Kidney CJASNTransplantation ePress. Published on March 29, 2021 as doi: 10.2215/CJN.14570920 Long-Term Management Challenges

De Novo Malignancies after Kidney Transplantation

David Al-Adra,1 Talal Al-Qaoud,1 Kevin Fowler ,2 and Germaine Wong3,4,5

Abstract Cancer is an important outcome after kidney transplantation because it is the second leading cause of death in most Western countries. The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex- matched general population, driven largely by viral- and immune-related cancers. Once cancer develops, outcomes are generally poor, particularly for those with melanoma, renal cell carcinoma, and post-transplant lymphoproliferative disease. 1Department of Moreimportantly,effectivescreeningandtreatmentstrategiesarelimitedinthishigh-riskpopulation.Inthisreview,webegin Surgery, University with a patient’s journey that maps the experience of living with a kidney transplant and understand the patient’s knowledge, of Wisconsin School of education, and experience of cancer in the context of transplantation. The epidemiology and burden of cancer in recipients of Medicine and Public Health, Madison, kidney transplants, along with the up-to-date screening and treatment strategies, are discussed. We also focus on the current Wisconsin understanding of optimal care for recipients of kidney transplants who are living with cancer from the patients’ perspectives. 2The Voice of the CJASN 17: ccc–ccc, 2022. doi: https://doi.org/10.2215/CJN.14570920 Patient, Inc., Columbia, Missouri 3Sydney School of Patient’s Voice regarding their awareness of their health risks, including . Public Health, As someone living with a kidney transplant for 16 cancer. Moreover, the survey could also gain insights into University of Sydney, years, this article resonated with me. When my the recipients’ ability to self-manage their health risks. In Sydney, New South nephrologist identified me as a pre-emptive candidate Wales, Australia turn, this information would guide the community in 4 for a kidney transplant, he educated me immediately their patient education and activation efforts. Centre for Kidney Research, Kids on the cardiovascular risks post-transplant. In addi- Research Institute, The tion, he persuaded me to adopt routine exercise into Children’s Hospital my lifestyle as a proactive measure. That recommen- Introduction at Westmead, dation has served me well because I have maintained Kidney transplantation is the best treatment option for Westmead, New South Wales, Australia routine exercise post-kidney transplant. 5 acceptable candidates with kidney failure because it Centre for Transplant I have a sense of control in mitigating my cardio- improves the quality (1) of life and overall survival for and Renal Research, vascular risk. Beyond routine exercise, I have ensured patients on maintenance dialysis (2). It is also the most Westmead Hospital, my BP is within the recommended range. I strive to cost-effective treatment strategy for those needing KRT (3). Westmead, New South Wales, Australia maintain a heart-healthy diet, and my transplant nephrol- However, transplantation is not a cure. Patients ogist prescribed a cholesterol-lowering medication imme- require life-long immunosuppression to maintain Correspondence: diately after my transplant when my metabolic panel was optimal allograft function. One of the most feared Dr. Germaine Wong, out of range. Recently, I scheduled an appointment with complications associated with immunosuppression Sydney School of a preventive cardiologist. That appointment resulted after kidney transplantation is cancer (4). Cancer is Public Health, Faculty in the prescription of a sodium-glucose cotransporter-2 also considered as one of the core clinical outcomes of Medicine and inhibitor to reduce the risk of prediabetes, and a follow- Health, University of by clinicians, patients, and caregivers, and there is Sydney, Camperdown, up appointment for a computed tomography scan. now consensus among key stakeholders suggesting 2006, NSW, Australia. In contrast, my experience with managing cancer cancer should be included as an outcome in all Email: germaine. risks has not been clear. Although the risks of skin interventional trials of kidney transplantation (5). [email protected]. cancer were communicated, I had to ensure the After cardiovascular disease, cancer is the second gov.au guidelines were followed closely. For example, from leading cause of death among recipients of transplants the very beginning, I scheduled quarterly surveillance in most Western countries (6). The higher risks and appointments with my dermatologist. Initially, quar- poorer cancer outcomes have prompted clinicians and terly appointments were discouraged until skin bi- policy makers to adopt preventive policies, such as opsy specimens were positive. Mole mapping was human papillomavirus (HPV) vaccination (7) and initially discouraged until the dermatologists discov- cancer-screening strategies, to detect cancers at their ered irregular moles. Nonetheless, I feel confident earliest possible stage before they progress into now in managing the risk of skin cancers. For my advanced-stage, incurable disease (8). It is also im- other cancer risks, a proactive path remains elusive. perative to understand the mechanistic insights into Because the United States is moving to 3-year outcomes cancer cell development under the influence of im- for transplant metrics, this affords the US transplant munosuppression and devise innovative treatment community to assess the effectiveness of patient educa- strategies for recipients of transplants. This review tion. As a first step, I would like to see the American focuses on the incidence, mechanisms, diagnosis, Society of Transplantation and the American Society of prevention, and treatment of cancer after kidney Nephrology survey recipients of kidney transplants transplantation.

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Incidence of All-Cause and Site-Specific Cancer after Risk Factors for Cancer Development Transplantation There are many reasons for the higher cancer risk after The cumulative incidence of solid organ cancer ranges transplantation. Some of these factors, such as increasing between 10% and 15% (6,9–11) at around 15 years after age, male sex, smoking, and prolonged sun exposures, transplantation. For skin cancers, the cumulative incidence are shared by patients in the general population. Other reaches .60% in Europe, Australia, and New Zealand. The risk factors, including immunosuppression use (T cell– excess overall cancer risk in patients with kidney transplant depleting agents), acute rejection (17), sensitization status exceeds that of the general population by approximately two- to (18), and duration of dialysis before transplantation (19), three-fold after adjustment for age and sex. The magnitude of are specific to those with kidney disease and transplant the higher risk is also dependent on cancer types, with the populations. Although long-term immunosuppression is a greatest risk in viral-related and immune-driven cancers such as major contributor to cancer development after transplan- post-transplant lymphoproliferative disease (PTLD), anogenital tation, there is now convincing observational evidence to cancer, and Kaposi sarcoma (12,13). Interestingly, certain solid suggest that having CKD (irrespective of the CKD stage) is organ cancers such as breast and prostate cancers are not associated with higher cancer risk and poor cancer out- increased in recipients of transplants (Figure 1). comes (20,21). Many of these cancers, such as renal cell carcinoma and multiple myeloma, are over-represented in the CKD/kidney-failure populations. Cancer may also de- Cancer Mortality in Recipients of Kidney Transplants velop in recipients of kidney transplants because of impaired Once cancers develop, the risk of death is high. Obser- tumor surveillance and immunity to viral or other tumor vational data in most Western countries have shown the antigens. The observed higher cancer risk is further com- standard mortality ratios for all cancer types are at least pounded in patients who have had a previously treated – 1.8–1.9 times higher compared with the age- and sex- pretransplant malignancy (22 24). Recent studies indicate a matched general population. The risk is greatest among higher incidence of all-cause mortality in recipients of solid those with melanoma, urogenital cancers, and non- organ transplants who have a pretransplant malignancy than Hodgkin lymphoma, with an overall risk of cancer- those without, but the cause of death may not necessarily be – related death exceeding five to ten times that of those driven by cancer recurrence alone (24 26). fi without kidney transplants (Figure 2) (14). The exact The speci c types of cancer that develop after trans- reasons for the higher risk of death are unclear, but may plantation also vary by geographic areas. Observational be due to potential differences in the cancer cell biology in and registry data from Europe, North America, Australia, recipients of transplants resulting from long-term immu- and New Zealand indicate the most common cancer types nosuppression, associated comorbidities, and low uptake of are nonmelanoma skin cancers (NMSCs), PTLD, and lip – recommended prevention and screening strategies (15). cancer (10,27 29). In contrast, data from non-Western Patients are primarily committed to and preoccupied with Asian and Middle Eastern transplant cohorts suggest their kidney and graft health, and their present health needs. higher incidences of urothelial transitional cell carcinoma, Cancer screening and prevention may impose multiple renal cell carcinoma, and gastrointestinal cancers in their burdens on patients’ daily lives (16), hence, effective patient populations (9). It is unclear why these regional variations education and heightened awareness are key. exist, but it may be related to distinct regional dietary supplementations, such as aristolochic acid, which have been associated with urothelial carcinoma (30). A nation- wide population study of 4716 recipients of kidney trans- plants in Taiwan reported an excess risk of liver cancer of approximately five-fold compared with the sex- and age- matched general population (31). Taiwan is an endemic area for chronic hepatitis B virus (HBV) infection in Far East Asia. The estimated prevalence rate of HBV antigenemia in recipients of kidney transplants is estimated to be 9%–24%. HBV is also a major risk factor of liver cancer. This finding supports the hypothesis of a loss of control of oncogenic viral replication and control in the context of chronic immunosuppression. For cancer associated with kidney disease and kidney failure, such as kidney and bladder cancer, the overall standardized incidence ratios (SIRs) are 44 and 43, respectively. When stratified by sex, women have a much higher risk than men for kidney (SIR, 94.6; 95% confidence interval [95% CI], 75 to 120) and bladder cancers (SIR, 120; 95% CI, 77 to 134) (31). Figure 1. | The standardized incidence ratios of different cancer types in recipients of kidney transplants indicate that the overall risk of cancer is higher for certain cancer types compared to the age- and Mechanisms of Cancer Development after sex-matched general population. The size of the circle represents the Transplantation absolute risk of developing cancer compared with the age- and sex- Maintenance immunosuppression decreases acute and matched general population. chronic rejection, and subsequent allograft loss. Although CJASN 17: ccc–ccc, July, 2022 De Novo Malignancies after Kidney Transplantation, Al-Adra et al. 3

