Radiotherapy in Stage I Seminoma of the Testis
Authors: Alan Horwich
Journal: Journal of Clinical Oncology (2004)

The analysis of excess mortality in a cohort of 453 men cured of early stage testicular seminoma by orchiectomy and radiotherapy at the M.D. Anderson Cancer Center (MDACC) [1], presented in this issue of the Journal of Clinical Oncology, raises questions about current standard practice, especially in stage I disease, in which only 1 in 5 men actually has subclinical metastases. The authors reported a standardized mortality ratio (SMR) of 1.59 emerging 15 years following radiotherapy, and specific analyses revealed a cardiac SMR of 1.61, and a cancer SMR of 1.91. In most countries of the world, adjuvant retroperitoneal node radiotherapy is the postorchiectomy standard of care for patients with stage I testicular seminoma, the most common presentation of testicular cancer. Though radiation is known to have carcinogenic potential, the practice of adjuvant radiotherapy in seminoma is based on the perception that the relatively low dose of radiotherapy delivered as an adjuvant to abdominal lymph nodes should be associated with a low excess risk of cancers and would not cause severe heart damage [2-4]. The report from the MDACC challenges these perceptions. Questions to address include the precision and generalizability of the analyses, their relevance to modern radiotherapy practice and the safety of alternative approaches to management of stage I seminoma. The study was based on patients treated between 1951 and 1999. Although those studies from the earlier years contributed more to the number of person-years at risk and to the number of events, their staging and treatment methods were least like current practice. Whereas it is now accepted that radiation fields should be restricted to the paraaortic region of the abdomen, and the dose to 20 Gy [5,6], the patients in the MDACC series had much more extensive radiotherapy. For example, 31 men received whole-abdominal radiotherapy, and, before 1971, most men had prophylactic mediastinal radiotherapy—a significant risk factor for long-term toxicity in this and other analyses. It is notable that the most common second cancer in the MDACC report was lung cancer. Additionally, even in recent years at the MDACC, patients with bulky abdominal metastases as large as 10 cm in diameter were treated with large radiation fields [7]; whereas in most centers, they would have been treated with chemotherapy [8-10]. Retrospective cohort analyses are prone to the systematic bias that patients suffering an event are more likely to be known about than those who remain well. In this series, the median follow-up of survivors was 13.3 years, even though half the patients had been treated more than 20 years earlier. Data from most of the cohort was censored before the period when excess toxicities occurred, which amplifies the change seen in actuarial risk figures. The SMR is based on comparison with US age-specific and cause-specific mortality. The implicit assumption is that the population of men treated for testicular cancer at the MDACC was typical of the US male population in terms of risk factors. If there were regional variations in risk factors, such as tobacco abuse, ethnicity, diet, deprivation, or sun exposure, then overall US mortality would represent an imprecise control, though there is no evidence to suggest whether this might increase or decrease the relative risks (RRs) that were calculated. Though there is evidence in the literature for increased cardiovascular risk and for increased incidence of second cancer after cure of testicular tumors, most reports either rely on epidemiological data, which may not have accurate and complete treatment records, or arise also from management of nonseminomas, for which a variety of chemotherapeutic agents have been used and for which radiotherapy doses were higher. Travis et al [11] analyzed second malignancies in 28,843 patients surviving at least 1 year after diagnosis of testicular cancer, treated between 1935 and 1993, and who had been registered within 16 populationbased cancer registries in the United States, Canada, Sweden, Finland, Denmark, and the Netherlands. Seven thousand four hundred seventy-six men with seminoma had initial treatment with radiotherapy; data on any subsequent treatment were not available. There was a significantly elevated RR of second cancers (RR, 1.45; P .05), but this was JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 4 FEBRUARY 15 2004