A Proposal for a Targeted Screening Program for Renal Cancer

Abstract

Renal cancer kills over 26,000 people per year in Europe and 13,000 in the United States (1, 2). If identified before metastatic spread, kidney cancer is usually surgically curable (3), whereas the median survival with disseminated cancer is only 2 years (4). Turney et al. proposed in 2006 that a screening program using ultrasound could have a major impact on renal cancer mortality (5). The suggestion was criticized on the basis that the natural history of renal cancer was poorly understood, and that the treatment of renal masses would not be of net benefit in older populations (6). In the past 7 years, however, the natural history and epidemiology of renal cancer have become much clearer. Moreover, nephron-sparing surgery and minimally invasive ablation are now better established (7), changing the cost-benefit ratio for treatment in older populations. These developments mean that a targeted renal cancer screening program is now a real option. The evidence for such a screening program is presented in three parts: first, an update on the natural history and risk factors; second, a calculation of the benefits and harms of screening in different populations, and third, lessons from other cancer screening programs. Finally, a clinical algorithm to aid with screening and treatment choices is presented. Diagnosis of renal cancer is made by imaging of the kidneys: a solid mass on ultrasound scan (USS) or an enhancing mass on computed tomography (CT) is considered malignant until proven otherwise. Histological examination shows that approximately 85% of masses are malignant (8). Historically, imaging of the kidneys was performed in symptomatic patients. With the increasing use of imaging for other abdominal complaints, however, many renal masses are identified as incidental findings. These “incidentalomas” now account for the majority of renal cancers (8). Incidental renal masses tend to be smaller than symptomatic masses (9), but they are not harmless. In a study of nearly 4,000 patients with incidental renal tumors, 14.4% died of cancer over an average 4-year follow-up, despite treatment (10). Most solid renal masses are presumed to be malignant and excised. There is therefore relatively little data on the natural history of untreated masses. However, a meta-analysis covering 234 patients that did not undergo immediate surgery found a mean tumor size at diagnosis of 2.6 cm and a mean growth rate of 0.28 cm per year (11). A subsequent study of 106 patients found that one-third of masses did not grow over a 25-month follow-up (12), while in a prospective study of 82 patients undergoing active surveillance for a median duration of 3 years, most masses grew, but 10% were stable, and 5% regressed (13). It is unknown whether these were benign masses. Larger masses generally grow faster than smaller masses, and bigger tumor size predicts a shorter average survival (10, 14). With slow initial growth rates, it may take several years for a mass to develop to a size that causes complications. Nevertheless, a comparison of the prevalence of incidental renal masses and of symptomatic renal cancer suggests that most incidental masses will progress to clinical disease, with a sojourn time of between 3.7 and 5.8 years (15). Screening aims to identify a cancer early, i.e., while the tumor is small, localized, and treatable. The natural history of small masses suggests that this aim can be achieved, as most grow slowly. Screening programs are most efficient if they target high-risk populations. The incidence of renal cancer varies with gender, age, and ethnicity. The incidence is roughly twice as high in men as in women (2), increases with age (16), and is higher in African Americans and lowest in Asian Americans (17). A number of lifestyle and medical factors can increase the risk of kidney cancer. In particular, smoking (18), obesity (19), hypertension (20, 21), family history (22), multi-parity for women (23), end-stage renal disease (24), and exposure to carcinogens (2) are recognized risk factors. Heavy smoking, severe hypertension, and morbid obesity each double the risk of renal cancer, while a family history increases the risk fourfold. Certain segments of the population are therefore at increased risk. For example, an obese, hypertensive man who smoked heavily would be 8 times as likely to have kidney cancer as a normotensive, non-smoking, thin man, and 16 times as likely as a normotensive non-smoking thin woman. The identification of these risk factors means that screening can be targeted at high-risk populations. It is clearly possible to identify renal masses before they cause symptoms: these are incidentalomas. A retrospective analysis of all the cases of kidney cancer in Iceland found that incidental tumors were on average 2.6 cm smaller and of lower stage and grade than symptomatic tumors (9). This supports the hypothesis that imaging in asymptomatic patients can identify renal masses earlier, when they are smaller. CT can identify renal masses of less than 3 cm more than 90% of the time, compared to 67–79% of the time for USS (25). If a renal mass is identified early, treatment is usually curative. The 5-year survival with localized renal cancer is 91% but with distant spread only 11% (16); this reflects both the slow natural progress of the disease and the effectiveness of surgical treatment of small tumors. The tools to identify at risk populations, to diagnose renal cancer early, and to treat early renal cancer effectively are therefore all currently available. The hoped-for benefit of a screening program for renal cancer would be a reduction in cancer mortality. The potential harms include the cost of screening, the direct harm from the screening investigations, and the harm from unnecessary procedures like biopsies or surgery in individuals with a false-diagnosis or an overdiagnosis (i.e., a positive screen in a patient with a cancer that would not have caused...