inhibiting apoptosis in other cells by opening the mito- chondrial permeability transition pores (37). The potential oncogenic potential of azathioprine is well known and well recognized. Azathioprine sensitizes the skin to UVA radiation and causes the accumulation of 6-thioguanine in the DNA, leading to a higher risk of NMSCs (38). Mammalian target of rapamycin (mTOR) inhibitors, on the contrary, may have potential antitumor effects by inhibiting cancer growth through cell-cycle arrest and initiation of apoptosis. Growth inhibition of tumor cells has been demonstrated in vitro for cells from tumors, such as small cell lung cancer, sarcoma, neuroblastoma, glio- blastoma, osteosarcoma, pancreatic cancer, breast cancer, prostate cancer, leukemia, and B-cell lymphomas (39). On a molecular level, several mechanisms have been identified for mTOR inhibitor–mediated tumor inhibition. Specifi- cally, mTOR inhibitors can induce apoptosis in a cell type–specific fashion. It can also induce cell death in B-cell lymphoma lines, phosphatase and tensin homolog-lacking human tumors, and dendritic cells, possibly through p53 activation and reduction in the cyclin and survi- vin levels (39). Figure 2. | The standardized mortality ratios ofdifferentcancer types Induction therapy with T cell–depleting agents (includ- in recipients of kidney transplants indicate that the overall risk of ing polyclonal agents, such as anti-thymocyte globulin, and cancer-related death is higher for certain cancer types compared to monoclonal agents, such as anti-CD52 and, historically, the age- and sex-matched general population. The size of the circle Ortho Kung T3 [muromonab-CD3]) increases the risks of represents the absolute risk of dying from cancer compared with the cancers, such as PTLD and melanoma (40). In addition, age- and sex-matched general population. T cell–depleting agents used in the treatment of acute rejection of the kidney allograft also heighten the risk of the precise mechanisms are unclear, the effects of immu- cancer development (17). The mechanisms behind the nosuppression on dampening the immune system may short-term use of these therapies and the development of create a variety of pathways for cancer development. One cancer years later are uncertain. However, after T-cell potential mechanism is through poor immune control of depletion, there is often an incomplete T-cell recovery (41), known oncogenic viruses in patients on immunosuppres- which may have a long-term effect on immune homeosta- sion. For example, increases in viral-associated cancers, sis, leading to an impaired immune system (42,43) and such as Kaposi sarcoma (human herpesvirus 8), PTLD subsequent cancer development. (Epstein–Barr virus [EBV]), and lip and anal cancers (HPV) are common in patients with suppressed immune systems (32). Another mechanism of immunosuppression-related Common Cancers after Transplantation cancer development is through accumulation of mutations Although the risk of overall cancer development is high that would otherwise be repaired or recognized by the after transplantation, the risks of certain cancer types are immune system. This mechanism may be predominant in much higher than others. Here, we discuss the three most skin cancers, where immunosuppression impairs the cells’ common cancer types: renal cell carcinoma, skin can- ability to repair ultraviolet (UV) radiation–induced DNA cer, and PTLD. damage. More specifically, immunosuppression can lead to a decrease of xeroderma pigmentosum complementation Renal Cell Carcinoma groups A and G, which are components of nucleotide Compared with the general population, recipients of excision repair (33). kidney transplants have a higher risk (up to seven-fold) of Currently, there is no conclusive evidence to suggest one renal cell carcinoma (44–48). Due to increased abdominal type of immunosuppression is more oncogenic than others imaging, the majority of kidney masses detected in patients (34). However, experimental studies in hepatocellular post-transplantation are typically early, low-grade, small carcinoma, human lung adenocarcinoma cells, and renal kidney masses (8,49); of which, 75%–80% are renal cell cell carcinoma have shown that tacrolimus increases the carcinoma, with the risk of metastasis at presentation being level of TGF‐b and thereby promotes tumor progression ,2% (50). Ninety percent of renal cell carcinomas develop and metastasis. In addition, calcineurin inhibitors inhibit in the native kidneys as opposed to the allograft. Risk signaling via calcineurin and NF of activated T cells, which factors for development of renal cell carcinomas post- can activate p53, a hallmark of some NMSCs (35). Cyclo- transplantation include male sex (female hazard ratio [HR], sporine also has direct effects on tumor development and 0.56; 95% CI, 0.47 to 0.66), increasing age (601 years; HR, progression, through TGF-b or IL-6 overexpression path- 6.59; 95% CI, 4.29 to 10.15), African descent (HR, 1.50; 95% ways (36). Recent evidence has shown cyclosporine is CI, 1.24 to 1.80), and longer time on dialysis (31 years; HR, capable of inhibiting DNA repair, thereby accumulating 2.23; 95% CI, 1.58 to 3.13) (46). With regard to disease mutations, inducing apoptosis in activated T cells, and etiology, patients transplanted for kidney failure secondary 4 CJASN

