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Keywords:

  • Cancer;
  • kidney transplantation;
  • risk;
  • screening

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary Prevention and Lifestyle Choices
  5. Immunization and Chemoprevention
  6. Is Increased Prevalence of Cancer Enough to Justify Screening?
  7. Can Screening Have Negative Consequences?
  8. Do Screening Tests Perform Well in the Transplant Population?
  9. Can We Improve Decision Making for Transplant Recipients?
  10. References

Kidney transplant recipients are at higher risk of cancer at most sites, and cancer after transplantation causes considerable morbidity and mortality. To optimize long-term patient outcomes, clinicians balance the prospect of graft failure and dialysis, with competing risks of diabetes, cardiovascular and cerebrovascular disease and the risk of malignancy. In this paper we critically examine the assumptions underpinning primary prevention, immunization, chemoprevention and screening programs, and highlight considerations when applying evidence to the kidney transplant population, and suggest a clinical research agenda that aims to define a rational approach to managing posttransplant cancer risk.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary Prevention and Lifestyle Choices
  5. Immunization and Chemoprevention
  6. Is Increased Prevalence of Cancer Enough to Justify Screening?
  7. Can Screening Have Negative Consequences?
  8. Do Screening Tests Perform Well in the Transplant Population?
  9. Can We Improve Decision Making for Transplant Recipients?
  10. References

It has been known for many years that solid organ transplant recipients are at higher risk of cancer at most sites. More recently, risk has been described in detail for kidney transplant recipients (1,2). Cancer is a major cause of morbidity after transplantation, with up to one-third of deaths with a functioning allograft due to cancer (3). Yet, with an aging transplant population the presence of additional comorbidity is increasingly common, and so, in aiming to optimize long-term patient outcomes, clinicians' advice must balance the prospect of graft failure and dialysis, with competing risk of diabetes, cardiovascular and cerebrovascular disease and the risk of malignancy.

Once transplanted, how should we advise our patients, and balance our anxieties of known increased cancer risk, with a reasoned approach to cancer prevention, screening and management? In the face of uncertainty, a temptation is to advise all preventative and screening strategies possible, without considering evidence of benefit, or of potential harm, based on the assumption that activity must prevail over masterly inactivity. Through better understanding the principles behind cancer prevention and screening, and their application in a posttransplant population, could we develop a more rational approach?

In this paper we aim to critically examine the assumptions underpinning primary prevention, immunization, chemoprevention and screening programs, and highlight the existing evidence from the transplant population, and where this does not exist, from the general population. Finally, we suggest an agenda for improving the evidence base we use for cancer risk decision making after kidney transplantation.

Primary Prevention and Lifestyle Choices

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary Prevention and Lifestyle Choices
  5. Immunization and Chemoprevention
  6. Is Increased Prevalence of Cancer Enough to Justify Screening?
  7. Can Screening Have Negative Consequences?
  8. Do Screening Tests Perform Well in the Transplant Population?
  9. Can We Improve Decision Making for Transplant Recipients?
  10. References

Primary prevention aims to prevent or minimize occurrence of cancer by limiting or removing exposures that are associated with increased cancer risk (Figure 1). For kidney recipients, two important exposures that contribute to increased cancer risk are unavoidable. End-stage kidney disease (ESKD) in itself is associated with increased cancer risk at many sites and after transplantation, the additional burden of the immunosuppression necessary for continued graft function amplifies cancer risk further (1,2,4). Table 1 summarizes the relative increase in common cancers for kidney recipients, when compared to the general population.

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Figure 1. The natural history of chronic disease: The overlap of cancer and end-stage kidney disease comorbidities creates decision-making difficulties in applying preventive medicine.

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Table 1.  Rate ratios of common cancers in kidney recipients, based on registry analyses, compared with rates in the age- and sex-matched general population
Cancer site (ICD code)2006(1) Australia Vajdic2007(15) Canada Villeneuve2000(16) Denmark Birkeland2003(17) Sweden Adami2004(18) United States Kasiske
  1. na = Estimate not available.

