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Journal of Clinical Oncology, Vol 20, Issue 8 (April), 2002: 2031-2037
© 2002 American Society for Clinical Oncology

Activity of Oxaliplatin in Patients With Relapsed or Cisplatin-Refractory Germ Cell Cancer: A Study of the German Testicular Cancer Study Group

By C. Kollmannsberger, O. Rick, H.-G. Derigs, N. Schleucher, P. Schöffski, J. Beyer, R. Schoch, H.G. Sayer, A. Gerl, M. Kuczyk, C. Spott, L. Kanz, C. Bokemeyer

From the Departments of Hematology/Oncology at University of Tuebingen Medical Center, Tuebingen; Charite, University of Berlin, Berlin; University of Mainz, Mainz; Hannover Medical School, Hannover; University of Marburg, Marburg; University of Kiel, Kiel; University of Jena, Jena; and University of Munich, Munich; Department of Internal Medicine, West German Cancer Center, Essen; and Department of Urology, University of Hannover, Hannover, Germany.

Address reprint requests to C. Bokemeyer, MD, Department of Hematology/Oncology, University of Tuebingen Medical Center, Otfried-Mueller-Str 10, 72076 Tuebingen, Germany; email: carsten. bokemeyer{at}med.uni.tuebingen.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To investigate the efficacy and toxicity of oxaliplatin, a diaminocyclohaxane platinum derivative with incomplete cross-resistance to cisplatin in patients with relapsed or cisplatin-refractory germ cell cancer.

PATIENTS AND METHODS: Thirty-two patients with nonseminomatous cisplatin-refractory germ cell cancer or relapsed disease after high-dose chemotherapy (HDCT) plus autologous stem-cell support were treated with single-agent oxaliplatin 60 mg/m2 on days 1, 8, and 15 repeated every 4 weeks (group 1; n = 16) or oxaliplatin 130 mg/m2 given on days 1 and 15 of a 4-week cycle (group 2; n = 16). Patients were pretreated with a median of seven (range, three to 13) cisplatin-containing treatment cycles; 78% had received carboplatin/etoposide-based HDCT before oxaliplatin therapy. Twenty-seven patients (84%) were considered refractory (n = 20; 63%) or absolutely refractory (n = 7; 22%) to cisplatin therapy.

RESULTS: Overall, four patients achieved a partial remission (13%; 95% confidence interval, 1% to 24%). Two additional patients achieved disease stabilization. All responses were observed in cisplatin-refractory patients, including three who had not responded to previous HDCT. Patients received a median two cycles of oxaliplatin with a median cumulative dose of 350 mg/m2. Hematologic toxicity was generally mild, with five patients developing grade 3/4 thrombocytopenia. Nonhematologic side effects consisted mainly of nausea/vomiting. One patient developed grade 3 neurotoxicity.

CONCLUSION: Considering the particularly unfavorable prognostic characteristics of this patient population compared with patients from previous trials for new drugs in germ cell cancer, eg, paclitaxel and gemcitabine, a 13% overall response rate and a 19% response rate in the group treated with oxaliplatin 130 mg/m2 seems to be of interest. Oxaliplatin may be a palliative treatment option for this patient population, and evaluation in combination regimens is warranted.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
TODAY, APPROXIMATELY 70% to 80% of patients with metastatic testicular germ cell cancer can be cured with cisplatin containing combination chemotherapy regimens.1 However, only 20% to 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.2-5 Patients who progress during or relapse after salvage chemotherapy exhibit an extremely poor prognosis, and long-term survival is achieved in less than 5% of patients.6,7 The identification of new active drugs remains a priority in these intensively pretreated patients. Several cytotoxic agents, including topotecan, ifosfamide, vinorelbine, iproplatin, paclitaxel, and, more recently, bendamustine and gemcitabine have been investigated in cisplatin-refractory patients.8-17 However, despite several phase II studies, only low-dose oral etoposide, ifosfamide, paclitaxel, and gemcitabine have been identified as active in cisplatin-refractory patients with response rates of approximately 15% to 20%.9,13,14,16-18 On the basis of its activity in cisplatin-refractory patients, paclitaxel was subsequently successfully included into second-line combination regimens in relapsed patients and is currently evaluated within a randomized trial of the European Organization for Research and Treatment of Cancer as part of the primary treatment in patients with intermediate prognosis according to the International Germ Cell Cancer Cooperative Group classification.3,19,20

