Cancer Screening in Renal Transplant Recipients: What Is the Evidence?

Home , Liver transplantation, Renal ultrasonography

Germaine Wong,*† Jeremy R. Chapman,‡ and Jonathan C. Craig† *National Health and Medical Research Council Centre for Clinical Research Excellence in Renal Medicine, Children’s Hospital at Westmead and ‡Centre for Transplant and Renal Research, Westmead Hospital, Westmead, and †School of Public Health, University of Sydney, Sydney, New South Wales, Australia

Increased cancer risk is well established in the renal transplant population. Little, however, is known about the benefits and harms of cancer screening, treatment effectiveness, and the overall cancer prognosis in renal transplant recipients. In this study, we critically appraised guidelines for cancer screening in the renal transplant and general populations using standard criteria for an evidence-based screening program. Guidelines were included when they were applied to adult participants, had objectives specific to cancer screening, and were written in English. Recommendations for breast and colorectal cancer screening in the general population were supported by evidence of cancer-specific mortality benefits from randomized, controlled trials of cancer screening. Convincing evidence from observational studies had demonstrated population cervical cancer screening was effective, also, test performance of mammography, faecal occult blood testing, and Pap smear were accurate. Population breast, colorectal, and cervical cancer screening also appeared to be good value for money in the general population. On the contrary, recommendations for cancer screening in renal transplant recipients were entirely extrapolated from data in the general population. Studies in the general population have led to the development of cancer screening guidelines in transplant recipients. Because of increased cancer risk, differences in diagnostic test performance, competing risks for deaths from causes such as cardiovascular disease and reduced overall life expectancies, validity of their recommendations are uncertain. Future studies are needed to address these issues to provide the necessary evidence for informed decision-making. Clin J Am Soc Nephrol 3: S87–S100, 2008. doi: 10.2215/CJN.03320807

here is now consistent evidence that shows renal trans- apy are often limited by comorbidities such as cardiovascular plant recipients are approximately three times more disease. Transplant physicians and recipients are also reluctant T likely to develop cancers than the general population to initiate reduction in immunosuppression and to receive ag- (1,2). This excess risk is type specific and greatest for Kaposi’s gressive immunotherapy for fear of adding graft rejection and sarcoma (200 times increased risk) and nonmelanocytic and loss to the morbidities directly attributed to cancers. In this melanocytic skin cancer (nine to 20 times increased risk) (1,2). setting of increased risk and poor clinical outcomes, screening, For nonskin cancers, the risk is greatest in cancers associated which detects early-stage diseases and allows curative treat- with viral infections, such as cervix in situ, vulvovaginal, and ment, is effective in reducing cancer-related mortality and mor- posttransplantation lymphoproliferative diseases (2). For other bidity in the general population (3,4). solid-organ cancers, such as colorectal and lung cancers, the Screening, however, is not without harms. The extent and risk is increased by approximately two to three times when magnitude of harms must be considered before screening is compared with the general population. Cancers that cause end- recommended. The harms of screening are to be individualized stage kidney disease (ESKD), such as multiple myeloma and and weighed against the risks of disease and benefits of early renal cell carcinoma, have an excess risk of 2.5 and seven times, detection. If the relative risk for disease is greater for the respectively, after renal transplantation (2). Table 1 shows the individual and the relative harms of screening is reduced, then cumulative and relative risk for cancers (excluding all nonmela- screening with early disease detection is therefore desirable. nocytic skin cancers) in the US and Australian renal transplant Conversely, if the risk for disease is low, then the relative harms populations. of screening may outweigh the relative benefits, and, conse- Survival among transplant recipients with advanced-stage quently, it would be less attractive to screen. The harms of cancer is extremely poor. The average 5-yr survival for all screening may be associated with true-positive and -negative cancers in the Australian and New Zealand transplant popula- and false-positive and -negative results. The diagnosis of in- tion is Ͻ10%. Surgical intervention and intensive chemother- consequential true-positive diseases may lead to investigation and treatment of diseases that may or may not affect an individual’s life. A true-negative result is reassuring but can incur costs during the investigative process. False-negative results Correspondence: Dr. Germaine Wong, Centre for Kidney Research, Children’s Hospital at Westmead, Locked bag 4001, Westmead, NSW 2145, Australia. Phone: are potentially dangerous because they provide false assur- ϩ61-0-2-98455-1488; Fax: ϩ61-0-2-9845-1493; E-mail [email protected] ances, which subsequently lead to delay and misdiagnoses.

