Int. J. Cancer: 83, 848–851 (1999) r 1999 Wiley-Liss, Inc. Publication of the International Union Against Cancer Publication de l’Union Internationale Contre le Cancer TREATMENT OF PATIENTS WITH CISPLATIN-REFRACTORY TESTICULAR GERM-CELL CANCER Carsten BOKEMEYER1*, Christian KOLLMANNSBERGER1, Andreas HARSTRICK2, Jörg BEYER3, Arthur GERL4, Jochen CASPER5, Bernd METZNER6, Jörg T. HARTMANN1, Hans-Joachim SCHMOLL8 and Lothar KANZ1 for the GERMAN TESTICULAR CANCER STUDY GROUP (GTCSG) 1Department of Internal Medicine, University of Tuebingen Medical Center, Tuebingen, Germany 2Department of Internal Medicine, Westdeutsches Tumorzentrum, University of Essen, Essen, Germany 3Department of Internal Medicine, Virchowklinikum, University of Berlin, Berlin, Germany 4Department of Internal Medicine, Klinikum Grosshadern, University of Munich, Munich, Germany 5Department of Internal Medicine, University of Rostock Medical Center, Rostock, Germany 6Department of Internal Medicine, Städt. Kliniken Oldenburg, Oldenburg, Germany 7Department of Internal Medicine, Klinik Bad Triss, Oberandorf, Germany 8Department of Internal Medicine, University of Halle-Wittenberg Medical Center, Halle, Germany With the use of cisplatin-based combination chemotherapy, metastatic testicular germ-cell tumors can be cured in 70% to 80% of patients. The combination of cisplatin, etoposide and bleomycine (PEB) is considered standard therapy. Patients refractory to cisplatin-based chemotherapy have a markedly poor prognosis. Several chemotherapeutic agents have been evaluated in intensively pre-treated or cisplatinrefractory patients. Neither the anthracyclines nor vinorelbine, topotecan or biological agents such as suramin and retinoic acid have demonstrated clinical activity. Paclitaxel has been evaluated at different doses and schedules and yielded a response rate of 21% (range 11–30%), with single patients achieving complete remissions. This has led to the inclusion of paclitaxel in salvage regimens in combination with cisplatin and/or ifosfamide. Two studies have evaluated gemcitabine in refractory germ-cell tumors and demonstrated a response rate of 17% (95% CI 7–28%) in 52 intensively pre-treated patients, two-thirds of whom had relapsed after previous high-dose chemotherapy plus autologous stemcell transplantation. The non-hematological toxicity of weekly gemcitabine at doses of 1,000 to 1,250 mg/m2 was tolerable, and hematological side effects included thrombocytopenia in approximately 20% of patients. Ongoing studies in refractory germ-cell tumors performed by the German Testicular Cancer Study Group are evaluating bendamustine, an alkylating agent with activity in breast and small-cell lung cancer, and oxaliplatin, a platinum derivative with incomplete crossresistance to cisplatin. Future trials combining new active agents may examine alternating treatment strategies in patients with poor-prognostic disease or as salvage treatment. Int. J. Cancer 83:848–851, 1999. r 1999 Wiley-Liss, Inc. Platinum-based combination chemotherapy, such as PEB (platinum, etoposide, bleomycine) or PEI (platinum, etoposide, ifosfamide), is considered standard treatment for patients with metastatic testicular cancer, achieving long-term cure rates of approximately 70% to 80% (Bokemeyer, 1998). Patients relapsing after conventional chemotherapy are currently included in clinical trials using high-dose chemotherapy plus autologous stem-cell transplantation. However, patients relapsing after high-dose salvage chemotherapy or progressing during cisplatin-based first-line chemotherapy have an extremely poor prognosis, particularly those with disease totally refractory to platin-based regimens (Beyer et al., 1996). For these patients, identifying new agents with significant anti-tumor activity in germ-cell cancer remains a priority. Treatment of these patients must take into account both potential activity and the avoidance of severe side effects. With most patients now being pre-treated with high-dose chemotherapy plus autologous stem-cell transplantation, the tolerability of new agents after this treatment strategy requires further evaluation. DRUGS WITH NO OR MINOR ACTIVITY IN REFRACTORY GERM-CELL TUMORS Several agents have been evaluated in patients with refractory testicular cancer, but until recently no drugs with