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© 1999 American Society for Clinical Oncology Phase II Trial of Gemcitabine in Refractory Germ Cell TumorsFrom the Department of Medicine, Division of Hematology/Oncology, Indiana University Medical Center, Indianapolis, IN. Address reprint requests to Lawrence H. Einhorn, MD, Indiana Cancer Pavilion, 535 Barnhill Dr, Room 473, Indianapolis, IN 46202-5289
PURPOSE: This phase II study was designed to determine the toxicity and activity of single-agent gemcitabine in heavily pretreated patients with germ cell tumors. PATIENTS AND METHODS: From March 1996 through November 1997, 21 patients were enrolled onto a phase II study of gemcitabine 1,200 mg/m2, given on days 1, 8, and 15 every 4 weeks. One patient was unassessable because he never received any gemcitabine. Thirteen of 20 patients had received three prior regimens, and 13 patients were platinum refractory (progression during or within 4 weeks of platinum treatment). There were five extragonadal cases and two patients with late relapse (relapse beyond 2 years). RESULTS: Gemcitabine was well tolerated. Only one patient had grade 3 or 4 nonhematologic toxicity (grade 3 nausea). Six of 20 patients had grade 3 leukopenia. There were no episodes of granulocytopenic fever, and no patient required platelet transfusion. Three (15%) of 20 patients achieved an objective response, including one complete remission. Three additional patients had a minor radiographic or serologic response. CONCLUSION: Gemcitabine had definite activity in this heavily pretreated germ cell tumor patient population.
GERM CELL TUMORS are the most chemosensitive solid tumor, and they represent a model for a curable neoplasm.1 First-line cisplatin combination chemotherapy will cure 70% to 75% of patients with disseminated germ cell cancer.2,3 Salvage chemotherapy with standard-dose cisplatin plus drugs not previously used, such as ifosfamide, will cure 20% to 25% of patients not cured with their initial induction chemotherapy.4,5 Third-line treatment with high-dose chemotherapy along with autologous bone marrow or peripheral stem-cell support also has curative potential.6,7 At Indiana University, we currently use this approach as initial salvage therapy.8 Studies in testicular cancer treatment have provided a productive foundation for new drug discovery. Cisplatin was initially discovered to be effective as a single agent in patients refractory to actinomycin D and/or vinblastine plus bleomycin,9 and it subsequently became the major component of a curative combination chemotherapy regimen.10 Etoposide11 and ifosfamide12 demonstrated single-agent activity in patients with prior cisplatin combination chemotherapy. Each of these agents was incorporated with cisplatin and became a part of a curative salvage chemotherapy.13,14 Despite these results with cisplatin-based salvage chemotherapy regimens, approximately 15% to 20% of germ cell tumor patients are currently incurable and are candidates for phase I or phase II studies. Gemcitabine, a deoxycytidine analog, is active against a variety of solid tumors.15 Phase II studies have established the standard dose to be 1,000 to 1,250 mg/m2 given weekly for 3 weeks of every 4-week period. The only published information concerning gemcitabine in refractory germ cell tumors is the case report of a woman with an ovarian germ cell tumor. She received single-agent gemcitabine after five prior platinum combination regimens and achieved a partial remission for more than 5 months.16 We initiated a phase II clinical trial using gemcitabine in heavily pretreated patients who were deemed incurable.
Eligibility requirements included a clinical or serologic diagnosis of progressive metastatic germ cell neoplasm (gonadal or extragonadal), with disease not amenable to cure with either salvage surgery or chemotherapy. Patients had to have received initial cisplatin combination therapy. In addition, patients had to have received one cisplatin salvage chemotherapy regimen. Patients could not have had more than three prior regimens. Patients whose disease progressed during their initial induction chemotherapy were eligible for gemcitabine as second-line therapy.
Written informed consent was required. Patients needed to have adequate hematologic function (granulocyte count Treatment consisted of gemcitabine 1,200 mg/m2, administered intravenously over 30 minutes on days 1, 8, and 15 of each 28-day cycle. The protocol stipulated a maximum of six cycles. Therapy was temporarily withheld if the granulocyte count was lower than 1,200/mm3 and/or the platelet count was lower than 75,000/mm3 on the day of a proposed treatment. There was a subsequent 25% dose reduction for granulocytopenic fever, a bleeding episode with the platelet count below 40,000/mm3, or a platelet count of 20,000/mm3 or lower. A complete response (CR) was defined as the complete disappearance of all objective evidence of disease. A partial response (PR) was defined as a decrease of 50% or more in the sum of the perpendicular diameters of measurable disease for at least 1 month. If elevated marker(s) were the only evidence of progressive disease, a decrease of at least 90% was required for a PR.
