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Journal of Clinical Oncology, Vol 22, No 3 (February 1), 2004: pp. 464-467 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.178 Relapse-Free and Overall Survival in Patients With Pathologic Stage II Nonseminomatous Germ Cell Cancer Treated With Etoposide and Cisplatin Adjuvant ChemotherapyFrom the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, and Departments of Urology and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: motzerr{at}mskcc.org
PURPOSE: To assess the long-term relapse-free survival and overall survival of patients with stage II nonseminomatous germ cell tumor (NSGCT) who received two cycles of adjuvant etoposide and cisplatin (EP) after primary retroperitoneal lymph node dissection. PATIENTS AND METHODS: Eighty-seven patients with completely resected pathologic stage II NSGCT were treated with adjuvant EP chemotherapy. Adjuvant EP consisted of two cycles of etoposide (100 mg/m2) plus cisplatin (20 mg/m2) per day, administered days 1 to 5 at a 21-day interval. RESULTS: Ten patients (11%) had pN1 disease, 73 (84%) had pN2 disease, and four (5%) had pN3 disease. Eighty-six patients received two cycles of EP, and one patient received an additional two cycles of EP after a transient marker increase after his first cycle. Eighty-seven patients are alive, and 86 patients (99%) remain relapse-free at a median follow-up of 8 years (range, 0.9 to 13.5 years). CONCLUSION: Two cycles of adjuvant EP is highly effective in preventing relapse in patients with pathologic stage II pN1 and pN2 NSGCT. An alternative treatment strategy is surveillance with full-course chemotherapy at relapse. Because there is a higher risk of relapse for patients with pN2 disease, these patients are offered adjuvant chemotherapy.
Nearly 95% of patients with testicular germ cell tumor (GCT) are cured with surgery and/or combination chemotherapy administered according to stage [1]. Retroperitoneal lymph node dissection remains the standard treatment for patients with clinical stage I and low-volume stage II nonseminomatous germ cell tumor (NSGCT). In patients for whom regional lymph node metastases are completely resected at retroperitoneal lymph node dissection (pathologic stage II), two treatment options exist. First, two cycles of adjuvant chemotherapy results in a relapse-free survival of nearly 100% [2]. Alternatively, patients may be observed closely, with full-course chemotherapy reserved for relapse. The latter approach spares some patients chemotherapy, but treatment for those who relapse requires more extensive chemotherapy (three or four cycles) and possibly additional surgery. The choice of management for patients with pathologic stage II disease is influenced by patient compliance and extent of lymph node involvement within the pathologic specimen from retroperitoneal lymph node dissection. The probability of relapse for patients with N1 disease according to the American Joint Committee on Cancer (AJCC) is one third or less, and therefore, observation in compliant patients is preferable [3-7]. For patients with a more advanced stage (N2), adjuvant chemotherapy may be preferred because more than half of these patients will relapse on observation alone [8]. Also, adjuvant chemotherapy is mandated in patients who are unlikely to adhere to the close surveillance procedures necessitated by this approach. Most prior reports of adjuvant chemotherapy included patients treated with cisplatin, vinblastine, and bleomycin or cyclophosphamide, dactinomycin, vinblastine, bleomycin, and cisplatin in the treatment of advanced, metastatic (M1) GCT. These regimens were replaced by the combination of cisplatin and etoposide with bleomycin, which was shown to be superior based on improved efficacy and less toxicity [9]. The regimen developed at the Memorial Sloan-Kettering Cancer Center (MSKCC) for good-risk disseminated NSGCT is four cycles of etoposide plus cisplatin (EP). Because this regimen was highly effective and well tolerated in patients with metastases, we conducted a single-arm phase II trial of two cycles of adjuvant EP given to patients with pathologic stage II GCT at high risk for relapse [2]. As previously reported, 50 patients were treated and remained relapse-free at a median follow-up of 35 months [2]. Since that clinical trial was completed, we treated an additional 37 patients with EP adjuvant therapy. This report examines relapse-free and overall survival as well as toxicity associated with two cycles of EP adjuvant therapy administered at MSKCC to a total of 87 patients. The 50 patients previously described are included with extended follow-up.
