, Italy; I.L. Noronha, Hospital Sao Joaquim da Beneficencia Portuguesa, Sao Paulo, Brazil; R. Oberbauer, Allgemeines Krankenhaus der Stadt Wien, Wien, Austria; P.J. O'Connell, Westmead Hospital, Westmead, Australia; S.A. Ojeda, Centro Médico Nacional de Occidente, Hospital de Pediatria, Guadalajara, Jalisco, Mexico; M. Ostrowski, Klinika Chirurgii Ogolnej i Transplantacyjnej Pomorskiej, Szczecin, Poland; L. Paczek, Klinica Immunologii, Warszawa, Poland; S. Palekar, Newark Beth Israel Medical Center, Newark, NJ; G.E. Palti, Hospital Aleman, Buenos Aires, Argentina; M.D. Pascoe, Groote Schuur Hospital, Cape Town, South Africa; J. Paul, Hospital Miguel Servet, Zaragoza, Spain; J.R. Pinto, Hospital Curry Cabral, Lisboa, Portugal; C. Ponticelli, Ospedale Maggiore di Milano, Milano, Italy; B. Pussell, Prince of Wales Hospital, Randwick, Australia; P.R. Rajagopalan, Medical University of South Carolina, Charleston, SC; R. Reyes, Clinica San Cosme, Aguascalientes, Mexico; D. Roth, University of Miami/Jackson Memorial Medical Center, Miami, FL; G. Russ, Queen Elizabeth Hospital, Woodville, Australia; J. Cavaliere Sampaio, Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil; J. Sanchez-Plumed, Hospital Universitario La Fe, Valencia, Spain; F.P. Schena, Univeristy of Bari, Policlinico, Bari, Italy; R.O. Schiavelli, Hospital General de Agudos Dr. Cosme Argerich, Buenos Aires, Argentina; S. Schwartz-Sorensen, Nefrologisk afdelning, Kobenhavn, Denmark; N. Shah, Saint Barnabas Medical Center, Livingston, NJ; A. Shoker, St. Paul's Hospital, Saskatoon, Saskatchewan, Canada; H. Tedesco Silva Jr, Hospital do Rim e Hipertensao-Fundacao Oswaldo Ramos, Sao Paulo, Brazil; J.P. Squifflet, University Hospital St. Luc, Brussels, Belgium; S. Steinberg, Sharp Memorial Hospital, San Diego, CA; B. Suwelack, Medizinische Klinik und Poliklinik D Universitatsklinikum Muenster, Muenster, Germany; A. Vathsala, Singapore General Hospital, Singapore, Singapore; J. Vella, Maine Medical Center, Portland, ME; S. Vitko, IKEM Transplantcenter, Prague, Czech Republic; R. Wali, University of Maryland Medical System, Baltimore, MD; R. Walker, Royal Melbourne Hospital, Parkville, Australia; S. Weinstein, Lifelink Transplant Institute, Tampa, FL; J. Welchel, Piedmont Hospital, Atlanta, GA; J.A. Yamamoto, Hospital de Pediatria del Centro Medico Nacional Siglo XXI, Mexico; H.C. Yang, Pinnacle Health Systems, Harrisburg Hospital, Harrisburg, PA; M. Zand, University of Rochester-Strong Memorial Hospital, Rochester, NY.
The authors thank Christine Innes (Wyeth Research, Collegeville, PA) and Karine Rutault (Wyeth Research, Paris, France) for their contributions to study coordination and data review, and Bernadette Maida (Wyeth Research, Collegeville, PA) for her contribution to study design and data review. The authors also thank Eric Gibson for important statistical advice that led to substantial improvements in the article, Bernice Yost for data support, and Susan A. Nastasee (Wyeth Research, Collegeville, PA) for medical writing assistance. The authors also thank Linda Schneider of On Assignment Clinical Research for assistance with medical writing and Albert Balkiewicz of Peloton Advantage, LLC, for editorial assistance with manuscript preparation, both of which were funded by Pfizer Inc.
1. Danovitch GM. Immunosuppressive medications and protocols for kidney transplantation
. In: Danovitch GM, ed. Handbook of kidney transplantation
. Philadelphia: Lippincott Williams & Wilkins 2004, p 72.
