European Journal of Cancer (2012) xxx, xxx– xxx

A v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m

jour na l homepage : www.e jcancer . in fo

Risk of de novo cancers after transplantation: Results from acohort of 7217 kidney transplant recipients, Italy 1997–2009

Pierluca Piselli a,⇑,r, Diego Serraino b,r, Giuseppe Paolo Segoloni c, Silvio Sandrini d,Gian Benedetto Piredda e, Maria Piera Scolari f, Paolo Rigotti g, Ghil Busnach h,Piergiorgio Messa i, Donato Donati j, Francesco Paolo Schena k, Maria Cristina Maresca l,Giuseppe Tisone m, Massimiliano Veroux n, Vito Sparacino o, Francesco Pisani p,Franco Citterio q, The Immunosuppression and Cancer Study Group s

a Department of Epidemiology, INMI “L. Spallanzani”, Rome, Italyb S.O.C. Epidemiology and Biostatistics, IRCCS Centro di Riferimento Oncologico, Aviano, Italyc S.C. Nefrologia-Dialisi-Trapianto, AOU “S. Giovanni Battista”, Torino, Italyd Rheumatology and Clinical Immunology, and Nephrology, Spedali Civili, Brescia, Italye Department of Renal Pathology, Azienda Ospedaliera G. Brotzu, Cagliari, Italyf Nephrology, Dialysis, Renal Transplantation Unit, S. Orsola University Hospital, Bologna, Italyg Kidney and Pancreas Transplantation Unit, Department of Surgery and Organ Transplantation, University of Padua, Padua, Italyh S.C. Nefrologia, Niguarda Ca’ Granda Hospital, Milano, Italyi General Surgery and Kidney Transplantation Unit, Policlinico University Hospital IRCCS, Milan, Italyj Renal Transplant Unit, Azienda Ospedaliera Ospedale di Circolo, Varese, Italyk Renal, Dialysis and Transplant Unit, University of Bari, Policlinico, Bari, Italyl Treviso Transplant Centre, Treviso General Hospital, Treviso, Italym Transplant Unit, Surgical Clinic, Department of Surgery, Tor Vergata University of Rome, S Eugenio Hospital, Rome, Italyn Department of Surgery, Transplantation and Advanced Technologies, University Hospital of Catania, Italyo Renal Unit, Leonardo Sciascia Kidney Transplantation Center, Civic Hospital, Palermo, Italyp Renal Failure and Transplant Surgery, University of L’Aquila, L’Aquila, Italyq Department of Surgical Science, Renal Transplant Unit, Catholic University, Rome, Italy

0959-8049/$ - see front matter � 2012 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.ejca.2012.09.013

⇑ Corresponding author: Address: Dipartimento di Epidemiologia e Ricerca Pre-Clinica, Istituto Nazionale per le Malattie Infettive “L.Spallanzani”, Via Portuense, 292, 00149 Rome, Italy. Tel.: +39 06 55170900; fax: +39 06 5582825.

E-mail address: pierluca.piselli@inmi.it (P. Piselli).r These authors have equally contributed to the paper.s Other members of the Immunosuppression and Cancer Study Group: Antonio Famulari, Federica Delreno (Renal Failure and Transplant

Surgery, University of L’Aquila, L’Aquila); Giuseppe Grandaliano, Marco Fiorentino (Policlinico di Bari); Sergio Stefoni, Paola Todeschini,Laura Panicali, Chiara Valentini (“S. Orsola-Malpighi” Hospital, Bologna); Francesca Valerio, Nicola Bossini, Gisella Setti (Spedali Civili ofBrescia); Maria Benigna Michittu, Maria Gavina Murgia, Bruno Onano (“Brotzu” Hospital, Cagliari); Pierfrancesco Veroux, Giuseppe Giuffrida,Alessia Giaquinta, Domenico Zerbo (Policlinco, Catania); Laura Di Leo, Maria Luisa Perrino, Valeriana Colombo, Maria Chiara Sghirlanzoni(“Niguarda Ca’ Granda” Hospital, Milan); Antonio Leoni (“Maggiore-Mangiagalli“ Hospital, Milan); Barbara Buscemi (Policlinico of Palermo);Manuela Lazzarin, Stefano Zanini (Policlinico of Padua); Gionata Spagnoletti, Maria Paola Salerno, Evaldo Favi (Policlinico “A. Gemelli”,Rome); Linda De Luca (Policlinico “Tor Vergata” of Rome); Antonio Lavacca (“Molinette” Hospital, Turin); Carmelo Cascone, Bice Virgilio(Treviso Hospital); Fiorella Dossi, Andrea Fontanella, Andrea Ambrosini, Marco Di Cicco (“Ospedale di Circolo”, Varese); Giuseppe MariaEttorre, Lucia Miglioresi (Azienda Ospedaliera San Camillo-Forlanini, Rome); Claudia Cimaglia, Alessandro Agresta, Vincenzo Puro, GiuseppeIppolito (INMI “L. Spallanzani”, Rome); Lucia Fratino, Luigino Dal Maso, Paolo De Paoli (IRCCS Centro di Riferimento Oncologico, Aviano).

