Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study

D. Pectasides1,*, M. Pectasides1, D. Farmakis1, G. Aravantinos2, M. Nikolaou1, M. Koumpou1, A. Gaglia1, V. Kostopoulou1, N. Mylonakis1 and D. Skarlos3

1 Second Department of Medical Oncology, Metaxas Memorial Cancer Hospital, Piraeus; 2 Third Department of Medical Oncology, ‘Ag. Anargiri’ Cancer Hospital, Athens; 3 Second Department of Medical Oncology, ‘Eric Dynan’ Hospital, Athens, Greece

Received 10 July 2003; revised 3 November 2003; accepted 19 December 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

To investigate the efficacy and toxicity of the combination of gemcitabine and oxaliplatin (GEMOX) in patients with relapsed or cisplatin-refractory non-seminomatous germ cell tumors (NSGCT).

Patients and methods:

Twenty-nine patients with relapsed or cisplatin-refractory NSGCT were treated with gemcitabine 1000 mg/m2 on days 1 and 8 followed by oxaliplatin 130 mg/m2 on day 1 every 3 weeks for a maximum of six cycles. Twenty-four patients (83%) were considered refractory and five (17%) absolutely refractory to cisplatin.

Results:

Twenty-eight patients were assessable for response. Overall, nine patients (32%) achieved a favourable response (complete response, four; partial response, five). One of the complete responders relapsed after 7 months and went into disease-free status lasting for 11+ months after resection of lung metastases. The rest of the complete responders are continuously disease-free at 14+, 19+ and 28+ months with the study regimen plus or minus surgery. One of the complete responders had absolutely cisplatin-refractory disease and another one presented with a late relapse. Toxicity was primarily hematological and generally manageable: 62% of patients experienced grade 3/4 neutropenia, 10% neutropenic fever and 41% grade 3/4 thrombocytopenia. Non-hematological toxicity consisted mainly of nausea/vomiting. Three patients (10%) developed grade 3 neurotoxicity and discontinued treatment.

Conclusions:

The combination of GEMOX is an active, moderately toxic and easily administered regimen in patients with relapsed or cisplatin-refractory NSGCT. The 14% long-term disease-free status accomplished in this heavily pretreated patient population is quite encouraging.

Key words: cisplatin-refractory disease, gemcitabine, germ cell tumors, oxaliplatin, salvage therapy, testicular cancer


    Introduction
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 Introduction
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Cisplatin-based chemotherapy with or without surgical resection of residual disease will cure 70–80% of patients with advanced germ-cell tumors (GCT) [1, 2]. However, 20–30% of patients develop disease progression during or after initial chemotherapy and require effective salvage chemotherapy. Approximately 20–40% of patients who relapse after first-line chemotherapy will achieve long-term survival with the use of platinum-containing standard-dose or high-dose salvage chemotherapy with autologous stem cell support [36]. The prognosis of patients who progress during or relapse after salvage chemotherapy is extremely poor, with <5% long-term disease-free survival. The identification of new agents with antitumor activity in these GCT patients remains a priority.

Gemcitabine, a deoxycytidine analog, is active against a variety of tumors. Two phase II trials including 51 patients evaluated the role of gemcitabine, at a dose of 1000–1200 mg/m2 on days 1, 8 and 15 every 28 days, in refractory GCT [7, 8]. The overall response rate was 17%. No patient with absolutely refractory disease responded to gemcitabine. The main side-effect was myelotoxicity, primarily thrombocytopenia.

Oxaliplatin is a water-soluble derivative of 1,2-diamino-cyclohexane platinum. In vitro data in non-seminomatous GCT (NSGCT) cell lines indicate incomplete cross-resistance between cisplatin and oxaliplatin, hence providing a rationale for the evaluation of oxaliplatin in cisplatin-refractory patients [9]. In a phase II study, 32 patients with cisplatin-refractory GCT were treated with single-agent oxaliplatin at 60 mg/m2 on days 1, 8 and 15 every 28 days or at 130 mg/m2 on days 1 and 15 every 28 days [10]. Four patients (12.5%) achieved a partial response (PR) and two additional patients achieved stable disease (SD). Myelotoxicity was generally mild and the non-hematological side-effects were infrequent. One patient developed grade 3 neurotoxicity.