significant anti-tumor activity had been identified. Table I summarizes the phase II studies of these drugs. Anthracyclines, including mitoxantrone and epirubicin, at high doses have been evaluated in 3 clinical trials (Williams et al., 1985; Harstrick et al., 1990; Stoter et al., 1992). Myelosuppression, particularly following high epirubicin at doses of 120 to 135 mg/m2, has been the major side effect. Among a total of 48 patients reported in 3 trials, 1 patient with 2 prior complete responses to cisplatin therapy of less than 4 months duration each (early relapse) achieved a partial remission of lung metastases lasting for 6 months (Harstrick et al., 1990). Overall, these data do not demonstrate a significant clinical activity of anthracyclines in platin-refractory testicular cancer. Mitomycin C was evaluated in 7 pre-treated patients. Despite 2 responses, hematological and pulmonary toxicity prohibited further evaluation of this drug (Hoskins et al., 1990). A phase I/II study of vinorelbine in refractory testicular cancer was also prematurely closed due to lack of responses and extensive myelotoxicity (Bokemeyer et al., 1993). Topotecan, a novel topoisomerase-I inhibitor with activity in ovarian cancer, has been evaluated in 14 patients with relapsed cisplatin-refractory germ-cell tumors. As expected, myelosuppression was the major toxicity of topotecan, but no responses were observed (Puc et al., 1995). Recent trials have also investigated the use of biological agents for the treatment of relapsed germ-cell tumors. Based on in vitro results in 2 human teratocarcinoma cell lines, suramin was evaluated in a phase II study in 14 intensively pre-treated patients. Serum ␣-fetoprotein levels declined in 1 patient, but no complete or partial response was observed. Suramin doses were based on a normogram, allowing examination of individual therapeutic levels (Motzer et al., 1993). The second biological agent evaluated in a phase II trial was all-trans-retinoic acid. In vitro results showed differentiation in response to retinoic acid in 6 human germ-cell tumor cell lines. Subsequently, 16 patients were treated with retinoic acid for an average of 7 weeks and responses were noted (Moasser et al., 1995). It is unclear whether retinoids with improved receptor selectivity or improved pharmacological dosing achieve better results. PACLITAXEL IN CISPLATIN-REFRACTORY DISEASE Since the mechanisms of action of and resistance to paclitaxel are different from those to DNA-damaging agents, such as cisplatin *Correspondence to: Department of Medicine II, University of Tuebingen, Otfried-Mueller-Strasse 10, D-72076 Tuebingen, Germany. Fax: ⫹49 7071/ 29 36 75. E-mail: [email protected] THERAPY IN CISPLATIN-REFRACTORY PATIENTS 849 TABLE I – AGENTS PREVIOUSLY EVALUATED IN CISPLATIN-REFRACTORY TESTICULAR GERM-CELL TUMORS WITH MINOR OR NO ACTIVITY Study Number of Response patients rate Agent Williams et al. (1985) Harstrick et al. (1990) Stoter et al. (1992) Hoskins et al. (1990) Mitoxantrone Epirubicin (high-dose) Epirubicin (high-dose) Mitomycin C 14 16 18 7 0/14 1/16 0/18 2/7 Bokemeyer et al. (1993) Motzer et al. (1993) Moasser et al. (1995) Murphy et al. (1992) Drasga et al. (1987) Puc et al. (1995) Vinorelbine Suramin All-trans retinoic acid Iproplatin Iproplatin Topotecan 7 14 16 15 14 15 0/7 0/14 0/14 0/14 1/14 0/14 Toxicity/comments — Myelosuppression Myelosuppression Pulmonary toxicity and myelosuppression No severe neurotoxicity Individual dosing Duration 7 weeks — Nausea/vomiting Myelotoxicity TABLE II – ACTIVITY OF SINGLE-AGENT PACLITAXEL IN RELAPSED/REFRACTORY GERM-CELL TUMOR Study Number of patients Paclitaxel dose (mg/m2 ) Infusion duration (hr) Responses Bokemeyer et al. (1994) Motzer et al. (1994) Nasario et al. (1995) Bokemeyer et al. (1996) Sandler et al. (1998) Total 10 31 15 24 18 98 135–225 250 ⫹ G-CSF 250 ⫹ G-CSF 225 170–200 3 24 24 3 24 3 PR (30%) 3 CR, 5 PR (26%) 0 CR, 2 PR (13%) 2 CR, 4 PR (25%) 2 PR (11%) 5 CR, 16 PR (21%) G-CSF, granulocyte colony-stimulating factor; CR, complete remission; PR, partial remission. and ifosfamide, the role of paclitaxel in platinum-resistant tumors remains an important clinical issue. Paclitaxel has demonstrated significant clinical tumor activity in breast and ovarian cancer, with neurotoxicity as the main limiting side