to glomerular diseases (HR, 1.24; 95% CI, 1.05 to 1.47), management options with good outcomes include topical hypertensive nephrosclerosis (HR, 1.55; 95% CI, 1.29 to fluorouracil and imiquimod cream, photodynamic therapy, 1.86), and vascular disease (HR, 1.53; 95% CI, 1.15 to 2.03) and surgical excision or electrodesiccation and curettage. appear to have the greatest associated risk; in contrast, For biopsy sample–proven cutaneous squamous cell car- patients with kidney failure secondary to diabetes (HR, cinoma in recipients of transplant, Mohs micrographic 0.77; 95% CI, 0.62 to 0.94) or autosomal dominant poly- surgery, with histologic confirmation of negative margins, cystic kidney disease (HR, 0.81; 95% CI, 0.62 to 1.06) have a offers the most definitive method of treatment, with cure lower risk of renal cell carcinomas. De novo renal cell rates of 95%–100% (59). In inoperable cases, primary carcinomas should be definitively managed according to radiation therapy may achieve local cure rates. Patients urologic guidelines on the basis of risk stratification and who develop multiple squamous cell carcinomas (more staging (51,52), in conjunction with patient factors (age, than five) every year, those who have aggressive squamous comorbidities, functional status) and kidney-mass charac- cell carcinomas, or those with early onset of squamous cell teristics (size, biopsy specimen findings, growth kinetics). carcinomas can be considered for chemoprophylaxis. These The outcome of renal cell carcinomas after radical may include retinoids (63) and nicotinamide (64). In treatment in the transplant population is comparable patients with metastatic cutaneous squamous cell carci- with that of the general population, with 5-year, disease- noma, systemic chemotherapy and/or immunotherapy are specific and overall patient survival rates of 68%–97% and recommended (59). 69%–88%, respectively (53–56). Negative prognostic factors Patients treated with calcineurin inhibitors are at partic- include presence of symptoms at diagnosis, higher Fuhr- ularly high risk for Kaposi sarcoma. Decreasing the in- man grade (.2), absence of transplantation, and advanced- tensity or switching immunosuppressive agents to an stage disease (53–56). Renal cell carcinoma in the kidney mTOR inhibitor is the cornerstone of treatment. Regression allograft is rare, and multicenter data have demonstrated of Kaposi sarcoma has been reported after switching from an incidence of 0.1%. Most are low-grade T1 lesions, clear calcineurin inhibitors to sirolimus by restoring effector and cell carcinomas, or papillary renal cell carcinomas, and memory T-cell immune activity against human herpesvirus occur more commonly in males. The majority of tumors 8 (65). The risk of developing malignant melanoma is were treated by partial nephrectomy (67%), radical ne- elevated by approximately five- to eight-fold in recipients phrectomy (19%), and percutaneous ablation (12%); sur- of transplants, and these patients have much poorer veillance was rarely used. This experience suggests that outcomes than the general population (59). Among all nephron-sparing surgery was safe and an appropriate skin cancer types, melanoma has the highest mortality (66). option with good long‐term functional and oncologic History of pretransplant melanoma is the strongest risk outcomes, evading return to dialysis (56,57). Overall factor for post-transplant melanoma, followed by White duration and intensity of immunosuppression, rather race and older age (.50 years). Primary treatment is than individual components of the drug regimen, influence surgical with wide excision and adequate margins, based risk of renal cell carcinoma. The management of these on Breslow thickness, as per the National Comprehensive malignancies should be individualized and use a patient- Cancer Network guidelines (59). Adjustment of immuno- centered approach to ensure optimal care (58). suppression is individualized to each patient on the basis of the extent of melanoma and transplant function.

Skin Cancer Skin cancer is the most common cancer type in recipients Post-Transplant Lymphoproliferative Disease of kidney transplants and is more aggressive than skin PTLD is a well-recognized complication after kidney cancers occurring in the general population. The most transplantation. Although it is a rare disease, it is associ- commonly reported skin cancers in recipients of kidney ated with poor outcomes. In most instances (approximately transplants include cutaneous squamous cell carcinoma, 90%), PTLD is associated with EBV. EBV is a common basalcellcarcinoma,Kaposi sarcoma, and malignant virus, and most people acquire the virus during childhood. melanoma, with keratinocyte carcinomas comprising Most present with mild or minimal symptoms, but the 90%–95% of these skin cancers (59,60). The pathogenesis virus can infection the B cells and remain dormant in these of skin carcinoma involves a complex interaction of risk cells during the latent phase. After transplantation, these factors, including exposure to UV radiation, HPV, pretrans- viruses can reactivate because of depressed T-cell function, plant skin cancer, older age, race, and sex (males at greater with a lack of T-cell control over B-cell proliferation, and risk than females). Additionally, immunosuppressive med- contributes to the development of PTLD. Most PTLDs are ications augment the carcinogenic effects (mainly cyclo- of B-cell types, with approximately 5% of patients having sporine and azathioprine) (61,62). Kaposi sarcoma is also the T-cell type. more commonly seen in certain ethnic groups, including The cumulative incidence of PTLD in the first 10 years patients from the Mediterranean, Africa, and Central after kidney transplantation is around 1%–2% in adult Europe. Although Kaposi sarcoma is a rare cancer, the recipients and approximately 3% in pediatric recipients of incidence of Kaposi sarcoma in recipients of transplants transplants (67). There is evidence to suggest that the exceeds 100 times that of the general population. incidence of PTLD has been decreasing in recent years. A Compared with the general population, recipients of recent analysis from the Australian and New Zealand transplants experience an excess risk of squamous cell Dialysis and Transplant Registry reported the incidence of carcinoma by approximately 250 times (59). In patients PTLD was higher in the period of 1995–2000 compared with actinic keratoses and squamous cell carcinoma in situ, with the current era, with an 8% reduction in the risk of CJASN 17: ccc–ccc, July, 2022 De Novo Malignancies after Kidney Transplantation, Al-Adra et al. 5

