ORIGINAL RESEARCH published: 19 May 2023 doi: 10.3389/ti.2023.11042 Incidence and Prognosis of Colorectal Cancer After Heart Transplantation: Data From the Spanish Post-Heart Transplant Tumor Registry Marta Sagastagoitia-Fornie 1*, Laura Morán-Fernández 2, Zorba Blázquez-Bermejo 3, Beatriz Díaz-Molina 4, Manuel Gómez-Bueno 5, Luis Almenar-Bonet 6, Amador López-Granados 7, Francisco González-Vílchez 8, Sonia Mirabet-Pérez 9, Elena García-Romero 10, Sobrino-Márquez Jose M. 11, Gregorio Rábago Juan-Aracil 12, Maria Angels Castel-Lavilla 13, Teresa Blasco-Peiro 14, Iris Garrido-Bravo 15, Luis De La Fuente-Galán 16, Javier Muñiz 17 and María G. Crespo-Leiro 18 1 Ferrol University Hospital Complex, Ferrol, Spain, 2University Hospital October 12, Madrid, Spain, 3Gregorio Marañón Hospital, Madrid, Spain, 4Central University Hospital of Asturias, Oviedo, Spain, 5Puerta de Hierro University Hospital Majadahonda, Madrid, Spain, 6La Fe Hospital, Valencia, Spain, 7Hospital Universitario Reina Sofía, Cordoba, Spain, 8Marqués de Valdecilla University Hospital, Santander, Spain, 9Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain, 10Bellvitge University Hospital, Barcelona, Spain, 11Virgen del Rocío University Hospital, Seville, Spain, 12University Clinic of Navarra, Pamplona, Spain, 13Hospital Clinic of Barcelona, Barcelona, Spain, 14Hospital Universitario Miguel Servet, Zaragoza, Spain, 15Hospital Universitario Virgen de la Arrixaca, Murcia, Spain, 16Hospital Clínico Universitario de Valladolid, Valladolid, Spain, 17 Grupo de Investigación Cardiovascular (GRINCAR), University of A Coruña, A Coruña, Spain, 18A Coruña University Hospital Complex (CHUAC), A Coruña, Spain *Correspondence: Marta Sagastagoitia-Fornie marta.sagastagoitia.fornie@ In this observational and multicenter study, that included all patients who underwent a sergas.es heart transplantation (HT) in Spain from 1984 to 2018, we analyzed the incidence, management, and prognosis of colorectal cancer (CRC) after HT. Of 6,244 patients Received: 09 November 2022 Accepted: 04 May 2023 with a HT and a median follow-up of 8.8 years since the procedure, 116 CRC cases Published: 19 May 2023 (11.5% of noncutaneous solid cancers other than lymphoma registered) were diagnosed, Citation: mainly adenocarcinomas, after a mean of 9.3 years post-HT. The incidence of CRC Sagastagoitia-Fornie M, increased with age at HT from 56.6 per 100,000 person-years among under 45 year olds Morán-Fernández L, Blázquez-Bermejo Z, Díaz-Molina B, to 436.4 per 100,000 person-years among over 64 year olds. The incidence rates for age- Gómez-Bueno M, Almenar-Bonet L, at-diagnosis groups were significantly greater than those estimated for the general López-Granados A, González-Vílchez F, Mirabet-Pérez S, Spanish population. Curative surgery, performed for 62 of 74 operable tumors, García-Romero E, Jose M. S-M, increased the probability of patient survival since a diagnosis of CRC, from 31.6% to Rábago Juan-Aracil G, 75.7% at 2 years, and from 15.8% to 48.6% at 5 years, compared to patients with Castel-Lavilla MA, Blasco-Peiro T, Garrido-Bravo I, De La Fuente-Galán L, inoperable tumors. Our results suggest that the incidence of CRC among HT patients is Muñiz J and Crespo-Leiro MG (2023) greater than in the general population, increasing with age at HT. Incidence and Prognosis of Colorectal Cancer After Heart Transplantation: Keywords: heart transplantation, prognosis, incidence, colorectal cancer, management Data From the Spanish Post-Heart Transplant Tumor Registry. Transpl Int 36:11042. Abbreviations: CRC, colorectal cancer; CIs, confidence intervals; HT, heart transplantation; ISHLT, International society for doi: 10.3389/ti.2023.11042 heart and lung transplantation; Pys, person-years; SPHTTR, Spanish post-heart-transplant tumor registry. Transplant International | Published by Frontiers 1 May 2023 | Volume 