Table 1. Cancer risk after renal transplantation in Australia and the United States

SIRb Cumulative Incidence Cumulative Incidencea Cancers (/100,000) (/100,000) United States Australia United States Australia Male Female

Kaposi sarcoma 213 140 21.30 17.4 62.0 Kidney/ureter 139 1010 10.39 14.1 14.6 Lymphoma 189 80 7.40 6.9 29.1 Bladder 90 126 5.03 1.6 3.6 Esophagus 40 70 4.00 2.4 2.8 Cervix 35 180 3.85 – 5.7 Liver 20 220 2.99 4.2 4.5 Melanoma 129 320 2.14 6.9 5.2 Lung/bronchus/trachea 85 690 1.89 2.3 3.6 Colorectal 169 510 2.51 1.6 2.8 Breast 100 1050 0.98 (female) 4.0 1.1 Prostate 40 1740 0.95 1.6 –

aCumulative incidence is calculated at 3 yr after transplantation. bStandardized incidence ratio (SIR) (ANZDATA) is calculated as the Љobserved/expectedЉ number of cases for each cancer type. The Љexpected number of casesЉ is calculated overall and for each type by comparing the observed number of cases seen in an age-matched New South Wales population using the mean population for same years. SIR (US Renal Data System) is calculated as the Љobserved/expectedЉ number of cases for each cancer type 3 yr after transplantation. The Љexpected number of casesЉ is calculated overall and for each type by comparing the observed number of cases seen in the age matched SEER population in year 2000 (1).

False-positive findings may result in inappropriate and exces- Standard Criteria for an Evidence-Based Screening Program sive investigations that could be harmful. Guidelines should There are many criteria for assessing screening guidelines and rec- therefore provide explicit, unbiased, and relevant evidence to ommendations. In this study, we used the “User’s Guide to the Medical inform an individual’s overall risk of disease, benefits, and Literature: How to Use Guidelines and Recommendations about harms when making the eventual decisions on screening (5). Screening” (5). Recommendations should be based on the four recommended criteria: Evidence from randomized, controlled trials (RCT) The aim of this article was to critically appraise practice guide- that earlier intervention is effective; the proposed screening strategies lines on cancer screening in the renal transplant and general are accurate and cost-effective; and that the extra benefits outweigh the populations on the basis of accepted criteria for an evidence- overall harms of the anticipated intervention. based disease screening program (5–7).

