Testicular Cancer European Urology - Phase II Study of Oxaliplatin and Gemcitabine Salvage Chemotherapy in Patients with Cisplatin-Refractory Nonseminomatous Germ Cell Tumor
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| European Urology - Phase II Study of Oxaliplatin and Gemcitabine Salvage Chemotherapy in Patients with Cisplatin-Refractory Nonseminomatous Germ Cell Tumor |
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| Wednesday, 08 November 2006 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Volume 50, Issue 5, Pages 1032-1039 (November 2006) 1. Introduction - Germ cell tumor (GCT) represents a model of solid tumor curable with chemotherapy. Cisplatin-based chemotherapy induces long-term remissions in approximately 80% of patients with advanced GCT as primary treatment, while in only 25–30% of patients at relapse/progression [1], [2]. Patients with cisplatin-refractory GCT have an extremely poor prognosis with long-term survival achieved in less than 5% of cases with standard-dose cisplatin-based chemotherapy [3]. Several treatment options have been investigated in this setting. Tandem high-dose chemotherapy based on carboplatin and etoposide showed impressive results with a 2-year failure-free survival of 32%, when used as the first salvage modality with the exception of mediastinal primary GCT [4]. As consequence, tandem high-dose chemotherapy is a possible option for these patients [4], [5]. However, in most cases multicycle high-dose chemotherapy is not effective or not feasible, so that the identification of new drugs and/or new combinations remains a priority. Several chemotherapeutic agents have been investigated in patients with cisplatin-refractory GCT, but only oral etoposide, paclitaxel, gemcitabine, and oxaliplatin have shown significant activity as single agents [3], [6], [7], [8], [9]. In the last years, a few phase II studies have investigated the combination of these chemotherapeutic agents in order to improve the outcome of these patients [10], [11], [12]. We investigated the feasibility and activity of a schedule with full doses of oxaliplatin and gemcitabine in patients with cisplatin-refractory GCT. 2. Patients and methods Eligibility criteria included GCT patients with at least disease stabilization or better but evidence of tumor progression within four weeks of the last cisplatin-based chemotherapy and patients with disease progression during cisplatin-based chemotherapy. Patients with evidence of tumor progression or relapse after salvage high-dose chemotherapy were also eligible. Other inclusion criteria were: age ≥18 years, bidimensionally measurable disease, ECOG performance status 0–2, adequate hematological, renal and liver functions (WBC>2500/μL, platelets >75000/μL, hemoglobin >9g/dL, creatinine <1.5mg/dL, total bilirubin <1.5-fold upper limit of normal, liver transaminases <3-fold upper limit of normal). Baseline evaluations included medical history and physical examination, estimation of ECOG performance status, complete blood cell count, creatinine and liver function tests, serum tumor marker levels (alpha-fetoprotein, beta-human chorionic gonadotropin, lactate dehydrogenase), documentation of all measurable disease by computed tomography, magnetic resonance imaging, X-ray or echotomography. The study was approved by the Institutional Ethical Committee and written informed consent was obtained from all patients. 2.1. Treatment regimen The treatment regimen consisted of gemcitabine 1250mg/m2 IV over 30minutes and subsequently oxaliplatin 130mg/m2 IV over 2hours given on day 1, and gemcitabine 1250mg/m2 IV over 30minutes on day 8, every three weeks. Concomitant antiemetic therapy consisted of 5-hydroxytryptamine-3 antagonists and dexamethasone. The next course was started only when the absolute neutrophil count (ANC) was more than 1,500/μL and the platelet count was greater than 75,000/μL. The gemcitabine dose at day 8 was reduced by 25% in case of ANC was 1000 to 1500/μL or the platelet count was 50,000 to 75,000/μL. The gemcitabine dose at day 8 was omitted in case of ANC was less than 1000/μL or the platelet count was less than 50,000/μL. The use of granulocyte colony-stimulating factor was allowed for treatment of prolonged severe neutropenia (ANC<500/μL) or neutropenic fever. 