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Risk factors associated with post–kidney transplant malignancies: an article from the Cancer-Kidney International Network

Risk factors associated with post–kidney transplant malignancies: an article from the... In kidney transplant recipients, cancer is one of the leading causes of death with a functioning graft beyond the first year of kidney transplantation, and malignancies account for 8–10% of all deaths in the USA (2.6 deaths/1000 patient-years) and exceed 30% of deaths in Australia (5/1000 patient-years) in kidney transplant recipients. Patient-, transplant- and medication-related factors contribute to the increased cancer risk following kidney transplantation. While it is well established that the overall immunosuppressive dose is associated with an increased risk for cancer following transplantation, the contributive effect of different immunosuppressive agents is not well established. In this review we will discuss the different risk factors for malignancies after kidney transplantation. Key words: immunosuppression, kidney transplantation, malignancy, risk factor brain and cervical cancer), others are increased substantially Introduction (lung, colon, liver, lymphoma, melanoma and non-melanoma Malignancy is one of the most common causes of death in kid- skin cancer). Cancer-related mortality rates are also higher in ney transplant recipients [1, 2]. In kidney transplant recipients, kidney transplant recipients compared with the general popu- the incidence of cancer is generally increased 2- to 3-fold com- lation [5]. pared with the general population [3, 4]. This increased cancer Patient-, transplant- and medication-related factors contrib- risk is not spread evenly over all types of cancers; while some ute to the increased cancer risk following kidney transplanta- cancer incidences are not increased (breast, prostate, ovarian, tion. Immunosuppression is considered the most important Received: July 12, 2017. Editorial decision: September 15, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Downloaded from by Ed 'DeepDyve' Gillespie user on 20 June 2018 316 | B. Sprangers et al. risk factor, as it decreases the immunologic control of oncogenic transplant recipients (145 104 cadaveric kidney transplant recip- viral infection and cancer immunosurveillance [4, 6]. Although ients) between 1985 and 2001 were studied [30]. Over the 10- it is accepted that the overall immunosuppressive dose is asso- year observation period, the risk for malignant lymphoma in ciated with the increased cancer risk following transplantation, renal transplant recipients was 11.8-fold higher compared with the contributive effect of different immunosuppressive agents a matched non-transplanted population, and most lymphomas is not well established at this time. Currently available immu- occurred in the first post-transplant year [30]. Recent data sug- nosuppressive agents influence different anticancer pathways gest that from 2005 to 2010, the 5-year incidence of post- and mammalian target of rapamycin (mTOR) inhibitors have transplant lymphoproliferative disease (PTLD) in adult kidney been reported to have a decreased cancer risk compared with transplant recipients has remained stable [31]. There was, how- alternative immunosuppressive therapies. However, recent ever, a substantial decline in PTLD rates for paediatric recipients studies have not been able to demonstrate improved survival in reported in patients transplanted from 2002 to 2012 compared kidney transplant recipients taking mTOR inhibitors. T cell– with those transplanted from 2000 to 2009 [31]. In all groups, depleting agents are very potent immunosuppressive agents PTLD risk was highest in Epstein–Barr virus (EBV)-seronegative used as induction therapy and to treat acute rejection (AR) in recipients [31]. In kidney transplant recipients, there is a slight kidney transplant recipients. While some studies have sug- predilection for the lymphoma to occur in the transplanted kid- gested an association between antibody induction and cancer ney. In addition, central nervous system lymphomas were most after transplantation [7–11], others have failed to demonstrate common after renal transplantation in the CTS [30]. this association [12–15]. On average, the age at diagnosis of post-transplant cancer is 40 years and the time from transplantation is 3–5 years [12, 28, 32]. However, these numbers vary substantially according to the Epidemiology and clinical presentation cancer subtype, with lymphoma and Kaposi sarcoma occurring early after transplantation [30, 33] and epithelial cancers later on Analyses from different registry data estimate the general increase [33, 34]. Although in other types of solid organ transplantation in cancer incidence in kidney transplant recipients to be two- to cancer tends to occur in the transplanted organ, in kidney trans- three-fold compared with the general population [3, 4, 16–25]. plant recipients, kidney cancers almost exclusively occur in the Estimates of cancer incidence obtained from different registries native kidneys [1] and there is a greater incidence of papillary differ widely, suggesting that data quality is problematic. This was type relative to the general population [35]. Acquired cystic kid- confirmed in a recent study by Yanik et al. [26], who compared can- ney disease is common in patients with advanced renal failure cer diagnoses collected in the Scientific Registry of Transplant and is associated with the development of kidney cancer [25, 36]. Recipients (SRTR) database with 15 linked cancer registries for col- In dialysis patients, the risks for thyroid cancer, myeloma and orectal, liver, lung, breast, prostate and kidney cancers, melanoma urinary tract cancers are increased, and this is mirrored in kidney and non-Hodgkin lymphoma (NHL). They concluded that SRTR transplant