Please cite this article in press as: Piselli P. et al.,Risk of de novo cancers after transplantation: Results from a cohort of 7217 kidney transplantrecipients, Italy 1997–2009, Eur J Cancer (2012), http://dx.doi.org/10.1016/j.ejca.2012.09.013

2 P. Piselli et al. / European Journal of Cancer xxx (2012) xxx–xxx

KEYWORDS Abstract To assess incidence and risk factors for de novo cancers (DNCs) after kidney trans-

Pre

Organ transplantationIatrogenic immunosup-pressionViral infectionsCancer risk

lease cite this article in presscipients, Italy 1997–2009, Eu

as: Pisellr J Canc

plant (KT), we carried out a cohort investigation in 15 Italian KT centres.Seven thousand two-hundred seventeen KT recipients (64.2% men), transplanted between1997 and 2007 and followed-up until 2009, represented the study group. Person years (PY)were computed from 30 days after transplant to cancer diagnosis, death, return to dialysisor to study closure. The number of observed DNCs was compared to that expected in the gen-eral population of Italy through standardised incidence ratios (SIR) and 95% confidence inter-vals (CI). To identify risk factors, incidence rate ratios (IRR) were computed.Three-hundred ninety five DNCs were diagnosed during 39.598 PYs, with Kaposi’s sarcoma(KS), post-transplant lymphoproliferative disorders (PTLD), particularly non-Hodgkin’ lym-phoma (NHL), lung, kidney and prostate as the most common types. The overall IR was 9.98/1.000 PY, with a 1.7-fold augmented SIR (95% CI: 1.6-1.9). SIRs were particularly elevatedfor KS (135), lip (9.4), kidney carcinoma (4.9), NHL (4.5) and mesothelioma (4.2). KT recip-ients born in Southern Italy were at reduced risk of kidney cancer and solid tumors, though ata higher KS risk, than those born in Northern Italy. Use of mTOR inhibitors (mTORi)exerted, for all cancers combined, a 46% significantly reduced risk (95% CI: 0.4–0.7).Our study findings confirmed, in Italy, the increased risks for cancer following KT, and theyalso suggested a possible protective effect of mTORi in reducing the frequency of post trans-plant cancers.� 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Kidney transplantation (KT) is an increasingly usedmedical procedure for treating End-Stage Renal Dis-eases (ESRD) in industrialised countries. In Italy, theoverall number of organ transplants increased 1.6 foldbetween 1992 (with 1083 transplants carried out) and2010 (2876 transplants).1 This increase is largely due tothe high success rate of renal transplantation in the lasttwo decades. The introduction of highly active immuno-suppressive drugs strongly contributed to lower acuterejection rates and to increased organ and patient sur-vival rates.2

A large body of evidence, however, indicates that thechronic use of immunosuppressive drugs is associatedwith increased risks of opportunistic diseases, particu-larly cancers.3–6 After 10 years of immunosuppression,KT recipients have a cumulative incidence of cancer ashigh as 20%.7 As compared to the age- and sex- matchedgeneral population, a 3-to-5-fold increased risk was doc-umented, among KT recipients, for skin cancers andurological malignancies, while for some virus-relatedcancers such as non-Hodgkin lymphomas (NHL) orKaposi sarcoma (KS) the risk was up to 100-foldhigher.4,8,9 Several large scale studies on the spectrumof de novo cancers (DNCs) following organ transplanta-tion were carried out in the United States,3,6 Canada,10

Japan,11 Australia and New Zealand,4,5,7 and NorthernEurope.12,13 Conversely, relatively few investigationswere conducted in Southern Europe on the cancer riskof KT recipients, as compared to the corresponding gen-eral population.9,14

A multicentre study was thus carried out among KTtransplant recipients in Italy to assess the spectrum of

i P. et al.,Risk of de novo cancers aer (2012), http://dx.doi.org/10.1016

DNCs. Specific aims were to quantify the potentiallyincreased risks, as compared to the general population,and to identify risk factors associated with cancerdevelopment.