Oxaliplatin (trans-1-diaminocyclohexane oxalatoplatinum) is a water-soluble derivative of 1,2-diaminocyclohexane platinum. The cytotoxicity of this agent is based on the formation of DNA adducts that inhibit replication and transcription. In comparison with cisplatin, oxaliplatin exhibits a favorable toxicity profile with a substantially lower rate of nephrotoxicity, ototoxicity, and myelosuppression. The dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy, the occurrence of which depends on the cumulative dose applied.21 Oxaliplatin has shown activity in cisplatin-resistant cell lines in vitro, and subsequent functional studies suggested mechanisms of DNA damage other than those of cisplatin or carboplatin.22 In vitro data on nonseminomatous germ cell cancer cell lines indicate incomplete cross-resistance between cisplatin and oxaliplatin, providing the rationale for the evaluation of oxaliplatin in cisplatin-refractory patients.23 The present study examined the feasibility and activity of single-agent oxaliplatin in intensively pretreated patients with relapsed or cisplatin-refractory germ cell cancer.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility criteria for this study included the diagnosis of germ cell cancer with evidence of tumor progression or relapse after at least two previous cisplatin-based chemotherapy regimens or after salvage high-dose chemotherapy with autologous stem cell support. Patients with disease progression during initial induction chemotherapy or during salvage therapy were also eligible. Additional inclusion criteria were the presence of bidimensionally measurable disease and/or elevated tumor markers; a Karnofsky performance status >= 50; and adequate hematologic (WBC > 2,500/µL, platelets > 75,000/µL), renal (creatinine clearance > 50 mL/min), and liver function (bilirubin <= 1.5-fold upper limit of normal; liver enzymes < three-fold upper limit of normal). No other concomitant chemotherapy, radiotherapy, or experimental medication was allowed. All patients gave their written informed consent. The study was approved by the University of Tuebingen Ethics Committee and by the local committees of the participating centers.

Pretreatment evaluation included history and physical examination, documentation of all measurable disease by x-ray or computed tomography scan, estimation of performance status, serum tumor marker levels (alpha-fetoprotein, beta-human chorionic gonadotropin, lactate dehydrogenase), liver function tests and creatinine, complete blood count with differential, and ECG.

Treatment
During the first part of the study, oxaliplatin was administered as a 2-hour infusion at a dose of 60 mg/m2 on days 1, 8, and 15, repeated every 4 weeks.24 In the second part of the study, the schedule was modified to oxaliplatin administered as a 2-hour infusion at a dose of 130 mg/m2 on days 1 and 15, repeated every 3 weeks to evaluate the activity of higher single doses.25-27 Concomitant antiemetic therapy included 5-hydroxytryptamine-3–antagonists as well as dexamethasone.

When hematologic parameters had not recovered until the next planned application, treatment was delayed for 1 week. When a delay for more than 2 weeks was required, the patient was taken off study. A dose reduction of 50% was planned for the subsequent two administrations in case of National Cancer Institute common toxicity criteria (NCI-CTC) grade 4 thrombocytopenia, granulocytopenia, or neutropenic fever. Dose re-escalations were allowed when no severe side effects occurred with the reduced oxaliplatin dose. No routine use of granulocyte colony-stimulating factor was recommended, but the use of growth factors on an individual basis in instances of severe neutropenia was allowed. In case of NCI-CTC grade 3/4, neurotoxicity treatment was stopped. For other nonhematologic NCI-CTC grade 3 toxicities, 50% dose reductions were suggested; in cases of NCI-CTC grade 4 toxicity, the decision about continuation of treatment was at the discretion of the treating physician. All patients were treated on an outpatient basis.