recipients [25]. This parallel between dialysis patients cancer data were strikingly incomplete, as only 36.8% of cancers and kidney transplant recipients does not hold true for all cancer were both registered in the SRTR database and cancer registries, types, as ovarian and prostate cancer were less frequent in kid- whereas 47.5% of cancers were only documented in cancer regis- ney transplant recipients than in the dialysis cohorts [23]. tries and 15.7% were only documented in the SRTR database [26]. The estimated sensitivity for identifying cancer was only 52.5% for the SRTR and 84.3% for cancer registries [26]. Pathogenesis and transplant-specific risk Data from the USA concerning 175 732 solid organ transplant factors recipients (58.4% kidney transplant recipients) during the period 1987–2008 showed that the standardized incidence ratio (SIR) Several factors have been linked to the increased incidence of for cancer overall was 2.1 (95% CI 2.06–2.14) higher compared malignancies among transplant recipients [6], including age, with the general population, with an excess absolute risk of 719 sun exposure, previous cancer, concomitant viral infection, cancer cases per 100 000 person-years [3]. The majority of the cumulative dose of immunosuppression, type of immunosup- patients included in these studies were kidney transplant recipi- pression, AR and the duration of pre-transplant dialysis (Table 1 ents [27]. It is important to note that this increase is not uniform and Figure 1)[38, 39]. Risk factors for patient death from for all cancer types; some cancers are not increased following cancer include male gender, a history of prior cancer and kidney transplantation, e.g. breast, prostate, ovarian, cervical and immunosuppression and lymphocyte-depleting antibodies [5]. brain cancers [3, 4, 20], and the incidence of breast cancer might even be reduced [3, 28]. In contrast, lymphoma, lung cancer, Donor transmission colon cancer, melanoma and non-melanoma skin cancer and liver cancer are increased 2- to 4-fold. In a study by Engels et al. A variety of donor-transmitted malignancies have been docu- [3], skin cancer was the most common malignancy in solid organ mented, including melanoma and cancers of the lung, breast, transplant recipients, with a SIR for Kaposi sarcoma and non- colon, rectum and kidney, Kaposi sarcoma and glioblastoma melanoma skin cancer of 61.46 and 13.85, respectively. In addi- multiforme. Donor transmission as a cause of post-transplant tion, the SIRs for non-Hodgkin and Hodgkin lymphoma, liver can- malignancy is a rare but dreaded event, as it might result in cer, gastrointestinal cancer and melanoma were also increased metastatic disease in the transplant recipient [40–47]. Reported [3]. In more recent reports from both the Australia and New transmission rates are <0.03%, but these are likely under- Zealand Dialysis and Transplant Registry (ANZDATA) registry reported and underdiagnosed [41, 48, 49]. The most common [29] and European and North American registries [23], excluding transmitted cancer types are renal cancer, lung cancer, mel- non-melanocytic skin cancers, genitourinary tract cancers are anoma and lymphoma [46, 50, 51]. The risk of donor transmis- the most frequent malignancies in renal transplant recipients. sion depends on the type and extent of the original donor In an analysis of the Collaborative Transplant Study (CTS) cancer. A donor history of melanoma, lung carcinoma or chorio- database, the incidence and impact of malignant lymphoma carcinoma seems to be associated with high transmission risk after solid organ transplantation in 195 938 solid organ and death and organs from such donors should not be accepted Downloaded from by Ed 'DeepDyve' Gillespie user on 20 June 2018 Risk factors for post-transplant malignancies | 317 Fig. 1. Cancerogenesis following kidney transplantation (adapted from Riella [37]). Table 1. Risk factor for post-transplant malignancies post–kidney transplant malignancies [54, 55]. With increasing recipient age, this is an important factor in the overall increas- Patient-related risk factors Recipient age ing incidence of post-transplant cancer in kidney transplant Previous cancer recipients. Time on dialysis before transplantation has also Sun exposure been identified as a risk factor for developing post-transplant Viral infection malignancy. In a study based on the ANZDATA database, Wong Duration of dialysis et al. [38] reported a linear relationship between the duration of Transplant-related risk factors Donor transmission dialysis and the risk of solid organ cancer after transplantation, Donor type irrespective of recipient age. In a very interesting article, Yanik Rejection et al. [56] evaluated the incidence of cancer types depending on Medication-related risk factors Net immunosuppression non-renal function interval (time on dialysis either on wait list Induction therapy or after transplant failure) or kidney function interval (time Maintenance therapy with a functioning graft and thus on immunosuppression), applying a linkage between the SRTR and several US cancer registries. While the incidence of infection-related and for transplantation [46]. In contrast, organs from donors with immune-related cancer (Kaposi sarcoma, NHL, lip cancer and renal cell cancer without capsular invasion and central nervous non-epithelial skin cancer) was higher during kidney function system tumours (except medulloblastoma) are acceptable, as intervals, end-stage renal disease (ESRD)-related cancer inci- the risk seems to be low, reflecting the limited metastatic dence (kidney cancer and thyroid cancer) was lower during kid- potential of these tumours [46, 52]. Regarding outcome, early ney function intervals. Every change of status (non-renal donor-transmitted cancer (diagnosed 6 weeks of transplanta- function interval/kidney function interval) was associated with tion) was associated