developing PTLD from 2000 onward (67). There also survival benefits (74). Despite the lack of trial-based appears to be a bimodal distribution in PTLD incidence, evidence to support routine screening in this high-risk with the risk of PTLD being the highest in the 12 months group, routine population-based cancer screening for post-transplant, and it then decreases until the fifth year breast, colorectal, and cervical cancer is recommended after transplantation. Pretransplant EBV seronegativity and and should be aligned to the guidelines as per the general primary EBV infection are important risk factors for early population (75) (Table 1). Some guidelines also suggest EBV-positive PTLD, particularly in younger recipients of routine skin checks by dermatologists in recipients of trans- transplants, and may explain the higher risk of disease plants who are at high risk, and abdominal ultrasounds and early post-transplant. In contrast, a significant proportion serum a-fetoprotein levels should be checked every 6 months (approximately 40%–50%) of late B-cell PTLDs involves for those with underlying liver disease and chronic HBV EBV-negative lesions (68). infections. For patients who are at risk of developing renal cell Compared with adult recipients of transplants, the risk of carcinoma (such as those with a history of acquired cystic developing lymphoproliferative disease in pediatric recip- disease, those with a family history, those who are heavy ients of transplants is at least 30-times higher than the age- smokers, and those who use long-term analgesics), ultraso- and sex-matched general population. Apart from younger nographic screening (annually or biennially) of the native age at transplantation, male sex, use of T cell–depleting kidneys may be considered to detect occult malignancy (76). agents, Ortho Kung T3 (muromonab-CD3), and high dose Patients with kidney disease and kidney transplants tacrolimus, negative recipient EBV serology (with positive undergo radical changes to their overall health and well- donor EBV serology) incur a four-fold excess risk of PTLD, being, which could be overwhelming for the patients and after accounting for potential confounding factors (67). The their caregivers. Many patients are unprepared to un- use of costimulatory blockade, such as belatacept, has also dertake a multitude of tests on issues they may see as been found to be associated with a higher risk of PTLD, distant (83,84). From the patient’s perspective, decisions about particularly cerebral PTLD in patients who are EBV cancer screening are becoming increasingly complex. Screen- negative, and when used in higher doses (69). ing decisions must be made with clear considerations of The treatment goal of PTLD is to cure the disease, and the patients’ preferences and values, incorporating the potential mainstay of treatment is immunosuppression reduction. harms and benefits of the various options. A shared decision- However, the response to immunosuppression reduction making process, defined as an approach where clinicians and varies considerably between individuals. Prior work reported patients share the best available evidence when faced with the the use of rituximab and chemotherapy (doxorubicin, cyclo- task of making decisions, and where patients are supported to phosphamide, vincristine, prednisone) have improved overall consider options to achieve informed preferences, should be survival, with 5-year survival at around 60% (70). Rituximab adopted to guide decision making (85,86). is also generally well tolerated with minimal side effects, and factors that predicted response included positive EBV status and normal lactate dehydrogenase levels (70). Human Papillomavirus Vaccination in Recipients of Once PTLD develops, the risk of death is high. Epide- Kidney Transplants miologic studies have shown that the risk of death among The incidence of HPV-related anogenital cancer is at least recipients of kidney transplants who have PTLD is .14- ten- to 15-fold higher in recipients of kidney transplants fold higher than recipients without PTLD. However, compared with the age- and sex-matched general popula- contemporary data have shown there is an improvement tion. Quadrivalent vaccines (against genotype 6, 11, 16, and in overall survival in more recent times due to the use of 18) and, more recently, the HPV 9-valent vaccines (against chemotherapies, such as rituximab, and other novel ther- five additional genotypes of 31, 33, 45, 52, and 58) are apies, such as immunotherapy. Registry analyses have highly effective and have an overall efficacy of 99%–100% indicated the overall survival after PTLD was around for the prevention of cervical intraepithelial neoplasia in 62%–68% at 1 year and approximately 41%–48% at 10 years randomized clinical trials. HPV vaccination is indicated in (71). The risk of death also appears to be dependent on site, both males and females aged 9–25 years in the general with those having bone marrow/reticuloendothelial disease population for the prevention of HPV-related malignancies. experiencing the greatest risk of death, followed by extra- Some recent data have shown that it is also efficacious in nodal and nodal disease. The median time from diagnosis to women up to the age of 45 years. In the transplant population, death is 6 months. Apart from site, other predictive factors of HPV vaccines are generally safe. However, seropositivity was death included male sex and increasing age of diagnosis. only detected in approximately 50%–60% of patients, de- pending on genotypes, and higher tacrolimus levels were also detected in nonresponders (87). Although HPV vaccination is Cancer Screening Strategies in Transplant Recipients recommended for women after transplantation, it may be High-quality, randomized controlled trials have shown more efficacious to vaccinate before transplantation. that cancer screening through early detection reduces cancer-specific mortality in the general population (72). In patients with kidney disease, some have questioned the Management of Recipients of Kidney Transplants Who benefits of routine screening (73). Although some cancers Have Cancer are more common in patients with kidney disease, the Immunosuppression Management and Treatment in expected patient survival, particularly for those on dialysis, Transplant Recipients with Cancer is shorter than the time to develop cancers, suggesting Management of immunosuppression in recipients of screening may not be as effective in terms of costs and transplants who are living with cancer is complex and 6 CJASN

Table 1. Recommendations for cancer screening in recipients of kidney transplants

Cancers Recommendations Evidence

Breast For women aged 50–74 years, screening mammography Extrapolation from general population once every 2 years. For women ,50, the decision to start regular screening should be an individual one (77). Prostate For men aged 55–69 years, screening decisions should be Extrapolation from general population individualized after a conversation with their clinician about the potential benefits and harms. For men $70 years, the potential benefits may not outweigh the expected harms, and these men should not be routinely screened for prostate cancer (78). Cervical AnnualPap testing orHPVtestingevery3–5yearsstartingat In view of the higher risk of disease, some have suggested the age of 25 years until 74 years (72). more frequent Pap testing. However, no evidence to suggest increased frequency of HPV testing. Bowel For adults aged 45–75 years, fecal immunochemical testing Screening using fecal immunochemical testing is accurate in biennially, sigmoidoscopy every 5 years, or colonoscopy recipients of kidney transplants. However, it may be every 5–10 years (79). associated with higher risk of complications associated with diagnostic colonoscopies (80). Lung For adults aged 55–79 years, annual low-dose computed Extrapolation from general population tomography scans for those who have smoked one pack per day for 30 years or equivalent (two packs per day for 15 years) (81). Skin Monthly self-skin examination and 6- to 12-monthly total Expert opinions body skin examination by expert physicians and dermatologists (82). Renal Routine screening for renal cell carcinoma using US is not Population-based screening using US for all recipients of cell recommended for all recipients of transplants, except for kidney transplants is not cost-effective (76). high-risk individuals. Liver RoutinescreeningusingUS,with andwithouta-fetoprotein, Extrapolation from general population every 6 months in patients with cirrhosis. PTLD Routine monitoring of patients at high risk (donor EBV Expert opinions seropositive/recipient seronegative) for EBV by NAT. Once in the first week after transplantation, monthly for the first 3–6 months, and every 3 months until the end of the first post-transplant year (82).

Pap, Papanicolaou; HPV, human papillomavirus; US, ultrasonography; PTLD, post-transplant lymphoproliferative disease; EBV, Epstein–Barr virus; NAT, nucleic acid amplification techniques. challenging. A concerted approach between transplant interaction and/or the CD28-CD80/86 axis with cytotoxic professionals, oncologists, and allied health professionals T lymphocyte–associated protein-4 Ig has revolutionized is therefore needed to ensure optimal care for our patients. the treatment of a variety of malignancies through Meticulous understanding of the underlying immunologic immune-system activation against the cancer (93–95). risk and cancer severity is needed to optimize immuno- However, the use of checkpoint inhibitors is limited in suppression dose to prevent the risk of acute rejection, recipients of transplants given the potential for rejection while balancing against the need to induce regression of with nonspecific immune-system activation (96,97). Al- the malignant lesion and prevent future progression. In the though checkpoint inhibitors are effective in treating absence of quality evidence, judicious reduction in the melanoma, non–small cell lung cancer, and renal cell overall immunosuppression load for patients with early- to carcinoma in the general population, their use in the moderate-stage malignancy may be a reasonable first step, kidney transplant population requires further investigation and this should be conducted in consultation with the and cannot be recommended at this time, outside of a patients, where they are informed about the potential study protocol. adverse effects, and all strategies should be tailored to the individual’s needs. For patients with squamous cell carci- noma, there is now trial-based evidence to suggest con- Putting Patients’ Perspectives at the Heart of version to an mTOR inhibitor may reduce the risk of cancer Cancer Management Patients with cancer and transplant may experience in the longer term (88,89). However, mTOR-inhibitor use multiple symptoms, and the burden of self-management may also be associated with a higher risk of death (90,91). in the context of multiple morbidities is immense. Un- Therefore, there are insufficient data to consider mTOR derstanding patients’ personal experiences in their journey inhibitors as protective against other cancer types apart for the fight of cancer is crucial because this will provide from squamous cell carcinoma and Kaposi sarcoma (92). important insights to guide clinicians and health care professionals to deliver relevant and appropriate care. Immunotherapy The use of multimodal interventions to alleviate concur- The use of immune-checkpoint inhibitors targeting the rent, multiple symptoms is an example of where a multi- programmed death-1/programmed death ligand-1 disciplinary team could deliver the suitable measures for CJASN 17: ccc–ccc, July, 2022 De Novo Malignancies after Kidney Transplantation, Al-Adra et al. 7

