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Cyclophosphamide and Carboplatin and Selective Consolidation in Advanced Seminoma

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Cyclophosphamide and Carboplatin and Selective Consolidation in Advanced Seminoma 72 Vol. 6, 72–77, January 2000 Clinical Cancer Research Cyclophosphamide and Carboplatin and Selective Consolidation in Advanced Seminoma Robert J. Amato,1 Randall Millikan, tive in a significant proportion of patients with nonseminoma- Dania Daliani, Lori Wood, tous tumors but ineffective in patients with seminoma (1). The Christopher Logothetis, and Alan Pollack major advance in chemotherapy of seminoma came with the incorporation of cisplatin. In the initial reports of the use of Departments of Genitourinary Medical Oncology [R. J. A., R. M., cisplatin as a single agent in patients with germ cell tumors, D. D., L. W., C. L.] and Radiation Oncology [A. P.], The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 long-term, disease-free survival was reported in patients with seminoma but not in patients with nonseminomatous tumor (2). The apparent increased sensitivity of the seminomas to cisplatin ABSTRACT and relative resistance to the vinblastine/bleomycin regimen led This prospective Phase II study assesses the clinical us to study cisplatin-based chemotherapy regimens in patients efficacy and complications of a treatment regimen of com- with advanced seminoma. The addition of an alkylating agent to bination chemotherapy with cyclophosphamide and carbo- cisplatin for these patients was prompted by the significant platin and selective consolidation in advanced seminoma. Of antitumor activity of these agents and their reported synergy 46 patients who entered the study between December 1992 with cisplatin (3–6). and October 1998, 46 were evaluable. Thirty-two achieved a Besides being more sensitive to cytotoxic chemotherapy complete remission (70%; 95% confidence interval, 56– than nonseminomatous germ cell tumors, seminoma is known to 83%) after chemotherapy alone. Fourteen achieved a com- be more radiation sensitive (7). Furthermore, comparison of the plete remission (30%; 95% confidence interval, 18–46%) two tumor types by surgical resectability of residual masses after chemotherapy plus consolidation. Forty-three of the 46 after chemotherapy highlights an important difference between patients (93%; 95% confidence interval, 82–97%) remained the two. Whereas the standard practice in nonseminomatous in remission after a median follow-up period of 27.4 months. germ cell tumors is elective surgery for residual disease, in No patient experienced nephrotoxic, neurotoxic, or ototoxic seminomas the situation is quite different. Pronounced fibrotic effects or hemorrhagic cystitis. No patient had neutropenic changes make surgery for seminomas much more difficult and fever requiring hospitalization. Thirteen % required plate- complications more frequent. Finally, the metastatic spread of let transfusions, and 9% required transfusions of packed seminomas appears to be more indolent and predictable than RBCs. For patients with advanced seminoma, treatment that of other germ cell tumors. The therapy of seminoma at the with cyclophosphamide and carboplatin and selective con- M. D. Anderson Cancer Center has focused on exploiting these solidation is safe and effective. differences. In our initial experience of treating seminoma patients with INTRODUCTION a regimen combining cisplatin and cyclophosphamide and se- At the University of Texas M. D. Anderson Cancer Center, lective consolidation, we concluded that the combination was the treatment protocol for patients with advanced seminoma is effective. Ninety-two % of the patients had survived, free of different from that for patients with nonseminomatous germ cell disease, for long periods (8). The major side effects were those tumor. The difference in strategy is based on the apparent attributed to repeated doses of cisplatin, i.e., nephrotoxicity, greater sensitivity of the seminoma to both chemotherapy and neurotoxicity, and ototoxicity. Encouraged by the therapeutic radiation therapy, the relative difficulty of surgical resection, success of that initial trial, we expanded our study to evaluate and unique clinical features. combinations of cisplatin analogues and alkylating agents in an The different sensitivities to chemotherapy of seminoma attempt to find a treatment with a similar high cure rate without and nonseminomatous germ cell tumors were most apparent the relatively high complication rate. The first alternative we during the initial development of chemotherapy for germ cell evaluated was the combination of carboplatin and ifosfamide. tumors, before the availability of cisplatin. The combination These two agents were selected because of their individual chemotherapy regimen of vinblastine and bleomycin was effec- antitumor activities and