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© 2001 American Society for Clinical Oncology Role of Postchemotherapy Adjunctive Surgery in the Management of Patients With Nonseminoma Arising From the MediastinumFrom the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, the Division of Biostatistics, Department of Biostatistics and Epidemiology, and the Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York; and the Department of Medicine, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY. Address reprint requests to Robert J. Motzer, MD, Memorial Hospital, 1275 York Ave, New York, NY.
PURPOSE: To evaluate the role of postchemotherapy surgery in patients with nonseminomatous germ cell tumors arising from the anterior mediastinum. PATIENTS AND METHODS: Thirty-two patients with nonseminoma arising from a mediastinal primary site were treated on a clinical trial at our center, and they underwent postchemotherapy surgery. The results of postchemotherapy surgical resection, frequency of viable tumor found during postchemotherapy surgery, and prognostic factors for survival were assessed. RESULTS: Complete resection of all gross residual disease was achieved in 27 patients (84%). Histologic analysis of resected residua postchemotherapy revealed viable tumor in 66%, teratoma in 22%, and necrosis in 12% of the specimens. Viable tumor included embryonal carcinoma, choriocarcinoma, yolk sac carcinoma, seminoma, and teratoma with malignant transformation to nongerm cell histology (eg, sarcoma). Clinical characteristics associated with a shorter survival after surgery included the presence of viable tumor in a resected specimen (P = .003) and more than one site resected during surgery (P = .06). There were no statistically significant differences in survival for patients who underwent surgical resection with normal markers compared with patients with elevated serum tumor markers (P = .33). A trend toward shorter survival was found in patients with increasing tumor markers before surgery compared with patients with normal and declining serum tumor markers (P = .09). CONCLUSION: Surgical resection of residual mass after chemotherapy plays an integral role in the management of patients with primary mediastinal nonseminoma. Teratoma and viable tumor were found in the majority of resected residua after chemotherapy. Because patients who undergo conventional salvage chemotherapy programs rarely achieve long-term disease-free status, selected patients with elevated markers after chemotherapy are considered candidates for surgical resection.
NEARLY 80% OF patients with metastatic germ cell tumors (GCTs) arising from the testis achieve long-term complete remission with standard cisplatin induction therapy comprised of etoposide and cisplatin with or without bleomycin.1 In contrast, the 5-year overall survival rate for patients with primary mediastinal nonseminoma is 40%.2 Therefore, patients with this primary site and nonseminoma histologic findings are classified as "poor risk," regardless of extent of metastases or concentration of levels of serum tumor markers.2-5 This poor prognosis is unique to nonseminoma arising from the anterior mediastinum, because patients with pure seminoma have a high chance of cure regardless of primary site. Patients with nonseminoma arising from the mediastinum whose first-line chemotherapy fails have a poor response to salvage chemotherapy; less than 10% are long-term survivors with either standard dose ifosfamide-based therapy or high-dose chemotherapy with autologous stem-cell rescue.6-8 For patients with normalized serum tumor markers, resection of residua after chemotherapy is an integral part of the management of testicular nonseminomatous GCTs.9 Surgical resection after chemotherapy serves to assess response, remove chemotherapy-resistant disease, and direct additional chemotherapy.1 There are few published reports on the benefit of postchemotherapy surgery in patients with mediastinal nonseminoma.10 We report the experience and role of postchemotherapy surgery in patients with a nonseminomatous GCT arising from a mediastinal primary site. The frequency of viable tumor at surgery, prognostic factors for survival, and role of surgery in patients with elevated markers are reported.