2.2. Definitions Disease was considered cisplatin-refractory when at least disease stabilization or a remission had been achieved, but tumor progression occurred within 4 weeks of the last cisplatin-based chemotherapy. Also, patients with evidence of tumor progression or relapse after salvage high-dose chemotherapy were also considered in the cisplatin-refractory group. Disease was considered absolutely refractory when disease progression had occurred while patients were receiving cisplatin-based treatment. Response and toxicity were graded according to WHO criteria and NCI-CTC (version 2.0) scale, respectively [13]. A clinical complete response (CR) to chemotherapy was defined as the disappearance of all clinical, radiographic, and biochemical evidence of disease for at least 4 weeks. A pathological complete response (pCR) included patients in whom surgical complete resection of residuum yielded necrosis, fibrosis, or mature teratoma without evidence of viable malignant cells. Surgical complete response (sCR) was used to define cases in whom complete surgical resection of residual masses showed viable malignant cells. Partial response (PR) was defined as a greater than 50% decrease in bidimensional tumor measurements with a greater than 90% reduction in tumor markers (PRm− with normalization of previously elevated tumor markers; PRm+ without complete normalization). Stable disease (SD) was considered as less than 50% decrease or less than 25% increase in bidimensional tumor measurements or stable tumor markers. Progressive disease (PD) was defined as greater than 25% increase in bidimensional tumor measurements or by increasing tumor markers of more than 10%, or appearance of new lesions. Survival and follow-up time were calculated from the beginning of gemcitabine and oxaliplatin chemotherapy until the date of death or last follow-up. 2.3. Statistical analysis The study was devised as a two-stage design according to Simon [14]. Alpha and beta errors were set at 10%. A response rate of more than 15% was considered to be of interest, and so 18 patients were entered in the first stage. If no responses were noted in the first stage, that arm would be terminated. Otherwise, if one or more responses were noted, additional 18 patients needed to be accrued for a total of 36 patients. Survival was calculated from the beginning of oxaliplatin and gemcitabine treatment until the date of death or the date of the last follow-up examination. 3. Results Between May 2002 and June 2005, eighteen patients with cisplatin-refractory GCT were enrolled onto the study. The trial was closed after the first step because of slow recruitment. All patients were assessable for toxicity and response. All patients were male with a median age of 32 years (range 19–51). Primary site was testis in twelve cases, retroperitoneum in four, and mediastinum in two. All patients were heavily pretreated with a median number of eight (range, 3–12) cisplatin-containing chemotherapy cycles before gemcitabine plus oxaliplatin therapy. Moreover, four patients (22%) had received a single high-dose chemotherapy course. In addition, two patients (11%) had experienced relapse later than 2 years (late relapse). Seven patients (39%) were classified as cisplatin-refractory, while eleven (61%) as absolutely cisplatin-refractory. Patient characteristics are listed in Table 1.
The total number of cycles administered was 60, with a median of 3 cycles (range 1–6) for each patient. No toxic death occurred. No patients terminated therapy because of toxicity. Dose reductions and treatment delay were required in five cases. Toxicity is summarized in Table 2. Overall, hematological toxicity was the most prevalent side-effect consisting of grade 3–4 neutropenia in seven patients (one complicated with pneumonia), grade 3 thrombocytopenia in four, and grade 3 anemia requiring packed red blood cell transfusions in two patients. Non-hematological toxicities occurred in three patients who presented grade 3 peripheral sensory neurotoxicity, two with grade 3 asthenia, and one with grade 3 vomiting. Overall, an objective response was obtained in 3 cases (17%), SD in three, while PD in twelve. One patient achieved a clinical CR, one a PRm− in whom complete surgical resection of residual masses yielded mature teratoma only (pCR), and one a PRm+ in whom complete surgical resection of residual masses yielded viable tumor cells (sCR). The last patient had previously undergone high-dose chemotherapy and experienced relapse later than 2 years (Table 3, patient no 1). These three patients were characterized by testicular primary embryonal carcinoma. They remained disease-free at 44+, 20+, and 18+ months of follow-up. Results are presented in detail in Table 3.