patients transitioning between many disciplines of care. Institute; and being employed by The Voice of the Patient, Inc. All Patients living with kidney transplants are often frustrated remaining authors have nothing to disclose. with the lack of innovative strategies to prevent the risk of acute rejection from under-immunosuppression, and can- Funding cer resulting from over-immunosuppression (98). There- None. fore, a personalized, rather than a one-size-fits-all approach is most preferred. Ongoing dialogues between clinicians ’ Acknowledgments and patients, and close attention to the patients overall The authors would like to thank Ms. Madeline Hall and the personal needs, limited not only to health issues, are crucial University of Wisconsin Department of Surgery Communications ’ to ensure our patients voices are heard. For patients who and Marketing Division for assistance with the figure creation. have progressed to advanced-stage malignancy, complete immunosuppression withdrawal is a difficult decision for both patients and clinicians. Patients may experience signs References and symptoms of acute rejection, and, to some, it may also 1. Laupacis A, Keown P, Pus N, Krueger H, Ferguson B, Wong C, Muirhead N: A study of the quality of life and cost-utility of renal represent a loss of hope and complete medical abandon- transplantation. Kidney Int 50: 235–242, 1996 ment. Some clinicians may consider stopping either or both 2. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, the calcineurin inhibitors and antiproliferative agents Held PJ, Port FK: Comparison of mortality in all patients on di- gradually and rotate to higher-dose corticosteroids to alysis, patients on dialysis awaiting transplantation, and recipi- prevent the anticipated symptoms. Therefore, a multidis- ents of a first cadaveric transplant. N Engl J Med 341: 1725–1730, 1999 ciplinary, integrated approach that involves the transplant 3. Wong G, Howard K, Chapman JR, Chadban S, Cross N, Tong A, and palliative care team is crucial. The team should consist Webster AC, Craig JC: Comparative survival and economic of a palliative care physician to assist with the medical aspects benefits of deceased donor kidney transplantation and dialysis in of managing the high symptom burden, together with a social people with varying ages and co-morbidities. PLoS One 7: worker, dietician, clinical psychologist, and other allied health e29591, 2012 4. Tong A, Budde K, Gill J, Josephson MA, Marson L, Pruett TL, Reese workers to address the psychosocial, functional, and nutri- PP, Rosenbloom D, Rostaing L, Warrens AN, Wong G, Craig JC, tional issues experienced by our patients. Crowe S, Harris T,Hemmelgarn B, Manns B, Tugwell P,Van Biesen W, Wheeler DC, Winkelmayer WC, Evangelidis N, Sautenet B, Howell M, Chapman JR: Standardized outcomes in nephrology- transplantation: A global initiative to develop a core outcome set Conclusions for trials in kidney transplantation. Transplant Direct 2: e79, 2016 Cancer is the leading cause of morbidity and mortality in 5. Tong A, Gill J, Budde K, Marson L, Reese PP, Rosenbloom D, patients with kidney transplants. Having cancer is a Rostaing L, Wong G, Josephson MA, Pruett TL, Warrens AN, Craig devastating event for patients and their families because JC, Sautenet B, Evangelidis N, Ralph AF, Hanson CS, Shen JI, the lifestyle changes and the complex feelings caused by the Howard K, Meyer K, Perrone RD, Weiner DE, Fung S, Ma MKM, Rose C, Ryan J, Chen LX, Howell M, Larkins N, Kim S, Thangaraju diagnoses are overwhelming. The priorities of optimizing S, Ju A, Chapman JR; SONG-Tx Investigators: Towardestablishing allograft function with immunosuppression are often core outcome domains for trials in kidney transplantation: Report challenged and superseded by having a “cure” for the of the standardized outcomes in nephrology-kidney trans- cancer, and may involve immunosuppression reduction or plantation consensus workshops. Transplantation 101: 1887–1896, 2017 cessation to reduce the risk of cancer relapse and improve 6. Krynitz B, Edgren G, Lindelo¨f B, Baecklund E, Brattstro¨mC, long-term cancer survival. Currently, the evidence to define Wilczek H, Smedby KE: Risk of skin cancer and other malig- the amount of immunosuppression by which a clinician nancies in kidney, liver, heart and lung transplant recipients 1970 could safely reduce is unknown. More importantly, evi- to 2008--A Swedish population-based study. Int J Cancer 132: dence to support primary prevention and screening pro- 1429–1438, 2013 7. Wong G, Howard K, Webster A, Chapman JR, Craig JC: The health grams in recipients of transplants are largely extrapolated and economic impact of cervical cancer screening and human from the general population, and the findings may not papillomavirus vaccination in kidney transplant recipients. necessarily be applicable to the transplant population. Transplantation 87: 1078–1091, 2009 Collaborative efforts between health care professionals, 8. Miao Y, Everly JJ, Gross TG, Tevar AD, First MR, Alloway RR, Woodle ES: De novo cancers arising in organ transplant recipients policy makers, trialists, and patients are needed to ensure are associated with adverse outcomes compared with the general quality evidence—in the form of intervention trials, large- population. Transplantation 87: 1347–1359, 2009 care observational studies, and qualitative and health 9. Zhang J, Ma L, Xie Z, Guo Y, Sun W, Zhang L, Lin J, Xiao J, Zhu Y, service research—are generated to support the long-term Tian Y: Epidemiology of post-transplant malignancy in Chinese care of our recipients of transplants. renal transplant recipients: A single-center experience and liter- ature review. Med Oncol 31: 32, 2014 10. Villeneuve PJ, Schaubel DE, Fenton SS, Shepherd FA, Jiang Y,Mao Disclosures Y: Cancer incidence among Canadian kidney transplant recipi- K. Fowler reports receiving honoraria from the American Society ents. Am J Transplant 7: 941–948, 2007 11. Kasiske BL, Snyder JJ, Gilbertson DT,Wang C: Cancer after kidney of Nephrology and AstraZeneca; having consultancy agreements transplantation in the United States. Am J Transplant 4: 905–913, with Bayer, eGenesis, Gilead, Hansa Biopharma, Human and Health 2004 Services Technical Expert Panel, Otsuka, Palladio Biosciences, Re- 12. Webster AC, Craig JC, Simpson JM, Jones MP, Chapman JR: sponsum CKD, Retrophin, and Talaris; serving on the board of di- Identifying high risk groups and quantifying absolute risk of rectors for the Cardio-Renal Society and on the board of directors for cancer after kidney transplantation: A cohort study of 15,183 CJASN recipients. Am J Transplant 7: 2140–2151, 2007 Kidney Health Initiative; serving as a patient editor for ; 13. Webster AC, Wong G, Craig JC, Chapman JR: Managing cancer fi serving as a scienti c advisor or member of Global Renal Exercise risk and decision making after kidney transplantation. Am Group, International Society of Nephrology, and Kidney Research JTransplant8: 2185–2191, 2008 8 CJASN