their relatively mild toxicity profiles. Ninety-one % of the patients remain free of disease with a median follow-up of 78 months (9). No patients experienced deterioration of renal function, symptomatic peripheral neurop- athy, ototoxic effects, or hemorrhagic cystitis. There were no Received 6/9/99; revised 9/15/99; accepted 9/16/99. The costs of publication of this article were defrayed in part by the treatment-related deaths. Ten % of the patients had neutropenic payment of page charges. This article must therefore be hereby marked fever requiring hospitalization. Twenty-six % required transfu- advertisement in accordance with 18 U.S.C. Section 1734 solely to sion of packed RBCs for a hemoglobin level of Ͻ8 g/dl or indicate this fact. 1 symptomatic anemia. Twenty-four % required platelet transfu- To whom requests for reprints should be addressed, at Department of Ͻ 3 Genitourinary Medical Oncology, The University of Texas, M. D. sions for a platelet count 20 cells/mm or for symptoms of Anderson Cancer Center, 1515 Holcombe Boulevard, Box 013, Hous- bleeding. Ninety-eight % are alive and disease free with a ton, TX 77030. Phone: (713) 792-2830; Fax: (713) 745-0827. median follow-up of 84 months. Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2000 American Association for Cancer Research. Clinical Cancer Research 73 Further modification of our chemotherapy program to re- Table 1 Dose levels duce the number of days of administration of chemotherapy, to Level Carboplatin Cyclophosphamide switch from an inpatient to an outpatient regimen, to reduce 0 (starting dose) 400 mg/m2 800 mg/m2 hematological toxicity, and to further define the role of consol- Ϫ1 360 mg/m2 800 mg/m2 idation is our present goal. PATIENTS AND METHODS Study Population. To make this regimen less compli- chemotherapy at 28-day intervals. Granulocyte-colony stimulat- cated, we combined cyclophosphamide and carboplatin. To re- ing factor at 5 ␮g/kg/day s.c. was initiated on days 2–11. Doses duce hematological toxicity, we used granulocyte-colony stim- of cyclophosphamide and carboplatin were modified if indicated ulating factor beginning on day 2 of each chemotherapy cycle. by granulocyte counts, platelet counts, or nonhematological To further modify hematological toxicity, those patients with a toxicity (Table 2). Planned radiation therapy for those patients predicted creatinine clearance of Յ80 ml/min (calculated by with a residual mass consisted of a dose of 25 Gy. Crockcroft and Gault formulation for estimated creatinine clear- Statistical Analysis. All evaluable patients are included ance) not related to tumor volume received a modified dose of in this analysis. Response duration and survival were measured carboplatin. This is based on our retrospective analysis of our from the date of initiation of therapy. Survival curves were previous program, ifosfamide and carboplatin. Those patients generated by using the Kaplan-Meier method (8–10). with Ն3 cm residual mass after chemotherapy had a delay in Response Criteria. The treatment of advanced semi- deciding whether to have consolidation radiation therapy for 3 noma with chemotherapy classically results in a persistent re- months. Patients who continue to have regression of their re- sidual mass (8, 9, 11). Our own experience prompted us to adopt sidual mass will continue to be observed, whereas those patients the following criteria. Patients were classified as either having a who remain stable will receive consolidation radiation therapy. complete remission in response to chemotherapy or response to Patients were enrolled in the study between December chemotherapy that required consolidation. A complete remis- 1992 and October 1998. Fifty patients with a diagnosis of sion to chemotherapy was defined as disappearance of all clin- advanced seminoma were assessed by: a review of the histolog- ical and biochemical evidence of disease with either complete ical type; serum tumor marker assays for ␤-HCG,2 AFP, and resolution on radiographic examination or a stable residual mass total LDH and LDH isoenzyme-1; and computed tomographic Ͻ3 cm in maximum transverse diameter. A response to chem- scans of the thorax, abdomen, and pelvis. Patients with visceral otherapy requiring consolidation was defined as disappearance metastases were further staged by isotope bone scan. In addi- of all clinical and biochemical evidence of disease with a tion, a complete blood count with platelet count, electrolytes, persistent stable mass 3 cm or more in maximum transverse and assessment of renal and liver function was performed. diameter. Patients received a minimum of four courses of in- Forty-six of the patients met the following criteria and were duction chemotherapy, with an additional requirement of two evaluated in our study. Patients had histological confirmation of courses beyond complete remission
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