In view of the data on the single-agent activity of gemcitabine and oxaliplatin, we conducted a phase II trial to evaluate the combination of these two agents in patients with refractory GCT.


    Patients and methods
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Eligibility criteria included the diagnosis of GCT with evidence of relapse after at least two cisplatin-containing regimens or after high-dose salvage therapy (HDCT) or disease progression during initial induction chemotherapy or during salvage chemotherapy. Evidence of progression or relapse included the presence of metastatic lesions on imaging procedures (chest X-ray or computed tomography scan) and the presence of elevated tumor markers [ß human chorionic gonadotropin (ß-HCG) or {alpha}-fetoprotein (AFP)] at two consecutive measurements. Failure of previous chemotherapy was defined as either ≥25% increase in the sum of perpendicular diameter of measurable tumor lesions during prior therapy, appearance of new lesions or increase of ß-HCG, or AFP. Disease was defined as cisplatin-refractory when at least tumor stabilization or remission had been achieved but tumor progression occurred again within 4 weeks of the last administration of a cisplatin-based regimen. Disease was considered to be absolutely cisplatin-refractory when tumor progression developed while the patient was on cisplatin-based chemotherapy.

Further inclusion criteria were as follows: (i) Eastern Cooperative Oncology Group performance status of 0, 1 or 2; (ii) completion of prior therapy, including chemotherapy, radiotherapy or major surgery, at least 4 weeks before enrollment with complete recovery from toxicity caused by this therapy; (iii) absence of active, unresolved infection with completion of any parenteral antibiotic treatment at least 1 week before enrollment; (iv) absence of symptomatic cardiovascular or cerebrovascular disease; (v) adequate bone marrow reserve (absolute neutrophil count, ≥1500/µl; platelet count, ≥75 000/µl); (vi) adequate renal (serum creatinine ≤1.5 mg/dl) and hepatic functions [total serum bilirubin ≤3 x upper limit of normal (ULN), serum transaminases ≤4 x ULN].

The treatment regimen consisted of gemcitabine at a dose of 1000 mg/m2 administered as a 30-min intravenous (i.v) infusion on days 1 and 8, followed by oxaliplatin at a dose of 130 mg/m2 as a 2-h i.v. infusion on day 1 of a 3-week cycle for a maximum of six cycles. Antiemetic premedication included 5-H3 antagonists. In patients developing a flu-like syndrome after the administration of gemcitabine, dexamethasone (at a dose of 2 mg, administered 30 min before and 12 and 24 h after administration of gemcitabine) was added to the subsequent chemotherapy courses. Treatment was recycled at day 22 provided that the absolute neutrophil count was ≥1500/µl and the platelet count ≥75 000/µl. Day 1 of a new cycle was delayed up to 10 days to allow recovery from hematological toxicity. Doses for day 8 were modified according to hematological toxicity, as defined in Table 1. If day 8 was omitted, the cycle would continue with one dose not given. No routine use of hematopoietic growth factor was planned, but granulocyte-colony stimulating factor (G-CSF) was administered only in patients with an absolute neutrophil count ≤500/µl for ≥1 week, neutropenic fever or documented infection during neutropenia. A dose reduction of 50% was applied in case of grade 3 non-hematological toxicity, according to World Health Organization (WHO) toxicity criteria. Treatment was discontinued when grade 4 non-hematological toxicity or grade 3–4 neurotoxicity was encountered. All patients were treated on an out-patient basis. This study was approved by the Ethics Committee of our institutions and all patients gave informed consent.


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Table 1. Dose modifications in case of hematological toxicity
 
Pretreatment evaluation included physical examination, documentation of all measurable lesions by X-ray or computed tomography scan, determination of serum tumor marker levels [ß-HCG, AFP and lactate dehydrogenase (LDH)], complete blood count with differential count, liver function tests, creatinine clearance and electrocardiogram.