2. Methods

This retrospective cohort study used clinical and epi-demiological information collected among 8210 individ-uals who, between 1997 and 2007, underwent KT in 15centres from northern, central and southern Italy. Atotal of 993 KT recipients (12.0%) were excluded fromthe analysis due to the presence of one of the followingconditions: a previous transplant received before 1997(n = 688); a cancer diagnosis within the five years pre-ceding the transplant (n = 40); a DNC diagnosed within30 days after KT (n = 3); a follow-up shorter than30 days after KT (n = 223) and age at KT transplantbelow 18 years (n = 39).

The final cohort consisted of 7217 KT recipients(64.2% men) – who received 7299 organs. In each ofthe 15 participating centres, trained staff retrieved perti-nent information from clinical charts and performed anaudit for accuracy and consistency. The follow-up,including vital status, was updated to December 31st,2009. Data were thereafter transposed in a standardisedquestionnaire which included personal information suchas age at transplant, sex, area of origin and residence, aswell as transplant information, i.e. date of KT, trans-plant centre, cause of ESRD, donor status, use of calci-neurin inhibitors (CI), use of mTOR inhibitors (mTORi)and length of follow-up. Thereafter, data were enteredin an electronic database for the purposes of statisticalanalysis.

fter transplantation: Results from a cohort of 7217 kidney transplant/j.ejca.2012.09.013

Table 1Baseline characteristics of 7217 kidney transplant recipients understudy. Italy, 1997–2009.

Characteristics N (%)

SexMales 4633 (64.2)Females 2584 (35.8)

Age at transplant (years)639 2017 (28.0)40–49 1774 (24.6)50–59 2277 (31.6)P60 1149 (15.9)

Area of originNorthern Italy 2922 (40.5)Central Italy 785 (10.9)Southern Italy 3160 (43.8)Abroad 350 (4.9)

Cause of end-stage renal diseaseGlomerulonephritis 2868 (39.7)Diabetes mellitus 242 (3.4)Pyelonephritis/interstitial nephritis 690 (9.6)Adult polycystic kidney disease 1116 (15.5)Genetic, other 238 (3.3)Malignancy 13 (0.2)Uncertain 1116 (15.5)Other 934 (12.9)

Year at transplant1997–2000 2165 (30.0)2001–2004 2992 (41.5)2005–2007 2060 (28.5)

Status of the donorDeceased 6659 (92.3)Living 558 (7.7)

Follow-up: person years (PYs)Total 39598.3

P. Piselli et al. / European Journal of Cancer xxx (2012) xxx–xxx 3

Person-years (PYs) at risk for cancer were computedfrom 30 days following KT to date of the last follow-upvisit, date of death, date of cancer diagnosis, date ofreturn to dialysis or the end date of the study (December31st, 2009), whichever came first.

Cancer diagnoses were recorded during follow-up vis-its (scheduled at least once a year in the transplant cen-tre or in the follow-up clinic), histologically confirmedand coded according to the International Classification

of Diseases and Related Health Problems, 10th revision(ICD-10). Cancer incidence rates were calculated usingthe Kaplan–Meier product-limit method.15

The number of observed incident cancer cases in KTrecipients was compared to that expected, which wascomputed from sex-, age-, area of residence- and per-iod-specific incidence rates in the Italian general popula-tion. These rates derived from all Italian cancerregistries, as published in Cancer Incidence in Five Con-

tinents, vol. VII (for the period up to 1992), vol. VIII(1993–1997) and vol. IX (from 1998 thereafter).16 Stand-ardised incidence ratios (SIRs) were computed dividingthe number of observed cases by the number of theexpected. SIRs and 95% confidence intervals (CIs) weredetermined using the Poisson distribution.15

Incidence rate ratios (IRRs) and 95% CIs – adjustedfor age, sex, year of transplant and time since transplan-tation – were computed to assess the associationbetween these characteristics and cancer risk using Pois-son regression analysis.15

All statistical analyses were performed using commer-cially available software (SPSS version 19, SPSS Inc.,Chicago, Illinois; and STATA version 11, StataCorpLP, College Station, Texas).

