Phase II study of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer

Annals of Oncology 7: 31-34, 1996. O 1996 Kluwer Academic Publishers. Printed in the Netherlands.

Rapid publication Phase II study of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer C. Bokemeyer,1 J. Beyer,2 B. Metzner,3 U. Riither,4 A. Harstrick,5 L. WeiBbach,6 U. Kohrmann,7 W. Verbeek8 & H.-J. Schmoll9 1

Eberhard Karls University, Department of Internal Medicine II, Hematology/Oncology, Tubingen; 2Free University of Berlin, Virchowklinikum, Department of Internal Medicine, Berlin; 3 Stddt Kliniken Oldenburg, Department of Internal Medicine, Oldenburg; 4 Katharinenhospital, Department of Internal Medicine, Stuttgart; 5 University ofEssen, Westdeutsches Tumorzentrum, Essen; 6Krankenhaus Am Urban, Department of Urology, Berlin; 1Klinikum der Stadt Mannheim, Department of Urology, Mannheim; * University of Gottingen, Department of Hematology/Oncology, Gottingen; 'Martin-Luther University, Department of Hematology/Oncology, Halle, Germany

paclitaxel and 12 patients (50%) had previously received high-dose carboplatin/etoposide-based salvage therapy with Background: Despite generally high cure rates in patients autologous stem cell support. with metastatic testicular cancer, patients with incomplete Results: Six patients (25%) achieved major responses to responses to cisplatin-based first-line therapy or with re- paclitaxel with 2 CR (8%) and 4 PR with marker normalisalapsed disease have an extremely poor prognosis. Paclitaxel tion (17%). In addition, 5 patients (21%) showed disease represents an antitumor agent with demonstrated activity in stabilisation. Median duration of responses to paclitaxel was cisplatin-sensitive tumors. In addition, responses to paclitaxel 8 months (3-16+). Toxicity was tolerable, with mainly granuhave been observed in patients with platin-refractory ovarian locytopenia occurring in 50% of patients and peripheral cancers. The current phase II trial evaluates the role of pacli- neuropathy > grade II in 29%. taxel in male patients with cisplatin-refractory or relapsed Conclusion: Paclitaxel demonstrates significant antitumor malignant germ cell tumors. activity in 25% of patients with relapsed or cisplatin-refracPatients and methods: Twenty-four patients with relapsed, tory testicular cancer. Combination regimens including paclimostly cisplatin-refractory metastatic testicular cancer were taxel may be warranted. treated with paclitaxel as three-hour infusions of 225 mg/m2 at 3-weekly intervals. The patients had received a median of Key words: cisplatin resistance, chemotherapy, paclitaxel, 7 platinum-containing treatment cycles (range 3-12) prior to phase II study, testicular cancer Summary

Introduction

Platinum-based combination chemotherapy, such as PEB (platinurn/etoposide/bleomycin) or PEI (platinum/etoposide/ifosfamide), is considered standard treatment for patients with metastatic testicular cancer and will achieve long-term cure rates in approximately 70% to 80% [1]. However, patients relapsing after conventional or high-dose platinum-containing therapy have an extremely poor prognosis, particularly those with disease absolutely refractory to platinum-based salvage regimens [1]. For these patients identifying new agents with significant antitumor activity in germ-cell cancer remains a priority, since only a minority of patients will achieve durable complete responses to highdose salvage therapies. However, different phase n trials have failed to identify new agents with demonstrated effectiveness in relapsed germ-cell tumors [2,3]. Paclitaxel, a natural anticancer drug derived from the Pacific yew tree, has demonstrated activity in a variety

of solid tumors, particularly ovarian and breast cancers [4-6]. The mechanism of action of paclitaxel is the primature stabilisation of microtubule assembly, which disrupts the cytoskeletal framework necessary for tumor cell replication and metastatic spread [7]. Since the mechanisms of action and of resistance to paclitaxel are different from those of DNA-damaging agents, such as cisplatin and ifosfamide, the role of paclitaxel in platinum-resistant tumors remains an important clinical issue. A dose-intense paclitaxel regimen followed by the application of granulocyte colony-stimulating factor (G-CSF) has achieved a favourable response rate of 48% in patients with platinum-resistant ovarian cancer [5]. Based on our own previous experience during a preliminary phase I/H dose-finding trial of paclitaxel in cisplatin-resistant testicular cancer, we have conducted a formal phase II study in patients with relapsed or cisplatin-refractory male germ cell tumors using 225 mg/m2 of paclitaxel as a 3-hour infusion every 3 weeks.