RCT Evidence that Earlier Intervention Is Effective Concise Methods The benefits attained in screening trials are mediated by shift to a less Inclusion Criteria advanced stage and more effective treatment for earlier diseases. There Clinical practice guidelines of cancer screening in the general and are two types of screening trial designs. Participants could be randomly renal transplant populations were included. Inclusion of guidelines assigned to screening and no screening groups. Alternatively, all par- was restricted to English-language articles and those that applied to ticipants are screened but only those with positive results will be average-risk adult participants. For recommendations in the transplant randomly assigned to earlier or standard intervention. In RCT, benefits population, those that are applicable to renal transplant recipients were are defined as significant reduction in cancer-specific mortality and included. Cancer screening guidelines in other solid-organ transplant morbidity. Survival benefits, measured from the time of diagnosis, are populations, such as lung, liver, and heart, were excluded from the misleading as a result of length-time and lead-time bias. Individuals analysis. only seem to be living longer because indolent diseases, with minimal propensity to progress, are detected earlier, allowing people to live with the disease diagnosed for a longer period of time. Search Strategy An extensive literature search from Medline, Embase, and the Co- chrane Library databases for articles published between 1950 and 2006, Accuracies of the Screening Tool using MeSH terms such as “kidney transplantation,” “neoplasms,” and It may be reasonable to assume that an accurate screening tool, with “mass screening” and publication type “clinical guidelines” was con- optimal test sensitivity and specificity, achieves greater benefits and ducted. The bibliographies of the retrieved articles were also assessed fewer harms because it detects more true positives at an earlier stage to recover additional articles that were relevant to the topic. When and provides a window of opportunity to commence effective treat- duplicate guidelines from the same societies were found, the most ment and prevent progression of incurable metastatic disease. This, current versions were included. however, is based on the assumption that such diseases will alter the Clin J Am Soc Nephrol 3: S87–S100, 2008 Cancer Screening in Renal Transplant Recipients S89 individual’s overall survival and quality of life and not remain insig- biennial mammographic breast cancer screening reduces breast nificant during their lifetime. The trade-off for a better, sensitive test is cancer–related mortality by 20 to 30% (3,4). A stage shift to a overdetection of inconsequential diseases (8). For example, detecting in more benign phase was also observed, and in most cases, there a 75-yr-old man low-grade prostate cancer that does not manifest and was a reduction in the incidence of advanced diseases. The progress to symptomatic disease during his lifetime will incur unnec- sensitivity and specificity of mammography reported were 75 essary costs, treatment anxiety, and complications for the individual. and 94%, respectively (25). In these trials, test accuracies also varied substantially with age and breast density. Sensitivity Cost-Effectiveness of the Intervention and specificity were highest in older women with fatty breast Given that the demand for health care resources always exceed the tissue and lowest among younger women with denser breast supply, cost-effectiveness of any proposed intervention is important to tissue (26). policy makers. Economic evaluations, which present reliable effective- Recommendations for breast cancer screening in the renal ness estimates while adjusting the costs and trade-offs in the process, have been performed increasingly alongside clinical trials to provide a transplant population are based on screening guidelines in the holistic and comprehensive perspective in clinical decision-making. general population. No studies have evaluated the effectiveness The quality of the evaluation depends on the quality of the trial; and accuracies of mammographic screening in the transplant structure and design of the study; accuracy and validity of the collected population. While female transplant recipients have a similar data; and whether the researcher, using sensitivity analyses, has ex- breast cancer risk, before extrapolating from the general pop- plored the uncertainty appropriately and explicitly in the parameter ulations, consideration must be given to whether they might estimates. Economic evaluations are critically appraised using these attain the comparable benefits because of the reduced overall criteria. Failure to address any of these issues will result in invalid life expectancies, potential differences in test performance, and assessment. harms from mammographic breast cancer screening. Harms from Breast Cancer Screening. Potential harms in- Harms and Benefits of Screening clude psychological distress and pain and discomfort with The benefits of screening must outweigh all harms in any screening mammographic screening. Complaints from women include decision. If there is clear evidence of benefits from screening trials, then machine compression and roughness from the operator (27). screening may be beneficial only if harms are carefully considered and Exposure to mammographic x-rays also confers the risk for weighed for each individual. The benefits observed in screening trials may not be generalizable to all participants. The extent of harm varies radiation-induced breast cancer, which is greatest if exposure with uncertainty between individuals. Harms include both the physical occurs at a younger age. The risk of benign breast neoplasms and the psychological consequences associated with investigations and has been shown to increase in transplant recipients who have treatment of the disease. The choice of screening is therefore an in- used cyclosporine as part of their immunosuppressive regimen. formed decision with clear, unbiased information, provided by guide- These adenomas tend to be multiple, large, and dense. An lines and recommendations, about the risks, benefits, and harms for increased incidence of benign breast calcifications was ob- each individual. served in women who had ESKD and were on dialysis, which led to an increased callback rate for biopsies (28). False-positive Results findings will lead to unnecessary and exhaustive diagnostic Cancer screening guidelines specific to renal transplant recipi- procedures such as fine-needle and core biopsies of the breasts ents from European and American professional bodies were (29). reviewed (9–12). Guidelines from other international societies Cost-Effectiveness of Breast Cancer Screening. Economic for the general population were also extracted (13–21). Recom- analyses performed using estimates from RCT and population mendations made by the two transplantation societies, the studies have shown that breast cancer screening is relatively American Society of Transplantation (AST) and the European cost-effective in the general population. The incremental cost- Best Practice Guidelines on renal transplantation (EBPG) were effective ratio (ICER) ranged between $18,000 and $45,000 per compared with those applied to the general population using life-year saved (LYS) with biennial mammography (30,31). accepted criteria for an evidence-based screening program (5,6) Models of breast cancer screening in renal transplant recipients (as shown in Tables 2 through 4). suggest that breast cancer screening may be cost-effective in the average-risk nondiabetic white population (32). Breast Cancer Screening Most international guidelines suggest screening to commence Cervical Cancer Screening at age 50 for all women of average cancer risk. Screening Cervical cancer screening is recommended in the general pop- intervals recommended by most societies are between 12 and ulation. Most guidelines recommend regular cytologic testing 24 mo (22–24). The ATS and EBPG on renal transplantation to commence between the ages of 18 and 20 or when sexual recommend breast cancer screening in all female renal trans- activity begins. Some suggest that screening should be deferred plant recipients between 50 and 69 yr of age. Women between until 2 to 3 yr after first sexual intercourse (18,33–35). Waiting 40 and 49 yr could still undergo screening mammography 3 yr after first sexual intercourse ensures transient infections every 1 or 2 yr, but there is no evidence for or against screening that clear spontaneously will not be detected but allows suffi- in this age group (11,12). cient time to detect cancerous lesions derived from more per- Are the Recommendations Valid? Large randomized, sistent human papillomavirus (HPV) infection (18,35,36). controlled trials in the general population had confirmed that Cervical cancer, a virus-related neoplasia, is more aggres- 9 lnclJunlo h mrcnSceyo Nephrology of Society American the of Journal Clinical S90

Table 2. Recommendations for routinely screened cancers in the general populationa

RCT Evidence of Screening that Test Performance Earlier Intervention Works Cost-Effectiveness, Cancers Recommendations ICER ($/LYS) Trials Participants (n) Results Sensitivity (%) Specificity (%)