Length of follow-up (years)Median (IQR) 5.2 (2.9–7.8)

IQR = interquartile range.

Fig. 1. Cumulative incidence of de novo malignancies after kidneytransplant, according to cancer type and time since transplant. Italy,1997–2009.

3. Results

The 7217 KT recipients included in this analysis werefollowed-up for a total of 39,598 PYs, with a medianduration of follow-up of 5.2 years (Table 1). The major-ity were men (64.2%), aged less than 60 years (84.1%)and were transplanted upon in 2001 or later (70.0%).The vast majority received a kidney from a deceaseddonor (92.3%) (Table 1). Glomerulonephritis (reportedin 39.7%) and adult polycystic kidney disease (15.5%)were the two most common causes of ESRD leadingto transplant (Table 1).

During the period of observation, 395 cancers werediagnosed in 382 KT recipients (i.e. 5.3% of the studypopulation). Fig. 1 illustrates the cumulative risk of can-cer following KT. For all cancers and for solid tumours,the risk steadily increased with time after transplant. Itwas 4.8% after 5 years and 9.9% after 10 years for allcancers, and 3.1% and 7.2% for solid tumors. Con-versely, the incidence of KS showed a rapid rise in thefirst two years following transplant (1% at 2 years), lev-eling off thereafter (it was 1.2% at 10 years of follow-up).

Please cite this article in press as: Piselli P. et al.,Risk of de novo cancers after transplantation: Results from a cohort of 7217 kidney transplantrecipients, Italy 1997–2009, Eur J Cancer (2012), http://dx.doi.org/10.1016/j.ejca.2012.09.013

4 P. Piselli et al. / European Journal of Cancer xxx (2012) xxx–xxx

As compared to other cancer types, the risk of PTLDwas the lowest up to 9 years after transplant, when itreached the risk of developing KS (1.2% cumulativeincidence).

Fig. 2 compares, for all cancer types, incidence ratesobserved in KT with those expected in the correspond-ing general population of Italy. In male KT recipients,cancer rates steadily increased from 399.3/105 PYs,among those under 30 years of age, to 1713.0/105 PYs,in the group aged 65–69 years. Cancer incidence rateswere higher in male KT recipients than in the generalpopulation up to 60–64 years of age, with the differenceinversely related to ageing. A similar pattern wasrecorded among female KT recipients, though the differ-ence was less pronounced, with a tendency towardsequivalence starting at around 50 years of age (Fig. 2).

Three-hundred ninety five cases of DNCs wereobserved, as compared to 227.5 expected ones (Table2). This difference was statistically significant, with anoverall 1.7-fold elevated cancer risk in KT recipients(SIR = 1.7, 95% CI: 1.6–1.9) as compared to the generalpopulation of Italy. Particularly elevated SIRs werenoted for KS (135), NHL (4.5) and other haematologiccancers (2.8, overall). Regarding solid tumors, the typesfor which statistically significant SIRs were noticedincluded: lip cancer (SIR = 9.4); salivary gland carcino-mas (SIR = 5.8); carcinoma of the kidney (SIR = 4.9);mesothelioma (4.2); testis (4.1) and prostate cancers(1.7). A borderline statistically significant elevated riskof 10% (SIR = 1.1, 95% CI: 1.0–1.2) emerged for allsolid tumors combined (Table 2).

Fig. 2. Age-specific incidence rates for de novo malignancies observed in ksex. Italy, 1997–2009.

Please cite this article in press as: Piselli P. et al.,Risk of de novo cancers arecipients, Italy 1997–2009, Eur J Cancer (2012), http://dx.doi.org/10.1016

When SIRs were computed separately for men andwomen, few differences emerged in the two sexes. SIRfor KS was 101 in men and 439 in women, for lip theSIR was 7.9 in men and 42.9 in women (based on oneobserved case) while for melanoma the SIR was 2.3 inmen and 1.0 in women (Fig. 3).