Patient characteristics are listed in Table 1. Twenty-one patients were entered onto this study between March 1996 and November 1997. One patient was unassessable because he did not receive any study drug. Most patients (65%) had received three prior regimens. Five patients (25%) received only one prior regimen because they developed progressive disease during their initial cisplatin, etoposide, and bleomycin regimen. None of these five patients responded to gemcitabine. Five patients had a primary mediastinal nonseminomatous germ cell tumor. There were no responses in these five patients.
Gemcitabine was well tolerated in this patient population. Only one patient had grade 3 to 4 nonhematologic toxicity (grade 3 nausea). The major toxicity was thrombocytopenia, which was more severe in patients with prior high-dose chemotherapy. Two patients (10%) developed grade 4 and four patients (20%) developed grade 3 thrombocytopenia. However, no patient required platelet transfusion. There were no episodes of grade 4 leukopenia, and only two patients had grade 3 leukopenia. There were no cases of granulocytopenic fever. None of the patients had grade 3 to 4 anemia. There was no drug-related mortality. Three (15%) of 20 patients achieved an objective response, including one complete remission. The latter patient received gemcitabine after three prior chemotherapy regimens, including high-dose chemotherapy, as well as two postchemotherapy retroperitoneal lymph node dissections. He had multiple liver metastases, a 5- times 4-cm retroperitoneal mass, and a serum alpha-fetoprotein level of 16,660 ng/mL. He received all six cycles, but his disease progressed 2 months later. He failed to respond to subsequent gemcitabine and, later, paclitaxel. Of the two patients with PR, one received all six cycles and had a 6-month PR, and the other had a 2-month PR. Both of these patients had received prior high-dose chemotherapy. In addition, three other patients had a minor response, with a more than 50% but less than 90% decrease in tumor marker and/or more than 25% but less than 50% radiographic regression. These minor responses lasted 2, 3, and 5 months.
New drug discovery and the elucidation of active single agents have remained priorities in clinical investigations of testicular cancer, even in the postcisplatin era. Etoposide was the first drug to show activity after failure to cure with cisplatin combination chemotherapy.11 The combination of etoposide plus cisplatin was subsequently evaluated and became a standard salvage chemotherapy program after initial therapy with cisplatin, vinblastine, and bleomycin (PVB).13 Subsequently, a phase III study compared cisplatin and bleomycin plus either vinblastine or etoposide as first-line therapy. It demonstrated the superiority of etoposide and established bleomycin, etoposide, and cisplatin (BEP) as a standard regimen.17 Ifosfamide was evaluated at Indiana University in a phase II study in patients with refractory germ cell tumors.12 This patient population was less heavily pretreated than that in our current gemcitabine study, as most patients had been given only two prior regimens (PVB and BEP), and none had received prior high-dose chemotherapy. There were six PRs and one CR in 30 patients (23% overall response rate). A similar result was achieved in a study by Scheulen et al,18 with one CR and 16 PRs in 87 patients (20% response rate). This level of activity led to incorporation of ifosfamide as an active component of a curative salvage chemotherapy regimen after failure to cure with BEP.14 Since the introduction of active agents such as etoposide and ifosfamide, it has become increasingly difficult to define active new drugs, as patients in these trials are more heavily pretreated. The purpose of finding an active agent is to palliate patients with refractory disease and to combine the new agent with other active drugs in the hope of producing a more significant patient benefit. Daily oral etoposide has definite activity in refractory patients.19 However, this activity has never led to the development of a curative salvage chemotherapy regimen in combination with cisplatin or other agents. Paclitaxel has recently been demonstrated to have single- agent activity in germ cell tumors. Motzer et al20 achieved a 26% response rate in 31 patients who had received amaximum of six cycles of platinum combination chemotherapy. Their group has subsequently incorporated paclitaxel with other active drugs in the salvage setting, with encouraging results.21 Three other studies have been published with paclitaxel, with 11%, 13%, and 25% response rates.22-24 Overall, 18 (20%) of 88 patients in these four studies have achieved an objective response. Gemcitabine is effective in a variety of solid tumors and has demonstrated activity in the case report of a woman with a refractory ovarian germ cell tumor.16 Our current phase II study was conducted in a more heavily pretreated patient population than our prior ifosfamide study12 or a recent paclitaxel trial.20 Thirteen of 20 patients had received three prior regimens, 11 had prior high-dose therapy, and 13 were platinum refractory (progression within 4 weeks of last platinum regimen). Three objective responses were observed in our 20 patients, including a CR. In addition, three other patients had minor responses. It is hoped that gemcitabine can be combined with other active drugs, as has been done with etoposide and ifosfamide in the past; such a combination is currently being investigated with paclitaxel.21 The combination of cisplatin and gemcitabine is a commonly used regimen in non–small-cell lung cancer, and the two drugs have demonstrated in vitro synergism.25 Another approach is to combine gemcitabine with paclitaxel. We have recently completed a phase I study of weekly administration of paclitaxel and gemcitabine.26 There were no germ cell tumors in this patient population. Together with the Eastern Cooperative Oncology Group, we are currently evaluating a phase II combination of paclitaxel (110 mg/m2) plus gemcitabine (1,000 mg/m2) weekly for 3 weeks of every 4-week period in patients with refractory germ cell tumors. These patients will have progressive disease not amenable to cure with salvage chemotherapy or surgery. If significant activity is observed, it would then be logical to combine cisplatin with this two-drug combination.