From March 1989 to January 2001, 87 patients with completely resected pathologic stage II NSGCT were treated with two cycles of adjuvant EP. The first 50 patients signed informed consent and were treated on a prospective clinical trial approved by MSKCC's Institutional Review Board. After completion of the prospective trial, 37 patients were identified from a surgical database of patients undergoing retroperitoneal lymph node dissection and treated with two cycles of EP as adjuvant therapy for node-positive disease at MSKCC. All patients had completely resected pathologic stage II NSGCT at retroperitoneal lymph node dissection, normal or normalizing serum tumor markers, and no radiographic evidence of metastases by chest radiography after retroperitoneal lymph node dissection. The Institutional Review Board reviewed this retrospective analysis. As a part of this study, pathology was reviewed and reclassified according to the new AJCC staging system as pN1 (lymph node mass < 2 cm at greatest dimension or five nodes or less positive with none > 2 cm in dimension), pN2 (lymph node mass 2 cm to 5 cm in dimension; > five nodes positive with evidence of extranodal extension), or pN3 (lymph node mass > 5 cm in dimension). Primary bilateral or modified bilateral retroperitoneal lymph node dissection had been performed on all of the study patients. The boundaries of a bilateral retroperitoneal lymph node dissection include the renal vessels superiorly, the medial border of the ureters laterally, the bifurcation of the common iliac arteries inferiorly, and the anterior spinous ligament posteriorly. Therefore, the lymph nodes removed include those from the paracaval, precaval, retrocaval, interaortocaval, preaortic, para-aortic, and bilateral common iliac regions. The modified template for right-sided testis tumors included the infrahilar, paracaval, right common iliac, precaval, and retrocaval nodes, as well as the interaortocaval, preaortic, and para-aortic nodes above the inferior mesenteric artery. The modified template for left-sided tumors included the para-aortic, left common iliac, preaortic, and retroaortic nodes, as well as the precaval and interaortocaval nodes above the inferior mesenteric artery. The ipsilateral gonadal vessels were resected with all major branches and encompassing fibroadipose tissue in all cases. Suprahilar dissection was performed only if there was suspicious lymphadenopathy. Nerve-sparing technique with prospective dissection and preservation of postganglionic sympathetic fibers, the hypogastric plexus, and both sympathetic chains was performed in most cases [10]. Retroperitoneal lymph node dissections on all patients were reviewed and classified according to these definitions. The adjuvant EP regimen has been previously described [2]. In brief, two cycles of etoposide 100 mg/m2 plus cisplatin 20 mg/m2 per day were administered on days 1 to 5 of each cycle. The second cycle was begun on day 21. Each cycle was administered 21 days apart and accompanied by standard hydration and antiemetic regimens. Pretreatment patient characteristics, first date of adjuvant chemotherapy, date of relapse, and date of death or last follow-up were recorded for all patients. The Kaplan-Meier method was used to produce the relapse-free survival curve [11]. The short-term toxicity associated with two cycles of EP was reported in the prospective clinical trial [2]. Follow-up for the retrospective study included patient interview and questions to assess chronic toxicity, including neurotoxicity, ototoxicity, secondary malignancies, and fertility. Toxicities were graded according to the National Cancer Institute common toxicity criteria (version 2.0).
Patient Characteristics and Treatment The median age of patients was 30 years (Table 1). The majority of patients had either a full bilateral (44%) or modified bilateral (25%) retroperitoneal lymph node dissection, and 92% of the patients had retroperitoneal lymph node dissection performed at MSKCC. The predominant histology at retroperitoneal lymph node dissection was embryonal cell carcinoma (85%). Three patients had mixed nonseminoma and seminoma resected at orchiectomy and only pure seminoma resected at retroperitoneal lymph node dissection. When patients were classified according to recent AJCC stage, 10 (11%) had pN1 disease, 73 (84%) had pN2 disease, and four (5%) had pN3 disease. Eighty-six patients received two cycles of EP, and one patient was given four cycles based on a transient rise in alpha-fetoprotein, which had declined but was still elevated before initiation of chemotherapy.
Overall and Relapse-Free Survival All 87 patients are alive, and 86 remain relapse-free at a median follow-up of 8 years (range, 0.9 to 13.5 years; Fig 1). Therefore, the 8-year relapse-free survival rate is 98.9% (95% CI, 96.6% to 100%; Fig 2). One patient relapsed 4 months after two cycles of EP with a hepatic metastasis and abnormal elevation of serum alpha-fetoprotein. He was treated with four cycles of paclitaxel, ifosfamide, and cisplatin [12], achieved a complete response, and remains disease-free at 70+ months. According to the reclassification by newer AJCC staging classification, this patient had pN3 disease resected at retroperitoneal lymph node dissection [13].
Assessment of Chronic Toxicity Acute toxicities associated with two cycles of EP have been previously reported [2]. Two (3%) of 69 patients available for assessment of chronic toxicity complained of persistent ototoxicity (grade 2), and none complained of persistent paresthesias or other subjective evidence of neurotoxicity. Eight patients (12%) had grade 1 ototoxicity, and of the two patients who had grade 2 ototoxicity, one had tinnitus and the other had mild hearing loss. Eleven patients (16%) experienced grade 1 neurotoxicity; there was no grade 2 neurotoxicity. No patient is known to have an abnormally elevated creatinine or proteinuria. One patient developed a second malignancy, tonsillar cancer, and was treated with radiation and chemotherapy and is currently disease-free. None of the patients developed a second primary testicular cancer. At the time of the patient interview, 28 patients had attempted to conceive children after chemotherapy treatment. Nineteen patients (68%) succeeded; 11 patients (39%) had children by natural means, and eight patients (28%) had children by banked sperm (Table 2).