14. Au EH, Chapman JR, Craig JC, Lim WH, Teixeira-Pinto A, Ullah S, regimens after kidney transplantation. J Am Soc Nephrol 21: McDonald S, Wong G: Overall and site-specific cancer mortality 852–858, 2010 in patients on dialysis and after kidney transplant. JAmSoc 35. Wu X, Nguyen BC, Dziunycz P, Chang S, Brooks Y, Lefort K, Nephrol 30: 471–480, 2019 Hofbauer GF, Dotto GP: Opposing roles for calcineurin and ATF3 15. Wong G, Hayward JS, McArthur E, Craig JC, Nash DM, Dixon SN, in squamous skin cancer. Nature 465: 368–372, 2010 Zimmerman D, Kitchlu A, Garg AX: Patterns and predictors of 36. Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman screening for breast and cervical cancer in women with CKD. Clin M, Shimbo T, Suthanthiran M: Cyclosporine induces cancer J Am Soc Nephrol 12: 95–104, 2017 progression by a cell-autonomous mechanism. Nature 397: 16. James LJ, Wong G, Craig JC, Ju A, Williams N, Lim WH, Cross N, 530–534, 1999 TongA: Beliefs and attitudes to bowel cancer screening in patients 37. Durnian JM, Stewart RM, Tatham R, Batterbury M, Kaye SB: with CKD: A semistructured interview study. Clin J Am Soc Cyclosporin-A associated malignancy. Clin Ophthalmol 1: Nephrol 12: 568–576, 2017 421–430, 2007 17. Lim WH, Turner RM, Chapman JR, Ma MK, Webster AC, Craig JC, 38. McGurgan IJ, McGuigan C: Nonmelanoma skin cancer risk Wong G: Acute rejection, T-cell-depleting antibodies, and cancer awareness in azathioprine-treated myasthenia gravis patients. after transplantation. Transplantation 97: 817–825, 2014 Brain Behav 5: e00396, 2015 18. Lim WH, Chapman JR, Wong G: Peak panel reactive antibody, 39. Mossmann D, Park S, Hall MN: mTOR signalling and cellular cancer, graft, and patient outcomes in kidney transplant recipi- metabolism are mutual determinants in cancer. Nat Rev Cancer ents. Transplantation 99: 1043–1050, 2015 18: 744–757, 2018 19. Wong G, Turner RM, Chapman JR, Howell M, Lim WH, Webster 40. Cherikh WS, Kauffman HM, McBride MA, Maghirang J, Swinnen AC, Craig JC: Time on dialysis and cancer risk after kidney LJ, Hanto DW: Association of the type of induction immuno- transplantation. Transplantation 95: 114–121, 2013 suppression with posttransplant lymphoproliferative disorder, 20. Wong G, Hayen A, Chapman JR, Webster AC, Wang JJ, Mitchell P, graft survival, and patient survival after primary kidney trans- Craig JC: Association of CKD and cancer risk in older people. JAm plantation. Transplantation 76: 1289–1293, 2003 Soc Nephrol 20: 1341–1350, 2009 41. Bouvy AP, Kho MM, Klepper M, Litjens NH, Betjes MG, Weimar 21. Lowrance WT, Ordonez~ J, Udaltsova N, Russo P,Go AS: CKD and W, Baan CC: Kinetics of homeostatic proliferation and thymo- the risk of incident cancer. J Am Soc Nephrol 25: 2327–2334, poiesis after rATG induction therapy in kidney transplant patients. 2014 Transplantation 96: 904–913, 2013 22. Penn I: Evaluation of the candidate with a previous malignancy. 42. Mu¨ller TF, Grebe SO, Neumann MC, Heymanns J, Radsak K, Liver Transpl Surg 2[Suppl 1]: 109–113, 1996 Sprenger H, Lange H: Persistent long-term changes in lymphocyte 23. Acuna SA, Huang JW, Dossa F, Shah PS, Kim SJ, Baxter NN: subsets induced by polyclonal antibodies. Transplantation 64: Cancer recurrence after solid organ transplantation: A systematic 1432–1437, 1997 review and meta-analysis. Transplant Rev (Orlando) 31: 43. Crepin T,Carron C, Roubiou C, Gaugler B, Gaiffe E, Simula-Faivre 240–248, 2017 D, Ferrand C, Tiberghien P,Chalopin JM, Moulin B, Frimat L, Rieu 24. Acuna SA, Sutradhar R, Kim SJ, Baxter NN: Solid organ trans- P, Saas P, Ducloux D, Bamoulid J: ATG-induced accelerated plantation in patients with preexisting malignancies in remission: immune senescence: Clinical implications in renal transplant A propensity score matched cohort study. Transplantation 102: recipients. Am J Transplant 15: 1028–1038, 2015 1156–1164, 2018 44. Kasiske BL, Ramos EL, Gaston RS, Bia MJ, Danovitch GM, Bowen 25. Livingston-Rosanoff D, Foley DP,Leverson G, Wilke LG: Impact of PA, Lundin PA, Murphy KJ; Patient Care and Education Committee pre-transplant malignancy on outcomes after kidney trans- of the American Society of Transplant Physicians: The evaluation plantation: United Network for Organ Sharing database analysis. of renal transplant candidates: Clinical practice guidelines. JAm JAmCollSurg229: 568–579, 2019 Soc Nephrol 6: 1–34, 1995 26. Viecelli AK, Lim WH, Macaskill P,Chapman JR, Craig JC, Clayton 45. Hurst FP, Jindal RM, Fletcher JJ, Dharnidharka V, Gorman G, P, Cohney S, Carroll R, Wong G: Cancer-specific and all-cause Lechner B, Nee R, Agodoa LY, Abbott KC: Incidence, predictors mortality in kidney transplant recipients with and without pre- and associated outcomes of renal cell carcinoma in long-term vious cancer. Transplantation 99: 2586–2592, 2015 dialysis patients. Urology 77: 1271–1276, 2011 27. Adami J, Ga¨bel H, Lindelo¨fB,Ekstro¨m K, Rydh B, Glimelius B, 46. Karami S, Yanik EL, Moore LE, Pfeiffer RM, Copeland G, Ekbom A, Adami HO, Granath F: Cancer risk following organ Gonsalves L, Hernandez BY, Lynch CF, Pawlish K, Engels EA: Risk transplantation: A nationwide cohort studyin Sweden. Br J Cancer of renal cell carcinoma among kidney transplant recipients in the 89: 1221–1227, 2003 United States. Am J Transplant 16: 3479–3489, 2016 28. Navarro MD, Lo´pez-Andre´u M, Rodrı´guez-Benot A, Agu¨era ML, 47. Leveridge M, Musquera M, Evans A, Cardella C, Pei Y, Jewett M, Del Castillo D, Aljama P: Cancer incidence and survival in kidney Robinette M, Finelli A: Renal cell carcinoma in the native and transplant patients. Transplant Proc 40: 2936–2940, 2008 allograft kidneys of renal transplant recipients. JUrol186: 29. Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, 219–223, 2011 Stewart JH, Law M, Chapman JR, Webster AC, Kaldor JM, Grulich 48. Einollahi B, Simforoosh N, Lessan-Pezeshki M, Basiri A, Nafar M, AE: Cancer incidence before and after kidney transplantation. Pour-Reza Gholi F, Firouzan A, Ahmadpour P, Makhdomi K, JAMA 296: 2823–2831, 2006 Ghafari A, Taghizadeh A, Tayebi Khosroshahi H: Genitourinary 30. Lai MN, Wang SM, Chen PC, Chen YY, Wang JD: Population- tumor following kidney transplantation: A multicenter study. based case-control study of Chinese herbal products containing Transplant Proc 41: 2848–2849, 2009 aristolochic acid and urinary tract cancer risk. J Natl Cancer Inst 49. Finelli A, Ismaila N, Bro B, Durack J, Eggener S, Evans A, Gill I, 102: 179–186, 2010 Graham D, Huang W, Jewett MA, Latcha S, Lowrance W, Rosner 31. Li WH, Chen YJ, Tseng WC, Lin MW, Chen TJ, Chu SY,Hwang CY, M, Shayegan B, Thompson RH, Uzzo R, Russo P: Management of Chen CC, Lee DD, Chang YT, Wang WJ, Liu HN: Malignancies small renal masses: American Society of Clinical Oncology after renal transplantation in Taiwan: A nationwide population- clinical practice guideline. JClinOncol35: 668–680, 2017 based study. Nephrol Dial Transplant 27: 833–839, 2012 50. Umbreit EC, Shimko MS, Childs MA, Lohse CM, Cheville JC, 32. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM: Incidence Leibovich BC, Blute ML, Thompson RH: Metastatic potential of a of cancers in people with HIV/AIDS compared with im- renal mass according to original tumour size at presentation. BJU munosuppressed transplant recipients: A meta-analysis. Lancet Int 109: 190–194; discussion 194, 2012 370: 59–67, 2007 51. Campbell S, Uzzo RG, Allaf ME, Bass EB, Cadeddu JA, Chang A, 33. Kuschal C, Thoms KM, Boeckmann L, Laspe P, Apel A, Scho¨nMP, Clark PE, Davis BJ, Derweesh IH, Giambarresi L, Gervais DA, Hu Emmert S: Cyclosporin A inhibits nucleotide excision repair via SL, Lane BR, Leibovich BC, Pierorazio PM: Renal mass and lo- downregulation of the xeroderma pigmentosum group A and G calized renal cancer: AUA guideline. JUrol198: 520–529, 2017 proteins, which is mediated by calcineurin inhibition. Exp Der- 52. Ljungberg B, Albiges L, Abu-Ghanem Y,Bensalah K, Dabestani S, matol 20: 795–799, 2011 Ferna´ndez-Pello S, Giles RH, Hofmann F, Hora M, Kuczyk MA, 34. Gallagher MP,Kelly PJ, Jardine M,Perkovic V,Cass A, Craig JC, Eris Kuusk T, Lam TB, Marconi L, Merseburger AS, Powles T, Staehler J, Webster AC: Long-term cancer risk of immunosuppressive M, Tahbaz R, Volpe A, Bex A: European Association of Urology CJASN 17: ccc–ccc, July, 2022 De Novo Malignancies after Kidney Transplantation, Al-Adra et al. 9