Factors significantly affecting the overall risk ofdeveloping cancer in KT recipients were sex (womenwere at a nearly 30% lower risk than men), increasingage, time since transplantation (the risk diminished overtime), and use of mTORi. KT recipients ever treatedwith mTORi had a 46% reduction in cancer risk withrespect to those who never underwent anti-rejectiontreatment with mTORi (Table 3).

Some peculiar findings emerged when the analysis ofdeterminants of cancer risk was stratified for selectedcancer types. The risk of KS was strongly reduced after2 years of follow-up, and it was higher in KT recipientsborn in Southern Italy (IRR = 2.8, as compared tothose born in Northern Italy). For all solid tumors com-bined, women were at lower risk than men, ageingexerted a strong positive effect, and a follow-up longerthan two years was associated with a nearly 40%increased risk. Conversely, KT recipients from SouthernItaly showed a 30% to 40% reduction in the risk for allsolid tumors combined as compared to those fromNorthern Italy (Table 3) – the risk reduction was 60%for kidney cancer (data not shown).

KT recipients treated with mTORi were at a signifi-cantly decreased risk for KS (IRR = 0.5) and overallsolid tumors (IRR = 0.6, 95% CI: 0.4–0.9). Moreover,

idney transplant recipients and in the general population, according to

fter transplantation: Results from a cohort of 7217 kidney transplant/j.ejca.2012.09.013

Table 2Numbers of observed (Obs) and expected (Exp) cases of de novo malignancies in kidney transplant recipients, corresponding standardised incidenceratios (SIR), and 95% confidence intervals (CI). Italy, 1997–2009.

Type/site ICD-10 Obs No. Exp No. SIR (95% CI) p-Value

Kaposi’s sarcoma C46 74 0.5 135 (106–169) <0.001Post-transplant lymphoproliferative diseases (PTLD)

Alla 52 18.3 2.8 (2.1–3.7) <0.001NHL C82–C85, C96 40 8.9 4.5 (3.2–6.1) <0.001Leukaemia, all types C91–C95 8 5.2 1.6 (0.7–3.1) 0.30Hodgkin’s lymphoma C81 3 1.3 2.3 (0.5–6.8) 0.28

Solid tumoursAll 269 248.4 1.1 (1.0–1.2) 0.20Lung & trachea C33–C34 36 31.9 1.1 (0.8–1.6) 0.52Kidney C64 36 7.4 4.9 (3.4–6.8) <0.001Prostate C61 35 21.0 1.7 (1.2–2.3) <0.01Breast female C50 22 27.5 0.8 (0.5–1.2) 0.29Colon-rectum C18–C20 21 27.2 0.8 (0.5–1.2) 0.27Bladder C67 20 18.1 1.1 (0.7–1.7) 0.71Stomach C16 14 10.2 1.4 (0.8–2.3) 0.30Melanoma C43 11 6.0 1.8 (0.9–3.3) 0.08Thyroid C73 9 4.8 1.9 (0.9–3.6) 0.11Oral cavity C01–C10 8 5.0 1.6 (0.7–3.0) 0.20Utherus (Corpus) C54–C55 6 4.5 1.3 (0.5–2.9) 0.59Pancreas C25 5 5.8 0.9 (0.3–2.0) 0.97Lip C00 5 0.5 9.4 (3.1–22.0) <0.001Mesothelioma C38, C45 5 1.2 4.2 (1.4–9.8) <0.05Testis C62 5 1.2 4.1 (1.3–9.6) <0.05Liver C22 4 9.4 0.4 (0.1–1.1) 0.09Central nervous system C70–C72 4 4.3 0.9 (0.3–2.4) 0.85Salivary gland C07–C08 3 0.5 5.8 (1.2–16.9) <0.05Oesophagus C15 3 2.5 1.2 (0.3–3.6) 0.88Larynx C32 3 5.9 0.5 (0.1–1.5) 0.33Ovary C56 3 2.9 1.1 (0.2–3.1) 0.92Othersb 14 12.5 1.1 (0.6–1.9) 0.75

Total* 395 227.5 1.7 (1.6–1.9) <0.001

ICD-10: International Classification of Diseases tenth revision.* Non melanoma skin cancers are excluded from these analyses.

a It includes one case of multiple myeloma.b It includes: invasive cervical cancers (2), small intestine (2), anus (1), breast-male (1), conjunctiva (1), connective and soft tissue (1), gallbladder

(1), spermatic cord (1), hypopharynx (1), undetermined (3).