Patients were evaluated for response at every cycle by physical examination, chest X-ray and tumor markers. In cases where a computed tomography scan was required for evaluation of measurable disease, response was assessed every two cycles. Complete response (CR) was defined as the disappearance of all detectable disease, including normalization of ß-HCG and AFP levels and normalization of all abnormal tests, for at least 4 weeks. For patients whose only sign of disease was increased ß-HCG or AFP levels, the levels of the elevated marker had to fall and remain within normal range for at least 4 weeks. A reduction in size of a measurable lesion along with normalization of previously elevated tumor marker levels was considered to be a marker-negative partial response (PR–), while a ≥50% reduction of the sum of the perpendicular diameters of all measurable lesions plus a tumor marker decrease >50% for at least 4 weeks but without complete normalization was considered to be a marker-positive partial response (PR+). When an elevated tumor marker was the only evidence of disease, a decrease of ≥90% was required for a partial response (PR). Serum tumor markers were measured every 2–3 weeks. All patients were scheduled to receive at least two cycles of treatment. In case of a significant marker (≥50%) and/or radiological (≥25%) progression after the first cycle, the treatment was discontinued and the patient was classified as having a progressive disease (PD). In patients with disease response or stabilization, treatment was continued for at least two additional cycles after achievement of the best response, unless severe toxicity was encountered.

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.

Statistics
Using standard statistical methods, a two-stage design was used in the study protocol [11]. A response rate of 20% is comparable to that of other active drugs in this situation. If no CR or PR was noted in the first 14 patients, a response rate of >20% could be excluded with 95% confidence and accrual would stop. If at least one CR or PR was observed, at least 30 patients were to be entered into the study at the second stage, to determine the response rate more accurately.


    Results
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Twenty-nine patients with relapsed or cisplatin-refractory NSGCT were entered in this trial from October 1999 to March 2002. Patient characteristics are shown in Table 2. One patient refused further treatment after receiving the first day of the first cycle due to severe nausea/vomiting and fatigue/asthenia. All patients were assessable for toxicity and 28 for response. Seventeen patients (59%) had increased levels of AFP (range 39–8452 ng/ml) and 15 (52%) elevation of ß-HCG (range 115–93 760 U/l). Twenty-eight patients (97%) had previously received two or more platinum-based regimens and four (14%) had received carboplatin-based HDCT with autologous stem cell support. Twenty patients (69%) had been previously treated with paclitaxel, as single-agent or combination chemotherapy. Five cases (17%) had never responded to prior regimens and were considered absolutely refractory to chemotherapy and 24 (83%) had relapsed within 4 weeks of treatment and were considered refractory to cisplatin-based chemotherapy.


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Table 2. Patient characteristics (n = 29)
 
Nine of 28 patients [32%, 95% confidence intervals (CI) 15.8% to 52.3%] responded favourably to treatment, including four (14%, 95% CI 4.0% to 32.7%) with CR and five with PR (18%, 95% CI 6.0% to 36.9%). One patient with CR relapsed after 7 months with lung metastases without tumor marker elevation. This patient underwent resection of two small lung nodules and went into disease-free status lasting for 11+ months. The other three patients with CR were continuously disease-free at 14+, 19+ and 28+ months, respectively. One patient had a NED-status post-surgery after the complete resection of retroperitoneal lymph nodes; histology showed only fibrosis-necrosis. This patient was absolutely refractory to bleomycin, etoposide and cisplatin (BEP) and methotrexate, ifosfamide, etoposide and cisplatin (M-VIP) and he also had progressive disease being on paclitaxel. Of the other three CR patients, one patient was refractory to prior cisplatin-based chemotherapy and to carboplatin-based HDCT and one had a late relapse 4 years after the completion of primary chemotherapy. The latter presented with lung metastases and increased AFP (1234 ng/ml); he had cisplatin-refractory disease and had never received paclitaxel.