Breast Biennial 6 (94) 369,370 Cancer-specific Mammography Mammography 18,000 to 22,000 mammography for all mortality reduction 20 75% (25) 94% (25) (95) women older than 50 to 24% (94) yr (23,24) Colorectal Annual or biennial 4 (96) 329,642 Cancer-specific FOBT, unrehydrated FOBT, unrehydrated 10,000 to 30,000 (63,97) FOBT at age Ͼ50 (48); mortality reduction 15 81%; rehydrated, 92% 97%; rehydrated 90% combination of FOBT to 23% (96) (51) (51) and flexible sigmoidoscopy at age Ն50 (16,17) Cervical Cytological screening Convincing Pap smear, Pap smear, 25,000 to 50,000 to commence in evidence from conventional 84.6%; conventional 37.0%; (98) women age Ն21 yr observational studies liquid based, 94.2% liquid and/or women within have shown significant (44) based 57.7% (44) 3 mo of first sexual reduction in the intercourse (biennially incidence of advanced or triennially) (36) cervical cancer and cancer-specific lnJA o eho :S7S0,2008 S87–S100, 3: Nephrol Soc Am J Clin mortality after the introduction of population cervical cancer screening

a FOBT, fecal occult blood testing; ICER, incremental cost-effective ratio; LYS, life-year saved lnJA o eho :S7S0,2008 S87–S100, 3: Nephrol Soc Am J Clin

Table 3. Recommendations for cancers that are not routinely screened in the general populationa

RCT Evidence of Screening that Test Performances Earlier Intervention Works Cost-Effectiveness, Cancers Recommendations ICER ($/LYS) Trials (n) Participants (n) Results Sensitivity (%) Specificity (%)

Prostate No general consensus 2 (88) 57,511 No significant PSA 72.1 (CI 66.7 to PSA 93.2 (CI 63.1 to 65,000 to 125,000 USPSTF found no evidence to mortality reduction in the 100.0) (88) 100.0) (88) (93) recommend for or against intervention group DRE 53.2 (CI 49.0 to DRE 83.6 (CI 18.0 to routine screening using PSA 69.2) (88) 99.5) (88) and DRE (84) ACS recommends annual screening using PSA and DRE in men older than 50 (18) The American College of Physicians made no firm suggestions about screening and believes that the decision to screen should be individualized (85) Hepatocellular No firm recommendation; 2 (78) 19,884 No significant ␣-Fetoprotein ␣-Fetoprotein 95 112,993 to 284,000 however, screening using mortality reduction in 68.6 (78) (78) (82)

␣-fetoprotein testing and the intervention group Ultrasound 84.3 (78) Ultrasound S91 Recipients Transplant Renal in Screening Cancer abdominal ultrasound should Both 60.8 (78) 97.1 (78) be considered in high risk Both 95 (78) individuals (13) Lung No recommendation 6 (using CXR and/or sputum 103,441 No significant No data No data 19,000 to 62,000 exam) (71) mortality reduction in (99) the intervention group Renal No recommendation No RCT to show screening using No data No data No data renal ultrasound improves cancer-specific and overall mortality Skin Insufficient evidence to 1 RCT using total body skin Total body skin exam Total body skin exam 98 29,170 to 50,000 recommend for or against total exam is now under way (65) 94 (100) (100) (66) body skin examination (64)

a ACS, American Cancer Society; CXR, chest x-ray; DRE, digital rectal examination; PSA, prostate-specific antigen; RCT, randomized, controlled trial; USPSTF, US Preventive Services Task Force. S92 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: S87–S100, 2008

Table 4. Recommendations for cancer screening in renal transplant recipients

RCT Evidence that Earlier Test Cost-Effectiveness, Cancers Recommendation Intervention Works Performances ICER ($/LYS)

Breast Annual or biennial Nil No data 32,000 (32) mammography for all women older than 50 yr Women between 40 and 49 could still undergo screening, but no evidence for or against screening at this age (10,12) Colorectal Annual FOBT and/or 5-yearly Nil No data 25,189 (32) flexible sigmoidoscopy for individuals older than 50 yr (10,12) Cervical Annual cytological cervical Nil No data No data cancer screening and pelvic examination once sexually active (10,12) Prostate Annual DRE and PSA Nil No data 56,850 (32) measurement in all male renal transplant recipients older than 50 yr (10,12) Hepatocellular ␣-Fetoprotein and ultrasound Nil No data No data performed every 6 mo in high-risk individuals, but no firm confirmation (10,12) Skin Monthly self-skin examination, Nil No data No data total body skin examination every 6 to 12 mo by expert physicians and dermatologists (11,12) Renal No firm recommendation; Nil No data No data some suggested regular ultrasonography of the native kidneys (10,12)