36 | Article 11042 Sagastagoitia-Fornie et al. Colorectal Cancer After Heart Transplantation GRAPHICAL ABSTRACT | INTRODUCTION MATERIALS AND METHODS Throughout the last few decades, the life expectancy of patients We conducted a retrospective, observational, multicenter study that with a heart transplant (HT) has increased mainly due to included all patients who underwent a HT from the beginning of this advances in immunosuppression, conferring more weight to therapy in Spain in 1984 to the 31st December 2018. As a source of long-term causes of morbidity–mortality [1], such as information, we used the SPHTTR, which contains the records of malignancies [2, 3]. The risk of de novo malignancy in HT HT patients of Spanish hospitals. From a total of 8,482 patients recipients was reported to be 2—4 times higher than that in the included in the SPHTTR, we excluded 490 pediatric transplants general population [4–8]. According to the Spanish Post- (<16 years), 1,520 patients who died in the first 3 months after HT, Heart-Transplant Tumor Registry (SPHTTR), the most 112 combined transplants, and 116 due to retransplantation. The common cancer after HT is skin cancer, followed by remaining 6,244 patients were followed up to December 2019. noncutaneous solid cancers other than lymphoma. Within In order to assess the incidence of CRC in different subgroups, this latter group, gastrointestinal tumors are the second the data considered were sex, age at HT, pre-HT smoking history, most frequent, behind lung cancer [9, 10]. Colorectal cancer obesity, background of CRC pre-HT, immunosuppression (CRC) is the third most common malignancy in the general treatment, anti-viral prophylaxis received, development of CRC, population worldwide, after lung and breast cancers, although age at diagnosis of CRC, and duration of follow-up (terminated at it is the most common cancer in Spain [11]. Although CRC the earlier of death or the 31st December 2019). To evaluate the seems to increase slightly after transplantation, the effect of changes in immunosuppressive practice or HT protocols, representation of HT recipients in most such studies is low the era in which the HT was performed was introduced as an but results are controversial [12–14]. independent variable. Two eras were considered: the period before The aim of this study was to report on the incidence of CRC (1984–2000) and after (2001–2018) the introduction of (overall and among different subgroups), its characteristics, the interleukin-2 receptor (IL-2R) blockers in Spain. For treatment received, and survival among HT recipients. This characterization of post-HT CRC, additional variables were included analyzing SPHTTR data, which is updated yearly taken into account such as time between HT and CRC with information on tumors in all HT patients since the diagnosis, localization of the tumor (colon or rectum), beginning of this therapy in Spain in 1984, and compare these pathological features, extension at diagnosis (metastatic, results with a reference population. including lymph nodes, or localized), treatment received Transplant International | Published by Frontiers 2 May 2023 | Volume 36 | Article 11042 Sagastagoitia-Fornie et al. Colorectal Cancer After Heart Transplantation (surgery, chemotherapy, radiotherapy), surgical purpose TABLE 1 | Patient characteristics. (palliative, curative or none), and survival after CRC diagnosis. Number of patients 6,244 Total incidence (age standardized with the direct method for the world standard population aged >15 years), and incidence in Female 1,186 (19.0%) Mean (SD) age at HT 52.1 (11.5) age-at-diagnosis groups (<45, 45–54, 55–64, 65–74, ≥75 years), Age at HT were compared with GLOBOCAN 2018 estimates for the general <45 years 1,340 (21.5%) Spanish population [15]. A discrepancy between the age of 45–54 years 1,759 (28.2%) initiation of adulthood