All five patients with PR have subsequently progressed. The duration of PR was 2, 3, 4, 6 and 8 months and their survival time 2.5, 6, 9, 9 and 12.5 months, respectively. None of the patients with extragonadal mediastinal NSGCT responded to GEMOX combination chemotherapy.

The median overall survival time was 8.7 months (range 2.5–28+). Four patients are on continuous disease-free status ranging from 14+ to 28+ months.

The median number of cycles administered was two (range 1–6). Eight patients (28%) completed six cycles, while 19 patients discontinued their treatment due to progressive disease. Dose reductions and treatment delays due to myelotoxicity were required in 10% and 28% of patients, respectively.

Myelosuppression was the main side-effect and the only toxicity resulting in dose reductions or treatment delays (Table 3). Grade 3/4 neutropenia occurred in 18 patients (62%). Three patients (10%) were hospitalized because of febrile neutropenia and were successfully treated with broad spectrum antibiotics and granulocyte colony-stimulating factor (G-CSF) support. Twenty patients (69%) required G-CSF support for neutropenia, neutropenic fever or to maintain the treatment schedule. Twelve patients (41%) experienced grade 3/4 thrombocytopenia and five required platelet transfusions. However, no bleeding episodes were reported by the thrombocytopenic patients. Six patients (21%) developed grade 3/4 anemia, two of whom required blood transfusions. One patient discontinued treatment due to grade 3/4 nausea/vomiting and fatigue. Grade 3/4 nausea/vomiting was reported in eight patients (27%) and fatigue/asthenia in four (14%). Three patients (10%) developed grade 3 neurotoxicity and discontinued treatment. Other non-hematological side-effects were infrequent and not severe. There were no treatment-related deaths.


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Table 3. WHO grade 3–4 toxicity (n = 29)
 

    Discussion
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
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During the past few years, a number of new chemotherapeutic agents have demonstrated activity against relapsed or refractory GCT, including oral etoposide, ifosfamide, paclitaxel, gemcitabine and, more recently, oxaliplatin. Treatment options regarding salvage chemotherapy in patients with GCT who have failed cisplatin-based chemotherapy or carboplatin HDCT have not been established and the optimal salvage regimen has not yet been defined. Thus, the research for effective and well-tolerated salvage chemotherapeutic combinations represents one of the major challenges in the treatment of refractory GCT. In this context, paclitaxel and gemcitabine have been investigated as part of combination regimens [1215].

Gemcitabine has been evaluated as a single agent in two phase II trials in patients with relapsed or refractory GCT: the response rates were 15% and 19%, respectively [7, 8]. Thrombocytopenia was the main side-effect occurring in 25% of patients, followed by granulocytopenia in 12%. Non-hematological toxicity was infrequent and not severe. Dose reduction was required in 13 patients (25%) due to thrombocytopenia. For future studies, a schedule modification to weekly administration on days 1 and 8, every 21 days, was recommended.

Oxaliplatin has been found to be active in intensively pretreated GCT patients with poor prognostic features. Thirty-two patients with GCT refractory to cisplatin or who had relapsed after HDCT plus autologous stem cell support were treated with single-agent oxaliplatin [10]. The weekly administration achieved one PR+, while the higher dose given biweekly achieved one PR– and two PRs+. Two additional patients had disease stabilization. Hematological toxicity was generally mild, with five patients (16%) developing grade 3–4 thrombocytopenia and three (9%) grade 3 neutropenia. Non-hematological side-effects included mainly nausea/vomiting, while one patient developed grade 3 neurotoxicity.

