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Journal of Clinical Oncology, Vol 25, No 35 (December 10), 2007: pp. 5550-5552 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.8883
Optimal Management of Retroperitoneal Metastatic Nonseminomatous Testicular Cancer: Toward a Better Selection Between Scalpel and NeedleErasmus University Medical Center Rotterdam and Rotterdam Cancer Institute, Rotterdam, the Netherlands; and the Department of Medical Oncology, Rotterdam Cancer Institute, Rotterdam, the Netherlands During the past decades, both surgery and systemic chemotherapy have emerged as critically important modalities in the treatment of nonseminomatous germ cell cancer. Before the advent of cisplatin-based chemotherapy, retroperitoneal lymph node dissection (RPLND) had been established to be potentially definitive treatment in many cases of low volume (stage IIA, < 2 cm; stage IIB, < 5 cm) retroperitoneal metastatic disease.1,2 A full, bilateral, or modified template RPLND is a technically demanding procedure and requires a skillful and experienced surgeon. Nonetheless, if uneventful and definitive, a RPLND is devoid of late toxicity. After the recognition of the high curative potential of bleomycin, etoposide, and cisplatin (BEP) chemotherapy, even in the setting of widespread metastatic disease,3 many investigators have adopted primary chemotherapy also in stage IIA and IIB disease, reserving RPLND mainly to resect postchemotherapy residuals. At first glance, this approach seems straightforward given the greater than 90% disease-free survival and 95% disease-specific survival in good prognosis (low volume) metastatic disease by chemotherapy. Following primary RPLND, chemotherapy was also increasingly being used adjuvantly if pathologic stage II was confirmed, or to treat systemic relapse after RPLND. Hence, chemotherapy has increasingly been given as primary therapy. The prospect of primary chemotherapy to eradicate virtually all low- or limited volume retroperitoneal metastatic disease, and sparing most patients double treatment in terms of an additional RPLND, however, has not come true. Several studies using primary chemotherapy have demonstrated that up to 50% of patients with stage IIA and IIB retroperitoneal metastatic disease obtain no radiologic complete remission and even the tiniest remnants (< 5 mm in previously involved sites) may harbor remaining viable cancer, or residual mature teratoma.4,5 In the greater majority of patients who undergo postchemotherapy RPLND for radiologic residual disease, the resected specimens contain mature teratoma as the dominant histology. Although mature teratoma is considered benign, there is a lifetime risk of growth and secondary transition into malignancy. Therefore, mature teratoma should be considered potentially malignant, requiring surgical resection whenever feasible.
Two large European databases have allowed determination of the incidence and histology of residual masses in the retroperitoneal area following full induction chemotherapy.6,7 In a study of the Medical Research Council in 287 patients, 222 of whom had stage IIA/B nonseminoma, viable cancer was found in 18% and mature teratoma was present in 51% of patients who underwent surgery for postchemotherapy residuals.6 The frequency of surgery and histological findings is summarized in Table 1. A subset analysis is also available of the stage IIA/B patients treated in the study led by the European Organisation for Research and Treatment of Cancer of three versus four cycles of BEP in good prognosis testicular cancer.7 Of the total 812 patients entered onto the study, 300 patients had stage IIA or IIB nonseminoma. Radiologic residual disease (
This emphasizes the consideration to perform primary RPLND for localized stage IIA and IIB disease, with the use of (two cycles of) adjuvant chemotherapy in selected instances. It would especially be important if parameters can be defined that identify patients who can be treated exclusively by the surgical approach and do not need any chemotherapy. In this issue of the Journal of Clinical Oncology, Stephenson et al14 report on a series of patients with clinical stage IIA/B nonseminomatous testicular cancer, treated with either primary RPLND, or primary chemotherapy followed by RPLND. During the past two decades the investigators from the Memorial Sloan-Kettering Cancer Center (New York, NY) have kept to the approach of performing RPLND in virtually all stage IIA and IIB nonseminoma patients, either as primary definitive treatment, or after induction chemotherapy. Their currently reported database contains information of 252 patients, treated between 1989 and 2002, of whom 136 underwent primary RPLND and 116 received chemotherapy plus postchemotherapy RPLND. Over time, the choice for initial chemotherapy was guided by previously reported selection factors, including size of the adenopathy greater than 2 cm (stage IIB), elevated serum tumor markers, or radiological disease outside the primary landing zone.2 After the recognition of these prognostic factors, proportionally more patients received chemotherapy over time (22% during 1989 to 1993 v 68% in 1999 to 2002), and the relapse-free survival subsequently improved from 84% to 98%. The proportion of patients who received any chemotherapy, however, did not increase over time (70 v 79%; P = .16), which was explained mainly by an increase in the number of patients successfully treated by RPLND alone. Close examination of the two cohorts provides clinically valuable information. First, among the patients selected for primary chemotherapy, the histology of the resected specimens at postchemotherapy surgery did not change significantly over time in terms of the proportion of patients with necrosis (50% to 64%), viable cancer (6% to 13%), and mature teratoma (31% to 50%). Among 36 patients with postchemotherapy residuals 5 mm or less, still, viable cancer was found in 6% and mature teratoma in 25%, emphasizing the need for postchemotherapy