sive and develops rapidly in immunocompromised states HPV DNA testing, however, came at the expense of reduced (37,38). The American College of Obstetrics and Gynaecol- specificity of the test. This effect is greater on older than ogy specifies that women of high-risk groups should be younger women. In younger women (Ͻ35 yr of age), the over- screened more frequently (36). The two transplantation so- all test specificity of HPV DNA testing reduced to 90% (76.5 to cieties recommend annual cervical cancer screening with Pap 95.5%) compared with 95.5% with cytological testing. For smear and pelvic examination in all adult female renal trans- women Ն35 yr of age, the overall test specificity of HPV DNA plant recipients (10,12). testing is 93.3% (87.3 to 96.4%) (40). There is no RCT evidence Are the Recommendations Valid? Cervical cancer screen- to confirm its overall mortality and morbidity benefits as a ing using the Pap test was first introduced in the United States primary screening tool in the general population. in the early 1950 without evidence of mortality benefits from Evidence to support for or against the use of HPV DNA RCT. Observational studies, based on historical data across the alone or in combination with cytological testing in the renal United States and Europe, had demonstrated significant reduc- transplant population is also sparse. Use of immunosuppres- tion in incidence and mortality of invasive cancer since the sive therapy after transplantation may cause reactivation of introduction of population cytological cancer screening (39). latent diseases and reduction in host ability to contain HPV Some international societies now recommend the use of HPV infection. There is now emerging evidence to show an in- DNA as an adjunct to cytological screening in women who are creased incidence of oncogenic cervical HPV infections (HPV 16 older than 30 yr in the general population. HPV DNA has been and 18) among renal transplant recipients (41,42). Uncertainty, shown to perform better than cytological testing, with a test however, exists in the likely progression of these oncogenic sensitivity of almost 95% (40). The increase in sensitivity with infections and the significance of detecting early oncogenic Clin J Am Soc Nephrol 3: S87–S100, 2008 Cancer Screening in Renal Transplant Recipients S93