with a better outcome compared with late a changing incidence for NHL, melanoma, lung, pancreatic and donor-transmitted cancer [51]; 5-year survival was 83% for kid- non-epithelial skin cancers (higher during function intervals) ney recipients with donor-transmitted cancer compared with and kidney and thyroid cancers (higher during non-function 93% for recipients without donor-transmitted cancer (P¼ 0.077) intervals), suggesting potent short-term effects of kidney dys- [50, 51]. Recipients with transmitted renal cancers had the best function and immunosuppression on cancer incidence [56]. outcomes, with >70% 2-year survival post-transplantation [50], while patients with melanoma and lung cancers had <50% 2- year survival post-transplantation [50]. Previous cancer Donor type A history of cancer prior to kidney transplantation in the recipi- ent increases the risk of death by 30% [57].These findings were Differences in the type of transplant (living versus deceased) also confirmed in another study showing that kidney transplant have been associated with cancer risk. In a study by Ma et al. recipients with a pre-transplant cancer are 3.7 times more likely [53], the overall risks for cancer were 1080, 1444 and 2018 per to die of cancer post-transplantation [5]. Acuna et al. [58] per- 100 000 patient-years for recipients of living donor, standard formed an interesting meta-analysis including 32 cohort studies and expanded criteria deceased donor kidney recipients, on solid organ transplant recipients with a pre-transplant respectively. This increased risk with different donor types was malignancy in remission. They demonstrated that pre-trans- independent of age, sex, and time on dialysis [53]. Recipients of plant malignancy is associated with an increased risk of all- living-donor kidneys had a lower risk of cancer, particularly for cause mortality (pooled hazard ratio 1.51), cancer-specific mor- genitourinary cancer and PTLD [53]. tality (pooled hazard ratio 3.13) and of developing de novo malig- nancies (pooled hazard ratio 1.92) after transplantation Recipient age and time on dialysis compared with solid organ transplant recipients without a pre- Both in paediatric and adult kidney transplant recipients, recipi- transplant malignancy [58]. These studies clearly identify kidney ent age has been identified as an independent risk factor of transplant recipients with pre-transplant cancer as a high-risk Downloaded from by Ed 'DeepDyve' Gillespie user on 20 June 2018 318 | B. Sprangers et al. patient population requiring tailored screening and management Rejection and treatment strategies. As the total dose of immunosuppression is related to the risk of post-transplant malignancy, it is no surprise that rejection epi- Organ predilection sodes and anti-rejection therapy are associated with the risk of post-transplant malignancy, as doses of maintenance immuno- The incidence of specific malignancies varies according to the suppression including calcineurin inhibitors, antimetabolite transplanted organ [3]. While in some types of transplantation and/or corticosteroids are often increased during the treatment (lung and liver), post-transplant malignancies tend to occur in of rejection, thereby contributing to increased T cell dysfunction the transplanted organ, in kidney transplantation this does not [93]. Besides T cell dysfunction, systemic inflammation and appear to be the case (kidney cancer in kidney transplant recipi- concomitant release of cytokines and chemokines may promote ents primarily affects the native kidney) [3, 4, 16–23]. In addi- malignant transformation [94, 95]. In the CTS, anti-rejection tion, other cancer types vary depending on the transplanted therapy with OKT3 or anti-thymocyte globulin (ATG) increased organ. For example, the risk of NHL in lung transplant recipients the overall cancer risk [96]. In a recent analysis of the is doubled compared with kidney, heart or liver transplant [3]. ANZDATA, Lim et al. [29] studied the risk of incident cancer It is well established that kidney cancer is greatly increased among kidney transplant recipients who have experienced AR, in dialysis patients and kidney transplant recipients [3, 4, 16– stratified by the use of T cell–depleting antibodies. The study 23]. Prolonged time on dialysis has been identified as a risk fac- included 7153 kidney transplant recipients transplanted tor for the development of kidney cancer [59, 60] and the inci- between 1997 and 2009, of which 6.5% developed cancers. The dence of kidney cancer can be as high as 100 times the expected risk for cancer after first kidney transplantation was signifi- incidence [61, 62]. While kidney cancer in native kidneys is fre- cantly higher in patients experiencing AR treated with T cell– quent, cancer in the transplanted kidney is rare. In a European depleting antibodies (adjusted hazard ratio 1.42) compared with retrospective study, 20 patients were identified with kidney kidney transplant recipients not experiencing AR and the excess cancer in the transplanted kidney: 85% were papillary renal cell cancer risk was mainly confined to genitourinary tract cancers carcinoma (RCC) and 15% were clear cell RCC [63]. The tumours [29]. Also, treatment of rejection with high-dose steroids can were small at the time of diagnosis and all patients were man- adversely affect the risk for PTLD [97]. aged with ablation therapy (cryoablation or radiofrequent abla- tion) without a reduction or change in their immunosuppressive therapy [63]. Maintenance immunosuppression Maintenance immunosuppression is essential after kidney Sun exposure transplantation to prevent allograft rejection. Although it is accepted that overall immunosuppression dose is associated In the development of skin cancer, sun exposure is an estab- with an increased cancer risk following transplantation, the lished risk factor [64–66]. The application