The treatment of patients with testicular germ cell tumors (GCT) has evolved significantly over the past 30 years, primarily because cisplatin-based chemotherapy plus adjunctive surgery cures advanced, metastatic tumors. Treatment of localized and regional disease has also been influenced by the availability of effective systemic therapy. The multiplicity of available treatment approaches has resulted in management controversies, including the optimal treatment of clinical stage I nonseminomatous germ cell tumor (NSGCT). Nerve-sparing retroperitoneal lymph node dissection (RPLND), adjuvant chemotherapy with two cycles of bleomycin, etoposide, and cisplatin (BEP 2), or surveillance have all achieved long-term survival in nearly 100% of patients with clinical stage I NSGCT. Treatment recommendations are frequently governed by patientand tumor-specific factors, such as lymphovascular invasion (LVI). Patients with T1 tumors (organ confined, lacking LVI) have an approximately 15% to 20% chance of relapse after orchiectomy. For these patients, active surveillance with appropriate therapy at relapse (often full-course chemotherapy) at relapse is the preferred option. Management with active surveillance assumes that the patient meets defined criteria, including compliance for follow-up. In contrast, patients with T2 stage I NSGCT (usually associated with LVI) have an approximately 50% chance of harboring occult metastatic disease. In the United States, nerve-sparing RPLND is the preferred option for patients with T2-4 stage I tumors, as well as for those with T1 tumors who are not compliant for rigorous follow-up or who choose NSRPLND over active surveillance. A third, more recent, treatment option has been studied in patients with T2 tumors. BEP 2 is associated with relapse-free survival in more than 95% of instances. This approach was developed in response to the possibility of systemic disease and relapse after RPLND, and to address the lack of experienced urologists outside of specialized centers. The experience reported with this approach has involved patients with high-risk stage I (T2-4; mostly organ-confined tumors with LVI [T2]) because these patients have a 50% probability of harboring regional or distant metastases. The main disadvantage to this approach is the exposure of all patients to the acute and longterm toxicities associated with cisplatin-based combination chemotherapy. Late consequences of chemotherapy are now well recognized, and the spectrum broadens as long-term follow-up of GCT patients who received cisplatin-based chemotherapy increases. Regardless of the approach, it is imperative that the chosen strategy adheres to established follow-up protocols, proven surgical techniques, and standard chemotherapy programs. In the United States, guidelines have been established by the National Comprehensive Cancer Network. In this issue, Albers et al report the results of a phase III multiinstitutional study that compared one cycle of BEP to a unilateral RPLND in an unselected group of patients with clinical stage I NSGCT, nearly 60% of whom had T1 tumors. Three issues need to be considered: stage of disease at treatment, unilateral RPLND, and one cycle of BEP. With 60% of patients having T1 disease, it could be anticipated that approximately 80% of these patients would be cured by orchiectomy alone. Furthermore, among the 40% with greater than T1 disease, six patients in the RPLND arm had pathologic stage IIB disease and one had IIC disease. It is unlikely that that one cycle of BEP would achieve a significant cure rate in these high-volume, clinically understaged tumors. In addition, among studies reporting the results of BEP 2, identification of relapse after chemotherapy would include those occurring as a consequence of chemotherapy resistant, persistent disease in the retroperitoneum, such as growing teratoma and slow-growing NSGCT tumors. Because many relapses from these tumors would be expected at a later time, they have not yet been realized in this study with relatively short follow-up. Thus, the patient population with a high likelihood of cure from orchiectomy alone (than with T1 disease) and the relatively short follow-up likely affected the comparison of one cycle of BEP to surgery. The use of one cycle of BEP remains investigational for patients with clinical stage I NSGCT; if chemotherapy only is chosen as the treatment option, BEP 2 for T2 disease remains the standard regimen. Thirty-two patients (18%) in the RPLND arm of the Albers et al study had tumor-positive nodes (pN1-25; pN2-6, pN3-1) found at RPLND, and all received BEP 2 postoperatively, twice as much chemotherapy as their unresected, randomly assigned counterparts in the one cycle of BEP arm. Given the high proportion of locoregional failures in RPLND node negative–patients who did not receive chemotherapy, additional relapses would likely have occurred in the pathologic stage II patients had they not received BEP 2 adjuvant chemotherapy. Hence, the chemotherapy comparisons are not equivalent. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 18 JUNE 2
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Nov 3, 2008
Alexandros Lekas + 4
Open Access