All (excluding nonmelanocytic skin)3.3 (3.1,3.5)2.5 (2.3,2.7)3.6 (3.1,4.1)  3.9 (3.6,4.2)na
Breast (female, C50)1.0 (0.8,1.3)1.3 (1.0,1.7)1.5 (0.7,2.6)  1.0 (0.6,1.5)1.1 (0.9–1.3)
Colon (C18)2.4 (1.9,2.9)1.4 (1.0,1.8)na  2.4 (1.5,3.5)na
Cervix (C53)2.5 (1.5,4.3)1.6 (0.6,3.4)na  2.0 (0.7,4.7)5.7 (4.2–7.2)
Lung (C33–C34)2.5 (2.0,3.0)2.1 (1.7,2.5)na  1.7 (1.1,2.5)2.8 (2.5–3.0)
Prostate (C61)1.0 (0.7,1.3)0.9 (0.6,1.3)na  1.1 (0.7,1.7)1.6 (1.4–1.8)
Melanoma (C43)2.5 (2.1,3.1)1.9 (1.2,3.0)1.4 (0.3,3.9)1.8 (1,3) 6.3 (5.4–7.0)

General lifestyle choice policies recommended for the general population such as healthy eating and stop-smoking campaigns have benefits in beyond cancer prevention, and it is generally agreed and should be encouraged and implemented in the transplant population (5,6). Modifiable life style risk factors known to impact on cancer risk in the general population are also important in transplant recipients. The association between nonmelanocytic skin cancers and melanoma with ultraviolet radiation (UV) is well established. Incidence of skin cancer increases with duration of residence in locations of high-ambient UV radiation.

Compared with the general population, in transplant recipients skin cancer develops at a younger age, and occurs more frequently at multiple sites. There is reversal of the ratio of basal cell carcinomas (BCC) to squamous cell carcinomas (SCC), with SCC occurring more commonly (in the general population the ratio of BCC: SCC is 4:1). Skin cancers also behave more aggressively, with more frequent recurrence after resection and metastasis, and can cause death (7). The best protection against solar radiation is a combined approach of avoidance of the sun during peak UV hours (10 am to 4 pm), protective clothing and application of sunscreen to sun-exposed areas (8). Despite this, awareness among renal allograft recipients of their increased skin cancer risk is poor (60%), and only a proportion of recipients use regular and appropriate sun-protective behaviors (9). Randomized trial (RCT) evidence shows that education changes people's behavior: kidney recipients who received intensive written education about the benefits of sun protection were significantly more adherent to recommendations for sun-protective behavior (10).

Immunization and Chemoprevention

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary Prevention and Lifestyle Choices
  5. Immunization and Chemoprevention
  6. Is Increased Prevalence of Cancer Enough to Justify Screening?
  7. Can Screening Have Negative Consequences?
  8. Do Screening Tests Perform Well in the Transplant Population?
  9. Can We Improve Decision Making for Transplant Recipients?
  10. References

The pathogenic role of infections in carcinogenesis may offer opportunity to intervene to reduce risk. Although immunization against infections known to have oncogenic potential may seem an obvious preventive strategy for transplant recipients, achieving a protective immune response following vaccination is not always possible. In general, relative antibody response to a vaccine appears to correlate with the degree of chronic kidney disease, which is likely to be due to the general immunosuppressive effect of uremia. People on dialysis have a reduced response to vaccination, with a lower antibody titer and an inability to maintain adequate antibody titers over time (11). Antibody response after transplantation is usually even worse, particularly in the first posttransplant year, when the burden of iatrogenic immunosuppression is most intense.

Vaccination against Hepatitis B is currently recommended before the commencement of renal replacement therapy, along with Varicella zoster and Hepatitis A, to maximize overall response and seroconversion (12). Although primarily directed to prevent blood-borne infection and subsequent liver disease in people with ESKD, Hepatitis B vaccination has a role in reducing risk of hepatocellular carcinoma, as people with chronic infection with hepatitis B experience greatly increased risk.