After treatment with gemcitabine and oxaliplatin, most of patients were subjected to further chemotherapy at progression. One patient achieved a short-lasting PRm+ after high-dose epirubicin. Two patients received the epirubicin-cisplatin combination (1 SD, 1 PD); two daily oral etoposide (1 SD, 1 PD), two paclitaxel, ifosfamide and cisplatin (TIP) (both PD), two weekly paclitaxel (both PD), one taxotere (PD), one weekly gemcitabine (PD). After a median follow-up of 7 months (range, 1 to 44+ months) for all patients, three (17%) are continuously disease-free at 44+, 20+, and 18+ months, four are alive with disease (14+, 8+, 7+, 6+), while eleven died of their disease. Median overall survival for all patients was 7 months (range, 1 to 44+ months). 4. DiscussionThe prognosis for patients with cisplatin-refractory GCT remains poor, in spite of the positive results obtained with multicycle high-dose chemotherapy in a subset of these patients [3], [4], [5]. New chemotherapeutic regimens with significant antitumor activity are needed to offer an opportunity to achieve long-term survival for this group of young patients. Only few agents have been found active in patients with cisplatin-refractory GCT [15]. Paclitaxel, gemcitabine, and oxaliplatin as single-agents showed objective responses in only approximately 10% to 20% of these patients, but long-term remissions were not reported [7], [8], [9]. Instead, the two-drug combination of paclitaxel and gemcitabine showed a response rate of 30%, with one durable clinical CR, and the combination of paclitaxel and oxaliplatin which obtained a PRm− with a sCR after post-chemotherapy surgery [10], [16].We previously reported a preliminary experience with a chemotherapeutic regimen consisted of a weekly administration of the three-drug combination of gemcitabine, paclitaxel and oxaliplatin in patients with cisplatin-refractory GCT [17]. Only one partial response (ORR=11%) was achieved, lasting 5 months. Median overall survival for all patients was 5 months (range, 1 to 15 months). However, we need to consider that in most cases dose reductions and treatment delay were required due to grade 3–4 hematological toxicity. Pizzocaro et al. are reported preliminary results in abstract form of another weekly administration of a three-drug combination regimen including paclitaxel, cisplatin and gemcitabine as third-line treatment in GCT patients [12]. Toxicity was substantial, while activity in cisplatin-refractory patients was not clearly assessable because no information on prognostically relevant patient characteristics was reported. However, the toxicity of the weekly three-drug combinations seems considerably high for this heavily pretreated group of patients. Other authors showed that oxaliplatin at full doses, but not as weekly administration possess activity in cisplatin-refractory GCT [9]. Paclitaxel has been recently incorporated into second-line chemotherapeutic regimens and is currently investigated in phase III trials as part of a primary chemotherapy regimen [18], [19]. On the basis of these observations, we planned the phase II study with gemcitabine and oxaliplatin at full doses in a three-week schedule. In the present study, the combination of gemcitabine and oxaliplatin showed three cases (17%) of a prolonged CR lasting 44+, 20+ and 18+ months. In one case, the surgical resection of residual masses played a fundamental role to achieve a disease-free status (Table 3, patient no 1). The achievement of a response in these patients is very important, because the induction of a partial remission may allow the resection of residual masses and subsequently may offer a chance for some patients to achieve long-term survival [15]. These results are encouraging considering the poor prognostic characteristics of the study patient group (Table 3). Moreover, they appear better than those obtained with paclitaxel, gemcitabine and paclitaxel as single agents and those achieved with the combination therapies of gemcitabine–paclitaxel and oxaliplatin–paclitaxel (Table 4) [6], [7], [8], [9], [16]. Our results are in line with those reported by Bokemeyer et al. [20] and Pectasides et al. [21] in two recent studies with the same combination regimen and similar patient characteristics (Table 4). Overall, of sixty-eight patients reported in these three clinical studies of the gemcitabine–oxaliplatin combination in cisplatin-refractory GCT, seven (10%) achieved prolonged CR, in all cases characterized by testicular primary GCT.