Definitions
Disease was considered to be cisplatin refractory when at least tumor stabilization or a remission was achieved but tumor progression occurred again within 4 weeks of the last cisplatin-based chemotherapy. Disease was considered to be absolutely cisplatin refractory when tumor progression developed while the patient was receiving cisplatin-based therapy.28,29

Response and toxicity were graded according to World Health Organization and NCI-CTC (version 2.0) criteria, respectively.30 In addition, reduction of the size of a tumor lesion and normalization of previously elevated tumor markers were considered to be a partial remission with tumor marker normalization (PR-), whereas a reduction >= 50% in the sum of the perpendicular diameters of measurable disease plus a tumor marker decrease for at least 1 month but without complete normalization was considered to be a marker-positive partial remission (PR+). When elevated markers were the only evidence of progressive disease, a decrease of at least 90% was required for a PR. Serum tumor markers were determined every 2 to 4 weeks. Evaluation of measurable disease by radiographic means was performed every 4 weeks. All responses as well as the diagnosis of stable disease had to be reconfirmed after a 4-week interval. All patients were scheduled to receive at least two cycles of treatment. However, in case of a significant marker (>= 50%) and/or radiological progression (>= 25%) after one cycle, the treatment was stopped and the patient was classified as having progressive disease. In patients with tumor responses or disease stabilization, therapy was continued for at least two more cycles after achievement of the best response unless severe toxicity occurred.

Survival and follow-up time were calculated from the beginning of oxaliplatin therapy until the date of death or the date of last follow-up, respectively, using the Kaplan-Meier test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Overall, 32 patients with relapsed or cisplatin-refractory metastatic nonseminomatous germ cell cancer were enrolled between October 1998 and January 2001. The first 16 patients were treated with oxaliplatin given once weekly at a dose of 60 mg/m2 for 3 consecutive weeks followed by 1 week of rest (group 1), and 16 additional patients received oxaliplatin 130 mg/m2 every 2 weeks (group 2). Patient characteristics are listed in Table 1. All patients were assessable for toxicity and response.


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  		Table 1.  Patient Characteristics (N = 32)
 
Overall, four responses (13%; 95% confidence interval [CI], 1% to 24%) were observed in these 32 patients (Table 2). One marker-positive partial response (6%) of 8 weeks’ duration and no temporary disease stabilizations occurred in group 1, whereas three patients (19%) in group 2 achieved a partial response (Table 3). In addition, two patients (13%) in group 2 both also considered to be cisplatin refractory had a temporary disease stabilization that lasted for 5 and 6 months, respectively. All other patients progressed during oxaliplatin treatment.


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  		Table 2.  Response to Single-Agent Oxaliplatin
 

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  		Table 3.  Characteristics of Responding Patients
 
A total of 68 oxaliplatin cycles, 27 in group 1 and 41 in group 2, were applied with a median of two cycles (range, one to eight) per patient. The median cumulative oxaliplatin dose was 350 mg/m2 (range, 180 mg/m2 to 900 mg/m2) in group 1 and 520 mg/m2 (range, 520 mg/m2 to 2,080 mg/m2) in group 2. Dose reductions and treatment delays were required in six (7%) and 18 (22%) of 82 oxaliplatin administrations in group 2. In group 1, no dose reductions were performed and treatment was delayed in three (4%) of 81 oxaliplatin administrations. Toxicity is summarized in Table 4. Overall, nonhematologic toxicity was tolerable, and nausea/vomiting, non-neutropenic fever, and neurotoxicity were the main side effects. Three patients (9%) developed grade 3 nonhematologic toxicity, two patients developed nausea/vomiting (one from each group), and one patient developed peripheral neurotoxicity (group 2). The last patient had been pretreated with one cycle of standard etoposide, ifosfamide, and cisplatin followed by three high-dose chemotherapy cycles consisting of paclitaxel, cisplatin, etoposide, and ifosfamide (total cumulative cisplatin dose, 400 mg/m2; total cumulative paclitaxel dose, 675 mg/m2) and subsequently received oxaliplatin with a cumulative dose of 520 mg/m2. Myelosuppression was moderate; four patients (13%) developed grade 3 thrombocytopenia and one patient (3%) developed grade 4 thrombocytopenia. Granulocytopenia grade 3 occurred in three patients (9%), but no grade 4 granulocytopenia was seen. There were no cases of neutropenic fever and no treatment-related deaths.