effect. The German Testicular Cancer Study Group (GTCSG) evaluated paclitaxel in a phase I/II study at doses of 135 to 225 mg/m2 given as 3 hr infusions every 3 weeks in patients with intensively pre-treated testicular cancer (Bokemeyer et al., 1994). A dose of 225 mg/m2 ⫻ 3 weeks was used for the consecutive phase II study, which revealed 6 responders among 24 patients (25%) (Bokemeyer et al., 1996). Despite intensive pre-treatment with a median of 7 (3–12) previous cisplatin-based regimens, peripheral neuropathy was tolerable, with 29% ⱖ WHO grade II. Other side effects included granulocytopenia WHO grade III/IV in 12 patients (50%) and thrombocytopenia in 4 patients (16%). Other investigators have used even higher dose of 250 mg/m2 but with routine application of G-CSF (Sandler et al., 1998; Motzer et al., 1994). These phase II studies, including 31 and 15 patients, revealed response rates of 26% and 13%, respectively. The available phase II studies on single-agent paclitaxel are summarized in Table II. In total, among 98 patients, a response rate of 21% (range 11–30%) was observed. Interestingly, single patients pre-treated with high-dose chemotherapy plus autologous stem-cell transplantation responded to paclitaxel. Moreover, even single patients with absolutely platinumrefractory disease responded to paclitaxel (Bokemeyer et al., 1996), which was already observed in in vitro experiments with chemotherapy-resistant testicular cancer cell lines. More recent trials have evaluated paclitaxel in combination with cisplatin and/or ifosfamide as first-line salvage in patients with favorable or unfavorable prognostic criteria at relapse. The GTCSG has used a regimen of paclitaxel, ifosfamide and cisplatin (TIP) given for 3 cycles and followed by high-dose chemotherapy with thiotepa, etoposide and carboplatin (TEC) for patients with relapsed disease (Beyer et al., 1998). The EORTC has started a study which includes paclitaxel in combination with PEB chemotherapy as first-line treatment in patients with intermediate-prognosis germ-cell tumors. These and other ongoing investigations should shed more light on the question of whether paclitaxel adds to the cure rates achievable in patients with metastatic germ-cell tumors. GEMCITABINE IN RELAPSED DISEASE Only 20% to 40% of patients undergoing high-dose chemotherapy plus autologous stem-cell transplantation for relapse will be cured. Thus, there is considerable need for the development of less toxic and effective palliative treatment after high-dose chemotherapy. Pont et al. (1997) have evaluated data on 47 evaluable patients from 9 centers receiving chemotherapy at progression after highdose chemotherapy for germ-cell cancer. On multivariate analysis, the interval since high-dose chemotherapy treatment and the use of ifosfamide and/or paclitaxel were favorable prognostic factors for survival (Pont et al., 1997).This study clearly demonstrated that chemotherapy is feasible after previous high-dose chemotherapy with stem-cell transplantation. Two studies have evaluated the role of gemcitabine in refractory germ-cell tumors based on the rationales that, at present, most patients have already received paclitaxel as part of their salvage therapy. In addition, gemcitabine represents a nucleoside analogue with an overall low toxicity and without cross-resistance to cisplatin. Inclusion criteria for these study were refractory germ-cell cancer after at least 2 previous standard-dose chemotherapy regimens, relapse after high-dose chemotherapy or progressive disease despite adequate cisplatinbased therapy (Table III). The study aims were to define both the activity and toxicity of single-agent gemcitabine as well as the feasibility of its use after high-dose chemotherapy. Investigators at Indiana University treated 21 patients on a schedule with 1,250 mg/m2 weekly for 28 days. They reported 1 complete and 2 partial remissions, for an overall response rate of 15% (Einhorn et al., 1999). The GTCSG included 31 patients in a protocol examining gemcitabine at a dose of 1,000 mg/m2 weekly for 28 days. Six patients (19%) achieved a response to gemcitabine, including 3 of 22 patients (17%) after previous high-dose chemotherapy, 3 of 19 patients (16%) previously treated with paclitaxel and 1 of 4 patients (25%) with mediastinal germ-cell