P. Piselli et al. / European Journal of Cancer xxx (2012) xxx–xxx 5

the risk reduction was of borderline statistical signifi-cance for NHL (IRR = 0.3, 95% CI: 0.1–1.1) (Table 3).

4. Discussion

This epidemiological investigation allowed the updateof our previous estimates9,17 on the spectrum of cancersamong KT recipients in Italy. About 10% of KT recip-ients developed cancer after 10 years of immunosuppres-sion with an overall 1.7-fold higher risk than in thecorresponding general population. The magnitude ofthis overall excess risk was somewhat lower than previ-ously reported in transplant patients from the UnitedStates, Australia, Japan and Northern Europe,3,4,6,11,12

but it was comparable when non-melanoma skin cancerswere excluded from analyses.

The spectrum of cancers that turned out to beelevated in this cohort of Italian KT recipients wasconsistent with those recently documented, by large

Please cite this article in press as: Piselli P. et al.,Risk of de novo cancers arecipients, Italy 1997–2009, Eur J Cancer (2012), http://dx.doi.org/10.1016

population-based studies, in the United States3 and Aus-tralia.4 However, for some sites known to be at elevatedfrequency in transplant recipients, the augmented SIRswere of borderline statistical significance because ofthe small number of observed cases (e.g. thyroid, mela-noma). For few other sites, including lung, liver, pros-tate and mesothelioma the SIRs were inconsistent withthe ones we previously documented in Italy,17 or withother international studies.4–6 Smoking is poorly associ-ated with ESRD leading to KT, and a lack of associa-tion between KT and lung cancer was already reportedby us.17 A detailed pre-transplant screening for severediseases is now ongoing, in Italy, among KT candidates,a procedure that may help limiting cancer occurrence inhigh-risk transplant candidates. For instance, KT candi-dates with severe liver diseases (e.g. cirrhosis) areexcluded from transplants, thus reducing the frequencyof KT recipients at higher risk of liver cancer. Moreover,the newly introduced powerful antiviral treatments have

fter transplantation: Results from a cohort of 7217 kidney transplant/j.ejca.2012.09.013

Fig. 3. Standardised incidence ratios (SIR) and 95% confidence intervals (CI) for most common de novo malignancies, according to sex. Italy,1997–2009.

6 P. Piselli et al. / European Journal of Cancer xxx (2012) xxx–xxx

contributed, in the last decade, to reduce the clinicalprogression of infection with HBV or HCV.18 Lack ofliver cancer risk in KT recipients was recently noted inthe United States;3 an observation worth stressing inview of the potential contribution in prolonging the sur-vival of KT recipients.

We found a statistically significant 4-fold increasedSIR for mesothelioma, a site for which previous findingswere inconsistent.3,4 The elevated frequency of mesothe-lioma could be due, in this cohort of KT recipients, to ahigh prevalence of individuals occupationally exposed toasbestos. However, detailed information on occupa-tional exposures of study subjects was not available,and this hypothesis could not be verified. It is alsoknown that an undefined proportion of mesotheliomaoccurring in individuals not exposed to asbestos maybe attributed to infection with the simian polyomavirusSV40, a strong carcinogen for pleural cancer in experi-mental animals.19 Accordingly, an investigation con-ducted in an Italian hyper endemic area formesothelioma showed the presence of viral sequencesof SV40 in cancer tissue, supporting a potential rolefor this infection.20 This observation warrants furtherinvestigation specifically among immunosuppressedindividuals, a setting in which our knowledge on the

Please cite this article in press as: Piselli P. et al.,Risk of de novo cancers arecipients, Italy 1997–2009, Eur J Cancer (2012), http://dx.doi.org/10.1016

relationship between infection and cancer has greatlyimproved in the last two decades.