2. Agraharkar ML, Cinclair RD, Kuo YF, et al. Risk of malignancy
with long-term immunosuppression
in renal transplant recipients. Kidney Int
2004; 66: 383.
3. Baccarani U, Adani GL, Montanaro D, et al. De novo malignancies after kidney and liver transplantations: Experience on 582 consecutive cases. Transplant Proc
2006; 38: 1135.
4. Bordea C, Wojnarowska F, Millard PR, et al. Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation
2004; 77: 574.
5. Yoshimura N, Akioka K, Ushigome H, et al. Twenty-five-year survival of living related kidney transplants: Thirty-five years' experience. Transplant Proc
2007; 37: 687.
6. Bustami RT, Ojo AO, Wolfe RA. Immunosuppression
and the risk of post-transplant malignancy
among cadaveric first kidney transplant recipients. Am J Transplant
2004; 4: 87.
7. Caillard S, Agodoa LY, Bohen EM, et al. Myeloma, Hodgkin disease, and lymphoid leukemia after renal transplantation: Characteristics, risk factors and prognosis. Transplantation
2006; 81: 888.
8. Ghorbani A, Mozafari A, Karimi S, et al. Isolated primary pulmonary Kaposi's sarcoma in a renal transplant recipient: A case report. Transplant Proc
2007; 39: 3471.
9. Kauffman HM, Cherikh WS, McBride MA, et al. Post-transplant de novo malignancies in renal transplant recipients: The past and present. Transpl Int
2006; 19: 607.
10. Rascente M, Pisani F, Barletta A, et al. Malignancies after kidney transplantation
. Transplant Proc
2005; 37: 2529.
11. Samhan M, Al-Mousawi M, Donia F, et al. Malignancy
in renal recipients. Transplant Proc
2005; 37: 3068.
12. Morath C, Mueller M, Goldschmidt H, et al. Malignancy
in renal transplantation. J Am Soc Nephrol
2004; 15: 1582.
13. Nafar M, Einollahi B, Hemati K, et al. Development of malignancy
following living donor kidney transplantation
. Transplant Proc
2005; 37: 3065.
14. Vajdic CM, McDonald SP, McCredie MRE, et al. Cancer incidence before and after kidney transplantation
2006; 296: 2823.
15. Wimmer CD, Rentsch M, Crispin A, et al. The janus face of immunosuppression
—de novo malignancy
after renal transplantation: The experience of the Transplantation Center Munich. Kidney Int
2007; 71: 1271.
16. Bastiaannet E, Homan-van der Heide JJ, Ploeg RJ, et al. No increase of melanoma after kidney transplantation
in the northern part of The Netherlands. Melanoma Res
2006; 17: 349.
17. Morales J, Fierro A, Benavente D, et al. Conversion from a calcineurin inhibitor
-based immunosuppressive regimen to everolimus in renal transplant recipients: Effect on renal function and proteinuria. Transplant Proc
2007; 39: 591.
18. Campistol JM, Eris J, Oberbauer R, et al. Sirolimus
therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol
2006; 17: 581.
19. Webster AC, Woodroffe RC, Taylor RS, et al. Tacrolimus versus ciclosporin as primary immunosuppression
for kidney transplant recipients: Meta-analysis and meta-regression of randomised trial data. BMJ
2005; 331: 810.
20. Iaria G, Anselmo A, De Luca L, et al. Conversion to rapamycin immunosuppression
after kidney transplantation
: Case reports. Transplant Proc
2007; 39: 2036.
21. Yakupoglu YK, Buell JF, Woodle S, et al. Individualization of immunosuppressive therapy. III. Sirolimus
associated with a reduced incidence of malignancy
. Transplant Proc
2006; 38: 358.
22. Barth RN, Janus CA, Lillesand CA, et al. Outcomes at 3 years of a prospective pilot study of Campath-1H and sirolimus immunosuppression
for renal transplantation. Transpl Int
2006; 19: 885.
23. Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression
with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation
2005; 80: 883.
24. Kreis H, Oberbauer R, Campistol JP, et al. Long-term benefits with sirolimus
-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol
2004; 15: 809.
25. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy
-treated renal transplant recipients: Results from five multicenter studies. Clin Transplant
2004; 18: 446.
26. Sindhi R, Seward J, Mazariegos G, et al. Replacing calcineurin inhibitors with mTOR inhibitors in children. Pediatr Transplant
2005; 9: 391.