guidelines on renal cell carcinoma: The 2019 update. Eur Urol 75: Block A, Di Russo G, Lin CS, Garg P, Charpentier B: Belatacept- 799–810, 2019 based regimens versus a cyclosporine A-based regimen in kidney 53. Frasca` GM, Brigante F, Volpe A, Cosmai L, Gallieni M, Porta C: transplant recipients: 2-year results from the BENEFIT and BEN- Kidney transplantation in patients with previous renal cancer: A EFIT-EXT studies. Transplantation 90: 1528–1535, 2010 critical appraisal of current evidence and guidelines. J Nephrol 70. Elstrom RL, Andreadis C, Aqui NA, Ahya VN, Bloom RD, Brozena 32: 57–64, 2019 SC, Olthoff KM, Schuster SJ, Nasta SD, Stadtmauer EA, Tsai DE: 54. Gigante M, Neuzillet Y,Patard JJ, Tillou X, Thuret R, Branchereau J, Treatment of PTLD with rituximab or chemotherapy. Am Timsit MO, Terrier N, Boutin JM, Sallusto F, Karam G, Barrou B, JTransplant6: 569–576, 2006 Chevallier D, Mazzola CR, Delaporte V,Doeffler A, Kleinclauss F, 71. Francis A, Johnson DW, Craig J, Teixeira-Pinto A, Wong G: Post- Badet L; members of the Comite´ de Cancerologie de l’Association transplant lymphoproliferative disease may be an adverse risk Franc¸aise d’Urologie (CCAFU); Comite´ de Transplantation de factor for patient survival but not graft loss in kidney transplant l’Association Franc¸aise d’Urologie (CTAFU): Renal cell carci- recipients. Kidney Int 94: 809–817, 2018 noma (RCC) arising in native kidneys of dialyzed and transplant 72. Curry SJ, Krist AH, Owens DK, Barry MJ, Caughey AB, Davidson patients: Are they different entities? BJU Int 110[11 Pt B]: KW, Doubeni CA, Epling JW Jr, Kemper AR, Kubik M, Landefeld E570–E573, 2012 CS, Mangione CM, Phipps MG, Silverstein M, Simon MA, Tseng 55. Ranasinghe WK, Suh N, Hughes PD: Survival outcomes in renal CW, Wong JB; US Preventive Services Task Force: Screening for transplant recipients with renal cell carcinoma or transitional cell cervical cancer: US preventive services task force recommen- carcinoma from the ANZDATA database. Exp Clin Transplant 14: dation statement. JAMA 320: 674–686, 2018 166–171, 2016 73. Wong G, Howard K, Tong A, Craig JC: Cancer screening in people 56. Tillou X, Guleryuz K, Doerfler A, Bensadoun H, Chambade D, who have chronic disease: The example of kidney disease. Semin Codas R, Devonec M, Dugardin F, Erauso A, Hubert J, Karam G, Dial 24: 72–78, 2011 Salomon L, Se´ne´chal C, Salusto F, Terrier N, Timsit MO, Thuret R, 74. Wong G, Howard K, Chapman JR, Craig JC: Cost-effectiveness of Verhoest G, Kleinclauss F; members of the Renal Transplantation breast cancer screening in women on dialysis. AmJ Kidney Dis 52: Committee of the French Urological Association (CTAFU): 916–929, 2008 Nephron sparing surgery for de novo kidney graft tumor: Results 75. Wong G, Chapman JR, Craig JC: Cancer screening in renal from a multicenter national study. Am J Transplant 14: transplant recipients:What is the evidence? ClinJAmSocNephrol 2120–2125, 2014 3[Suppl 2]: S87–S100, 2008 57. Griffith JJ, Amin KA, Waingankar N, Lerner SM, Delaney V, Ames 76. Wong G, Howard K, Webster AC, Chapman JR, Craig JC: SA, Badani K, Palese MA, Mehrazin R: Solid renal masses in Screening for renal cancer in recipients of kidney transplants. transplanted allograft kidneys: A closer look at the epidemiology Nephrol Dial Transplant 26: 1729–1739, 2011 and management. Am J Transplant 17: 2775–2781, 2017 77. Mehta JM, MacLaughlin KL, Millstine DM, Faubion SS, Wallace 58. Yanik EL, Siddiqui K, Engels EA: Sirolimus effects on cancer in- MR, Shah AA, Fields HE, Ruddy BE, Bryan MJ, Patel B, Temkit MH, cidence after kidney transplantation: A meta-analysis. Cancer Buras MR, Golafshar MA, Kling JM: Breast cancer screening: Med 4: 1448–1459, 2015 Women’s attitudes and beliefs in light of updated United States 59. Mittal A, Colegio OR: Skin cancers in organ transplant recipients. preventive services task force and American Cancer Society Am J Transplant 17: 2509–2530, 2017 guidelines. J Womens Health (Larchmt) 28: 302–313, 2019 60. Greenberg JN, Zwald FO: Management of skin cancer in solid- 78. Fleshner K, Carlsson SV, Roobol MJ: The effect of the USPSTF PSA organ transplant recipients: A multidisciplinary approach. Der- screeningrecommendation onprostatecancerincidencepatterns matol Clin 29: 231–241, ix, 2011 in the USA. Nat Rev Urol 14: 26–37, 2017 61. Walsh SB, Xu J, Xu H, Kurundkar AR, Maheshwari A, Grizzle WE, 79. Berger BM, Parton MA, Levin B: USPSTF colorectal cancer Timares L, Huang CC, Kopelovich L, Elmets CA, Athar M: Cy- screening guidelines: An extended look at multi-year interval closporine a mediates pathogenesis of aggressive cutaneous testing. Am J Manag Care 22: e77–e81, 2016 squamous cell carcinoma by augmenting epithelial- 80. Wong G, Hope RL, Howard K, Chapman JR, Castells A, Roger SD, mesenchymal transition: Role of TGFb signaling pathway. Mol Bourke MJ, Macaskill P, Turner R, Williams G, Lim WH, Lok CE, Carcinog 50: 516–527, 2011 Diekmann F, Cross NB, Sen S, Allen RDM, Chadban SJ, Pollock 62. Brem R, Li F, Karran P: Reactive oxygen species generated by CA, Tong A, Teixeira-Pinto A, Yang JYH, Williams N, Au EHK, Kieu thiopurine/UVA cause irreparable transcription-blocking DNA A, James L, Craig JC: One-time fecal immunochemical screening lesions. Nucleic Acids Res 37: 1951–1961, 2009 for advanced colorectal neoplasia in patients with CKD (DETECT 63. Chen K, Craig JC, Shumack S: Oral retinoids for the prevention of study). J Am Soc Nephrol 30: 1061–1072, 2019 skin cancers in solid organ transplant recipients: A systematic 81. Aldrich MC, Mercaldo SF, Sandler KL, Blot WJ, Grogan EL, Blume review of randomized controlled trials. Br J Dermatol 152: JD: Evaluation of USPSTF lung cancer screening guidelines 518–523, 2005 among African American adult smokers. JAMA Oncol 5: 64. Chen AC, Martin AJ, DalziellRA, McKenzie CA, Lowe PM, ErisJM, 1318–1324, 2019 Scolyer RA, Dhillon HM, Vardy JL, Bielski VA, Halliday GM, 82. Kidney Disease: Improving Global Outcomes (KDIGO) Trans- Damian DL: A phase II randomized controlled trial of nicotin- plant Work Group. KDIGO clinical practice guideline for the care amide for skin cancer chemoprevention in renal transplant re- of kidney transplant recipients. Available at https://kdigo.org/wp- cipients. Br J Dermatol 175: 1073–1075, 2016 content/uploads/2017/02/KDIGO-2009-Transplant-Recipient- 65. Sunil M, Reid E, Lechowicz MJ: Update on HHV-8-associated Guideline-English.pdf malignancies. Curr Infect Dis Rep 12: 147–154, 2010 83. Kiberd BA, Keough-Ryan T, Clase CM: Screening for prostate, 66. Robbins HA, Clarke CA, Arron ST, Tatalovich Z, Kahn AR, breast and colorectal cancer in renal transplant recipients. Am Hernandez BY,Paddock L, Yanik EL, Lynch CF, Kasiske BL, Snyder JTransplant3: 619–625, 2003 J, Engels EA: Melanoma risk and survival among organ transplant 84. Wong G, Li MW, Howard K, Hua DK, Chapman JR, Bourke M, recipients. J Invest Dermatol 135: 2657–2665, 2015 Turner R, Tong A, Craig JC: Health benefits and costs of screening 67. Francis A, Johnson DW, Teixeira-Pinto A, Craig JC, Wong G: In- for colorectal cancer in people on dialysis or who have received a cidence and predictors of post-transplant lymphoproliferative kidney transplant. Nephrol Dial Transplant 28: 917–926, 2013 disease after kidney transplantation during adulthood and 85. Bomhof-Roordink H, Ga¨rtner FR, Stiggelbout AM, Pieterse AH: childhood: A registry study. Nephrol Dial Transplant 33: Key components of shared decision making models: A systematic 881–889, 2018 review. BMJ Open 9: e031763, 2019 68. Luskin MR, Heil DS, Tan KS, Choi S, Stadtmauer EA, Schuster SJ, 86. Cassidy BP, Getchell LE, Harwood L, Hemmett J, Moist LM: Porter DL, Vonderheide RH, Bagg A, Heitjan DF, Tsai DE, Reshef Barriers to education and shared decision making in the chronic R: The impact of EBV status on characteristics and outcomes of kidney disease population: A narrative review. Can J Kidney posttransplantation lymphoproliferative disorder. Am Health Dis 5: 2054358118803322, 2018 J Transplant 15: 2665–2673, 2015 87. Kumar D, Unger ER, Panicker G, Medvedev P, Wilson L, Humar A: 69. Larsen CP,Grinyo´ J, Medina-Pestana J, Vanrenterghem Y,Vincenti Immunogenicity of quadrivalent human papillomavirus vaccine in F, Breshahan B, Campistol JM, Florman S, Rial MC, Kamar N, organ transplant recipients. Am J Transplant 13: 2411–2417, 2013 10 CJASN