Patients Forty-nine patients with primary mediastinal nonseminomatous GCTs were treated with chemotherapy on prospective clinical trials at Memorial Sloan-Kettering Cancer Center (MSKCC) from August 1979 to June 1999.11-17 Thirty-two of these patients underwent surgical resection of residual disease within 3 months after completion of chemotherapy and are the subjects of this review. All met the criteria for a prechemotherapy histologic diagnosis of primary mediastinal nonseminoma GCT, as follows: (1) tumor arising from the anterior mediastinum; (2) no evidence of a testicular mass revealed by ultrasound or physical examination; and (3) histologic diagnosis confirmed at MSKCC. All patients signed informed consent for a clinical trial approved by the MSKCC institutional review board. Treatment regimens and results of the clinical trials have been published previously,11-16 with the exception of six patients who were treated on an ongoing randomized intergroup trial for poor-risk patients (induction bleomycin, etoposide, and cisplatin [BEP] for two cycles followed by high-dose chemotherapy and autologous stem cell support v four cycles of BEP). Seventeen (35%) of the 49 patients did not undergo postchemotherapy surgery and are excluded. Twelve patients had progressive disease and did not undergo postchemotherapy surgical resection, four patients underwent surgical resection before treatment with chemotherapy and did not have residua postchemotherapy, and one patient refused surgery.
Surgery and Classification of Histologic Findings Resected specimens were categorized according to the following criteria: Necrosis referred to findings of necrotic debris only in the resected specimen. Histologic analysis of a resected specimen was categorized as teratoma when mature or immature teratoma was found in the absence of malignant transformation or GCT findings such as embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, or seminoma. Any of the latter histological findings were considered viable GCT. Teratoma with malignant transformation refers to a form in which one of the components of teratoma resembles a somatic malignancy such as sarcoma histologically.18 Any specimen that included teratoma with malignant transformation was classified as malignant transformation, regardless of whether the specimen included mature or immature teratoma or a viable GCT. Specimens that included either a GCT or malignant transformation were called viable tumor.
Statistical Methods Survival distributions were estimated using the Kaplan-Meier method.19 The relationship between survival and each of the variables was analyzed by use of a permutation test based on the log-rank statistic.20 Two-sided P values were calculated from the permutation distribution under the null hypothesis of equality of the two survival distributions.
Patient Characteristics Evidence of extramediastinal disease before chemotherapy was present in 63% (n = 20) of the 32 patients, and 90% of patients had metastasis to the lung. Although mixed GCT was the most common histologic finding at initial biopsy (56%), pure yolk sac carcinoma was present in 28% of patients ( Table 1). Two patients with pure teratoma had elevated serum tumor markers before chemotherapy was initiated. Seven patients presented to MSKCC with cisplatin-refractory and progressive disease, and they were enrolled onto a second-line high-dose chemotherapy program.16 Twenty-five patients who had not been treated with cisplatin-based chemotherapy previously were enrolled onto a first-line chemotherapy regimen.11-15
Surgical Procedures and Response The median time to surgery was 41 days (range, 20 to 81 days) from the last cycle of chemotherapy. Complete resection of all gross residual disease was achieved in 27 patients (84%). In 11 (34%) of 32 patients, only the mediastinum was resected. Twenty-one patients (66%) had two or more sites resected; in the majority, the mediastinum and one other site were resected. Nineteen patients (59%) exhibited normal AFP and/or HCG before surgical resection, whereas 13 (41%) patients had elevated serum tumor markers before surgery (two with HCG only and 11 with AFP only). Seven of the 13 patients with elevated markers had declining markers before surgical resection and six had increasing markers. Of the 13 patients who demonstrated elevated markers, 10 (77%) had a complete resection of disease; six of these patients had declining markers, and four had increasing markers.
Postchemotherapy Residua
Histologic analysis of the resected residua was categorized by presurgical serum tumor markers and is listed in Table 3. In patients with normal markers before surgical resection, 11 (58%) of 19 had viable tumor in resected residua, and five (26%) of 19 contained teratoma. Viable tumor was found in 10 (77%) of 13 patients, and teratoma was revealed in two (15%) of 13 patients with elevated markers before surgical resection.
Survival The median survival of the 32 patients who underwent postchemotherapy surgery was 10 months (95% confidence interval, 6 to 45 months), and the median follow-up for survivors was 40 months (range, 9 to 139 months) ( Fig 1). Ten patients were alive as of the last follow-up examination, including seven with no evidence of disease continuously, two who relapsed and had no evidence of disease after further surgery and chemotherapy, and one patient who is alive with disease.