of sun block and contributive effect of different immunosuppressive agents is administration of nicotinamide have both been demonstrated not established. The mechanisms linking immunosuppression to reduce the incidence of non-melanoma skin cancer [67–70]. dose to the increased incidence of cancer are numerous and include decreased immune surveillance of tumours, decreased Viral infection antiviral responses resulting in a specific increase of virus- At least four viruses are believed to be co-carcinogenic in trans- induced tumours and possibly the direct carcinogenic effect of planted patients: EBV (Hodgkin’s and NHL), human herpesvirus immunosuppressive drugs such as cyclosporine and azathio- 8 (HHV8; Kaposi sarcoma) [71–73], human papillomavirus (HPV; prine (Table 2)[6]. cervix, vulva, vagina, anus and some oro-pharynx cancers) and The cumulative immunosuppressive dose (net immunosup- Merkel cell polyomavirus (Merkel cell skin carcinoma). EBV has pressive dose for the entire life) is associated with the risk for conclusively been implicated in the pathogenesis of PTLD fol- cancer post-transplant. For example, patients previously treated lowing kidney transplantation [74, 75] and EBV status is one of with immunosuppression for primary glomerular disease [128]or the most important risk factors for PTLD. More than 50% of for AR [29] are at higher risk to develop cancer. Hibberd et al. [128] PTLD cases are EBV related, and EBV mismatch between donor reported an association between pre-transplantation immuno- and recipient (an EBV-negative receptor engrafted with an EBV- suppression and increased risk for four cancer groups: anogenital positive donor) is associated with a 20-fold increased risk for cancer, NHL, breast cancer and urinary tract cancer (excluding PTLD [76–78]. Moreover, primary EBV infection post-transplant kidney). Grulich et al. [4] analyzed seven studies of people with is a major risk factor for EBV-positive PTLD in early onset PTLD HIV/AIDS (n¼ 444 172) and five of transplant recipients [15]. Additionally, other viruses have been associated with the (n¼ 31 977) for 20 of the 28 types of cancers. A significantly development of cancer, e.g. hepatitis B and C (HBV and HCV; increased cancer incidence was found in both populations, and liver cancer) and BK polyomavirus (urological cancers) [79–87]. most cancers that occurred at increased rates involved oncogenic The central role of the immune system in the control of onco- viruses (e.g. EBV, HHV8, HPV, HBV and HCV). The rates of most genic viruses was emphasized by the findings of Grulich et al. common epithelial cancers (breast or prostate cancer) were not [4], where a similar increase of virus-associated cancers was increased [4]. The similarity of the pattern of increased risk of observed in solid organ transplant patients and patients with cancer in the two populations suggests that it is immune defi- HIV/AIDS. As far as cytomegalovirus (CMV) and post-transplant ciency rather than other risk factors for cancer that is responsible malignancy are concerned, conflicting results have been for the increased risk. Of note, there were also some discrepan- reported [88–92], so at this time it is not clear whether CMV cies noted, as some cancer types (thyroid, kidney, melanoma and infection is associated with an increased risk of post-transplant bladder cancers) were increased in the transplant population but cancer. A recent study demonstrated that cancer risk after kid- not in the HIV/AIDS cohorts. ney transplantation during childhood is particularly increased Although results suggest that currently available immuno- for virus-related cancers [54]. suppressive agents influence different anticancer pathways Downloaded from by Ed 'DeepDyve' Gillespie user on 20 June 2018 Risk factors for post-transplant malignancies | 319 Table 2. Immunosuppressive drugs and oncogenesis Immunosuppressant agent Method of action Role in carcinogenesis Calcineurin inhibitor Inhibition of IL-2 production Production of TGF-b [98, 99] through binding and inhibition Production of VEGF [98, 100] of cyclophilin (cyclosporine) and Production of interleukin-6 (IL-6) (promotion of EBV-induced B-cell growth) FKBP-12 (tacrolimus), [101] respectively Promotion of invasive behaviour of non-transformed cells [98] Reduced ability to repair radiation-induced DNA damage Enhanced apoptotic effects of taxol and IFN-c on human gastric and bladder cancer cells [102, 103] Increased rate of lymfoproliferative disorders in HSV-infected mice [104] Azathiopurine Inhibition of DNA and RNA synthe- Intercalation at the DNA level, inhibiting repair splicing and eliciting codon sis through incorporation of thi- misreads [105] opurine analogues Increased development of microsatellite DNA instability [106] Mycophenolate mofetil Inhibition of inosine monophos- Anti-proliferative effect on leukaemia and solid tumour phate dehydrogenase and de Inhibition of adhesion molecules [107, 108–114] novo purine biosynthesis Suppressed glycosylation and expression of several adhesion molecules [109, 115] Inhibition of adhesion of colon adenocarcinoma cells to endothelial cells [116] mTOR inhibitors Inhibition of mTOR pathway Direct antitumour effect by inhibition of mTOR pathway [117, 118] Inhibition of angiogenesis Inhibition of p70 S6K: decreasing cancer cell proliferation [119, 120 Inhibition of interleukin-10: decreasing tumour cell JAK/STATs activity [120] Inhibition of cyclins: blocking cell-cycle activity [121] Decreased VEGF-A and VEGF-C signalling: impaired tumour angiogenesis [101, 119, 122, 123] Inhibition of growth signals in PTLD-associated EBV B-cell lymphomas [124] Inhibition of replication of EBV-positive B cells, T cells and NK cells [125, 126] Inhibition of ultraviolet B–induced metalloproteinase activation [127] [101], it is not clear whether currently used medications such as plasma cells, which may explain the