HPV DNA strains in the prevention of future cancers. Early screening using flexible sigmoidoscopies in the general popu- detection and effective eradication of these infections is worth- lation (52,53). while only if there is evidence to show that such practices Despite having an increased risk and reduced prognosis, no reduce cancer-related morbidity and mortality. clinical trials to date have evaluated the benefits of colorectal Harms from Cervical Cancer Screening. Screening is a test cancer screening in renal transplant recipients. Studies have done on asymptomatic, well women. Screening may identify suggested the positive predictive value (PPV) of FOBT screen- inconsequential diseases that are not clinically significant. De- ing in the chronic kidney disease (CKD) population (stages 3 to tection of low-grade diseases and false-positive results can lead 5) increases as the severity of CKD increases (54). The impact of to invasive diagnostic procedures, unnecessary treatment, and renal transplantation on the test performance of FOBT screen- unwarranted psychological distress. In certain societies and ing, however, is unknown, but there are good reasons to believe ethnic backgrounds, the diagnosis and labeling of someone that false-positive rates would be increased for a variety of with high risk for cervical cancer could create potential preju- reasons, including increased tendency to bleed as a result of dice and stigma against the individual; however false-negative infectious complications, angiodysplasia, direct mucosal drug results could delay diagnosis and treatment, creating a false toxicity, and minor mucosal inflammation (32,55). sense of security and assurance. Harms from Colorectal Cancer Screening. FOBT itself Cost-Effectiveness of Cervical Cancer Screening. A num- might seem harmless, but the diagnostic colonoscopy that fol- ber of economic models have evaluated population cervical lows carries significant morbidity risks. Potential complications cancer screening from different countries. Data used in these from a colonoscopy include perforations, bleeding, abdominal models originated from historical and observational evidence pain, splenic trauma, subcutaneous emphysema, and problems of cervical screening. Most concluded that cervical cancer related to sedation and anesthetic. Patients with CKD and other screening in the general population is cost-effective. The aver- underlying risk factors for kidney dysfunction, such as diabe- age ICER ranged between $25,000 and $50,000/LYS with bien- tes, are also at increased risk for acute phosphate nephropathy nial and triennial screening (43,44). The cost-effectiveness of after oral phosphate bowel cleansing agents (56–58). Self-test- cervical cancer screening among renal transplant recipients has ing FOBT is not at all pleasant. It is often untidy and embar- not been assessed. rassing for the patient. Patients with false-positive results would have to endure the psychological and physical trauma of Colorectal Cancer Screening exhaustive diagnostic procedures, which seem futile in some Most practice guidelines suggested the use of flexible sigmoid- cases. oscopy in combination with annual fecal occult blood testing Cost-Effectiveness of Colorectal Cancer Screening. Cost- (FOBT) screening every 5 yr in the United States (16–19). In effectiveness and cost-utility analyses have shown that colorec- Australia, biennial immunochemical FOBT is the recommended tal cancer screening is cost-effective in the general population. screening tool of the National Health and Medical Research In the Australian colorectal cancer screening pilot study, the Council of Australia (45). All positive test results must then be ICER ranged between A$20,000 and $24,000/LYS with pro- followed by total colonic examination using colonoscopy for grams targeted at ages between 50 and 74 and between 55 and verification of diagnosis and for treatment if required. 74, respectively (59). Using outcomes and costs data from the The AST recommends annual FOBT screening and flexible RCT, the estimated ICER was US $10,000 to $17,000/LYS (60– sigmoidoscopy screening every 5 yr to begin in all renal trans- 64). The cost-effectiveness of colorectal cancer screening in plant recipients from the age of 50 yr (12). There is no recom- renal transplant recipients remains unanswered. Renal trans- mendation to begin screening at an earlier age, despite strong plant recipients confer different disease prevalence, risks, and evidence to suggest that colorectal cancers occur at a much overall survival, all of which could potentially influence the younger age in transplant recipients (46). The EBPG suggested cost-effectiveness of screening and treatment. Without reliable the use of annual FOBT screening in renal transplant recipients evidence to confirm the true benefits of FOBT screening in renal according to the national recommendation in the general pop- transplant recipients, it is inappropriate to implement popula- ulation (10). tion colorectal cancer screening in renal transplant recipients. Are the Recommendations Valid? It has been proven by The choice and method of colorectal cancer screening in the four large RCT that screening for early colorectal cancers and average-risk transplant recipient should be assessed on an in- precancerous polyps with guaiac FOBT reduces colorectal can- dividual basis. cer mortality (47–50). The test sensitivity varies between 46% (unrehydrated) and 92% (rehydrated) and specificity between Recommendation for Skin Cancer Screening 97% (unrehydrated) and 90% (rehydration) (51). The benefits The American and European transplantation organizations rec- and harms of colorectal cancer screening using flexible sig- ommend skin cancer screening in renal transplant individuals moidoscopy are uncertain in both the general and transplant using monthly self-skin examination and 6- to 12-monthly total populations. Prospective case-control studies have suggested a body skin examination by expert physicians and dermatolo- cancer-specific mortality reduction of 35% with screening every gists. The US Preventive Services Task Force concluded that 3 to 5 yr. These studies, however, were subjected to recall and there is insufficient evidence to recommend for or against pop- interviewer biases. Large RCT are now under way in the United ulation skin cancer screening using total skin examination (64). States and Europe to assess the benefits of colorectal cancer The American College of Preventive Medicine recommended S94 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: S87–S100, 2008 that high-risk individuals be screened regularly, but no recom- and minor bleeding, pain, and infections. Major bleeding mendation was made for individuals with low risk for skin events can lead to graft dysfunction and loss. The psychological cancers (21). impact of receiving a diagnosis of a serious malignant disease is Are the Recommendations Valid? There is no evidence enormous on an individual. It can lead to unwanted anxiety from RCT to verify that total body skin cancer examination and stress on both the patients and their families. reduces skin cancer mortality and no data to suggest that early Cost-Effectiveness of Renal Cancer Screening. There are treatment for either melanoma and nonmelanocytic skin can- no data on the cost-effectiveness of renal carcinoma screening cers found by screening reduces the overall skin cancer–related in both the renal and general populations. Cost-effectiveness, mortality and morbidity in the general and renal transplant treatment outcomes, and benefits must be considered before populations. An RCT that involves Ͼ600,000 participants is promoting the use of expensive, potentially harmful diagnostic now being conducted in Queensland, Australia, to evaluate the and screening procedures. mortality and morbidity benefits of skin cancer screening using self-skin and total body skin examination by physician (65). The Recommendations for Lung Cancer Screening results of this landmark trial will be available in the next Most of the American cancer screening guidelines also found decade. insufficient evidence to recommend for or against lung cancer Harms from Skin Cancer Screening. False-positive results screening using chest x-ray, sputum cytology, and low-dosage from skin cancer screening can generate anxiety and unneces- computed tomography (CT) in the general population sary biopsies and procedures in transplant individuals. Risks (18,33,68–70). There is no recommendation for population lung for poor wound healing, bleeding, and postoperative infections cancer screening in average-risk, asymptomatic individuals in are significantly higher in the renal transplant population as a Australia and New Zealand. Screening for lung cancers is also result of heavy immunosuppression use. Misdiagnosis of mel- not recommended in renal transplant population. anoma can also create psychological and financial impact on these individuals. No studies so far have evaluated the extent of Are the Recommendations Valid? harm in relation to any of the recommended skin cancer screen- None of the six RCT in the general population using chest ing tools in both the transplant and general populations. x-rays alone or combined with sputum cytology demonstrated Cost-Effectiveness of Skin Cancer Screening. The incre- mortality benefits in the screened populations (71). In fact, two mental cost-effectiveness ratio for skin cancer screening using of the trials showed that lung cancer mortality was significantly total body skin examination by expert dermatologists was es- greater in the group with more frequent chest x-ray screenings timated to be $29,170 per LYS (66). This is comparable to most than less intense screening after a longer follow-up period established screening programs. This analysis is based on the (72,73). There is now