32 Patients and methods The phase n trial was approved by the Hannover University Ethics Committee. All patients gave their informed consent. Eligibility criteria included the presence of progressive testicular cancer and bidimensionally measurable disease; Karnofsky performance status >60%, WBC > 3000/ul, platelets > 100.000/nl, and adequate renal and liver function (liver enzymes < 3-fold upper normal value, glomerular filtration rate > 60 ml/min). Patients with relapsed disease after at least 2 previous cisplatin-based chemotherapies or with tumor progression after high-dose chemotherapy plus stem cell rescue or patients with tumor progression during cisplatin-based firstline or salvage chemotherapy were included. Exclusion criteria were: pretreatment with paclitaxel or concurrent treatment with other cytotoxic chemotherapy or radiation of the indicator lesions, the presence of an active infection, a known allergy to paclitaxel or to cremophor-containing drugs, neuropathy > grade II and symptomatic cardiac disease. Pretreatment evaluations included history and physical examination with documentation of measurable disease and performance status, serum tumor marker levels (AFP, fJ-HCG, LDH), liver function tests and creatinine, complete blood count with differential, ECG, chest radiograph and CT scans of all accessible tumor sites.

remission and 5 achieved partial remissions and normalisation of tumor markers (PR m-). The median duration of response for these patients was 8+ months (3-16+). Two patients with PR m - underwent secondary resection of residual tumors; in 1 patient vital carcinoma was resected, in the other patient only tumor necrosis was found. Based on the previous treatment 4 of 18 patients with platinum-resistant disease (22%), defined as progression during platinum-containing chemotherapy or within 4 weeks after the end of a platinum-containing therapy, have achieved responses. Two of 12 patients (17%) treated with high-dose carboplatin/etoposide-based salvage regimens also responded to paclitaxel. However, one patient relapsed within 3 months. Of 3 patients with mediastinal primary tumors one achieved a partial remission. After a median follow-up of 10 months (3-24) 4 patients are currently alive without signs of active disease. Eleven patients (46%) have died. Toxicity

Treatment 2

Paclitaxel was administered as a 3-hour infusion of 225 mg/m every 3 weeks in an outpatient setting. All patients received prophylactic premedication with dexamethasone 20 mg orally 12 and 6 hours before paclitaxel and ranitidine and diphenhydramine each 50 mg i.v. 30 minutes prior to paclitaxel application. Dose reductions were performed in instances of severe (grade Ill/grade IV WHO) non-hematological toxiciry. No routine use of hematopoietic growth factors was planned but G-CSF could be given on an individual basis in instances of severe leukopenia. Due to the previous chemotherapy with platinum-containing regimens in these patients, the recommendations for antiemetic therapy included 5HT3-antagonists and in some cases additional steroids. Paclitaxel was supplied in Cremophor EL as a solvent and the drug solution was prepared in 5% dextrose. Infusions were given via a polyvenyl-chloride-free infusion set.

Response assessment Response and toxicity were graded according to WHO criteria. In addition, reduction of the size of a tumor and normalisation of previously elevated tumor markers (PR m-) were considered to be favourable responses. In these cases surgical resection of all residual masses was attempted if technically feasible. All patients were scheduled for at least 2 cycles of paclitaxel in order to be eligible for response assessment. In patients with tumor responses or at least disease stabilisation treatment was continued for a maximum of 8 cycles of paclitaxel.

Results Response

In general, the toxicity of paclitaxel treatment was considered tolerable. Eight patients required dose reductions from 225 mg/m2 to 175 mg/m2 and 4 patients Table 1. Patient characteristics and response. No. patients included and evaluable Median age Gonadal/extragonadal primary Sites of metastases Lungs Retro peritoneum Mediastinum Liver Bone CNS Elavation of serum tumor markers AFP P-HCG Median no. of platinum cycles during previous treatment Median time since last chemotherapy Response to paclitaxel Complete (CR) Chemotherapy alone 1 pat Chemotherapy + surgery 1 pat PR with marker normalisation Stable disease Progression Duration of response Status Alive, CR or progression free Alive with active disease Dead

24 27 years (18-47) 21/3 15 (63%) 12 (50%) 7 (29%) 5 (21%) 2 (8%) 1 (4%) 16 (67%) 14 (58%) 7 (3-12) 4 months (1-7) 2 (8%) 4 (17%) 5 (21%) 13 (54%) 8 months (3-16+) 4 (17%) 8 (38%) 11 (46%) Responses

Twenty-four patients with a median age of 27 years (18-47) were included. A total of 77 cycles of paclitaxel were applied with a median of 3 cycles (2-8) per patient. Patient characteristics and responses are summarized in Table 1. Six patients (25%) responded to paclitaxel treatment: 1 of them achieved a complete