used in the SPHTTR (16 years) and the 55–64 years 2,516 (40.3%) lower limit of the 15–44 years age group used for the world ≥65 years 629 (10.0%) Pre-HT smokinga 976 (21.0%) standard population was deemed of no consequence in this study. Obesityb 683 (11.3%) This research protocol was approved by the institutional Pre-HT colon or rectum tumorc 16 (7.4%) review board of each participating center. HT era Confidence intervals (CIs) for incidence rates in HT patient age 1984–2000 2,553 (40.9%) 2001–2018 3,691 (59.1%) groups were calculated using the quadratic approximation to the Induction therapy 4,992 (83.0%) Poisson log likelihood for the log rate parameter [16]. Confidence Aciclovir or Ganciclovir after HTd 3,387 (60.6%) intervals for GLOBOCAN 2018 age-group–specific incidence rate a Out of 4,653 patients for whom relevant data were available. estimates were calculated using the exact method described by b Out of 6,048 patients for whom relevant data were available. Armitage and Berry [17] with Epidat 4.2 [18]. Confidence intervals c Out of 215 patients for whom relevant data were available. for age-standardized overall incidence rates were calculated as per d Out of 5,586 patients for whom relevant data were available. Fay and Feuer [19, 20] using Epidat 4.2. Adjusted estimates of relative risk were obtained by means of a Poisson regression analysis. A world standard population was used to obtain The mean age at diagnosis was 66.0 years (SD 8.8), with three adjusted rates in HT patients and the Spanish general patients under 45, nine aged 45–54 years, 29 aged 55–64 years, population [20]. Postdiagnosis survival curves were constructed 62 aged 65–74 years, and 13 ≥ 75 years. by a Kaplan-Meier method and compared using log rank tests to estimate the statistical significance of differences. Except where otherwise stated, all statistical calculations were Incidence Comparison With the General performed using Stata v12.0. Spanish Population Contrary to what is observed in the general population, the incidence of CRC post-HT remained fairly constant with RESULTS increasing age, particularly among males. However, both age- and sex-specific CRC incidences as well as age-standardized Study Population overall rates were several-fold higher in every group than This study included 6,244 patients (1,186 women [19.0%] and GLOBOCAN 2018 estimates for the Spanish population, 5,058 men [81.0%]) with a total follow-up of 55396.5 person- except for the subgroup of men over 75 for whom no years (pys), median follow-up of 8.8 years, and a mean age at HT statistically significant differences were found (Figure 1). of 52.1 years. A total of 976 (21.0%) patients were smokers pre- HT, 683 (11.3%) obese, and 16 (7.4%) had a history of CRC before HT surgery. A total of 2,553 patients (40.9%) underwent HT in Colorectal Cancer Characteristics After the pre-IL2R–blocker era, and 3,691 (59.1%) in the most recent Heart Transplantation era. Of the total patients, 83.0% received induction therapy and The mean time between HT and diagnosis of CRC was 9.3 years 60.6% antivirals post-HT (Table 1). The used (SD 5.5 years). Information on tumor extension status at immunosuppressive agents are listed in (Table 2). diagnosis was available in 107 cases, the cancer being metastatic in only 12 patients (11.3%). Regarding histopathological characteristics, 91 (85.1%) were Incidence of Colorectal Cancer After Heart adenocarcinomas (Table 4). We had no information on the Transplantation treatment received by 18 patients. Curative surgery was With regard to tumors, 2,498 cases were registered, of which performed on 62 patients (63.3%) and palliative surgery on 12 116 were CRC (4.6% of all tumors and 11.5% of noncutaneous (12.2%), whereas 24 patients (24.5%) did not undergo any solid cancers other than lymphoma). Of these 116 cases, surgical treatment. Chemotherapy was