Few randomized controlled trials (RCTs) are available to inform clinicians on the management of clinical stage I nonseminomatous testicular cancer (CS I NSGCT). Guidelines based on expert opinion are consistent in acknowledging the importance of microscopic vascular or lymphatic invasion (MVI) as a prognostic factor and in stating that CS I NSGCT can be managed with surveillance, adjuvant chemotherapy, retroperitoneal pelvic lymph node dissection (RPLND), or combinations of these approaches. It is generally agreed that all approaches ultimately result in similar cancer cure rates. Cancer cure rates are excellent regardless of the management option selected. Overall and disease-free survival rates are over 95% for all management approaches, even though recurrence rates are higher in the patients managed by surveillance.
To address the efficacy of adjuvant chemotherapy, a meta-analysis of recurrence rate data from eligible trials was performed. These data must be interpreted with caution, as a proportion of patients would be expected to be cured by orchidectomy alone, and, by including them in the calculation of recurrence rates, the true efficacy of chemotherapy to eradicate micrometastatic disease is overestimated. The analysis also does not account for differences in recurrence risk over time. While the lack of statistical heterogeneity might imply a strong consistency among the studies, it actually might more strongly reflect the fact that the numbers of recurrences are very low in all the studies. Finally, there are some limitations to the meta-analysis method used. First, the logit method used to calculate the confidence intervals is a conservative one, and likely overestimates these intervals. Second, the addition of 0.5 to the number of recurrences and total patients, while necessary to perform the meta-analysis, does inflate the resulting estimate of recurrence by a small but not trivial amount, given the small number of recurrences. A sensitivity analysis not reported here suggested that this inflation might be in the order of 0.5%.
In this setting, clinicians expect adjuvant chemotherapy to provide at least 95% efficacy in the eradication of micrometastatic disease. The upper 95% confidence limits of the estimated recurrence rates exceed 5% for all regimens reported. Closest to this benchmark are two cycles of bleomycin, etoposide, and cisplatin (BEP) or cisplatin, vinblastine, and bleomycin (PVB) with an upper confidence limit of 7%. The small numbers of patients treated with each type of adjuvant approach certainly accounts for much of this lack of precision; however, it must be remembered that these estimates represent a "best case" scenario, and inadequate antitumour efficacy cannot be ruled out. The limitations of these data would support a default approach using three cycles of adjuvant BEP, as this is considered adequate therapy for patients with good prognosis metastatic NSGCT who are at higher risk of disease recurrence compared to CS I patients. However, the case for two cycles of adjuvant BEP is supported by the observation that two of the eight recurrences in this group consisted of mature teratoma only. There is also indirect evidence from another RCTl. Williams et al randomized 195 patients with PS II NSGCT to observation or two cycles of adjuvant BEP. The relapse rate in observation patients was 49% compared to 6% in patients treated with adjuvant chemotherapy. Five of the six recurrences in the adjuvant chemotherapy arm occurred before adjuvant chemotherapy was given. Evaluating only patients who received adjuvant chemotherapy, the recurrence rate was 1.1% (95% confidence interval [CI], 0.15% to 7.31%). Based on these additional data, it was the consensus of the Genitourinary Disease Site Group (GU DSG) that two cycles of BEP (with etoposide 500 mg/m2/cycle) represented adequate adjuvant chemotherapy in CS I NSGCT patients.
With respect to RPLND, because there is very little evidence concerning its efficacy in CS I NSGCT patients, a recommendation cannot currently be made. With respect to primary surveillance as a management option, while surveillance regimes require much more rigorous follow-up than does adjuvant treatment, including more frequent physician visits, computerized tomography (CT) scans, chest x-rays, and serum tumour marker tests, surveillance is generally associated with a lower level of toxicity and has comparable cancer-specific survival. Alternatively, some patients prefer adjuvant treatment, as they may find it difficult to adhere to the strict follow-up regime required by surveillance, or feel like they are waiting for a recurrence ("sword of Damocles" syndrome).
As salvage chemotherapy is able to provide a cancer cure with prompt detection of recurrence in virtually all patients, the Genitourinary Disease Site Group (GU DSG) consensus was that all CS I NSGCT patients be offered surveillance, provided they are considered appropriate for this approach and do not prefer immediate adjuvant treatment. Although not part of the scope of this review, there is evidence from a randomized trial conducted in patients with metastatic disease showing better survival rates among patients treated in multidisciplinary centres of excellence compared to patients treated in community centres. Therefore, it is suggested that primary surveillance be done in collaboration with a cancer centre experienced in the treatment of testicular cancer. The appropriate number of CT scans recommended with primary surveillance is unclear, but two scans at three and 12 months may be adequate in CS I patients without MVI. For patients who decline or who are not candidates for surveillance, immediate adjuvant chemotherapy with two cycles of BEP is recommended. RPLND may also be considered for this subset of men, but its benefits as an alternative or in addition to adjuvant chemotherapy are unclear. The philosophy underpinning these recommendations is to avoid the overtreatment of men cured by orchidectomy while maintaining the highest possible cancer cure rate in those destined to experience a recurrence.