Gemcitabine and oxaliplatin combination may offer an opportunity for patients with testicular cisplatin-refractory GCT to achieve long-term survival. Further investigation with other agents and/or drug combinations is needed in patients with extragonadal cisplatin-refractory disease, in particular in cases with mediastinal primary site. Editorial CommentThe treatment of cisplatin-refractory germ cell tumours remains a major therapeutic challenge. Long-term survival in these patients is rarely achieved. The results of the French multicentre sequential high-dose chemotherapy TAXIF trial [1] confirm that highly refractory patients clearly do not benefit from high-dose chemotherapy. The evaluation of new drugs and combinations represents a priority. Both single-agent gemcitabine and oxaliplatin have been identified as active with response rates of approximately 15–20% but no long-term remission was reported. The association of gemcitabine and oxaliplatin appeared to be one of the most interesting approaches. This study is the third report on GEMOX in the literature. The results subsequently confirm the data published by Kollmansberger [2] and Pectasides [3] using the same combination in a comparable patient population. The most important message, however, is that some patients in all three studies remain in continuous remission with or without additional surgery. In conclusion, the combination of these clinical reports demonstrates the feasibility of this salvage association with an acceptable toxicity profile despite the prior use of high-dose chemotherapy in these patients. Based on these highly promising results, this association should be incorporated earlier in the treatment of cisplatin-refractory germ cell tumours. References26. [1]. Sequential high-dose chemotherapy protocol for relapsed poor prognosis germ cell tumors combining two mobilization and cytoreductive treatments followed by three high-dose chemotherapy regimens supported by autologous stem cell transplantation. Results of the phase II multicentric TAXIF trial. Ann Oncol. 2005;16:411–418.27. [2]. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol. 2004;22:108–114. 28. [3]. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Ann Oncol. 2004;15:493–497. Supported by a grant from Istituto Oncologico Romagnolo. References 1. Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Horwich A, et al.. Guidelines on testicular cancer. Eur Urol. 2005;48:885–894. 2. Loehrer PJ, Gonin R, Nichols CR, Weathers T, Einhorn LH. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol. 1998;16:2500–2504. 3. Bokemeyer C, Kollmannsberger C, Harstrick A, Beyer J, Gerl A, Casper J, et al.. Treatment of patients with cisplatin-refractory testicular germ-cell cancer. Int J Cancer. 1999;83:848–851. 4. Vaena DA, Abonour R, Einhorn LH. Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables. J Clin Oncol. 2003;21:4100–4104. 5. De Giorgi U, Rosti G, Papiani G, Marangolo M. The status of high-dose chemotherapy with hematopoietic stem cell transplantation in patients with germ cell tumor. Haematologica. 2002;87:95–104. 6. Sandler AB, Cristou A, Fox S, Williams SD, Nichols CR, Turns M, et al.. A phase II trial of paclitaxel in refractory germ cell tumors. Cancer. 1998;82:1381–1386. 7. Einhorn LH, Stender MJ, Williams SD. Phase II trial of gemcitabine in refractory germ cell tumors. J Clin Oncol. 1999;17:509–511. 8. Bokemeyer C, Gerl A, Schoffski P, Harstrick A, Niederle N, Beyer J, et al.. Gemcitabine in patients with relapsed or cisplatin-refractory testicular cancer. J Clin Oncol. 1999;17:512–516. 9. Kollmannsberger C, Rick O, Derigs HG, Schleucher N, Schoffski P, Beyer J, et al.. Activity of oxaliplatin in patients with relapsed or cisplatin-refractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol. 2002;20:2031–2037. 10. Hinton S, Catalano P, Einhorn LH, Loehrer PJ, Kuzel T, Vaughn D, et al.. Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2002;20:1859–1863. 