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  		Table 4.  Main Toxicity Per Patient According to NCI-CTC (Version 2.0) Classification
 
With a median follow-up of 5 months (range, 1 to 26 months), all but two patients (6%) died of their disease. Median overall survival for all patients was 5 months (range, 1 to 26 months).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The incorporation of cisplatin into combination regimens has led to a significant improvement in survival of patients with germ cell cancer. Thus, the exploration of new drugs has been performed in intensively pretreated patients without established treatment options. However, the identification of new active agents not only may allow palliative treatment in refractory patients but also may offer new possibilities for combination therapy in patients at an earlier phase of their treatment course. Only very few of the agents studied, such as etoposide, ifosfamide, or, more recently, paclitaxel, have been found active in patients with refractory germ cell tumors and subsequently incorporated into combination regimens.9,13,14,31 Oxaliplatin has shown activity not only in platinum-sensitive tumor types such as ovarian and lung cancer but also in colorectal or breast cancer, where cisplatin does not represent an established treatment option.32 In addition, responses were observed in cisplatin-pretreated ovarian cancer patients, suggesting a mode of action and a pattern of resistance of oxaliplatin that differ from cisplatin.23,33-35

The present phase II study investigated the activity of oxaliplatin in patients with intensively pretreated or cisplatin-refractory germ cell cancer. Four objective remissions were achieved in 32 patients for an overall response rate of 13% (95% CI, 1% to 24%) with three responses occurring in the group of patients who were treated with oxaliplatin at 130 mg/m2 (three of 16; 19% [95% CI, 4% to 46%]). All responses occurred in cisplatin-refractory patients, three had not responded to previous high-dose chemotherapy, and three presented with late relapse (Table 3). As compared with the characteristics of patients who were treated within trials to evaluate the role of paclitaxel or gemcitabine in relapsed germ cell cancer, this study was conducted in a prognostically even more unfavorable group of patients on the basis of the number of patients who previously received high-dose chemotherapy plus autologous stem cell support, presented with a late relapse, or were considered to be cisplatin refractory. Thirty-four percent of our patients presented with a late relapse, 78% were pretreated with high-dose chemotherapy plus peripheral stem cell support, and 85% had to be classified as cisplatin refractory (Table 5). Considering these poor prognostic characteristics, a response rate of 13% seems to be comparable to the results reported for paclitaxel and gemcitabine, both of which are considered active in this therapeutic setting.13,14,16,17 Because all patients who responded to oxaliplatin were considered to be cisplatin refractory, our data also seem to confirm preclinical and clinical data of incomplete cross-resistance between oxaliplatin and cisplatin.23,25,35


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  		Table 5.  Comparison of Patient Characteristics in Recent Trials of New Agents (paclitaxel, gemcitabine) for the Treatment of Refractory Germ Cell Cancer
 