27. Zaltzman JS, Boucher A, Busque S, et al. A prospective 3-yr evaluation of tacrolimus-based immunosuppressive therapy in immunological high risk renal allograft recipients. Clin Transplant
2005; 19: 26.
28. Amornphimoltham P, Patel V, Sodhi A, et al. Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Cancer Res
2005; 65: 9953.
29. Asnaghi L, Bruno P, Priulla M, et al. mTOR: A protein kinase switching between life and death. Pharmacol Res
2004; 50: 545.
30. Chan S. Targeting the mammalian target of rapamycin (mTOR): A new approach to treating cancer. Br J Cancer
2004; 91: 1420.
31. Engl T, Makarevic J, Relja B, et al. Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: Impact on tumor recurrence and malignancy
. BMC Cancer
2005; 5: 4.
32. Satoh S, Tada H, Murakami M, et al. The influence of mycophenolate mofetil versus azathioprine and mycophenolic acid pharmacokinetics on the incidence of acute rejection and infectious complications after renal transplantation. Transplant Proc
2005; 37: 1751.
33. Lake JR, David KM, Steffen BJ, et al. Addition of MMF to dual immunosuppression
does not increase the risk of malignant short-term death after liver transplantation. Am J Transplant
2005; 5: 2961.
34. Vincenti F. Immunosuppression
minimization: Current and future trends in transplant immunosuppression
. J Am Soc Nephrol
2003; 14: 1940.
35. Schena FP, Pascoe MD, Alberú J, et al. Conversion from calcineurin inhibitors to sirolimus
maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation
2009; 87: 233.
36. Pardo R, Colin E, Regulier E, et al. Inhibition of calcineurin by FK506 protects against polyglutamine-huntingtin toxicity through an increase of huntingtin phosphorylation at S421. J Neurosci
2006; 26: 1635.
37. Buchholz M, Schatz A, Wagner M, et al. Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+
/calcineurin signaling pathway. EMBO J
2006; 25: 3714.
38. Sehgal SN, Molnar-Kimber K, Ocain TD, et al. Rapamycin: A novel immunosuppressive macrolide. Med Res Rev
1994; 14: 1.
39. Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: From bench to clinic. Curr Opin Invest Drugs
2002; 3: 295.
40. Mungamuri SK, Yang X, Thor AD, et al. Survival signaling by Notch1: Mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res
2006; 66: 4715.
41. Yan H, Frost P, Shi Y, et al. Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res
2006; 66: 2305.
42. Huang S, Shu L, Easton J, et al. Inhibition of mammalian target of rapamycin activates apoptosis signal-regulating kinase 1 signaling by suppressing protein phosphatase 5 activity. J Biol Chem
2004; 279: 36490.
43. Krauskopf A, Lhote P, Mutter M, et al. Vasopressin type 1A receptor up-regulation by cyclosporin A in vascular smooth muscle cells is mediated by superoxide. J Biol Chem
2003; 278: 41685.
44. Soraya S, Smaili K, Stellato A, et al. Cyclosporin A inhibits inositol 1,4,5-trisphosphate-dependent Ca2+
signals by enhancing Ca2+
uptake into the endoplasmic reticulum and mitochondria. J Biol Chem
2001; 276: 23329.
45. D'Angelo G, Duplan E, Vigne P, et al. Cyclosporin A prevents the hypoxic adaptation by activating hypoxia-inducible factor-1α pro-564 hydroxylation. J Biol Chem
2003; 278: 15406.
46. Brazin KN, Mallis RJ, Fulton DB, et al. Regulation of the tyrosine kinase Itk by the peptidyl-prolyl isomerase cyclophilin A. Proc Natl Acad Sci USA
2002; 99: 1899.
47. Cui Y, Mirkia K, Florence Fu YH, et al. Interaction of the retinoblastoma gene product, RB, with cyclophilin A negatively affects cyclosporin-inhibited NFAT signaling. J Cell Biochem
2002; 86: 630.
48. Oberbauer RA, Kreis H, Johnson RWG, et al. Long-term improvement in renal function with sirolimus
after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation
2003; 76: 364.
49. Liu GF, Wang J, Liu K, et al. Confidence intervals for an exposure adjusted incidence rate difference with applications to clinical trials. Statist Med
2006; 25: 1275.