88. Lim WH, Russ GR, Wong G, Pilmore H, Kanellis J, Chadban SJ: 94. Califano R, Gomes F,Ackermann CJ, Rafee S, Tsakonas G, Ekman S: The risk of cancer in kidney transplant recipients may be reduced Immune checkpoint blockade for non-small cell lung cancer: What in those maintained on everolimus and reduced cyclosporine. is the role in the special populations? Eur J Cancer 125: 1–11, 2020 Kidney Int 91: 954–963, 2017 95. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, 89. Ying T, Wong G, Lim WH, Clayton P, Kanellis J, Pilmore H, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Campbell S, O’Connell PJ, Russ G, Chadban S: Everolimus and Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, long-term clinical outcomes in kidney transplant recipients: A Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman registry-based 10-year follow-up of 5 randomized trials. Trans- IM, Sharma P; CheckMate 025 Investigators: Nivolumab versus plantation 103: 1705–1713, 2019 everolimus in advanced renal-cell carcinoma. N Engl J Med 373: 90. Badve SV,Pascoe EM, Burke M, Clayton PA, Campbell SB,Hawley 1803–1813, 2015 CM, Lim WH, McDonald SP, Wong G, Johnson DW: Mammalian 96. Abdel-Wahab N, Safa H, Abudayyeh A, Johnson DH, Trinh VA, target of rapamycin inhibitors and clinical outcomes in adult Zobniw CM, Lin H, Wong MK, Abdelrahim M, Gaber AO, Suarez- kidney transplant recipients. Clin J Am Soc Nephrol 11: Almazor ME, Diab A: Checkpoint inhibitor therapy for cancer in 1845–1855, 2016 solid organ transplantation recipients: An institutional experience 91. Knoll GA, Kokolo MB, Mallick R, Beck A, Buenaventura CD, and a systematic review of the literature. J Immunother Cancer 7: Ducharme R, Barsoum R, Bernasconi C, Blydt-Hansen TD, 106, 2019 Ekberg H, Felipe CR, Firth J, Gallon L, Gelens M, Glotz D, 97. d’Izarny-Gargas T,Durrbach A, Zaidan M: Efficacyand tolerance Gossmann J, Guba M, Morsy AA, Salgo R, Scheuermann EH, of immune checkpoint inhibitors in transplant patients with Tedesco-Silva H, Vitko S, Watson C, Fergusson DA: Effect of si- cancer: A systematic review. Am J Transplant 20: 2457–2465, 2020 rolimus on malignancy and survival after kidney transplantation: 98. Williams NC, Tong A, Howard K, Chapman JR, Craig JC, Wong G: Systematic review and meta-analysis of individual patient data. Knowledge, beliefs and attitudes of kidney transplant recipients BMJ 349: g6679, 2014 regarding their risk of cancer. Nephrology (Carlton) 17: 300–306, 92. de Fijter JW: Cancer and mTOR inhibitors in transplant recipients. 2012 Transplantation 101: 45–55, 2017 93. Bhatia S, Tykodi SS, Lee SM, Thompson JA: Systemic therapy of metastatic melanoma: On the road to cure. Oncology (Williston Published online ahead of print. Publication date available at Park) 29: 126–135, 2015 www.cjasn.org.