Prognostic Variables for Survival Factors associated with an adverse prognosis after resection included the presence of viable tumor in the surgical specimen (P = .003) and resection of two or more sites during surgery (P = .06) ( Table 4). The 2-year survival rate for patients with teratoma or necrosis in resected residua was 81% compared with 19% for those with viable tumor. The 2-year survival rate for patients who underwent only resection of the mediastinum was 62% compared with 28% for patients who had two or more sites resected.
Teratoma with malignant transformation to sarcoma was associated with a particularly short survival; five of six such patients were dead by 12 months, and the remaining patient is alive with disease at more than 25 months. Two patients were diagnosed with a hematologic disorder within 2 months of postchemotherapy resection; one developed acute myelogenous leukemia and the other developed non-Hodgkin’s lymphoma. Survival after surgery was examined according to serum tumor marker status after chemotherapy and before surgical resection. No difference in survival was detected in patients according to whether the postchemotherapy serum tumor marker was normal or elevated before surgery. We further characterized marker status as normal or elevated and declining versus elevated and increasing before surgery. There was a trend toward shorter survival in patients with increasing presurgical tumor markers (P = .09). The 2-year survival rate for patients with normal and declining markers was 44% compared with 17% for patients with increasing serum tumor markers. Surgical resection after first-line versus second-line chemotherapy did not influence survival; the outcome of both groups was equally poor.
Status of Patients With Elevated Serum Tumor Markers Before Surgery
Postchemotherapy resection plays an integral role in the management of patients with mediastinal nonseminoma, because these patients almost always present with bulky tumors and retain residua after chemotherapy. Viable tumor or teratoma was present in resected specimens from 88% of our patients, specifically 92% of patients who underwent resection after first-line chemotherapy and 71% of patients who underwent resection after second-line chemotherapy. Kesler et al10 reported similar results, in which viable tumor and teratoma were found in 76% of postchemotherapy resected residua ( Table 5). The frequency of viable GCTs found at resection is higher in this series than that reported generally for testicular GCTs, in which viable GCTs are found in 15% to 20% of resected residua after first-line chemotherapy and 50% of resected residua after second-line chemotherapy.1,21 Although this series included patients with elevated markers before surgical resection and patients who underwent resection after second-line chemotherapy, the 57% proportion of patients with viable GCTs and normalized markers after first-line chemotherapy was noteworthy. The high frequency of viable tumor (GCT and malignant transformation) and teratoma in this series emphasizes the integral role of postchemotherapy surgery in the management of patients with nonseminoma arising in the mediastinum. In this regard, patients may benefit from referral to specialized centers for surgical resection.
Teratoma with malignant transformation to nongerm cell elements was found in six patients after chemotherapy and another two patients at relapse. Patients who had teratoma with malignant transformation components experienced particularly poor outcomes, and of the six patients with initial sarcomatous transformation and the two subsequent patients who relapsed with evidence of sarcoma in resected specimens, none are both alive and disease-free. Although none of our patients with malignant transformation are alive and disease-free (one is alive with disease), it has been reported that surgical resection is required for potential cure, because disease with these histologic characteristics does not respond to GCT-directed cisplatin combination chemotherapy.18 In general, surgery for patients with testicular GCT is reserved for those with normalized markers, with the exception of desperation surgical salvage.22,23 The lack of effective salvage chemotherapy and long-term survival for patients who undergo surgery with elevated serum tumor markers after initial and salvage chemotherapy have led us and others to undertake surgery in selected patients with elevated markers (Table 5).10 In both series, no statistically significant difference in survival after surgery was found in patients with presurgical elevated markers versus patients with normal markers. We further characterized patients with elevated markers as declining or increasing and found a trend toward shorter survival for patients with elevated and increasing tumor markers compared with patients with normal and elevated but declining markers before surgical resection. It should be emphasized that this analysis is retrospective, and it included a relatively small number of patients. A larger experience would be required to evaluate the role of surgery in patients with an elevated and increasing serum tumor marker before surgical resection. Therefore, selected patients with presurgical elevated tumor markers are considered candidates for surgery. Because of the poor results associated with salvage chemotherapy, patients with one site of disease are likely to benefit from postchemotherapy resection despite elevated markers before surgical resection. In summary, resistance to first-line and salvage chemotherapy relative to gonadal GCTs, tendency toward malignant transformation to non-GCT elements, and hematologic malignancies have been cited as contributing factors to the poor prognosis associated with nonseminoma GCTs arising from the mediastinum.4,7,24-26 The poor outcome achieved by first-line treatment with BEP (< 50% durable complete remission) emphasizes the need to treat these patients on clinical trials. The lack of effective salvage treatment with conventional-dose and high-dose programs underscores the importance of surgical resection in the management and study of new drugs in patients with unresectable tumors. Patients should be considered candidates for surgery at specialized centers. Clarification of the biology of malignant transformation of primordial germ cells and drug-resistant GCTs must be a priority, so that new therapies in previously untreated and relapsed patients with primary mediastinal nonseminoma GCTs may be identified.