11. Soulié P, Garrino C, Bensmaine MA, Bekradda M, Brain E, Di Palma M, et al.. Antitumoral activity of oxaliplatin/cisplatin-based combination therapy in cisplatin-refractory germ cell cancer patients. J Cancer Res Clin Oncol. 1999;125:707–711. 12. Pizzocaro G, Nicolai N, Salvioni R, Gianni L. Paclitaxel, cisplatin, gemcitabine (TPG) third line therapy in metastatic germ cell tumors of the testis. Proc Am Soc Clin Oncol. 2001;20:194a;(abstr 773). 13. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207–211. 14. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1–10. 15. Farmakis D, Pectasides M, Pectasides D. Recent advances in conventional-dose salvage chemotherapy in patients with cisplatin-resistant or refractory testicular germ cell tumors. Eur Urol. 2005;48:400–407. 16. Theodore C, Flechon A, Fizazi K, Chevreau C, Delord JP, Lotz JP, et al.. A phase II multicentre study of oxaliplatin (Ox) in combination with paclitaxel (Px) in patients (pts) who failed cisplatin (CDDP) based chemotherapy (CT) for germ cell tumors (GCT). Proc Am Soc Clin Oncol. 2004;22:389;(abstr 4534). 17. De Giorgi U, Rosti G, Papiani G, Aieta M, Fochessati F, Paoluzzi L, et al.. Weekly gemcitabine, paclitaxel, oxaliplatin combination chemotherapy in patients with cisplatin-refractory germ cell tumor: preliminary experience. Am J Clin Oncol. 2004;27:457–460. 18. de Wit R, Louwerens M, de Mulder PH, Verweij J, Rodenhuis S, Schornagel J. Management of intermediate prognosis germ cell cancer. Results of a phase I-II study of taxol-BEP. Int J Cancer. 1999;83:831–833. 19. Mead GM, Cullen MH, Huddart R, Harper P, Rustin GJ, Cook PA, et al.. A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin) given as second-line (post-PEB) salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial. Br J Cancer. 2005;93:178–184. 20. Kollmannsberger C, Beyer J, Liersch R, Schoeffski P, Metzner B, Hartmann JT, et al.. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol. 2004;22:108–114. 21. Pectasides D, Pectasides M, Farmakis D, Aravantinos G, Nikolaou M, Koumpou M, et al.. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Ann Oncol. 2004;15:493–497. 22. Kollmannsberger C, Rick O, Klaproth H, Kubin T, Sayer HG, Hentrich M, et al.. Irinotecan in patients with relapsed or cisplatin-refractory germ cell cancer: a study of the German Testicular Cancer Study Group. Brit J Cancer. 2002;87:729–732. 23. Powles T, Shamash J, Berney D, Oliver RTD. Irinotecan in patients with relapsed or cisplatin-refractory germ cell cancer: a study of the German Testicular Cancer Study Group. Brit J Cancer. 2002;89:1140–1142. 24. Pectasides D, Pectasides M, Farmakis D, Aravantinos G, Nikolaou M, Koumpou M, et al.. Oxaliplatin and irinotecan plus granulocyte-colony stimulating factor as third-line treatment in relapsed or cisplatin-refractory germ cell tumor patients: a phase II study. Eur Urol. 2004;46:216–221. 25. Bedano PM, Brames MJ, Williams SW, Einhorn LH. A phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors. Proc Am Soc Clin Oncol. 2005;23:395;(abstr 4526). Ugo De Giorgia, Giovanni Rostia, Michele Aietab, Franco Testorec, Luciano Burattinid, Giuseppe Fornarinie, Emanuele Naglierif, Giovanni Lo Reg, Federica Zumaglinia, Maurizio Marangoloa a Istituto Oncologico Romagnolo-Department of Oncology and Hematology, Santa Maria delle Croci Hospital, Ravenna, Italy b Department of Oncology and Hematology, “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo (Foggia), Italy c Department of Medical Oncology, Ospedali Riuniti, Asti, Italy d Department of Oncology, Ospedali Riuniti Umberto I-Lancisi-Salesi, Ancona, Italy e Department of Medical Oncology, San Martino Hospital, Genova, Italy f Department of Medical and Experimental Oncology, Oncology Institute, Bari, Italy g Department of Oncology, Santa Maria degli Angeli Hospital, Pordenone, Italy Accepted 3 May 2006 published online 24 May 2006.
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