RPLND in most, if not all, patients primarily treated with three or four cycles of chemotherapy. Second, of the patients who underwent primary RPLND the use of two cycles of adjuvant EP (2EP) was mainly reserved for patients with pN2-N3 disease. Due to the successful application of the selection factors to choose for primary RPLND, the patients in this group received fewer cycles of chemotherapy on average (mean, 1.4 v 4.2 cycles; P < .001), and 51% of the primary RPLND patients avoided chemotherapy completely, without an apparent impact on disease-specific survival (DFS; 5-year DFS, 100% v 98%; P = .3). Of equal importance was the observation that 36% of the patients deemed (clinical) stage II, on RPLND were found to be pathological stage I. For those one third of patients with clinical stage IIA/B disease who have normal or normalized postchemotherapy alpha-fetoprotein and human chorionic gonadotropin, adenopathy 2 cm or less, and a solitary retroperitoneal mass in the primary landing zone, a primary RPLND may therefore be the more suitable approach, by which a subpopulation is spared chemotherapy with its associated acute and long-term toxicities. As Stephenson et al indicate, in these patients a significant percentage have (pathological) stage I disease, have mature teratoma (for which surgery is the only definitive treatment), and two thirds of those patients confirmed pathological stage II disease have PN1 disease, for which RPLND alone may be curative in up to 90%. For those patients with stage IIB disease, multiple affected lymph nodes, and/or elevated serum tumor markers, there is no clear standard of care treatment recommendation, as the majority of patients after three cycles of BEP (or four cycles of EP) still need postchemotherapy RPLND, and vice versa, the majority of patients undergoing primary RPLND need additional chemotherapy. The currently available data indicate that the approach of induction chemotherapy in all patients with clinical stage II A/B disease is far from ideal, as too many patients as yet require surgery, whereas now there seems a well characterized group of patients who can be treated by primary RPLND and can be spared chemotherapy completely. A more conservative approach toward the primary use of full induction chemotherapy is supported by increasing concerns with late cardiovascular morbidity and secondary solid malignancies in testis cancer survivors who have been treated with chemotherapy. The current report provides important guidance by substantiating the need for postchemotherapy surgery, as well as by further defining the patient category that may be better treated by primary definitive surgery. This lends support to the consideration that we may have adopted primary chemotherapy in all patients with low volume retroperitoneal disease too rapidly and that the time has come to shift the pendulum back to primary definitive surgery in some selected patients. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS I thank Laurence Collette, MSc, PhD, biostatistician at the European Organisation for Research and Treatment of Cancer Data Center for her help in providing the stage IIA/B nonseminoma subset analysis data of study European Organisation for Research and Treatment of Cancer 30941 (Table 1). REFERENCES 1. Donohue JP, Thornhill JA, Foster RS, et al: Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965 to 1989): Modifications of technique and impact on ejaculation. J Urol 149:237-243, 1993[Medline] 2. Stephenson AJ, Bosl GJ, Motzer RJ, et al: Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer impact of patient selection factors on outcome. J Clin Oncol 23:2781-2788, 2005 3. Bosl GJ, Motzer RJ: Testicular germ-cell cancer. N Engl J Med 337:242-253, 1997 4. Toner GC, Panicek DM, Heelan RT, et al: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: Recommendations for patient selection. J Clin Oncol 8:1683-1694, 1990[Abstract] 5. Oldenburg J, Alfsen GC, Lien HH, et al: Postchemotherapy retroperitoneal surgery remains necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses. J Clin Oncol 21:3310-3317, 2003 6. Horwich A, Stenning S: Initial chemotherapy for stage II testicular non-seminoma. World J Urol 12:148-150, 1994[Medline] 7. de Wit R, Roberts JT, Wilkinson PM, et al: Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: A randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 19:1629-1640, 2001 8. Loehrer PJ, Hui S, Clark S, et al: Teratoma following cisplatin-based combination chemotherapy for nonseminomatous germ cell tumors: A clinicopathological correlation. J Urol 135:1183-1189, 1986[Medline] 9. Mizutani Y, Sato N, Kawauchi A, et al: Cisplatin-induced in vivo differentiation of human embryonal carcinoma. BJU Int 89:454-458, 2002[CrossRef][Medline] 10. Huddart RA, Norman A, Shahidi M, et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513-1523, 2003 11. van den Belt-Dusebout AW, Nuver J, de Wit R, et al: Long-term risk of cardiovascular disease in 5-year suvivors of testicular cancer. J Clin Oncol 24:467-475, 2006 12. Travis LB, Fossa SD, Schonfeld SJ, et al: Second cancers among 40.576 testicular cancer patients: Focus on long-term survivors. J Natl Cancer Inst 97:1354-1365, 2005 13. van den Belt-Dusebout AW, de Wit R, Gietema JA, et al: Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 25:4370-4378, 2007 14. Stephenson AJ, Bosl GJ, Motzer RJ, et al: Non-randomized comparison of primary chemotherapy and retroperitoneal lymph node dissection for clinical stage II A and II B nonseminomatous germ cell testicular cancer. J Clin Oncol doi: 10.1200/JCO.2007.12.0808
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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1 cm) was reported in 132 patients (44%) after the completion of chemotherapy. Of these, 73 underwent surgery and 71 patients had complete resection of residual disease; in one patient residuals were partially resected, and one patient had biopsy alone. Mature teratoma was found in as many as 51 patients (70%; 