predisposition to infec- cyclosporine, tacrolimus, azathioprine or mycophenolate are tions and cancer complications associated with the use of these associated with different cancer risks [14, 129–131]. mTOR inhib- agents [138–140]. itors have been reported to have less cancer risk compared with The immunosuppressive potency of OKT3 is greater than alternative immunosuppressive therapies [132]; however, in a that of polyclonal lymphocyte–depleting agents and the use of recent systematic review, decreased cancer incidence in kidney OKT3 has clearly been associated with an increase in lymphoma transplant recipients treated with mTOR inhibitors did not risk [14, 141–143]. OKT3 is no longer commercially available, but result in improved overall survival [133]. As induction therapy is other forms of induction therapy are still currently in use and concerned, interleukin-2 (IL-2) receptor antagonist (IL-2Ra) from the late 1990s onwards, rabbit ATG (rATG) became the induction does not appear to be associated with an increase in most commonly used polyclonal agent in the USA [144, 145], cancer [39], whereas some studies find a small increase in can- and later worldwide [146, 107]. cer and cancer death with lymphocyte-depleting antibodies [5, Polyclonal induction therapy: When evaluating the cancer- 134, 135]. Moreover, there appear to be differences in the differ- inducing effect of different types of polyclonal lymphocyte- ent types of lymphocyte-depleting antibodies. depleting agents, the data are limited and hard to interpret. Available registry analyses have often combined all polyclonal Induction therapy lymphocyte-depleting agents into one category and often span Multiple agents have been used as induction therapy at the multiple decades. Combining different types of induction time of kidney transplantation [e.g. OKT3/muromonab, polyclo- agents (e.g. polyclonal induction agents or ATG) is problematic, nal lymphocyte-depleting antibodies, anti-IL-2 receptor (CD25) as there are clear differences in the risk of PTLD associated with antibodies and alemtuzumab (anti-CD52). As both CD4 and different preparations [141, 147]. Furthermore, over time the CD8 T cells are crucial in adaptive antiviral immunity, type of lymphocyte-depleting agent, the average dose of rATG depletion of both populations of T cells with T cell–depleting and the type and dose of concomitant immunosuppressive antibodies would increase the susceptibility of individuals to a agents have changed significantly. During the 1980s and early higher risk of virus-associated diseases [136]. Direct anti- 1990s, OKT3 and non-rATG preparations were most widely used tumour effects have also been attributed to CD4 T helper 1 [144, 145], and this was associated with a marked increase in cells, CD8 cytotoxic T cells and natural killer (NK) cells [137]. the incidence of PTLD [148, 149]. From the late 1990s onwards, Polyclonal T cell–depleting antibodies target a variety of T and rATG became the most commonly used polyclonal agent in the NK cell-derived antigens, including CD2, CD3, CD4, CD8 and USA [144, 145], and later worldwide [146]. Finally, in the 1980s CD16, but also markers expressed by leucocytes, B cells and rATG dosing was markedly higher than it is now (e.g. total dose Downloaded from by Ed 'DeepDyve' Gillespie user on 20 June 2018 320 | B. Sprangers et al. 14 mg/kg versus 6 mg/kg now) [150] and it has been demon- of secondary cancers (particularly skin cancers) compared with strated that higher rATG dosing is associated with a higher risk normal-dose (150–250 ng/mL) cyclosporine at a median of of PTLD [13]. 66 months follow-up [168]. Some evidence suggested a higher Earlier studies have suggested an association of induction risk for PTLD under tacrolimus versus cyclosporine [169, 170]. therapy with T cell–depleting antibodies with an increased risk However, subsequent analyses by the same group postulated of PTLD. In an analysis of the CTS, the SIR of lymphoma com- that this was the result of a lack of experience with the agent pared with a similar non-transplant population was higher with and overaggressive dosing at the time of introduction of tacroli- T cell–depleting antibody induction as compared with IL-2Ra or mus in clinical practice. Ultimately, reduced tacrolimus trough no induction therapy [143]. Also, a study of the SRTR and the levels led to substantial declines in the risk of PTLD [171]. An United States Renal Data System databases reported similar analysis of the CTS demonstrated that cyclosporine did not con- results (70% increased risk of PTLD in renal transplant recipients fer added risk for the development of NHL compared with aza- receiving monoclonal and/or polyclonal T cell–depleting anti- thioprine/steroid treatment, whereas treatment with FK506 bodies as induction therapy) [10, 14]. Also, an earlier analysis of increased the risk approximately 2-fold [96]. the ANZDATA registry demonstrated that the use of T cell– Azathioprine: The use of azathioprine has long been recog- depleting antibodies (as induction or as treatment for rejection) nized as an a etiologic factor in the development of neoplasia, was associated with a more than two-fold increased risk of especially in the development of late non-melanoma skin early onset NHL after transplantation [9]. Registry database malignancies (particularly squamous cell cancer) [23, 101, 172, studies reported results regarding rATG use and the occurrence 173]. Furthermore, azathioprine is associated with the develop- of PTLD have been mixed. Only three studies looked at rATG ment of myelodysplastic syndrome [106]. specifically and two found an increased risk for PTLD while one Mycophenolate mofetil: Some patient studies have sug- did not [10, 11, 151]. Other registry studies of PTLD risk have gested that the risk of developing malignancies is decreased grouped multiple lymphocyte-depleting induction agents