emerging evidence from observational assumption that the incidence of late-stage melanomas will studies to suggest that low-dosage spiral CT increases the de- decrease with periodic skin cancer screening. It is the savings tection rate of stage I lung cancer and 5-yr survival in high-risk from treating high-grade melanomas that offset most of the individuals (74). This finding, however, may represent overde- costs of screening. This assumption, however, has not been tection and lead-time bias with no real benefit in overall cancer- proven in RCT. specific mortality. One large RCT is in progress, with the aim to provide an unbiased assessment of lung cancer screening with Recommendation for Renal Cancer Screening this potential screening tool (75). Screening for renal carcinoma is not recommended in the gen- Harms from Lung Cancer Screening. Abnormalities such eral population. The incidence of renal cell carcinoma is in- as noncalcified nodules detected on radiology will result in creased in renal transplant recipients and, in particular, recip- additional testing: High-resolution CT, positron emission to- ients with acquired cystic disease of the kidneys (67). The AST, mography scanning, bronchoscopy, lung biopsy, and resection. however, also found no evidence to support regular screening These procedures are costly and invasive and are associated using ultrasonography or other radiology and urine cytology in with diagnostic- and treatment-related complication rates. renal transplant recipients. Greater effort is required to limit the extent of false-positive and Are the Recommendations Valid? Ultrasonography is -negative results. Further investigation is needed to evaluate thought to be the instrument of choice because it is relatively the risk for lung cancer from excessive radiation exposure, the inexpensive, noninvasive, and easily accessible, yet no studies issues of overdetection, and the emotional aspect of a false- have assessed its efficacy and accuracy as a screening test. positive and ambiguous test result among the transplant and Renal ultrasonography is insensitive in detecting small lesions; general populations. its effectiveness as a screening tool to detect early-stage disease Cost-Effectiveness of Lung Cancer Screening. An eco- is questionable, especially in abnormal end-stage kidneys, some nomic analysis was performed to assess the cost-effectiveness of which will have acquired cystic disease. of annual chest x-ray screening for lung cancer in the general Harms from Renal Cancer Screening. Findings of an ab- population using parameter estimates from the four RCT. The normality with ultrasonography screening will invariably lead base model showed an ICER of $20,000/LYS (76). This analysis to biopsies for histologic confirmation of disease. False-positive is based on the assumption that lung cancer screening using results will result in unnecessary invasive diagnostic proce- annual chest radiography reduces cancer-specific mortality by dures. Potential adverse events from biopsies include major 18%. The validity of this assumption is questionable when none Clin J Am Soc Nephrol 3: S87–S100, 2008 Cancer Screening in Renal Transplant Recipients S95 of the trials showed any mortality benefits. Although there is ated from false-negative tests is another concern. It is often evidence to demonstrate that the stage distribution is much difficult to diagnose small lesions on ultrasonography espe- more favorable in the screened groups, it is not justifiable to cially in the case of cirrhotic nodular liver. HCC is a disease assume that the effect of the stage shift correlates to the changes with rapid progression. It is highly aggressive, slight delay in in life expectancies of the screened individuals as held in the treatment can render the disease incurable. model. Cost-Effectiveness of HCC Screening. There is limited information regarding the cost-effectiveness of HCC screening in Recommendation for Hepatocellular Carcinoma Screening the general population and none in the renal transplant popu- Screening for hepatocellular carcinoma (HCC) is not recom- lation. The ICER of annual screening with ␣-fetoprotein and mended for average-risk individuals in the general population. ultrasonography compared with no screening varied between For the high-risk population, periodic ␣-fetoprotein testing and $23,034 and $26,689 per quality-adjusted life-year in two cost- ultrasound every 6 to 12 mo may be useful to detect HCC at an utility studies (80,81), whereas in others, it ranged between early stage (13). The British Society of Gastroenterology sug- $112,993 and $284,000/LYS (82,83). The cost-effectiveness of gested that screening be considered in both genders with es- HCC screening in the general population among high-risk in- tablished cirrhosis secondary to hepatitis B virus, hepatitis C dividuals is inconclusive. virus, and genetic hemochromatosis (14). The absolute risk for having HCC in women with alcoholic and primary biliary Recommendation for Prostate Cancer Screening cirrhosis as well as individuals with cirrhotic livers associated Prostate cancer screening remains debatable in both the general with autoimmune hepatitis and primary sclerosing cholangitis and renal transplant populations. The US Preventive Services is relatively low. If screening is proposed, then it should be Task Force found no evidence to recommend for or against performed every 6 mo with ␣-fetoprotein and abdominal ultra- routine prostate cancer screening using prostate-specific anti- sound (14). gen (PSA) and digital rectal examination (DRE) in average risk The AST made no firm recommendation for HCC screening individuals (84). The American Cancer Society recommended in renal transplant recipients. They concluded the use of ␣-fe- annual screening with PSA and DRE in men who are older than toprotein and abdominal ultrasound may be useful in the early 50 yr and have a life expectancy of at least 10 yr (18). The detection of HCC only in the high-risk groups. American College of Physicians made no firm suggestions Are the Recommendations Valid? A systematic review about prostate cancer screening but recommended that infor- that included only two RCT evaluated the effectiveness and mation about the risks and benefits of screening be given to accuracies of HCC screening in patients with hepatitis B surface each person by the health care provider and that the decision to antigen in the general population using ␣-fetoprotein and/or screen be individualized (85). The AST and the EBPG encour- abdominal ultrasonography on a biannual basis (77–79). None age annual prostate cancer screening with DRE and PSA mea- of the trials showed significant improvement in HCC mortality surement in all male renal transplant recipients who are older after initial follow-up, and neither of them assessed all-cause than 50 yr and have a life expectancy of at least 10 yr (10,12). mortality. Are the Recommendations Valid? The benefits of prostate Test accuracies, calculated from these trials, showed that the cancer screening in renal transplant recipients have not been ␣ overall sensitivity and specificity for -fetoprotein, with a cut- assessed in any studies. Two RCT, conducted in North America off point at 20 ng/L, ranged between 64.3 to 68.6% and 91 to and Europe, evaluated the effectiveness of prostate cancer 95%, respectively (78). Ultrasonography performed better than screening in average-risk men who were Ն50 yr using PSA and ␣ -fetoprotein with the overall sensitivity and specificity be- DRE in the general population. In the Quebec trial, there was a tween 71.4 to 84.3% and 93.8 to 97%, respectively (78). When 62% reduction of cancer-related mortality in the screened group ␣ -fetoprotein and ultrasonography were used in combination, (86). In the Norrkoping study, there were no significant differ- the sensitivity was 60% and specificity was 95% (78). It is ences in prostate cancer–related mortality and all-cause mor- apparent that neither method is ideal because both tests confer tality in the screened population (87). The inconsistencies be- high false-positive and -negative rates. Similar to most other tween the two trials could be related to the method of cancers, there is no evidence to suggest for or against HCC randomization, potential contamination of the unscreened screening in the average-risk renal transplant recipient. group by opportunistic screening, and the poor participation Harms from HCC Screening. None of the randomized rate in one of the trials. When these two trials were later controlled trials considered harms created by HCC screening. assessed in a systematic review, they did not show an improve- The diagnosis of HCC carries a significant psychologic and ment in prostate cancer–related mortality and morbidity (88). physical burden to an individual. Screening is only worthwhile PSA and DRE have been used as the screening tool for if the diagnosis is correct and there is effective treatment to prostate cancers in the past decade. A number of observational improve overall mortality outcomes. Based upon limited data, studies have evaluated the test accuracies of these tests. Most of the proposed screening tool is far from perfect. Surgical inter- these studies were flawed with verification biases whereby vention such as liver transplantation and surgical resection only those with a positive PSA or DRE finding were investi- might be favorable for early stage cancer but it carries signifi- gated by the reference standard, prostate biopsies. The overall cant postoperative complications, especially from acute hepatic pooled sensitivity, specificity, and positive PPV for PSA exam- decompensation, bleeding and infections. False-assurance cre- ined by a recent meta-analysis, with the accepted cutoff level of S96 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: S87–S100, 2008

