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Originally published as JCO Early Release 10.1200/JCO.2008.16.0416 on May 5 2008 © 2008 American Society of Clinical Oncology.
Stage I Testicular Cancer Management and Necessity for Surgical Expertise
the Urology Service, Department of Surgery, and the Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 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.1 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 x 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 patient- and tumor-specific factors, such as lymphovascular invasion (LVI).1-4 Patients with T1 tumors (organ confined, lacking LVI) have an approximately 15% to 20% chance of relapse after orchiectomy.2 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.2-4 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 NS-RPLND over active surveillance.
A third, more recent, treatment option has been studied in patients with 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.13 In this issue, Albers et al14 report the results of a phase III multi-institutional 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.14 In addition, among studies reporting the results of BEP x 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 x 2 for 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 x 2 postoperatively, twice as much chemotherapy as their unresected, randomly assigned counterparts in the one cycle of BEP arm.14 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 x 2 adjuvant chemotherapy. Hence, the chemotherapy comparisons are not equivalent. The type of RPLND influences the likelihood of relapse. In the Albers et al study, nine patients in the RPLND arm experienced locoregional recurrences —seven retroperitoneal and two inguinoscrotal. The authors report that "the retroperitoneal relapses were mainly located outside the template."14 The use of unilateral templates likely played a significant role in the surgical failure rate in the retroperitoneum. An adequately performed NS-RPLND remains the preferred treatment option in patients with T1 tumors who are noncompliant with surveillance or prefer surgery and those with T2-4 stage I NSGCT. A bilateral NS-RPLND is both a diagnostic and therapeutic procedure when performed in tertiary centers by experienced surgeons, obviating the need for templates that could compromise oncologic outcome.15,16 First, there is clinical evidence that the retroperitoneal nodes are usually the first, and often the only, site of metastatic disease in NSGCT.17 Second, despite effective cisplatin-based chemotherapy, unresected retroperitoneal metastasis can potentially result in repeat surgery, late relapse, and decreased survival.18,19 Third, chemoresistant teratoma is present in approximately 20% to 30% of patients with pathologic stage II disease.20,21 Fourth, RPLND is a curative procedure in approximately 90% of pN1 eliminating the need for adjuvant chemotherapy and 50% of pN2 patients for whom two cycles of etoposide plus cisplatin with or without bleomycin is often recommended.22 Nerve-sparing techniques also preserve antegrade ejaculation in more than 95% of patients. Bilateral infrahilar RPLND decreases both major and minor complications compared with RPLNDs that include suprahilar dissection. To avoid retrograde ejaculation from sympathetic nerve damage, modified ipsilateral templates have been described that reduce or avoid dissection in anatomic regions felt to be at less risk for metastatic spread.23-26 Recent data have shown, however, that the mapping studies supporting these modified templates underestimated retroperitoneal metastases.27-29 Furthermore, in the Weissbach study, it is not possible to accurately assess additional sites of potential metastatic disease because many of the patients received post-RPLND chemotherapy.29 In a retrospective study of 500 patients with clinical stage I and IIA NSGCT who underwent primary RPLND at Memorial Sloan-Kettering (New York, NY), the incidence, sites, and histology of disease outside of five reported modified templates were evaluated.30 Using a bilateral template as the standard operation, disease outside the various templates would have been observed in 3% to 23% of all patients and up to 11% of patients with pN1 disease.30 Specifically, the overall incidence of extra-template disease found by applying the Testicular Tumor Study Group modified template was 23% to 19% and 25% for right-sided and left-sided primary tumors, respectively. Furthermore, the incidence of extra-template disease without any evidence of in-template metastasis was 5%.30 Hence, it is likely that some patients experienced relapse because of an inadequate template. In the Albers et al 61-center trial, many of the surgeons performed relatively few procedures.14 Studies have shown that surgeons who handle high volumes of complex surgical procedures have a lower mortality rate as well as a higher cure rate.31,32 His group previously reported a 1.2% retroperitoneal relapse rate when RPLND was performed in their tertiary referral centers.33 Urologic surgeons from Indiana University (Indianapolis, IN) and MSKCC both report retroperitoneal relapse rates of lower than 1%.22,23 The surgical results of Albers et al in their phase III trial highlight the need for RPLND to be done by experienced surgeons. NSGCT has long served as a "model for a curable neoplasm."34 In testing the lower bound of efficacy, medical oncologists have developed less toxic treatments, without sacrificing efficacy, by conducting prospective randomized trials. The study by Albers et al contributes to this ongoing research by providing insights into the importance of multidisciplinary expertise, especially surgery, to optimize clinical outcomes. In fact, neither study arm tests an optimal standard of care. However, this study does show that effective treatment and potential curability for all patients with NSGCT, including those with low-stage tumors, is best served by urologists and medical oncologists with extensive expertise in this relatively uncommon, but highly curable, malignancy. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Joel Sheinfeld, Robert J. Motzer Administrative support: Joel Sheinfeld, Robert J. Motzer Collection and assembly of data: Joel Sheinfeld Manuscript writing: Joel Sheinfeld, Robert J. Motzer Final approval of manuscript: Joel Sheinfeld, Robert J. Motzer NOTES published online ahead of print at www.jco.org on May 5, 2008. REFERENCES
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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T2 tumors. BEP x 2 is associated with relapse-free survival in more than 95% of instances.