Emerging preventive measures of specific relevance to kidney graft recipients include human papillomavirus (HPV) vaccine against HPV-related cancers. HPV has been implicated in cancers of the anogenital tract (particularly cervical cancer in females) and the oropharynx and HPV DNA can be detected in up to 90% of skin cancers in transplant recipients (though a causative role of HPV infection has not been proven) (13). Bivalent (HPV-16/18) and quadrivalent (HPV-6/11/16/18) vaccines, are now available for the protection of HPV-naïve girls and women against primary HPV infection. Worldwide, HPV types 16 and 18 are associated with approximately 70% of cervical cancers, while HPV 6 and 11 cause 80% of genital warts (14). Up to 40% of infected women are infected with more than one HPV type. Recent RCTs in the HPV-naïve general population have shown both vaccines to be safe, immunogenic and approximately 90% effective against type-specific persistent infection (19,20). These trials showed antibodies persist for at least 5 years after vaccination, but the precise level of antibody needed for protection against new infection is unknown. While HPV vaccination can still protect women with current HPV infection from acquiring coinfection with additional HPV types, it has no effect on HPV infections present at the time of vaccination. Cost-effectiveness models of general population vaccination are hampered by substantial uncertainty regarding major issues such as duration of protection, the effect of herd immunity and the prevalence of vaccine-specific HPV types circulating in the population, which differs by geographical area, and may be altered should widespread vaccination be implemented (21).

Will HPV vaccination be helpful to kidney transplant recipients, who have higher overall HPV infection rates? Routine posttransplant vaccination may be ineffective for two reasons: because recipients may already be infected with HPV, and if naive, may have delayed antibody response, lower seroconversion rates and a more rapid decline in antibodies than the general population. Early pretransplant (preferably predialysis) HPV vaccination in girls and young women is probably safe and may be beneficial in reducing the incidence of HPV-16- and 18-related cervical disease/neoplasia.

The role of chemoprevention in preventing skin cancers in transplant recipients is less certain (Figure 1). HPV (HPV-5 and 8) associated with warts and cutaneous squamous cell dysplasia, is more prevalent among transplant recipients than the general population (22). Oral retinoids, acting via cellular retinoid receptors, alter gene transcription and allow apoptosis of cancer cells, in particular squamous epithelial cells. RCT evidence shows a moderate reduction in the incidence of SCC among individuals randomized to the oral retinoid acitretin (23). All trials of oral retinoids included participants 10–15 years posttransplant, and the majority of participants had had prior skin cancers, so the role of oral retinoids in primary prevention is not established, particularly when side effects such as deranged liver function, dyslipidemia, headache, rash, skin peeling, potential teratogenicity and effect on graft function are considered. Duration of treatment is also unclear, as there is some evidence of rebound effect, with lesions reappearing after treatment discontinuation (23).

Is Increased Prevalence of Cancer Enough to Justify Screening?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary Prevention and Lifestyle Choices
  5. Immunization and Chemoprevention
  6. Is Increased Prevalence of Cancer Enough to Justify Screening?
  7. Can Screening Have Negative Consequences?
  8. Do Screening Tests Perform Well in the Transplant Population?
  9. Can We Improve Decision Making for Transplant Recipients?
  10. References

Early detection and intervention is intuitively attractive, particularly for cancer when the consequences of disease are serious and it seems obvious that early detection must be beneficial. The practice of screening apparently healthy people for hidden disease dates back to the late 1800s, and became increasingly popular, largely based on the assumption that detecting any abnormality was worthwhile (24). However, there followed increasing recognition that early detection of disease was of no value unless it improved health outcomes, and that screening could cause harm. The principles of applying screening tests were elaborated in 1968 by Wilson and Jungner for the World Health Organization, and remain relevant even today (Table 2) (25). In screening people without symptoms to identify those with an increased likelihood of disease, we must be committed to further investigation of abnormal results and treatment, and be sure that treatment can stop disease from progressing, and that effective treatment will improve survival duration and quality of life. Posttransplantation cancer surveillance poses a particularly difficult dilemma for clinicians and patients, where a person is known to be at high risk for a condition, but definitive evidence regarding effectiveness of intervention in screen-detected disease is unknown. Benefits of screening to permit early discovery of cancer must be weighed against the potential harms and costs of screening numbers of individuals with survival rates lower than the general population, who also experience considerable mortality from nonmalignant causes. In the rush to adopt medical innovations, many screening tests are performed without a clear understanding of these arguments, the accuracy of the tests or understanding of the effectiveness of treatment in altering the course of disease once cancer is found through screening.