Two different dose levels and schedules of oxaliplatin were applied. During the first part of the study, 60 mg/m2 of oxaliplatin was given on days 1, 8, and 15 of a 28-day cycle. This dose and schedule were chosen particularly to avoid myelotoxicity in these heavily pretreated patients while at the same time achieve a high-dose intensity. One partial radiological response of 2 months’ duration was observed. The oxaliplatin schedule was changed to 130 mg/m2 given every 2 weeks in the second part of this study. The rationale for the higher single dose of oxaliplatin was based on in vitro data that suggested a relationship between cell kill and peak drug concentrations of oxaliplatin, both in cisplatin-resistant and cisplatin-sensitive colony-forming units of various tumor types.25 In addition, a recent retrospective analysis of oxaliplatin dose intensity given in a bimonthly fluorouracil/folinic acid/oxaliplatin regimen in colorectal cancer patients showed significantly improved response rates and progression-free survival for higher oxaliplatin doses.26 In our group of patients who were treated with biweekly 130 mg/m2 of oxaliplatin, three partial responses and two disease stabilizations were achieved. These findings may indicate that an increase in peak serum concentration may lead to a higher activity of oxaliplatin.

The toxicity of oxaliplatin therapy was generally tolerable. Similar to other studies in heavily pretreated patients, including those with previous high-dose chemotherapy plus stem cell support, hematotoxicity mainly consisted of thrombocytopenia.16,17 However, no episodes of severe bleeding occurred, and no platelet transfusions were required. Mild neurotoxicity was seen in 56% of patients, but only one patient (treated at 130 mg/m2 biweekly) developed grade 3 neurotoxicity. Patients with mild (first-degree) preexisting neurotoxicity from previous cisplatin treatment had also been included into this study. However, the potential of oxaliplatin to induce neurotoxicity might be underestimated as a result of the limited number of cycles delivered per patient with a median cumulative dose of 350 mg/m2 reached in these patients. It is known that the peripheral sensory neurotoxicity with functional impairment affects more than 10% of patients when cumulative doses of more than 600 mg/m2 are applied.21

A number of phase I/II studies have already demonstrated the feasibility of combining oxaliplatin with other drugs, eg, cyclophosphamide, paclitaxel, gemcitabine, or even cisplatin.36-40 On the basis of the activity of oxaliplatin shown in the present study, we have started a new protocol to evaluate the combination of weekly gemcitabine/biweekly oxaliplatin in patients with refractory germ cell cancer. In vitro, supra-additive efficacy has been reported for the sequence of gemcitabine followed by oxaliplatin. A recent phase II study reported a response rate of 23% and a tolerable toxicity profile for the combination of gemcitabine and paclitaxel, demonstrating that combination chemotherapy is feasible in these heavily pretreated patients.41


   ACKNOWLEDGMENTS
 
Supported by an educational grant from Sanofi-Synthelabo, Inc, Berlin, Germany.

The contribution of the following centers and physicians is acknowledged: University of Bonn (P. Albers); University of Greifswald (P. Abel), Krankenhaus Barmherzige Brüder Trier (W. Weber); Krankenhaus Schwäbisch Hall (T. Geer); Krankenhaus Hameln (H. Dürk); Klinikum Kaiserslautvern (H. Link); Krankenhaus Karlsruhe (T. Kubin); Siloah Krankenhaus Hannover (M. Sosada); and University of Heidelberg (M. Rieger; J. Tilgner).


   NOTES
 
Data were presented in part at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, May 12-15, 2001, San Francisco, CA.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Bosl GJ, Motzer RJ: Medical progress: Testicular germ-cell cancer. N Engl J Med 337: 242-253, 1997[Free Full Text]

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3. Rick O, Bokemeyer C, Beyer J, et al: Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by autologous stem cell rescue in patients with relapsed or refractory germ cell cancer. J Clin Oncol 19: 81-88, 2001[Abstract/Free Full Text]

4. Broun ER, Nichols CR, Mandanas R, et al: Dose escalation study of high-dose carboplatin and etoposide with autologous bone marrow support in patients with recurrent and refractory germ cell tumors. Bone Marrow Transplant 16: 353-358, 1995[Medline]

5. Motzer RJ, 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[Abstract/Free Full Text]

6. Nichols CR, Roth BJ, Loehrer PJ, et al: Salvage chemotherapy for recurrent germ cell cancer. Semin Oncol 5: 102-108, 1994 (suppl 12)