indicated in 32 cases 99 were diagnosed in men and 17 in women. The incidence (33.7%) and radiotherapy in 13 (13.7%). of CRC increased with age at HT from an average of 56.6 per 100,000 pys among under 45 year olds to 436.4 per 100,000 pys among over 64 year olds. No statistically Prognostic Impact of Colorectal Cancer significant differences were observed related to sex, pre-HT After Heart Transplantation smoking history, obesity, HT era, immunosuppressive Within 2 and 5 years after diagnosis, overall Kaplan–Meier practice or antiviral prophylaxis (Table 3). survival fell to 59.1% and 39.1%, respectively. No statistically Transplant International | Published by Frontiers 3 May 2023 | Volume 36 | Article 11042 Sagastagoitia-Fornie et al. Colorectal Cancer After Heart Transplantation TABLE 2 | Patients receiving each kind of immunosuppressor (percentages), by period post-HT. <3 months 3–12 months 1–2 years After 2 years At any time Cyclosporine 58.2 52.8 46.5 38.5 59.1 Azathioprine 36.2 32.4 27.7 19.4 37.2 Prednisone 85.6 76.6 56.4 44.4 86.0 Tacrolimus 30.1 26.5 19.5 18.3 39.3 MMF 49.7 42.3 34.0 35.4 62.6 Sirolimus 0.7 0.8 0.9 3.8 4.5 Everolimus 1.5 2.6 3.3 7.0 9.7 OKT3 23.4 0.2 0.1 0.1 23.6 Anti-thymocyte globulin 5.6 0.8 0.2 0.1 5.6 Basiliximab 27.7 0.1 0.0 0.0 27.7 Daclizumab 7.0 0.2 0.0 0.0 7.0 N = 6,242 TABLE 3 | Incidence of colorectal tumors per 100,000 person-years among heart transplant patients and different subgroups. Follow-up, cases, incidence rates and relative risk. Group Follow-up (Pys) Cases Incidence rate 95% CI RR 95% CI p Total 55396.5 116 209.4 174.6 251.2 Sex Male 44763.6 99 221.2 181.6 269.3 1 Female 10632.9 17 159.9 99.4 257.2 0.7 0.4 1.2 0.215 Age at HT (years) <45 14147.8 8 56.6 28.3 113.1 1 45–54 16485.9 32 194.1 137.3 274.5 3.4 1.6 7.5 0.002 55–64 20638.3 58 281.0 217.3 363.5 5.0 2.3 10.4 <0.001 ≥65 4124.5 18 436.4 275.0 692.7 7.7 3.4 17.8 <0.001 Pre-HT smoking 8721.0 13 149.1 8.6 256.7 0.6 0.4 1.1 0.124 Obesity 5520.2 9 163.0 84.8 313.3 0.8 0.4 1.5 0.471 Pre-HT colorectal tumor 115.9 2 1726.3 431.7 6902.5 8.3 2.1 33.5 <0.001 HT era 1984–2000 28797.4 56 194.5 149.7 252.7 1 2001–2018 26599.1 60 225.6 175.1 290.5 1.2 0.8 1.7 0.424 Immunosuppression OKT3 (Yes/No) 16864.4 44 260.9 194.2 350.6 1.4 0.9 2.0 0.104 ATG (Yes/no) 6530.4 14 214.4 127.0 362.0 1.0 0.6 1.8 0.982 Basiliximab (Yes/No) 14547.9 25 171.9 116.1 254.3 0.8 0.5 1.2 0.205 Daclizumab (Yes/no) 4096.0 11 268.6 148.7 484.9 1.3 0.7 2.4 0.424 Antiviral prophylaxis Aciclovir (Yes/No) 20118.5 42 208.8 154.3 282.5 0.9 0.7 1.4 0.788 Ganciclovir (Yes/No) 18822.8 39 207.2 151.4 283.6 0.9 0.6 1.4 0.768 Aciclovir or Ganciclovir 30373.0 67 220.6 173.6 280.2 1.1 0.73 1.56 0.734 significant differences were observed in the survival curves related corresponded to the GLOBOCAN 2018 estimate for the to sex (women vs. men), nor to age at diagnosis (under vs. over general Spanish population. 55). Curative surgery, performed in 62 of the 74 operable cases, Solid organ transplant recipients are at increased risk of cancer increased the probability of survival since diagnosis from 31.6% [3]. Regarding HT in particular, Youn et al. [4] found that more to 75.7% at 2 years, and from 15.8% to 48.6% at 5 years, compared than 10% of adult HT recipients from the International Society to inoperable patients (Figure 2). for Heart and Lung Transplantation (ISHLT) registry developed de novo malignancy between years 1 and 5 after transplantation, and this outcome was associated with greater mortality. The DISCUSSION largest increase was detected in skin cancer, followed by noncutaneous solid cancer, even though, more specifically, the Incidence of Colorectal Cancer After Heart proportion of CRC cases was lower than in our cohort. This result Transplantation might be explained by the mean time between HT and the In this study, we found the incidence of CRC considerably diagnosis