Table 2.  Wilson and Jungner criteria for screening*
  1. *Adapted from Wilson, JM, and Jungner, G. Principles and Practice of Screening for Disease. Geneva: World Health Organization Papers (no 34), 1968.

Knowledge of diseaseIs the disease an important health problem?
Is there a recognizable latent or early symptomatic stage? The natural history including development from latent to declared disease, should be adequately understood
Can the population that needs treating be clearly defined, and called for screening?
Knowledge of the diagnostic testIs the test affordable (ideally cheap, easy to perform, widely available)?
Does the test accurately measure risk?
Is the test specific, sensitive, reliable (repeatable, good interoperator agreement), with good positive and negative predictive values?
Is the test acceptable to the population?
Can the test be subject to quality assurance?
Knowledge of treatment for diseaseDoes early treatment confer benefit?
Is there an agreed policy concerning whom to treat as patients?
Is treatment affordable and effective?
Is treatment acceptable to the patient?
Can treatment be subject to quality assurance?
Cost considerationsAre the costs of case finding (including diagnosis and treatment of patients diagnosed) economically balanced in relation to possible expenditures on medical care as a whole?
Is a screening program affordable? (opportunity cost must be considered)
Is the program auditable?

Can Screening Have Negative Consequences?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary Prevention and Lifestyle Choices
  5. Immunization and Chemoprevention
  6. Is Increased Prevalence of Cancer Enough to Justify Screening?
  7. Can Screening Have Negative Consequences?
  8. Do Screening Tests Perform Well in the Transplant Population?
  9. Can We Improve Decision Making for Transplant Recipients?
  10. References

Current guidelines for cancer screening in the general population and the kidney transplant population are summarized in Table 2. General population screening for breast, colorectal and cervical cancers is effective, with demonstrated reduced mortality and morbidity. It is uncertain whether these guidelines, developed in the general population, are applicable and can be generalized to all transplant recipients because of the expected differences in screening test performance, response to treatment and overall life expectancy.

An important potential harm of screening is the overdetection and overtreatment of inconsequential disease, where conditions that would not have become clinically significant or progressed to cause harm during an individual's lifetime are detected by screening. RCTs and population-based cohort studies of breast cancer screening consistently show that cancer overdetection occurs, and recent work suggests sensitivity of mammography for both cancers that will progress and for overdetected cancers (that would not have been detected in the women's lifetime) may be increasing (26). Up to one-third of invasive breast cancers detected in women by screening would not have been detected in the women's lifetime without screening, and with overdiagnosis comes consequent overtreatment of breast cancer (26).

Aside from discomfort, radiation exposure, adverse effects of follow-up tests, time spent and the costs and inconvenience incurred, important potential harms from screening include anxiety and adverse psychological effects of ‘labeling’ or early diagnosis. A negative screening result may give false reassurance and potentially cause a delayed presentation of symptomatic disease. This is true for both false negatives (when disease is present but undetected by screening), and for true negatives (if disease develops in the ‘interval’ between screening the next scheduled screen, and the reassurance afforded by the previous negative test results in delayed clinical presentation). A body of research in the general population that shows some people with abnormal screening tests who are subsequently found not to have cancer (false-positive test results) also experience negative labeling that persists, even after being told everything is normal. In a study of women with abnormal mammograms but no disease, 17% had persistent worries about breast cancer that affected their daily functioning, several months after investigations had been completed. This is a group of people without disease, in whom screening efforts might promote a sense of vulnerability instead of health and so might do more harm than good (27). To our knowledge, the impact of these negative aspects of screening have not been investigated in the transplant population, who may be more or less resilient, having already dealt with the burden of one chronic disease, ESKD, and having undergone the process of transplantation.