7. Porcu P, Bhatia S, Einhorn LH: Results of treatment after relapse from high-dose chemotherapy in germ cell tumors. J Clin Oncol 18: 1181-1186, 2000[Abstract/Free Full Text]

8. Puc HS, Bajorin D, Bosl GJ, et al: Phase II trial of topotecan in patients with cisplatin-refractory germ cell tumors. Invest New Drugs 13: 163-165, 1995[CrossRef][Medline]

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10. Bokemeyer C, Droz JP, Hanauske A, et al: Treatment of relapsed nonseminoma germ cell tumors with vinorelbine: A trial of the phase I/II study group of the Association of Medical Oncology of the German Cancer Society. Onkologie 16: 29-31, 1993

11. Drasga RE, Williams S, Einhorn LH, et al: Phase II evaluation of iproplatin in refractory germ cell tumors: A Southeastern Cancer Study Group trial. Cancer Treat Rep 71: 863-864, 1987[Medline]

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13. 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[Abstract/Free Full Text]

14. Motzer RJ, Bajorin D, 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[Abstract/Free Full Text]

15. Kollmannsberger C, Gerl A, Schleucher N, et al: Phase II study of bendamustine in patients with relapsed or cisplatin-refractory germ cell cancer. Anticancer Drugs 11: 535-539, 2000[CrossRef][Medline]

16. Bokemeyer C, Gerl A, Schöffski P, et al: Gemcitabine in patients with relapsed or cisplatin-refractory testicular cancer. J Clin Oncol 17: 512-516, 1999[Abstract/Free Full Text]

17. Einhorn LH, Stender MJ, Williams SD: Phase II trial of gemcitabine in refractory germ cell tumors. J Clin Oncol 17: 509-511, 1999[Abstract/Free Full Text]

18. Miller JC, Einhorn LH: Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 17: 36-39, 1990[Medline]

19. Motzer RJ, Sheinfeld J, Mazumdar M, et al: Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 18: 2413-2418, 2000[Abstract/Free Full Text]

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23. Dunn TA, Schmoll HJ, Grünwald V, et al: Comparative cytotoxicity of oxaliplatin and cisplatin in non-seminomatous germ cell lines. Invest New Drugs 15: 109-114, 1997[CrossRef][Medline]

24. Buechele T, Schoeber C, Kroening H, et al: Weekly high-dose (HD) 5-fluorouracil (5-FU) and folic 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 17: 287a, 1998 (abstr 1106)

25. Raymond E, Lawrence R, Izbicka E, et al: Activity of oxaliplatin against human tumor colony-forming units. Clin Cancer Res 4: 1021-1029, 1998[Abstract]

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28. Nichols CR, Tricot G, Williams SD, et al: Dose-intensive chemotherapy in refractory germ cell cancer: A phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol 7: 932-939, 1989[Abstract]

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31. Fitzharris BM, Kaye S, Saverymuttu S, et al: VP-16 as a single agent in advanced testicular tumors. Eur J Cancer 16: 1193-1197, 1980

32. Raymond E, Chaney SG, Taamma A, et al: Oxaliplatin: A review of preclinical and clinical studies. Ann Oncol 9: 1053-1071, 1998[Abstract/Free Full Text]

33. Fukuda M, Ohe Y, Kanzawa F, et al: Evaluation of novel platinum complexes, inhibitors of topoisomerase I and II in non-small cell lung cancer (NSCLC) sublines resistant to cisplatin. Anticancer Res 15: 393-398, 1995[Medline]

34. Rixe O, Ortuzar W, Alvarez M, et al: Oxaliplatin, tetraplatin, cisplatin, and carboplatin: Spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute’s Anticancer Drug Screen panel. Biochem Pharmacol 52: 1855-1865, 1996[CrossRef][Medline]