with the use of mycophenolate mofetil [107, 174, 175], while together for the purpose of analysis, in some cases including other studies could not demonstrate a reduction in cancer inci- OKT3 [14, 152–155]. Three prospective randomized trials fol- dence with mycophenolate- versus non-mycophenolate-based lowed patients up to 5 years after kidney transplantation [156– therapy [174]. An SRTR analysis reported that the introduction 158]. The incidence of PTLD and the follow-up time were too of mycophenolate mofetil was associated with the greatest limited to allow for meaningful conclusions [159–162]. Finally, a decrease in relative risk for the development of PTLD [14]. When systematic review by Marks et al. [13] evaluated the rate of PTLD patient outcomes during different eras of immunosuppression in recipients of kidney or heart allografts and pointed to the were compared, the use of MMF was also found to be associated importance of antiviral prophylaxis, as in this study; the with a reduction in the incidence of PTLD [9, 174, 176]. In absence of antiviral prophylaxis was the greatest risk factor for patients, the principal anti-tumour mechanism associated with the development of PTLD rather than the use of induction mycophenolate mofetil use may be due to the decreased inci- therapy. dence of AR. IL-2R antagonist induction: In the CTS, induction therapy mTOR inhibitors: While for most classes of immunosuppres- with polyclonal and IL-2Ra induction was not associated with sive agents there is a dose-dependent relationship between the significant increases in the risk of PTLD when compared with dosage of the immunosuppressive agent and secondary malig- no induction therapy [14]. However, universal use of IL-2Ra nancies, this does not hold true for mTOR inhibitors such as induction is increasingly questioned, as it does not provide ben- sirolimus and everolimus. In humans, evidence suggests that efit in low-risk kidney transplant recipients compared with no sirolimus may confer a decreased risk of malignancy compared induction therapy, while being inferior compared with ATG in with other immunosuppressive medications [101, 133, 177–181]. high-risk kidney transplant recipients [161, 163–165]. In a recent Case reports and case series have reported that in renal trans- observation study, rATG was associated with a decreased risk of plant recipients with Kaposi sarcoma, switching from cyclo- adverse outcomes (including mortality) compared with alemtu- sporine to sirolimus resulted in total resolution of the Kaposi zumab and basiliximab as induction therapy [166]. sarcoma [179, 182, 183]. In the TUMORAPA study, where patients Alemtuzumab: In the Transplant Cancer Match study, the with a history of squamous cell carcinoma were studied, con- use of alemtuzumab as induction therapy was associated with a version to sirolimus significantly reduced the risk for relapse 79% increase in NHL, a 2.5-fold increase in colorectal cancer and when compared with those who were maintained on 3-fold increase in thyroid cancer after transplantation [142]. calcineurin inhibitor–based therapy [184]. For non-melanoma Other studies have reported mixed results regarding the use of skin cancer, Campbell et al. [185] reported that conversion to alemtuzumab and PTLD; although one study did not find an sirolimus after 1-year post-transplant resulted in a lower yearly association [11], another using a more recent Organ incidence rate of non-melanoma skin cancer and also a lower Procurement and Transplantation Network cohort did [78]. A incidence of new or recurrent non-melanoma skin cancer. recent study in small bowel allograft recipients receiving alem- Individual studies regarding the incidence of cancer associated tuzumab demonstrated earlier onset of lymphoplasmacytic with the use of sirolimus have been conflicting [177, 186–193]. In hyperplasia, the most indolent form of B lymphocyte clonal a study linking the US SRTR database with 15 population-based expansion, compared with patients receiving the IL-2Ra induc- cancer registries and national pharmacy claims, cancer inci- tion agent daclizumab [167]. dence in 32 604 sirolimus-exposed and sirolimus non-exposed kidney transplant recipients was studied. The incidence of pros- tate cancer was higher during sirolimus use (hazard ratio 1.86), Maintenance therapy while the incidence of other cancers was similar or lower, with Calcineurin inhibitors: In kidney transplant recipients, both a 26% decrease in overall cancer incidence excluding prostate cyclosporine and tacrolimus are associated with an increased carcinoma (hazard ratio 0.74). The authors postulate that the risk of malignancy [101]. In a French prospective randomized increase in prostate cancer diagnosis is due to sirolimus, effects study involving 231 renal allograft recipients, low-dose (75– on screen detection. In addition, two meta-analyses have been 125 ng/mL) cyclosporine was associated with a lower incidence Downloaded from by Ed 'DeepDyve' Gillespie user on 20 June 2018 Risk factors for post-transplant malignancies | 321 Table 3. Recommendations for waiting times after cancer [203–206] published demonstrating a lower overall cancer incidence with the use of sirolimus [133, 194]. In the meta-analysis of Knoll Decisions regarding waiting time should be individualized and it et al. [133], including 21 randomized controlled trials with should be expalined to all patients with a history of cancer that patient-level data from 5876 patients, it was demonstrated that they are at increased risk of de novo malignancy post-transplanta- sirolimus was associated with a 40% reduction in malignancy tion. Recommended waiting periods before transplantation do not risk and a 56% reduction in the risk of non-melanoma skin cancer guarantee no recurrence of malignancy after transplantation (0.44, 0.30 to 0.63) compared with controls. This effect is restricted