No. pts. platinum resistant No. pts. after high-dose therapy No. pts. with mediastinal primary Prior best response Favorable response (CR/PR m-) Incomplete response

18 (75%) 12 (50%) 3 (13%)

4 (22%) 2 (17%) 1 (33%)

9 (38%) 15 (62%)

3 (33%) 3 (20%)

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were treated with G-CSF during prolonged granulocytopenia. In general, granulocytopenia was of short duration, lasting no longer than a median of 4 days (2-9). Severe infections occurred in 3 patients. Dose modifications and toxicity are summarized in Table 2. Fifty percent of the patients developed WHO grades HI or IV leukopenia and 16% grades HI or IV thrombocytopenia. Non-hematological toxicity consisted mainly of peripheral neuropathy > grade II in 7 patients (29%). One patient developed cardiac arythmias during the second cycle of paclitaxel infusion and further treatment was discontinued. Table 2. Dose modifications and toxicity. Total no. cycles of paclitaxel Median no. cycles of paclitaxel No. pts with dose reductions No. pts treated with G-CSF Hematologic toxicity Grades HI/TV granulocytopenia Grades W7TV thrombocytopenia Severe infections Non-hematologic toxicity Allergic reactions Peripheral neuropathy > grade II Cardiac toxicity (arrythmia) Mucositis grades D7III Liver enzyme elevation > 3 x normal

77 3 (2-8) 8 (34%) 5 (21%) 12 (50%) 4 (16%) 3 (12%) 0 (0%) 7 (29%) 1 (4%) 4 (16%) 3 (12%)

Discussion The antirumor activity and toxicity of paclitaxel have been increasingly studied in patients with different malignancies and effective and safe schedules of continuous infusions ranging from 3-24 hours every 3 weeks have been established [5, 6, 8, 9]. The current investigation demonstrates the safe administration of paclitaxel 225 mg/m2 as a 3-hour infusion every 3 weeks in patients with relapsed or refractory testicular cancer. Six favorable responses (25%) have been observed among 24 patients. Two of these responders have been without signs of active disease for more than one year. Of note, responses have been observed in patients with clinically-determined platinum-resistant disease (4 of 18: 22%), confirming our previous experience during an initial phase I dose-finding trial of paclitaxel in male germ-cell cancer patients [10]. Furthermore, 1 of 3 patients with an extragonadal mediastinal primary rumor, a subgroup with a particularly poor prognosis, has responded to paclitaxel treatment. These results are in accordance with a phase II trial reported from Memorial Sloan Kettering Cancer Center in 31 patients with germ-cell rumors who received paclitaxel as first salvage therapy [11]. However, no responses to paclitaxel have been observed in patients previously treated with high-dose therapy. Among our patients only 2 of 12 have responded to paclitaxel after prior high-dose treatment with stem-cell support, and

one of them relapsed again 3 months later. Based on a total of 65 patients reported in the literature to have received paclitaxel treatment within 3 different clinical trials the total response rate of 26% in this heavily pretreated population clearly demonstrates that paclitaxel represents a highly active drug in this disease [12]. Responses to paclitaxel have been observed even in patients with cisplatin-refractory disease [10]. The activity of both paclitaxel and cisplatin against a teratocarcinoma cell line has been demonstrated in vitro [12, 13]. Different mechanisms of resistance are suspected for these two drugs [14, 15]. Pretreatment with paclitaxel seems not to increase the DNA-interstrand or protein-associated cross-Unking induced by cisplatin, but preliminary studies have revealed that the platinum-DNA-damage repair is slowed following prior treatment with paclitaxel [14]. A deficiency in the removal of platinum-DNA cross-links has been described in testicular cancer cell lines and was considered to be an explanation for the general sensitivity of this tumor type to platinum-based therapy [16]. The development of platinum resistance has been atrributed to an increased DNA-damage-repair capacity [15]. These experimental results open up speculation on the clinical interaction between resistance to cisplatin or paclitaxel in testicular cancer. Since we have previously reported on patients with demonstrated cisplatinrefractory disease responding again to cisplatin after intermittent treatment with paclitaxel, the interaction between treatment with both drugs should be further explored [10]. The toxicity profile of paclitaxel has been mainly hematological with severe neutropenia occurring in 50% of patients in the current trial. Therefore, without the use of a hematopoietic growth factor, which was used in the study by the Memorial Sloan Kettering Cancer Center, we recommend a dose of 175-200 mg/ m2 of paclitaxel every 3 weeks in pretreated patients with testicular cancer. Neurotoxicity is also an important side effect. However, the patients had two risk factors predisposing them for neurotoxicity associated with paclitaxel: prior exposure to cisplatin and treatment with paclitaxel at a dose > 200 mg/m2 [7]. Neurotoxicity was reversible in 3 of 7 patients. In summary, paclitaxel has antitumor activity in germ cell tumors that warrants study in combination regimens. Clinical trials in other malignancies have shown that paclitaxel can be given in combination with cisplatin with or without ifosfamide [17, 18]. Our current trial uses the combination of paclitaxel, ifosfamide and cisplatin (TIP) followed by G-CSF as first-line salvage therapy in patients with testicular cancer in order to reduce the tumor load and to generate peripheral blood stem cells for subsequent high-dose chemotherapy. An expanding role for paclitaxel in the treatment of germ cell cancer is anticipated.