With regard to solid tumors, strong statistically sig-nificant SIRs were noted for lip cancer (SIR = 9.4), car-cinomas of the salivary glands (SIR = 5.8), kidney(SIR = 4.9) and testicular (4.1) carcinoma; the increasedrisk for kidney cancer was mainly due to cancers local-ised in the native kidney (31 out of 36 new cases). Theassociation of acquired immune depression and theoccurrence of these cancers is not a novelty, since ithas already been observed among HIV infected individ-uals and/or recipients of organ transplants.3,6,9,17

As expected, virus-related cancers were strongly asso-ciated with elevated oncologic risks. Involved sitesincluded KS (SIR = 135), associated with Kaposi herpesvirus type 8 (KSHV) infection, NHL (SIR = 4.5), asso-ciated with infection with the Epstein-Barr virus (EBV),lip cancer (SIR = 9.4) and salivary glands (SIR = 5.8)associated with human papilloma virus infection(HPV).2,4

The very high risk quantified for KS, particularly inwomen (i.e. 439), is peculiar of studies performed inthe Mediterranean area or in Middle East Countries,where KS often represents the largest group of DNCs(up to 70% of all malignancies).7,21,22 The frequency of

fter transplantation: Results from a cohort of 7217 kidney transplant/j.ejca.2012.09.013

Table 3Incidence rate ratio (IRR) and 95% confidence intervals (CI) for de novo malignancies (excluding non-melanoma skin cancers) among kidneytransplant recipients (adjusted for sex, age and calendar year at transplant). Italy, 1997–2009.

Total Kaposi NHL SolidIRR (95% CI) IRR (95% CI) IRR (95% CI) IRR (95% CI)

SexMen 1 1 1 1Women 0.7 (0.6–0.9)a 0.9 (0.5–1.4) 0.6 (0.3–1.2) 0.7 (0.5–0.9)a

Age (years)<40 1 1 1 140–59 2.5 (1.8–3.7)a 3.6 (1.4–9.2)a 0.7 (0.3–1.5) 3.9 (2.2–6.8)a

60+ 4.9 (3.4–7.2)a 5.0 (1.9–13.0)a 0.9 (0.4–2.2) 8.8 (5.0–15.2)a

Calendar year at transplantation1997–2000 1 1 1 12001–2004 0.9 (0.8–1.2) 0.9 (0.6–1.5) 0.5 (0.2–1.0)a 1.0 (0.8–1.3)2005–2007 1.2 (0.9–1.6) 1.5 (0.8–2.7) 0.5 (0.2–1.5) 1.4 (1.0–1.9)b

Length of follow-up (years)<2 1 1 1 12+ 0.8 (0.6–1.0)a 0.1 (0.1–0.2)a 0.6 (0.3–1.1) 1.4 (1.1–1.9)a

Status of the donorDeceased 1 1 1 1Living 0.6 (0.4–1.0)b 0.4 (0.1–1.7) 1.1 (0.4–3.0) 0.6 (0.3–1.1)

Area of origin (Italy)North 1 1 1 1Centre 0.9 (0.6–1.3) 0.2 (0.0–1.6) 0.2 (0.0–1.5) 1.1 (0.8–1.6)South 0.9 (0.7–1.1) 2.8 (1.6–4.9)a 0.8 (0.4–1.6) 0.6 (0.5–0.8)a

Abroad 1.0 (0.6–1.8) 2.8 (1.0–8.2)b 1.6 (0.5–5.6) 0.6 (0.3–1.4)

Area of residence (Italy)North 1 1 1 1Centre 0.7 (0.5–1.0)b 0.6 (0.2–1.6) 0.3 (0.1–1.4) 0.8 (0.6–1.2)South 0.9 (0.7–1.2) 2.2 (1.3–3.6)a 0.6 (0.3–1.3) 0.7 (0.5–0.9)a

Ever use of Calcineurin Inhibitors (CI)No 1 1 1 1Yes 1.1 (0.6–2.0) 1.6 (0.4–6.4) 1.0 (0.1–7.3) 1.0 (0.5–2.0)

Ever use of mTOR inhibitors (mTORi)No 1 1 1 1Yes 0.5 (0.4–0.7)a 0.5 (0.2–0.9)a 0.3 (0.1–1.1)b 0.6 (0.4–0.9)a

a p < 0.05.b p < 0.10.

P. Piselli et al. / European Journal of Cancer xxx (2012) xxx–xxx 7

KS reflects the prevalence of infection with KSHV9 (awell-known aetiologic agent)23 – which ranges between5% in North America, Northern Europe and Asia, to30% in some Mediterranean Countries and regions(e.g. Southern Italy) and the Middle East, and to 50%in Central and Southern Africa.24 In this study, the riskof KS was about 3-fold higher in KT recipients born inSouthern Italy, where the prevalence of KSHV is amongthe highest in the Mediterranean area.24 Altogether,these observations confirm the importance of pre-trans-plant KSHV testing, at least in KT recipients born inareas with high prevalence rates of KSHV infection.