of CRC in our study being over 9 years, whereas the greater among Spanish HT patients than that which ISHLT registry included only tumors within 5 years post-HT. The Transplant International | Published by Frontiers 4 May 2023 | Volume 36 | Article 11042 Sagastagoitia-Fornie et al. Colorectal Cancer After Heart Transplantation FIGURE 1 | Incidence rates per 100,000 person-years for age-at-diagnosis groups, and age-standardized overall rates for colorectal cancer among HT patients (SPHTTR data) and for the general Spanish population (GLOBOCAN 2018). (A) men; (B) women. incidence rate of CRC after HT in our analysis was 209.4 per diagnosis without a clear justification. Our group [22] had 100,000 pys (4.6% of the total malignancies); Van Keer et al. [21] already noticed that the incidence rate ratio of lung cancer reported similar numbers in Leuven. between HT and general populations fell with increasing age, The incidence of CRC increased with age at HT, which was suggesting, as a possible explanation, that with aging the effect expected, given the known relationship between age and cancer, of immunosuppression is relatively reduced due to a gradual but surprisingly this trend was not observed with age at decline of the immune system. Transplant International | Published by Frontiers 5 May 2023 | Volume 36 | Article 11042 Sagastagoitia-Fornie et al. Colorectal Cancer After Heart Transplantation TABLE 4 | Characteristics of colorectal tumors at diagnosis (results expressed as n (%) unless otherwise stated). Number of colorectal tumors 116 Mean (SD) age (years) at diagnosis 66.0 (8.8) Mean (SD) time (years) since HT 9.3 (5.5) Location Colon 92 (79.3) Rectum 22 (19.0) Anal 2 (1.7) Histologya 107 Adenocarcinoma 81 (75.7) Metastatic adenocarcinoma 10 (9.4) Carcinoma 7 (6.5) Metastatic carcinoma 2 (1.9) Epidermoid carcinoma 3 (2.8) Lynphoproliferative Syndromes 4 (3.7) Surgeryb 98 None 24 (24.5) Paliative 12 (12.2) FIGURE 2 | Survival curves since diagnosis of colorectal cancer after HT Curative 62 (63.3) by type of surgical treatment (p < 0.001). Radiotherapyc 13 (13.7) Chemotherapyc 32 (33.7) Response to treatmentd 87 Complete 50 (57.5) Partial 17 (19.5) et al. [8] described no significant differences in relation to the None 20 (23.0) incidence of CRC among the United States (US) HT and general Aciclovir or Ganciclovir 2 (1.7) populations. A possible explanation could be that the reference a Out of 107 patients for whom relevant data were available. population considered in this US study might have been b Out of 98 patients for whom relevant data were available. unsuitable for their HT cohort. c Out of 95 patients for whom relevant data were available. d Out of 87 patients for whom relevant data were available. Potential Risk Factors Associated With Incidence Comparison With a Reference Colorectal Cancer Population Risk factors, such as obesity or smoking, have been associated Furthermore, the data reported in most studies are incidence rates with the development of CRC in the general population [24, 25], that are not normalized to the general population. The SPHTTR yet no statistically significant differences were observed in our data analyzed in our study showed an increased incidence of CRC analysis. Moreover, in spite of the fact that in our study the in patients undergoing HT compared to GLOBOCAN proportions of smokers and obese patients were lower than those 2018 estimates for the general population in Spain. This of non-smokers and non-obese patients, respectively, the risk of difference was maintained in successive age-at-diagnosis CRC was still higher. These findings, together, suggest that the groups and age-standardized overall rates, except for the increased incidence is not due to these modifiable factors. subgroup of men over 75 for whom although a rising trend Conversely, as was expected, even though the subgroup