tumors (Bokemeyer et al., 1999). The median progression-free interval was 4 months. However, single patients have responded for almost 1 year to gemcitabine. No patient with absolute refractory disease responded, but 3 patients with refractory disease had a marked decline of more than 90%. Combining toxicity data of 52 published patients to date, thrombocytopenia was the main side effect. It occurred in 25% of BOKEMEYER ET AL. 850 TABLE III – ACTIVITY OF SINGLE-AGENT GEMCITABINE IN RELAPSED/REFRACTORY GERM-CELL TUMORS Study Gemcitabine schedule (mg/m2 ) Total number of patients Bokemeyer et al. (1999) Einhorn et al. (1999) Total 1,000 on days 1, 8, 15 for 28 days 1,200 on days 1, 8, 15 for 28 days 31 20 51 Patients Previous HD-Ctx DDP-refractory Response rate Median survival 22 (71%) 11 (55%) 33 (65%) 17 (54%) 13 (65%) 30 (58%) 6 (19%) 3 (15%) 9 (17%) 6 months (2–23) not given HD-Ctx, high-dose chemotherapy; DDP, cis-Diammindichlorplatin. patients followed by granulocytopenia in 12%. Non-hematological toxicities were infrequent and not severe. Due to the thrombocytopenia, dose reductions were necessary in 13 patients (25%). For future patients, a schedule modification to weekly applications at day 1 and day 8 followed by retreatment at day 21 was suggested. While it has been demonstrated that single-agent gemcitabine is an effective palliative treatment in approximately one-fifth of patients with refractory germ-cell tumors, no data are available on its combination with either cisplatin derivatives or paclitaxel in this disease. ONGOING PROTOCOLS AND FUTURE PROSPECTS With the identification of 2 new active agents, paclitaxel and gemcitabine, interest in systematically exploring new agents in cisplatin-refractory disease is growing. The GTCSG has started a phase II study of relapsed testicular cancer to evaluate bendamustine, an alkylating agent with activity in lymphoma, breast cancer and small-cell lung cancer. Currently, 7 patients have been treated with bendamustine, 120 mg/m2 on days 1 and 2, repeated at 3-week intervals. Preliminary analysis demonstrates that application of bendamustine is associated with low, non-hematological toxicity. Treatment was successfully performed according to the planned schedule in 6 of the 7 patients. One patient had a temporary response to bendamustine of 4 weeks duration only. Completion of this study on 14 patients should fully determine the value of this agent. New platinum derivatives have been of long-standing interest in patients with cisplatin-refractory disease. Phase II studies performed in the late 1980s, which used iproplatin (CHIP), did not identify significant activity of this agent (Murphy et al., 1992). However, oxaliplatin, a diaminocyclohexane complex, has been developed for anti-cancer therapy, particularly for colon cancer. In vitro data on non-seminomatous germ-cell tumor cell lines indicate incomplete cross-resistance between cisplatin and oxaliplatin (Dunn et al., 1997). The second ongoing protocol of the GTCSG evaluates oxaliplatin at 60 mg/m2 once weekly for 4 weeks (repeated at day 36) in patients with intensively pre-treated testicular cancer. Oxaliplatin is associated with low hematotoxicity and neuropathy, including both cold sensitivity, and paresthesias is the dose-limiting side effect. Six patients are currently enrolled in this protocol, and 1 patient achieved partial remission of his lung metastases and a marked fall of ␣-fetoprotein values from 20,000 to 50 ng/ml. Oxaliplatin was applied to patients after high-dose chemotherapy without cumulative hematotoxicity. New drugs for testicular cancer have currently been developed only in intensively pre-treated patients. Two new agents, paclitaxel and gemcitabine, have demonstrated activity in approximately 20% of patients with refractory disease. The identification of these new agents may allow alternating treatment strategies in patients with advanced or relapsed disease using these agents as an early line of therapy. Furthermore, combinations of gemcitabine and paclitaxel or gemcitabine with platinum derivatives should be interesting. Cooperative efforts using common palliative treatment protocols of new drugs have allowed development of new treatment strategies in patients with testicular cancer. 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