Absolute contraindication for transplantation to patients converting to sirolimus from another immunosup- Uncontrolled or untreated malignancies pressive regimen, as analysis of de novo sirolimus trials revealed Multiple myeloma no difference in malignancy risk between sirolimus and controls Advanced breast cancer (Stage III or IV) [133]. Moreover, in a study analyzing Medicare claims data for • Colorectal cancer (Stage D) transplant recipients, de novo use of sirolimus was associated • Advanced prostate cancer (Grade 4 or 5, T3c, T4, Nþ,Mþ) with a 22% increased risk of PTLD [195]. Remarkably, in the meta- No waiting time analysis of Knoll et al. [133], the decreased risk of cancer develop- Superficial bladder cancer Non-metastatic, basal cell carcinoma ment was associated with an increased overall mortality risk due Prostatic cancer microscopic (focal, microscopic low-grade to cardiovascular and infection-related deaths. The authors spec- (Gleason’s grade 3), low risk) (T1a, T1c) disease ulate that increased sirolimus-induced cardiovascular risk factors Incidentally discovered T1 renal cell carcinoma (with no suspi- (anaemia, proteinuria, hyperglycaemia and hyperlipidemia) and cious histological features) overimmunosuppression with sirolimus might have contributed Monoclonal gammopathy of undetermined significance to these findings [133]. Based on these studies, universal siroli- 2-year waiting time mus use in kidney transplant recipients cannot be recommended Invasive bladder cancer at this time. In situ breast cancer Belatacept: For the co-stimulation blocker belatacept, an Localized cervical cancer inhibitor of T cell proliferation, PTLD risk appears similar to that Duke’s Stage A and B1 colorectal cancer seen under calcineurin inhibitor therapy [196], however, belata- Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, post-trans- cept is contraindicated in EBV-seronegative recipients. Although plant lymphoproliferative disorder, leukaemia initially a number of PTLDs of the central nervous system were In situ melanoma reported in patients treated with belatacept [197, 198], follow-up Lung cancer data of both the BENEFIT study and, more recently, a Phase 2 Prostatic cancer study where low immunologic risk patients were switched from Testicular cancer calcineurin inhibitor therapy to belatacept showed a mild albeit • Thyroid cancer small increase in post-transplant malignancies [199–202]. • Wilm’s tumour (a 1-year waiting period might be acceptable) 5-year waiting time Stage II breast cancer Screening • Extensive cervical cancer and non-in situ cancer of the uterus Colorectal cancer Stage C Since cancer before transplantation increases the risk of post- Melanoma transplant malignancy, guidelines have been developed outlining Large or invasive or symptomatic renal cell carcinoma waiting times for different types and stages of cancer (Table 3). A systematic review by Batabyal et al. [207] concluded that none of the available recommendations are backed by strong evidence. We recommend seeking an expert oncologist’s opinion regarding population. In a population-based cohort of Ontario between cancer-free survival, patient life expectancies and optimal cancer 1997 and 2010, 77.5, 69.8 and 91.4% of eligible solid organ trans- surveillance. Clinicians have to realize that even longer waiting plant recipients were not up to date with colorectal, cervical and times do not eliminate the risk for cancer recurrence and cancer- breast cancer screening, respectively [221]. Solid organ transplant related death [57]. In a Swedish population-based cohort of solid recipients with fewer co-morbidities, assessment by a primary organ transplant recipients, the increased rate of death was care provider and continuity of care by a transplant specialist at a greatest for patients with waiting times of 5 years but persisted transplant centre were associated with higher rates of becoming with waiting times of >10 years among recipients with prior screen up to date in this study [221]. aggressive cancer types (gastrointestinal, breast, kidney/ urothelial and hematologic malignancies) [57]. The optimal cancer screening strategy to detect post- Treatment of post-transplant cancer transplant cancers in an early stage is not defined (Table 4). In general, many experts recommend using general practice guide- In general, a reduction in immunosuppression is recommended lines in kidney transplant recipients [208–215]. Several centres or kidney transplant recipients upon cancer diagnosis. In the routinely screen for native kidney cancer, as the risk for kidney above-mentioned study of Yanik et al. [56], it was noted that the cancer is greatly increased in both the dialysis and kidney trans- incidence of infection-related cancers was higher and the inci- plant populations [3, 4, 16–23, 216, 217]. In a medical decision dence of ESRD-related cancers was lower during kidney function analysis, screening for kidney cancer in all transplant recipients intervals (time on immunosuppression), suggesting that a reduc- would have a small benefit at relatively high cost [218]. However, tion of immunosuppression affects different cancer types differ- directed screening using ultrasound in those with documented ently. Similar findings were reported by van Leeuwen et al. [222], acquired cystic kidney disease or those with a previous cancer in who performed a population-based retrospective cohort study a contralateral kidney might be cost effective. Modelling studies and compared the cancer incidence in kidney transplant recipi- by Wong et al. [219, 220] suggest that screening for colon and cer- ents during periods of transplant function (and immunosuppres- vical cancer would be cost effective in the kidney transplant sion) and after transplant failure (when immunosuppression is Downloaded from by Ed 'DeepDyve' Gillespie user on 20 June 2018 322 | B. Sprangers et al. ceased