This study shows that two cycles of adjuvant EP is effective adjuvant therapy for patients with pathologic stage II disease, resulting in a greater than 98% relapse-free survival rate at a median follow-up of 8 years. Among the 87 patients in our series, 89% had pathologic stage N2 or higher NSGCT. Treatment was well tolerated [2], and long-term toxicity was uncommon. Past efforts to reduce chemotherapy-related toxicity in the management of advanced GCT included replacement of vinblastine with etoposide, elimination or reduction in the dose of bleomycin, and reduction of the total number of treatment cycles. At MSKCC, these efforts included the use of four cycles of EP with elimination of bleomycin for patients with good-risk metastatic GCT [14]. This trial of two cycles of the adjuvant EP regimen [2] evolved as part of that effort. Two cycles of bleomycin, etoposide, and cisplatin have also been reported in a retrospective series to be an effective adjuvant regimen [15]. Either regimen may be considered in adjuvant therapy, but we prefer EP because it avoids the use of bleomycin, and our data show a more than 98% relapse-free survival rate [2]. Only one patient in our series relapsed, and by new AJCC criteria, this patient was identified as having N3 disease. Primary management for patients with clinical stage II disease often involves cisplatin combination chemotherapy before consideration of retroperitoneal lymph node dissection. On the basis of the increasing role for chemotherapy in the primary management of stage II NSGCT, patients with clinical stage N2 or higher would generally receive full-course chemotherapy before retroperitoneal lymph node dissection. In the rare instance where pN3 disease is present at retroperitoneal lymph node dissection, our preference is full treatment with four cycles of EP or three cycles of bleomycin, etoposide, and cisplatin. In summary, EP is an effective therapy when given in the adjuvant setting because it produces a high relapse-free survival for patients with pathologic stage II NSGCT. Similar results have been achieved with cisplatin, etoposide, and bleomycin, but our experience shows low toxicity and a relapse-free survival rate of greater than 98% with the two-drug regimen. An alternative treatment option is surveillance with full-course chemotherapy at relapse. Because there is a higher risk of relapse for patients with pN2 disease, these patients are offered adjuvant chemotherapy. Also, patients with pN1 disease may choose adjuvant chemotherapy over observation. Adjuvant chemotherapy for noncompliant patients remains mandatory, and patients with more advanced nodal disease (pN3) or unresected disease should receive full-course chemotherapy.
The authors indicated no potential conflicts of interest.
We thank Carol Pearce for her review of the manuscript.
Supported in part by National Institutes of Health grants Nos. K24 CA-82431 and 5T32-CA-09207-26. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Bosl GJ, Motzer RJ: Testicular germ-cell cancer. N Engl J Med 337:242–253, 1997 2. Motzer RJ, Sheinfeld J, Mazumdar M, et al: Etoposide and cisplatin adjuvant therapy for patients with pathologic stage II germ cell tumors. J Clin Oncol 13:2700–2704, 1995[Abstract] 3. Vugrin D, Whitmore WF, Cvitkovic E, et al: Adjuvant chemotherapy combination of vinblastine, actinomycin D, bleomycin, and chlorambucil following retroperitoneal lymph node dissection for stage II testis tumor. Cancer 47:840–844, 1981[CrossRef][Medline] 4. Vugrin D, Whitmore W, Cvitkovic E, et al: Adjuvant chemotherapy with VAB-3 of stage II-B testicular cancer. Cancer 48:233–237, 1981[CrossRef][Medline] 5. Vugrin D, Whitmore WF Jr, Herr H, et al: Adjuvant vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum chemotherapy regimen with and without maintenance in patients with resected stage IIB testis cancer. J Urol 128:715–717, 1982[Medline] 6. Hartlapp JH, Weissbach L, Bussar-Maatz R: Adjuvant chemotherapy in nonseminomatous testicular tumour stage II. Int J Androl 10:277–284, 1987[Medline] 7. Pizzocaro G, Monfardini S: No adjuvant chemotherapy in selected patients with pathologic stage II nonseminomatous germ cell tumors of the testis. J Urol 131:677–680, 1984[Medline] 8. Fraley EE, Narayan P, Vogelzang NJ, et al: Surgical treatment of patients with stages I and II nonseminomatous testicular cancer. J Urol 134:70–73, 1985[Medline] 9. Williams SD, Birch R, Einhorn LH, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316:1435–1440, 1987[Abstract] 10. Walsh P, Retik AB, Vaughan ED, et al (eds): Surgery of testicular tumors, in Cambell's Urology (ed 8). Philadelphia, PA, Elsevier Scientific Publications, 2002, pp 2920–2930 11. Kaplan FL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 52:457–481, 1958[CrossRef]
12. Motzer RJ, Sheinfeld J, Mazumdar M, et al: Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 18:2413–2418, 2000 13. DeVita VJ, Hellman S, Rosenberg SA (eds): Chapter 35, in Cancer: Principles and Practice (ed 6). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 1491–1518
14. Xiao H, Mazumdar M, Bajorin DF, et al: Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol 15:2553–2558, 1997 15. Behnia M, Foster R, Einhorn LH, et al: Adjuvant bleomycin, etoposide and cisplatin in pathological stage II non-seminomatous testicular cancer: The Indiana University experience. Eur J Cancer 36:472–475, 2000 Submitted July 24, 2003; accepted November 20, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
