Optimal Treatment in the Postorchiectomy Management of Clinical Stage I Seminoma

Clinical stage I seminoma is defined as seminoma localized to the testis without clinical, imaging, or biochemical evidence (ie, tumor markers) of disease beyond the testis. Radical orchiectomy is the treatment of choice. However, up to 20% of patients with clinical stage I seminoma eventually sustain relapse of their disease. Historically, active surveillance or radiation therapy has been practiced after orchiectomy.

Recent guidelines consider all three options—surveillance, chemotherapy, and radiotherapy—as appropriate treatment strategies for clinical stage I seminoma postorchiectomy. The preferred treatment option varies among physicians and is often guided by the patient’s wishes, expected compliance, and presence of known risk factors. In 2005, one dose of carboplatin (AUC 7) was reported to be an effective adjuvant therapy for patients with clinical stage I seminoma following orchiectomy. [After a longer follow-up of 6.5 years, single-agent carboplatin continued to be noninferior to radiation therapy in preventing relapse.

Active Surveillance
Many consider active surveillance to be the optimal management following orchiectomy for clinical stage I seminoma. This is based on the observation that only 15% to 20% of patients with stage I seminoma will develop disease relapse. Subsequently, approximately 80% of patients will never require adjuvant therapy, and for patients with relapsed disease, salvage therapy leads to outcomes comparable to that of adjuvant therapy. The most appealing aspect of active surveillance is the avoidance of long-term side effects associated with radiation and chemotherapy. However, this approach requires close follow-up for many years, which may not be applicable to patients who are unwilling to cooperate or who are expected to be noncompliant. In addition, some patients may be unwilling to accept a 20% chance of developing disease relapse in future.

There is no consensus on risk stratification for this population. In a retrospective study of 638 patients, testicular tumor size > 4 cm and invasion of the rete testis were found to be important predictors of relapse. Risk of relapse was 12% for patients with neither of these features, 16% with one, and 32% with both features. In a prospective cooperative group study, a risk-adapted management–based approach using two high-risk features was feasible. However, independent validation will be needed before this approach gains widespread acceptability.

Until validated evidence-based risk stratification becomes available or international consensus is reached, we favor an active surveillance approach following the National Comprehensive Cancer Network (NCCN) guidelines, which recommend history and physical examination; serum tumor markers (alpha-fetoprotein, beta-hCG, and lactate dehydrogenase) every 3 to 4 months for years 1 to 3, every 6 months for years 4 to 6, and then annually; CT scan of the abdomen and pelvis at each visit; and chest x-ray at alternative visits (up to 10 years).

Radiation Therapy
Historically, radiation therapy to the para-aortic strip (PA) plus ipsilateral iliac lymph nodes (also known as the dogleg field) of 30 Gy in 20 fractions was used as adjuvant therapy for stage I seminoma and resulted in cure rates of 97% to 100%. However, long-term follow-up data gathered over 15 to 20 years revealed excess risk of death in these patients as a result of secondary cancers, cardiovascular disease, or both.

The Medical Research Council of the United Kingdom sponsored prospective trials evaluating the efficacy of decreased-field radiation (PA field only vs dogleg field) or decreased radiation dose (20 Gy in 10 fractions over 2 weeks vs 30 Gy in 15 fractions during 3 weeks). These trials established the efficacy and safety of attenuated field or dose of radiation compared to the historical standard. Overall, the relapse rates were not higher and the survival rates not inferior with decreased field size or attenuated dose of radiation. Currently, PA field radiation therapy, with an attenuated radiation dose, is considered the standard of care for radiation therapy in the majority of centers.

In a retrospective study of 1,535 patients with stage I seminoma who were treated with PA field radiotherapy, the relapse rate at 5 years was 3.6%.However, there is concern that these patients are at risk for developing bulky pelvic recurrence. In addition, radiation therapy is not an option for a small proportion of patients with horseshoe kidney, pelvic kidney, or inflammatory bowel disease.

Chemotherapy
In a randomized, multicenter trial by the European Organisation for Research and Treatment of Cancer, 1,477 patients with stage I seminoma were treated with either radiotherapy (PA field only or dogleg field; n = 904) or one dose of carboplatin (AUC 7; n = 573).[1] After a median follow-up of 4 years, relapse-free rates for radiotherapy and carboplatin were similar and suggested noninferiority of carboplatin to radiotherapy in the treatment of stage I seminoma.

An updated report was presented at the American Society of Clinical Oncology 2008 annual meeting.[2] After a median follow-up of 6.5 years, single-dose carboplatin (AUC 7) continued to be noninferior to radiation therapy in terms of relapse-free rates. In addition, there was a significant reduction in contralateral testicular gem cell cancers in the carboplatin arm. In this study, the ethylenediamine tetra-acetic acid (EDTA) method was the preferred method for assessing glomerular filtration rate (GFR). A 24-hour urinary collection–based creatinine clearance (although not determined with the Cockcroft formula) was also used for assessing GFR. Patients on the chemotherapy arm received either one dose of carboplatin (AUC 7 × [GFR+25]) based on EDTA (n = 357), or 90% of this dose if based on creatinine clearance (n = 202). Patients who received at least 99% of the AUC 7 dose (n = 347), had 5-year relapse-free survival rates of 96.1%, compared to 92.6% in 212 patients treated at lower doses (P = .08). Although the results were not statistically significant, the trend of inferior relapse-free rates in patients who received lower-dose carboplatin signifies the importance of optimal dosing in carboplatin therapy.

It should be noted that the EDTA method accurately measures GFR, but it is time-consuming and not always readily available. The Cockcroft formula, although used commonly in medical practice, may be less accurate, resulting in suboptimal dosing of carboplatin and potentially inferior outcomes.

Conclusions
An evidence-based follow-up schedule is currently not available for patients with clinical stage I seminoma who elect to undergo active surveillance after orchiectomy. Up to 20% of patients who undergo active surveillance will relapse. The majority of these can be cured with salvage chemotherapy or radiotherapy. Nevertheless, the development of a validated risk-adapted strategy is needed to identify patients who would benefit from adjuvant therapy. Although radiation therapy historically has been the adjuvant therapy of choice, the use of single-dose carboplatin (AUC 7) is an effective alternative to radiotherapy for these patients. Until validated evidence-based risk-stratification tools become available or international consensus is reached, we favor an active surveillance approach following the NCCN guidelines in the management of patients with clinical stage I seminoma after orchiectomy.