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References 1. Einhorn LH. Treatment of testicular cancer A new and improved model. J Clin Oncol 1990; 8:1777-81. 2. Harstrick A, Schmoll HJ, Wilke H et al. High-dose epidoxorubicin in refractory or relapsed nonseminomatous testicular cancer A phase II study. Ann Oncol 1990; 375-6. 3. Bokemeyer C, Droz JP, Hanauske A et al. Treatment of relapsed germ cell tumors with vinorelbine: A trial of the phase I/II-study group of the association for medical oncology of the German cancer society. Onkologje 1993; 16:29-31. 4. McGuire WP, Rowinsky EK, Rosenshein NB et al. Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 1989; 111:273-9. 5. Kohn EC, Sarosy G, Bicher A et al. Dose-intense taxol: High response rate in patients with platinum-resistant recurrent ovarian cancer. J Nat! Cancer Inst 1994; 86:18-24. 6. Reichman BS, Seidman AD, Crown JP et al. Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer. J Clin Oncol 1993; 83:1797-805. 7. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature 1979; 277:655-67. 8. Brown T, Havlin K, Weiss G et al. A phase I trial of taxol given by a 6-hour intravenous infusion. J Clin Oncol 1991; 9: 1261-7. 9. Kris MG, O'Connell JP, Gralla RJ et al. Phase I trial of taxol given as a 3-hour infusion every 21 days. Cancer Treat Rep 1986; 70:605-7. 10. Bokemeyer C, Schmoll HJ, Natt F et al. Preliminary results of a phase I/n trial of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer. J Cancer Res Clin Oncol 1994; 120: 754-7. 11. Motzer RJ, Bajorin DF, Schwartz LH et al. Phase II trial of paclitaxel shows antitumour activity in patients with previously treated germ cell tumors. J Clin Oncol 1994; 12:2277-83. 12. Motzer RJ, Chou TC, Schwartz LH et al. Paclitaxel in germ cell

cancer. Semin Oncol 1995; 22 (Suppl 6> 12-5. 13. Chou TC, Motzer RJ, Tong Y et al. Computerized quantitation of synergy of various drugs against teratocarcinoma cells in vitro: A rational approach to clinical protocol design. Proc Am Assoc Center Res 1994; 35: 254 (Abstr 1520). 14. Reed E, Parker RJ, Dabholkar M. Taxol effect on cisplatinDNA adduct repair in human ovarian cancer cells. Second National Cancer Institute Workshop on Taxol, Alexandria, VA (Abstr) 1992. 15. Chao CCK, Lee YL, Cheng PW et al. Enhanced host cell reactivation of damaged plasmid DNA in HeLA cells resistant to cis-diamminedichloroplatinum (n). Cancer Res 1991; 51: 601-5. 16. Hill BT, Shellard SA, Whelan RDH et al. Deficient removal of the major platinum-DNA intrastrand crosslinks in the sequences pGpG and pApG appears characteristic of testicular teratoma cell lines derived from tumours from untreated patients and may account for their sensitivity to cisplatin. Proc Am Soc Oncol 1992; 11: 100 (Abstr 221). 17. Reed E, Kohn EC, Sarosy G et al. Paclitaxel, cisplatin, and cyclophosphamide in human ovarian cancer Molecular rationale and early clinical results. Semin Oncol 1995; 22 (Suppl 6): 90-6. 18. Forastiere AA, Susan GU. Single-agent paclitaxel and paclitaxel plus ifosfamide in the treatment of head and neck cancer. Semin Oncol 1995; 22 (Suppl 6): 24-7. Received 5 October 1995; accepted 21 November 1995. Correspondence to: Dr. C. Bokemeyer Eberhard Karls University Department of Internal Medicine II Hematology /Oncology Otfried-Muller StraBe 10 72076 Tubingen Germany