Apart from cancers associated with viral infections,which are more diffuse in southern than in northernItaly (e.g. KSHV and HCV), incidence rates for cancerare generally lower in the general population of theSouth of Italy than that of the North.25 This geographicgradient -attributable to a lower exposure to main risk

Please cite this article in press as: Piselli P. et al.,Risk of de novo cancers arecipients, Italy 1997–2009, Eur J Cancer (2012), http://dx.doi.org/10.1016

factors (e.g. smoking, alcohol, occupation) in the Southof Italy- is likely to explain the geographic differenceseen in the relative risk for cancer herein reported.

Although this study was not designed to assess theefficacy of anti rejection drugs in terms of adverse out-comes, we observed that KT recipients ever treated withmTORi had a nearly 45% reduction in the overall cancerrisk. The use of mTORi has already been associatedwith a reduced risk of KS, and reports from Campistolet al.26 and from Stallone et al.27 have shown that treat-ment with mTORi can control KS evolution. All thesedata suggest that immunosuppression protocols includ-ing mTORi could be useful at least in KT recipients athigh risk of KS development. Our study suggests thatthe use of mTORi may reduce the overall risk also forsolid cancers in KT recipients, as recently shown in theCONVERT trial.28 Furthermore, recent clinical reportshighlighted a positive effect of Everolimus in improving

fter transplantation: Results from a cohort of 7217 kidney transplant/j.ejca.2012.09.013

8 P. Piselli et al. / European Journal of Cancer xxx (2012) xxx–xxx

progression-free survival of women with breast cancer29

or of patients with advanced neuroendocrine tumors.30

Lack of information on cancer risk before transplant,particularly during the dialysis period, represents adrawback of this study, since uncertainty exists as tothe quantification of the increased cancer risk attribut-able to immunosuppression – in contrast with pre-exist-ing risk factors. However, the findings of a study oncancer risk before and after KT indicated that immuno-suppression was by far the reason of an elevated risk fora large spectrum of cancers.4

Although we could not perform a linkage with popu-lation-based cancer registries for all KT recipients, thestrict clinical follow-up of these is likely to ensure thecompleteness of the DNC reporting. However, we cannotexclude that underreporting of DNC has occurred. Otherstudy limitations included lack of information on impor-tant risk factors other than immunosuppression, includ-ing, e.g. smoking, alcohol and the documentation of thepresence of chronic viral infections. These should all beconsidered for an exhaustive interpretation of study find-ings. Several studies conducted in industrialised coun-tries, including northern Europe,3,4,7,12 have alreadyshown that KT recipients are at higher risk of cancer thanage- and sex-matched subjects in the general population.The findings from the present study, however, are origi-nal in Southern Europe for several aspects. These com-prise, among others, the size and the geographicheterogeneity of the cohort, the computation of SIRsbased on population-based cancer incidence rates fromall areas of Italy, the magnitude of risk for KS and thesuggestion of an elevated risk for mesothelioma.

In conclusion, our study confirms, on a large numberof KT recipients living in Italy, the increased risk of can-cers, particularly of those of viral aetiology, and it sug-gests that the use of mTORi could reduce the frequencyof post transplant DNCs.

Conflict of interest statement

None declared.

Acknowledgements

The authors wish to thank Mrs. Luigina Mei for edi-torial assistance. Sources of support: The studies of can-cer in immunosuppressed patients are supported by:Istituto Superiore di Sanita, Programma di Ricerca Naz-ionale sull’AIDS, Grant No. 20D.13, and Centro Nazio-nale Trapianti “Progetto Regione Basilicata”; Ministerodella Sanita, Ricerca Finalizzata and Programma di Ric-erca Corrente IRCCS INMI Spallanzani and IRCCSCentro di Riferimento Oncologico, Aviano; and by anunrestricted grant from Pfizer.

Please cite this article in press as: Piselli P. et al.,Risk of de novo cancers arecipients, Italy 1997–2009, Eur J Cancer (2012), http://dx.doi.org/10.1016

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