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Therapeutic Options Following Orchiectomy for Stage I Seminoma

Therapeutic Options Following Orchiectomy for Stage I Seminoma

ABSTRACT: Stage I seminoma represents the paradigm of a curable malignancy, with survival of 100% an expected outcome no matter what treatment option is chosen. However, consensus has not been reached among urologists and oncologists regarding the optimal postoperative management in men with clinical stage I testicular seminoma. Currently, men are offered active surveillance, adjuvant radiation therapy, or single-agent chemotherapy. Active surveillance is associated with an 80% chance of no relapse, with all such events salvageable. Radiotherapy has an almost universal cure rate but has the potential for long-term toxicities and an overtreatment rate of about 80%. Chemotherapy efficacy and toxicity data are still immature. Recent guidelines recognize that the options of surveillance, chemotherapy, and radiotherapy are appropriate in the treatment of patients with clinical stage I seminoma. We believe active surveillance to be the best option, then radiotherapy (considering the efficacy and safety data), with single-agent chemotherapy emerging as a possible alternative.

The Issues
No matter what treatment is chosen for testicular seminoma, survival approaches 100%. However, consensus has not been reached regarding optimal postoperative management for clinical stage I testicular seminoma.

Over the past 3 decades, the incidence rate of testicular seminoma has continually risen, and the majority of cases have been clinical stage I.[1] Nevertheless, the overall survival for all testicular cancers has improved significantly (P < .05) over the same period, from 83% to 96%.[2]

Seminomas generally have a lower stage at diagnosis than nonseminomatous germ cell tumors (NSGCT), are generally less advanced, and are associated with better survival. In fact, stage I seminoma represents the paradigm of a curable malignancy, with survival of 100% an expected outcome no matter what treatment option is chosen. However, consensus has not been reached among urologists and oncologists regarding the postoperative management of men with clinical stage I testicular seminoma.[3]

Currently, men are offered active surveillance, adjuvant radiation therapy, or single-agent chemotherapy (Table 1).[4] We will outline the treatment options for clinical stage I seminoma and discuss the controversies surrounding each approach.

Background and Risk-Adapted Strategies

TABLE 1
Comparison of Postsurgical Options for the Management of Stage I Seminoma

Over time, radiotherapy has established itself as an appropriate adjuvant treatment for clinical stage I seminoma, which significantly reduces the relapse rate.[5-9] Unfortunately, radiotherapy is associated with a doubling in the risk of developing a second malignancy compared with the general population; although absolute risks remain small.[10-14] Chemotherapy is probably equivalent to radiotherapy in terms of efficacy,[15] but long-term risks are unknown.[16] Active surveillance avoids overtreatment in the vast majority of patients, as only approximately 17% of patients are likely to relapse.[17] Therefore, recommendations for the treatment of clinical stage I seminoma have recently been updated.

The overriding theme of recent guidelines is the recognition that the options of surveillance, chemotherapy, and radiotherapy are all appropriate in the treatment of patients with clinical stage I seminoma.[4,18,19] Nevertheless, there are some caveats. For example, in the 2009 National Comprehensive Cancer Network (NCCN) Testicular Cancer Clinical Practice Guidelines, each of these options is rated category 1—that is, there is a uniform consensus among experts regarding their recommendation as approved treatment. In the fine print, however, surveillance is recommended as category 1 only for patients who have undergone previous radiotherapy, who have a horseshoe kidney, or who have inflammatory bowel disease. Surveillance is considered category 2B for others motivated to undergo follow-up and more intensive imaging. Meanwhile, chemotherapy has been raised to equal status with the more traditionally used radiotherapy as NCCN category 1 for all comers. This is despite long-term toxicity data and is based on early data demonstrating equivalent short-term efficacy with radiotherapy, with very few side effects.[15] Medical oncologists believe that along with its demonstrated efficacy, chemotherapy is less burdensome and toxic than radiotherapy, requires minimal hospital contact, reduces anxiety, and results in few reported relapses at just under 10 years’ follow-up. Moreover, salvage chemotherapy remains a viable option even if relapse occurs.[20-22]

The Options
Active surveillance
Radiotherapy
Chemotherapy

The most recent European Association of Urology (EAU) guidelines offer similar preferences, with surveillance as a grade B recommendation behind chemotherapy and radiotherapy (category A).[19]

Participants in the more recent European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer stated that all three treatment options—surveillance, adjuvant carboplatin, and adjuvant radiotherapy—are acceptable strategies for the management of patients with clinical stage I seminoma.[18] With such an approach, those at higher risk of relapse may be offered surveillance with more confidence. Those patients without risk factors for recurrence may be more likely to be offered adjuvant radiotherapy or chemotherapy. A significant proportion of patients may therefore avoid overtreatment. Risk stratification was based on the original work of Warde et al,[9] who identified rete testis invasion and size of primary tumor (> 4 cm) as risk factors for relapse in a pooled analysis of surveillance studies with 638 patients. The relapse rate was 17% for primary tumors > 4 cm without rete testis invasion, 12% for primary tumor < 4 cm and no rete testis invasion, and 14% for rete testis invasion and a primary tumor < 4 cm. The difficulty is that such strategies have not been supported in prospective cohorts. Whatever the approach, high-risk patients treated with adjuvant chemotherapy or radiation therapy still have a 3% to 4% relapse rate.[20] Possible susceptibility of germ cell tumor patients to other diseases is generally attributed to the late treatment effects of radiation (such as cardiotoxicity) or a second malignancy, thus contributing to a decreased survival compared with matched individuals in the general population.[24]

Active Surveillance

In a recent meta-analysis, the relapse rate for patients undergoing active surveillance was 17%, with disease-specific survival close to 100%.[17] Such data are compelling when considering active surveillance as an option. The benefits are clear: avoidance of overtreatment in over 80% of patients; knowledge that relapses are salvageable; no risk to fertility; no risk of acute toxicity, and no iatrogenic risk of cardiotoxicty or second malignancy. Against this, surveillance does oblige the patient to close follow-up and vigorous imaging; even in a study situation, this is not always achieveable.[25] Anxiety is also a potential effect of surveillance,[26] and this is where selection of patients who accept the risk of relapse is essential.

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