35. Sessa C, Bokkel-Huinink WW, du Bois A: Oxaliplatin in ovarian cancer. Ann Oncol 10: 55-57, 1999 (suppl 1)

36. Faivre S, Raymond E, Woynarowski JM, et al: Supraadditive effect of 2',2'-difluorodeoxycytidine (gemcitabine) in combination with oxaliplatin in human cancer cell lines. Cancer Chemother Pharmacol 44: 117-123, 1999[CrossRef][Medline]

37. Mavroudis D, Kourousis C, Kakolyris S, et al: Phase I study of the gemcitabine/oxaliplatin combination in patients with advanced solid tumors: A preliminary report. Semin Oncol 27: 25-30, 2000

38. Faivre S, Raymond E, Lokiec F, et al: Final results of the phase I-II and pharmacokinetic study GEM/OX combining gemcitabine (GEM) with oxaliplatin (OX) in patients (pts) with advanced non-small cell lung (NSCLC) and ovarian carcinoma (OC). Proc Am Soc Clin Oncol 20: 896, 2001 (abstr 2105)

39. Misset JL, Chollet P, Vennin Ph, et al: Multicentric phase II-III trial of oxaliplatin (LOHP) versus cisplatin (P) both in association with cyclophosphamide (C) in the treatment of advanced ovarian cancer (AOC): Toxicity efficacy results. Proc Am Soc Clin Oncol 16: 354a, 1997 (abstr 1266)

40. Faivre S, Kalla S, Cvitkovic E, et al: Oxaliplatin and paclitaxel combination in patients with platinum-pretreated ovarian carcinoma: An investigator-originated compassionate-use experience. Ann Oncol 10: 1125-1128, 1999[Abstract/Free Full Text]

41. Hinton S, Catalano PJ, Einhorn L, et al: Phase II trial of paclitaxel and gemcitabine in refractory germ cell tumors. Proc Am Soc Clin Oncol 20: 173a, 2001 (abstr 688)

Submitted June 14, 2001; accepted January 16, 2002.


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Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell tumors: a study of the German Testicular Cancer Study Group
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J Shamash, T Powles, K Mutsvangwa, P Wilson, W Ansell, E Walsh, D Berney, J Stebbing, and T Oliver
A phase II study using a topoisomerase I-based approach in patients with multiply relapsed germ-cell tumours
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L. H. Einhorn, M. J. Brames, B. Juliar, and S. D. Williams
Phase II Study of Paclitaxel Plus Gemcitabine Salvage Chemotherapy for Germ Cell Tumors After Progression Following High-Dose Chemotherapy With Tandem Transplant
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G. Sonpavde, T. E. Hutson, and B. J. Roth
Management of Recurrent Testicular Germ Cell Tumors
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G. V. Kondagunta and R. J. Motzer
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P. M. Bedano, M. J. Brames, S. D. Williams, B. E. Juliar, and L. H. Einhorn
Phase II Study of Cisplatin Plus Epirubicin Salvage Chemotherapy in Refractory Germ Cell Tumors
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U. De Giorgi
Is high-dose chemotherapy based on carboplatin, a late dose-intensification of a cisplatin-based salvage chemotherapy in germ cell tumour patients?
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K. Fizazi, S. Culine, and I. Chen
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Ann. Onc., August 1, 2004; 15(8): 1295 - 1295.
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D. Pectasides, M. Pectasides, D. Farmakis, G. Aravantinos, M. Nikolaou, M. Koumpou, A. Gaglia, V. Kostopoulou, N. Mylonakis, and D. Skarlos
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C. Kollmannsberger, J. Beyer, R. Liersch, P. Schoeffski, B. Metzner, J.T. Hartmann, O. Rick, K. Stengele, K. Hohloch, C. Spott, 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
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Phase I clinical study of infusional 5-fluorouracil with oxaliplatin and gemcitabine (FOG regimen) in patients with solid tumors
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F. Mayer, H. Stoop, G. L. Scheffer, R. Scheper, J. W. Oosterhuis, L. H. J. Looijenga, and C. Bokemeyer
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