Ͼ4 ng/ml, were 72.1, 93.2, and 25.1%, respectively. The results studies in this population, good-quality trials, preferably RCT, for DRE were 53.2, 86.2, and 17.8%, respectively (88). Test are needed to address the issues of mortality benefits, harms, performance of PSA and DRE has not been assessed in renal screening test accuracies, and the cost-effectiveness of cancer transplant recipients. In patients who had ESKD and were on screening in the renal transplant population. In the absence of dialysis, the overall test sensitivity of PSA was poor, with an such studies, an individualized approach to screening should estimated test sensitivity of 66.7% and PPV of 50% using a be used and based on the individual’s cancer risk, existing standard cutoff of Ͼ4 ng/ml (89). comorbidities, overall life expectancy, and preference for Two large, well-structured, and well-powered RCTs are now screening. Clinicians should give patients balanced information under way in the United States and Europe, involving Ͼ100,000 about their benefits and competing harms of screening so that people in each study to assess the effectiveness and efficacies of they can decide on their choice about screening. prostate cancer screening in average-risk individuals (90,91). The uncertainties and controversies may be resolved when the Acknowledgments results of these trials are reported in the next decades. G.W. conceived and designed the study, performed the literature Harms of Prostate Cancer Screening. Concern about the search, analyzed and interpreted the results, and wrote the manuscript; consequences of overdetection and overdiagnosis is most ap- J.R.C. conceived and designed the study, advised on the presentation of plicable in prostate cancer screening. Approximately 10 to 15% results, analyzed the results, and revised the manuscript; J.C.C. con- of men will develop clinically significant prostate cancer in ceived and designed the study, advised on the literature search, ana- their lifetime, but approximately 40% of men who are older lyzed and interpreted the results, advised on the presentation of results, than 80 yr have incidental prostate cancer found at autopsy and revised the manuscript. (92). The significance of diagnosing and treating inconsequential disease is unknown. In most instances, men are reluctant to Disclosures “watch and wait” after the detection of early-stage cancers, and None. clinicians are obliged to treat for the fear of medicolegal consequences. The treatment itself, however, is not at all benign. Complications such as erectile dysfunction, urinary/fecal in- References continence, and radiation cystitis can have major adverse phys- 1. 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