with a was observed it was not statistically significant. In addition, the background of CRC pre-HT was quite small, the likelihood of this incidence of CRC has been increasing over the past few years, developing CRC after HT was eight times greater. being at present the commonest tumor in Spain [11]. Therefore, The association between immunosuppression and increased to compare our cohort, which includes patients since 1984, to a risk of neoplasia is well known. However, it is difficult to identify general population obtained from GLOBOCAN 2018 might seem which immunosuppressive regimens are associated with an conservative but, nevertheless, the incidence post-HT was found increased risk of cancers. No statistically significant differences to be higher than in the general population. Despite GLOBOCAN were observed related to HT era or immunosuppressive agents in estimates that may possibly lead to an error owing to finite our study. Given a lack of information in the literature on the sampling, the aforementioned point, together with observed effect of immunosuppression specifically on CRC after HT, we differences, suggest a greater risk of CRC after HT, which can only compare such data with outcomes of malignancy in adds consistency to our results. Jäämaa-Holmberg et al. [23] more general subgroups such as patients with noncutaneous solid recently assessed cancer incidence and mortality in Finnish HT tumors. In this subgroup, in terms of induction therapy, recipients, both being markedly increased after HT, in OKT3 and anti-thymocyte globulin have been associated with comparison to the general Finnish population. Regarding an increase in cancers [5], whereas in the Youn et al. analysis [4], CRC, they reached similar conclusions, observing that the mycophenolate mofetil, which is known to have anti-proliferative incidence of colon cancer was 3.5–4 times higher than in the properties and prevent tumor dissemination by inhibiting general Finnish population, although no rectal cancer was endothelial cell proliferation and angiogenesis [25], showed a registered in their post-HT records. In contrast, Kellerman protective effect compared to azathioprine. Transplant International | Published by Frontiers 6 May 2023 | Volume 36 | Article 11042 Sagastagoitia-Fornie et al. Colorectal Cancer After Heart Transplantation Colorectal Cancer Characteristics After diagnosis and treatment since this improves health outcomes, Heart Transplantation particularly after a recent recommendation to move the age at Regarding the characterization of post-HT colorectal cancer, which to start screening for colorectal cancer in the general consistent with CRC in general, the main histopathological type population forward from 50 to 45 years [29]. was adenocarcinoma. Furthermore, in our HT cohort most CRC cases were not metastatic at diagnosis, possibly due the close follow-up HT patients undergo, even though recommendations DATA AVAILABILITY STATEMENT regarding CRC screening in HT recipients do not differ from those of the general population [26], which in Spain consists in fecal The raw data supporting the conclusion of this article will be occult blood test beginning at age 50, followed by endoscopic study made available by the authors, without undue reservation. if positive. However, even though only 11.2% of cases were metastatic at diagnosis, surprisingly almost 25% were not considered operable. We do not know if that decision was due ETHICS STATEMENT to high surgical risk or another reason. Curative surgery was performed in 63% of cases, increasing the probability of survival. The studies involving human participants were reviewed and approved by Comité de Ética de la investigación de A Limitations Coruña—Ferrol. The patients/participants provided their The limitations of our study ought to be taken into account when written informed consent to