Do Screening Tests Perform Well in the Transplant Population?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary Prevention and Lifestyle Choices
  5. Immunization and Chemoprevention
  6. Is Increased Prevalence of Cancer Enough to Justify Screening?
  7. Can Screening Have Negative Consequences?
  8. Do Screening Tests Perform Well in the Transplant Population?
  9. Can We Improve Decision Making for Transplant Recipients?
  10. References

There may also be differences in the performance of screening tests in the transplanted population compared with their performance in the general population. According to Wilson and Jungner's screening criteria (Table 1), a good screening test should have a high sensitivity, so that it does not miss disease. It must also be sensitive early in disease when the subsequent course can still be altered. If a screening test is sensitive only for late-stage disease, which has progressed too far for effective treatment, the test would be useless. A screening test should also have a high specificity to reduce the number of people with false-positive results who require additional diagnostic evaluation. To our knowledge, RCTs for cancer screening, which offer the strongest evidence to support or refute the efficacy of a test, have never been conducted in the transplant population, so the best evidence is limited to observational studies. Test performance of mammography appears inferior: women with ESKD have a higher frequency of breast calcification than women with normal kidney function, and a higher biopsy referral rate following mammographic screening (28). In addition, recipients who receive cyclosporine A as part of their immunosuppression regimen have denser breasts and higher incidence of benign adenomas compared to women without transplants (29). Current recommendations for prostate cancer screening in the general population are conflicting, as survival benefit has not been demonstrated, and because of overdetection of inconsequential disease (30,31), but despite this, and although risk is not increased for prostate cancer (Table 1) current guidelines in the transplant population do recommend screening for prostate cancer (Table 3). Free prostate-specific antigen (PSA) is eliminated from the blood by glomerular filtration, and so reduced glomerular filtration rate (GFR) may alter expected levels and hence the performance of PSA when used as a screening test (39). Interpretation of PSA results of transplant recipients against reference ranges established in men without renal disease may be inappropriate.

Table 3.  Current guidelines for cancer screening in the general population and after transplantation
Cancer siteCurrent guidelines and recommendationsRandomized trial evidence for screening
General populationTransplant population (5,6)General populationTransplant population
  1. FOBT = Fecal occult blood testing; DRE = digital rectal examination; PSA = prostate-specific antigen.

BreastBiennial mammography for all women older than 50 years (32)Annual or biennial mammography for all women older than 50 yearsCancer-specific mortality reduction by 20–24% (33)Nil
ColorectalAnnual or biennial FOBT at age >50 years, combination of FOBT and flexible sigmoidoscopy at age ≥ 50 years (34)Annual FOBT and/or 5-yearly flexible sigmoidoscopy for individuals older than 50 yearsCancer-specific mortality reduction by 15–23% (35)Nil
CervicalCytological screening to commence at age ≥ 21 years, or within 3 months of first sexual intercourse (biennially or triennially) (36)Annual cytological cervical cancer screening and pelvic examination once sexually activeNo RCT evidence, but historical evidence have shown significant reduction in cancer incidence and mortality since the introduction of population cervical cancer screeningNil
LungNo recommendation for screeningNot generally recommended, additional studies are needed before screening are recommended for high-risk patientsNilNil
ProstateNo general consensus   
USPSTF found no evidence to recommend for or against routine screening using PSA or DRA. (37)Annual DRE and PSA measurement in all transplanted men older than 50 yearsNilNil
HepatocellularNo firm recommendations, but screening using abdominal ultrasound and α-fetoprotein testing should be considered in high-risk individuals (38)No firm recommendation, but abdominal ultrasound and α-fetoprotein every 6 months in high-risk recipientsNilNil
Renal tractNo firm recommendationsNo firm recommendation, some suggested regular ultrasonography of the native kidneysNilNil
SkinInsufficient evidence to recommend for or against total body skin examinationMonthly self-skin exam, total body skin exam, every 6–12 months by expert physician or dermatologistsNilNil

The cost of implementing screening programs also needs to be considered in context. A recent economic evaluation that assessed cost-effectiveness of colorectal cancer screening in kidney transplant recipients concluded that fecal occult-blood test screening is cost-effective only when assumptions were made under the most favorable conditions (i.e. optimal test specificity, minimal false positive results, similar detection of earlier disease as experienced by general population under screening and survival comparable to the general population) (40). Others have shown that screening is effective only when exercised in recipients with minimal comorbidity and a life expectancy greater than 5 years (41).