or reduced) [222]. The SIRs for NHL, lip cancer and mela- noma were significantly elevated during periods of transplant function. For leukaemia and lung carcinoma, SIRs remained ele- vated after transplant failure, while the SIRs for kidney/urinary tract and thyroid cancers significantly increased after transplant failure. These data suggest that while the effect of immunosup- pression on cancer risk is rapidly reversible for some cancers (mainly infectious-related cancers), this does not hold true for other cancer types (ESRD-related cancers) [222]. Some centres convert patients with non-melanoma skin cancer to mTOR ther- apy, as randomized clinical trials have shown fewer skin cancers in mTOR-treated patients [184, 185]. Also, for other solid and hematologic cancers, mTOR inhibitors have had marginal success [223, 224]. However, routine conversion to mTOR inhibi- tors to improve outcomes in all cancers or to prevent long-term cancer development in all solid organ transplant recipients is not widely practiced at this time, as data are lacking to support this practice. Outcome Data suggest that cancer as a cause of death is on the rise. For example, in Australia and New Zealand, cardiovascular deaths are decreasing while cancer mortality is increasing [1]. Malignancy accounts for 8–10% of all deaths in the USA (2.6 deaths/1000 patient-years) and >30% of deaths in Australia (5/ 1000 patient-years) [1, 2]. The data regarding standardized mor- tality rates (SMRs) have been conflicting. While some studies have suggested that the cancer-related SMR has increased with the same magnitude as the SIR in transplant recipients [224], other studies have shown a more nuanced picture [5]. In a study from Hong Kong, the cancer SIR and SMR in kidney transplant recipients were very similar (2.9 and 2.3, respectively) [225]; high SMRs were associated with lymphoma, leukaemia, kidney, colon, lung, bladder, melanoma and stomach cancers, while lymphoma, liver, colorectal and lung were associated with excess absolute risk of >25 deaths/100 000 patient-years [225]. In a US registry analysis by Kiberd et al. [5], no overall excess mortality was observed in kidney transplant recipients. Cancer SMRs varied substantially with age group; cancer SMRs were 23-fold and 4.4-fold higher in patients <20 years and 20– 39 years of age, respectively, while cancer SMRs were lower in patients >60 years of age [5]. The cancer death rates were >500/ 100 000 patient-years for patients >60 years of age compared with 13/100 000 patient-years for patients 20–39 years of age [5]. So in older patients who are at the highest risk to die from can- cer, there is no increased risk to die from cancer in kidney trans- plant recipients. More specific data are available concerning post-transplant lymphoma. The 1-year survival in cadaveric kidney transplant recipients developing lymphoma was 60% and showed little improvement over the study period, while the 5-year survival was 40% [30]. Interestingly, in this analysis the time of lymphoma development after transplantation did not influence survival: 5-year survival in kidney transplantation with lymphoma development <90 days post-transplant and >365 days post-transplant was 41.4% and 37.0%, respectively [30]. Post-transplant lymphoma with lymph node involvement had a good prognosis while disseminated disease had a poor prognosis [30]. Conclusion Malignancy is one of the most common causes of death in kid- ney transplant recipients. In general, the cancer incidence in Downloaded from by Ed 'DeepDyve' Gillespie user on 20 June 2018 Table 4. Recommendations for post-transplant cancer screening Guideline Skin cancer Cervical cancer Breast cancer Colorectal cancer Prostate cancer Liver Lymphoma Others AST kidney 2000 [208] Self-screening Annually Every 1–2 years As in general Annually PSA Every 6–12 months Clinically every Annually prostate, Annually including PAP population and DRE AFP and US 3 months in first year lung and bladder EBPG 2002 [209] – Annually Recommended Recommended Annually PSA – – Annually prostate including PAP and DRE and kidney KDIGO 2009 [210] Self-screening As in general As in general As in general – Annual AFP and US – – Annually population population population NKF 2009 [211] Annually – – – – – – CST and CSN 2010 [212] Self-screening Annually PAP As in general As in general – Annual AFP and US – – Annually population population RA 2011 [213] Self-screening As in general As in general As in general –– – – Annually population population population KHA-CARI 2012 [214] Self-screening Annually – – – – – – Annually DRE, digital rectal examination; AFP, Alpha fetoprotein; US, Ultra sound examination; PAP, PAP-mean Risk factors for post-transplant malignancies | 323 12. Pedotti P, Cardillo M, Rossini G et al. Incidence of cancer solid organ transplant recipients is increased 2- to 3-fold com- pared with the general population [3, 4]. Moreover, cancer- after kidney transplant: results from the North Italy trans- related mortality rates are also higher in solid organ transplant plant program. Transplantation 2003; 76: 1448–1451 recipients compared with the general population [5]. Several 13. Marks WH, Ilsley JN, Dharnidharka VR. Posttransplantation risk factors for post-transplantation cancer development have lymphoproliferative disorder in kidney and heart transplant been identified and immunosuppression is considered the most recipients receiving thymoglobulin: a systematic review. Transplant Proc 2011; 43: 1395–1404 important risk factor, as it decreases the immunologic control of oncogenic viral infection and immunosurveillance. Currently 14. Cherikh WS, Kauffman HM, McBride MA et al. 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Risk factors associated with post–kidney transplant malignancies: an article from the Cancer-Kidney International Network

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