Supported in part by the National Cancer Institute (grant no. 2 R 35 CA 39844-14) and the Walther Cancer Institute, Indianapolis, IN
Presented in part at the 34th Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
1. Einhorn LH: Treatment of testicular cancer: A new and improved model. J Clin Oncol 8:1777-1781, 1990[Abstract]
2.
Bosl GJ, Motzer RJ: Testicular germ cell cancer. N Engl J Med 337:242-253, 1997
3.
Einhorn LH: Testicular cancer: An oncological success story. Clin Cancer Res 3:2630-2632, 1997 4. Loehrer PJ, Gonin R, Nicholas CR, et al: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16:2500-2504, 1998[Abstract] 5. Motzer RJ, Bajorin DF, Vlamis V, et al: Ifosfamide-based chemotherapy for patients with resistant germ cell tumors: The Memorial Sloan-Kettering Cancer Center experience. Semin Oncol 12:8-11, 1992 6. Broun ER, Nichols CR, Kneebone P, et al: Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. Ann Intern Med 117:124-128, 1992
7.
Motzer R, Mazumdar M, Bosl GJ, et al: High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: Treatment results and prognostic factors for survival and toxicity. J Clin Oncol 14:1098-1105, 1996 8. Broun R, Nichols C, Gize G, et al: Tandem high dose chemotherapy with autologous bone marrow transplantation for initial relapse of testicular cancer. Cancer 79:1605-1610, 1997[Medline] 9. Higby DJ, Wallace HJ, Holland JF: Diamminedichloroplatinum II: A phase I study showing response in testicular and other tumors. Cancer 33:1219-1225, 1974[Medline] 10. Einhorn LH, Donohue JP: Combination chemotherapy with cis-diamminedichloroplatinum, vinblastine, and bleomycin disseminated testicular cancer. Ann Intern Med 87:293-298, 1977 11. Fitzharris BM, Kaye SB, Saverymuttu S, et al: VP-16 as single agent in advanced testicular tumors. Eur J Cancer 16:1193-1197, 1980 12. Wheeler B, Loehrer PJ, Williams SD, et al: Ifosfamide: An active agent in refractory male germ cell tumors. J Clin Oncol 4:28-34, 1986[Abstract] 13. Williams SD, Einhorn LH, Greco FA, et al: VP-16-213 salvage therapy for refractory germinal neoplasms. Cancer 46:2154-2158, 1980[Medline] 14. Loehrer PJ, Lauer R, Roth BJ, et al: Salvage therapy in recurrent germ cell cancer: Ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 109:540-546, 1988
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van Moorsel CJA, Peters GJ, Pinedo HM: Gemcitabine: Future prospects of single-agent and combination studies. Oncologist 2:127-134, 1997 16. Maas K, Daikeler T, Kanz L, et al: Activity of gemcitabine in platinum-resistant ovarian germ cell cancer. Eur J Cancer 32:1437-1438, 1996 17. 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] 18. Scheulen ME, Niederle N, Bremer K, et al: Efficacy of ifosfamide in refractory malignant diseases and uroprotection by mesna. Cancer Treat Rev 10:93-101, 1983 (suppl A) 19. Miller JC, Einhorn LH: Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 17:36-39, 1990[Medline]
20.
Motzer RJ, Bajorin DF, Schwartz LH, et al: Phase II trial of paclitaxel shows antitumor activity in patients with previously treated germ cell tumors. J Clin Oncol 12:2277-2283, 1994 21. Motzer RJ, Bajorin DF, Bosl GJ, et al: Paclitaxel containing first-line salvage therapy selected by risk for patients with germ cell tumors. Proc Am Soc Clin Oncol 16:322a, 1997 (abstr) 22. Sandler AB, Christou A, Fox S, et al: A phase II trial of paclitaxel in refractory germ cell tumors. Cancer 82:1381-1386, 1998[Medline] 23. Nasario A, Amato RJ, Hutchinson L, et al: Paclitaxel in extensively pretreated nonseminomatous germ cell tumors. Urol Oncol 1:184-187, 1995
24.
Bokemeyer C, Beyer J, Metzner B, et al: Phase II study of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer. Ann Oncol 7:31-34, 1996 25. Bergman A, Ruiz vanHaperen VWT, Veerman G, et al: Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 2:521-530, 1998[Abstract] 26. Einhorn LH, Raghavan D, Kindler H, et al: A phase I trial of gemcitabine plus paclitaxel combination therapy in patients with refractory solid tumors. Proc Am Soc Clin Oncol 17:207a, 1998 (abstr) Submitted July 21, 1998; accepted October 8, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1,200/mm3 and platelet count 