Can We Improve Decision Making for Transplant Recipients?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary Prevention and Lifestyle Choices
  5. Immunization and Chemoprevention
  6. Is Increased Prevalence of Cancer Enough to Justify Screening?
  7. Can Screening Have Negative Consequences?
  8. Do Screening Tests Perform Well in the Transplant Population?
  9. Can We Improve Decision Making for Transplant Recipients?
  10. References

Increased prevalence of cancer among kidney recipients is not enough to justify increased efforts to detect cancers. A big picture view of cancer and transplantation reflects the life course experience of individuals with ESKD, and considers periods of dialysis, and acknowledges the reality of finite graft function. Decisions may therefore differ among patients, and also for individual patients at different time points, and need to recognize the fact that kidney recipients already have one chronic disease (ESKD) that will shorten their lives. By identifying key areas where current knowledge is weakest, and by concentrating research efforts on designing high-quality clinical studies to plug the gaps in knowledge of cancer after transplantation, we can improve rational decision making focused on maximizing quality of life and so create an agenda for improving care of transplant recipients.

There is little evidence of the natural history of progression of cancer in transplant recipients. To understand how cancer affects survival in the context of the competing risks of ESKD and cardiovascular disease ideally requires an inception cohort study of transplant recipients exploring the effects of cancer staging and comorbidity on expected survival. This might be achieved using transplant registry data linked to external data sources such as cancer and death registries. By concentrating on patient-centered outcomes, it might be possible to identify patient subgroups likely to benefit most from early intervention.

Ideally, the effects of cancer treatment interventions are tested using RCTs, but may not be feasible in the limited transplant population, even with collaborative effort. However, the field of oncology has a rich literature of trials examining treatment interventions. Better cross-collaboration with our oncology colleagues in both clinical and research arenas might allow informative subgroup analyses of cancer trial data to enhance understanding of whether the effects of treatment are different in individuals with chronic kidney disease or ESKD, in terms of understanding appropriate dosing, and the beneficial and adverse effects.

Perhaps a greater imperative is to collaborate to conduct RCTs of diagnostic test performance and cancer screening versus no screening (but observation and watchful waiting) in the transplant population, which would allow pragmatic investigation of test performance, psychological effects, quality of life and morbidity and mortality, as well as a greater understanding of likely costs, and estimates of the extent of inconsequential disease that will be generated by the screening programs. In designing such studies, avoidance of potential biases that particularly affect studies of screening interventions is the key. These are lead-time bias, where screening appears to improve survival time but actually increases ‘disease’ time after disease detection, so the duration of time from symptomatic disease to death remains unaltered, length-time bias, where outcomes appear better in screened group because more cancers with a good prognosis are detected (overdiagnosis of inconsequential disease is an extreme example) and compliance bias, where the observed effect is not due to screening itself, but due to the characteristics of individuals heeding and opting in to the offer of screening, compared with those who avoid screening.

Because it is becoming clear that prevention has both good and harmful effects, and that different people might judge the balance differently, perhaps what is most needed is to extend clinician–patients partnerships in decision making, to enable informed choice in the context of an individual's cancer risk, comorbidities, life expectancy and quality of life. The final decision about whether to screen is greatly influenced by the values different individuals place on each of the possible benefits and harms and their understanding of ethical, social and psychological effects. Making informed health decisions is complex at both the individual (consumer and clinician) and policy level (guidelines) and requires effective tools and methods to synthesize and communicate evidence. With better-quality evidence, we have the possibility of developing decision aids that allow individuals to weigh up the probable benefit and harms of interventions, tests and screening programs, using their own values and preferences.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary Prevention and Lifestyle Choices
  5. Immunization and Chemoprevention
  6. Is Increased Prevalence of Cancer Enough to Justify Screening?
  7. Can Screening Have Negative Consequences?
  8. Do Screening Tests Perform Well in the Transplant Population?
  9. Can We Improve Decision Making for Transplant Recipients?
  10. References
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