Supported in part by a grant from the Brian Piccolo Cancer Research Fund and grant no. CA-09207-23. We thank Carol Pearce for reviewing the manuscript.
Presented at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, May 20-23, 2000, New Orleans, LA.
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Lemarie E, Assouline PS, Diot P, et al: Primary mediastinal germ cell tumors: Results of a French retrospective study. Chest 102: 1477-1483, 1992 6. Toner GC, Geller NL, Lin SY, et al: Extragonadal and poor risk nonseminomatous germ cell tumors: Survival and prognostic features. Cancer 67: 2049-2057, 1991[Medline] 7. Saxman SB, Nichols CR, Einhorn LH: Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: The Indiana University experience. J Clin Oncol 12: 1390-1393, 1994[Abstract] 8. Broun ER, Nichols CR, Einhorn LH, et al: Salvage therapy with high-dose chemotherapy and autologous bone marrow support in the treatment of primary nonseminomatous mediastinal germ cell tumors. Cancer 68: 1513-1515, 1991[Medline] 9. 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]
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Bosl GJ, Gluckman R, Geller NL, et al: VAB-6: An effective chemotherapy regimen for patients with germ-cell tumors. J Clin Oncol 4: 1493-1499, 1986 12. Bosl GJ, Geller NL, Vogelzang NJ, et al: Alternating cycles of etoposide plus cisplatin and VAB-6 in the treatment of poor-risk patients with germ cell tumors. J Clin Oncol 5: 436-440, 1987[Abstract] 13. Motzer RJ, Cooper K, Geller NL, et al: Carboplatin, etoposide, and bleomycin for patients with poor-risk germ cell tumors. Cancer 65: 2465-2470, 1990[Medline]
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Motzer RJ, Mazumdar M, Gulati SC, et al: Phase II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Natl Can Inst 85: 1828-1835, 1993
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Motzer RJ, Mazumdar M, Sheinfeld J, et al: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18: 1173-1180, 2000 17. Vuky J, McCaffrey J, Ginsberg M, et al: Phase II trial of pyrazoloacridine in patients with cisplatin-refractory germ cell tumors. Invest New Drugs 18: 265-267, 2000[Medline] 18. Motzer RJ, Amsterdam A, Prieto V, et al: Teratoma with malignant transformation: Diverse malignant histologies arising in men with germ cell tumors. J Urol 159: 133-138, 1998[Medline] 19. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-81, 1958 20. Heller G, Venkatraman ES: Resampling procedures to compare two survival distributions in the presence of right-censored data. Biometrics 52: 1204-1213, 1996 21. Fossa SD, Aass N, Ous S, et al: Histology of tumor residuals following chemotherapy in patients with advanced nonseminomatous testicular cancer. J Urol 142: 1239-1242, 1989[Medline] 22. Eastham JA, Wilson TG, Russell C, et al: Surgical resection in patients with nonseminomatous germ cell tumor who fail to normalize serum tumor markers after chemotherapy. Urology 43: 74-80, 1994[Medline]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