Investigators from Indianapolis treated GCT patients believed to be incurable with surgery and/or chemotherapy with paclitaxel 110 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 4-week cycle for a maximum of six cycles [14]. They reported six (21.4%) responses, including three CRs. Two of the complete responders were continuously disease-free at 15+ and 25+ months. Toxicity was primarily hematological, but was manageable. Italian investigators combined paclitaxel 80 mg/m2, cisplatin 50 mg/m2 and gemcitabine 800 mg/m2 on days 1 and 8 of a 3-week cycle for four courses as third-line salvage therapy [15]. Among the 20 assessable patients, there were 10 (50%) major responses—five CRs and five PRs—including four pathologically documented CRs maintained for 3+, 10+, 18+ and 19+ months. One patient with clinical CR relapsed after 6 months. All patients developed grade 3–4 hematological toxicity and one patient grade 2/3 nephrotoxicity.

Recently, Bokemeyer et al. [16] reported the results of a combination of gemcitabine 1000 mg/m2 on days 1 and 8, followed by oxaliplatin 130 mg/m2 every 3 weeks in 29 patients with relapsed or cisplatin-refractory GCT. The overall response rate was 38%, including one CR. The median progression-free survival for responding patients was 3 months (range 1.4–9). Toxicity was generally acceptable. Grade 3/4 neutropenia and thrombocytopenia of short duration occurred in 16 (55%) and 13 (45%) patients, respectively. Grade 3 neurotoxicity was encountered in three patients (10%). The authors concluded that the combination is feasible and associated with significant activity, manageable toxicity and easy out-patient administration in patients with refractory GCT.

The results of our study (32% response rate, 14% prolonged disease-free rate) are encouraging, taking into consideration the poor prognostic features of the study patient group. More specifically, all patients were considered to be cisplatin-refractory, 10% presented with late relapses and 14% had received HDCT with autologous stem cell support. These results compare favourably to those derived with paclitaxel, gemcitabine and oxaliplatin monotherapy, and to those obtained from combination therapy with paclitaxel and gemcitabine [7, 8, 10, 14, 17, 18]. Moreover, the results presented here are in line with those obtained by Bokemeyer et al., who reported an overall response rate of 38% with the same combination and rather similar patient characteristics [16]. Since all complete responders had been considered to be cisplatin-refractory (two cases) or absolutely refractory (one case) or had presented with late relapse (one case), our results support the previous preclinical and clinical data indicating an incomplete cross-resistance between oxaliplatin and cisplatin [9]. In this study, the standard dose of 130 mg/m2 was selected for oxaliplatin, in view of in vitro data showing a relationship between cell killing and peak oxaliplatin concentrations, both in cisplatin-resistant and cisplatin-sensitive colony-forming units of various tumor types [19].

The toxicity of this combination was moderate but manageable. Myelosuppression was the main side-effect. Grade 3/4 neutropenia and thrombocytopenia occurred in 62% and 41% of patients, respectively. Among these heavily pretreated patients, three (10%) developed neutropenic fever and required hospitalization. Neurotoxicity was the dose limiting toxicity in this study regimen as three patients (10%) discontinued treatment due to grade 3 neurotoxicity. Since the cumulative dose of oxaliplatin was low, the peripheral sensory neuropathy was probably due to the pre-existing cisplatin-induced neurotoxicity.

In conclusion, the combination of oxaliplatin and gemcitabine showed an encouraging efficacy in patients with relapsed or cisplatin-refractory GCT, along with an acceptable toxicity profile and an easy out-patient administration. Most importantly, this combination seems to offer a possibility for long-term disease-free status, despite the poor prognostic features of the cases studied here.


    FOOTNOTES
 
* Correspondence to: Dr D. Pectasides, Second Department of Medical Oncology, Metaxas Memorial Cancer Hospital, 51 Botassi Street, 18537 Piraeus, Greece. Tel: +32-10-428-5015; Fax: +32-10-428-5025; E-mail: pectasid{at}otenet.gr Back


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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
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19. Buechele T, Schoeber C, Kroening H et al. Weekly high-dose (HD) 5-fluorouracil (5-FU) and folinic acid (FA) with addition of oxaliplatin (LOHP) after documented progression under high-dose infusional 5-FU/FA in patients (PTS) with advanced colorectal cancer (CRC): a preliminary report. Proc Am Soc Clin Oncol 1998; 17: 287a (Abstr 1106).