participate in this study. interpreting the reported results. First, the study was retrospective. Second, because no Spanish national cancer registry existed, the incidence of CRC in the general population was obtained from AUTHOR CONTRIBUTIONS GLOBOCAN 2018 estimates. However, as CRC incidence is increasing, comparing our data related to HT since 1984 to a MS-F and MGC-L conceived of the presented idea. JM verified 2018 reference population might underestimate the difference in the analytical methods. All authors were involved in the data incidences between both cohorts, strengthening our results. Third, collection, discussed the results and contributed to the final the SPHTTR may have been missing some tumors because, while manuscript. we do assure that every cancer included in our records is verified, some cases might not have been detected if diagnosed in a referral center where neither the patient nor their physician informed their FUNDING corresponding transplant unit. Nevertheless, this would again underestimate the incidence of CRC in our HT population and, This work was co-financed with FEDER funds from CIBERCV, therefore, strengthen our results. Finally, although all Spanish Instituto de Salud Carlos III, and from funds from the University hospitals performing HT in adults continually update data in of A Coruña. the SPHTTR, it does not contain information that might have been of interest to analyze, such as CRC location (right or left sided), TNM staging, more specific details related to treatment, the CONFLICT OF INTEREST implementation or not of CRC screening tests (fecal occult blood test or colonoscopy) in pre-HT protocols, and the use of statins The authors declare that the research was conducted in the [27] and aspirin [28] since some studies suggest these drugs might absence of any commercial or financial relationships that have a protective effect against CRC. could be construed as a potential conflict of interest. Conclusion We conclude that the incidence of CRC among HT patients is ACKNOWLEDGMENTS greater than in the general population in our country, increasing with age at HT. Curative surgery increased the probability of We are grateful to the researchers and staff of all the Spanish heart survival compared to palliative surgery or that of inoperable transplant centers that contributed data to this study; to the patients. This suggests that a post-cardiac transplant follow-up SPHTTR’s coordinator; and to Déborah Otero (ODDS, S.L.) for might require specific screening for this cancer to achieve early statistical analysis, tables and figures. 3. Engels EA, Pfeiffer RM, Fraumeni JF, Jr., Kasiske BL, Israni AK, Snyder JJ, et al. REFERENCES Spectrum of Cancer Risk Among US Solid Organ Transplant Recipients. JAMA (2011) 306(17):1891–901. doi:10.1001/jama.2011.1592 1. Dantal J, Soulillou JP. Immunosuppressive Drugs and the Risk of Cancer after 4. Youn JC, Stehlik J, Wilk AR, Cherikh W, Kim IC, Park GH, et al. Temporal Organ Transplantation. N Engl J Med (2005) 352(13):1371–3. doi:10.1056/ Trends of De Novo Malignancy Development after Heart Transplantation. 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The use, distribution or reproduction in other forums is permitted, Panamericana de la salud (OPS-OMS). Colombia: Universidad CES (2016). provided the original author(s) and the copyright owner(s) are credited and that the 19. Fay MP, Feuer EJ. Confidence Intervals for Directly Standardized Rates: a original publication in this journal is cited, in accordance with accepted academic Method Based on the Gamma Distribution. Stat Med (1997) 16(7):791–801. practice. No use, distribution or reproduction is permitted which does not comply doi:10.1002/(sici)1097-0258(19970415)16:7<791:aid-sim500>3.0.co;2-# with these terms. Transplant International | Published by Frontiers 8 May 2023 | Volume 36 | Article 11042