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Journal of Clinical Oncology, Vol 20, Issue 6 (March), 2002: 1512-1518
© 2002 American Society for Clinical Oncology

Gemcitabine Combined With Oxaliplatin in Advanced Pancreatic Adenocarcinoma: Final Results of a GERCOR Multicenter Phase II Study

By C. Louvet, T. André, G. Lledo, P. Hammel, H. Bleiberg, C. Bouleuc, E. Gamelin, M. Flesch, E. Cvitkovic, A. de Gramont

From Service d’Oncologie-Médecine Interne, Hôpital Saint-Antoine, Service d’Oncologie, Hôpital Tenon, and GERCOR, Paris; Clinique St Jean, Lyon; Service de Gastro-Entérologie, Hôpital Beaujon, Clichy; Service d’Oncologie, Hôpital d’Argenteuil, Argenteuil; Service d’Oncologie, Centre Paul Papin, Angers; Fondation Drevon, Dijon; and Cvitkovic Associés Consultants, Kremlin-Bicêtre, France; and Institut Jules Bordet, Brussels, Belgium.

Address reprint requests to Christophe Louvet, MD, Service d’Oncologie, Médecine Interne, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris, Cedex 12, France; email: christophe.louvet{at}sat.ap-ap-hop-paris.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Based on preclinical in vitro synergy data, this study evaluated the activity and toxicity of a gemcitabine/oxaliplatin combination in patients with metastatic and locally advanced pancreatic adenocarcinoma.

PATIENTS AND METHODS: Previously untreated metastatic and locally advanced unresectable pancreatic adenocarcinoma patients were enrolled onto this multicenter phase II study. Patients received gemcitabine 1,000 mg/m2 as a 10-mg/m2/min infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour infusion on day 2 every 2 weeks. Patients with metastatic disease were treated until evidence of progressive disease, whereas patients with locally advanced disease received six cycles in the absence of progression, followed when appropriate by concomitant radiochemotherapy.

RESULTS: Among 64 eligible patients included in eight centers, 30 had locally advanced and 34 had metastatic disease. Response rate for the 62 patients with measurable disease was 30.6% (95% confidence interval, 19.7% to 42.3%), 31.0% for locally advanced and 30.3% for metastatic patients. Among 58 assessable patients, 40% had clinical benefit. Median progression-free survival and median overall survival (OS) were 5.3 and 9.2 months, respectively, with 36% of patients alive at 1 year. Median OS for patients with metastatic disease and locally advanced disease were 8.7 and 11.5 months, respectively. With 574 treatment cycles (median per patient, nine; range, zero to 27), grade 3/4 toxicity per patient was 11% for neutropenia and thrombocytopenia, 14% for nausea or vomiting, 6.2% for diarrhea, and 11% for peripheral neuropathy, with no toxic deaths.

CONCLUSION: Palliative effects, response rate, and survival observed with this well-tolerated gemcitabine/oxaliplatin combination deserve additional evaluation. A comparative study of combination therapy versus gemcitabine alone is ongoing.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PANCREATIC ADENOCARCINOMA is the fifth most common cause of cancer death in Western countries.1 The estimated number of new cases of pancreatic cancer in France is approximately 5,000 per year.2 Only 1% to 4% of patients with pancreatic cancer survive 5 years after diagnosis.3 Between 10% and 20% of patients undergo surgery with curative intent, and the median survival of these patients is 15 to 19 months.4 In nonresectable disease, some chemotherapeutic agents have a palliative effect5,6 and prolong survival.5-7 No single-agent drug has produced reproducible response rates over 10% when subjected to independent expert radiologic evaluation. Clinical benefit is an alternative method for assessing efficacy of chemotherapy and includes improvement in performance status, decrease of pain or analgesic consumption, and weight gain.8

With its significant advantage in terms of clinical benefit and overall survival as compared with fluorouracil (5FU), gemcitabine (2'2'-difluorodeoxycitidine) has become a reference chemotherapeutic agent for palliation of advanced and symptomatic pancreatic cancers.5 Gemcitabine is an inactive prodrug and is metabolized into an active form through a saturable intracellular phosphorylation. An infusion rate of 10 mg/m2/min was found to be optimal to achieve the best conversion rate of active phosphorylated gemcitabine. A randomized phase II trial report by Tempero et al9 showed an encouraging trend in response rate (RR) and survival in metastatic pancreatic cancer patients when using gemcitabine as a 10 mg/m2/min delivery regimen benchmarked to the standard 30-minute infusion. However, results in patients with advanced pancreatic adenocarcinoma with single-agent gemcitabine are clearly not optimal. Recently reported comparative studies of gemcitabine-based combinations versus gemcitabine alone in pancreatic cancer patients include gemcitabine/5FU10,11 and gemcitabine/cisplatin12 combinations. Although these combinations sometimes showed higher activity than single-agent gemcitabine, they also had increased toxicity, limiting the use of these regimens in fragile patients.

Oxaliplatin is a diaminocyclohexane (DACH)-platinum compound that is active in several solid tumor types, including cisplatin/carboplatin refractory disease. A synergistic effect was observed with the combination of 5FU and oxaliplatin, both preclinically,13 and in previously untreated or 5FU-resistant metastatic colorectal cancer patients.14 Furthermore, in vitro studies showed a cytotoxic effect of oxaliplatin against pancreatic cancer cell lines.15 A randomized phase II trial in patients with advanced or metastatic pancreatic adenocarcinoma comparing oxaliplatin alone, 5FU alone, and 5FU combined with oxaliplatin showed no response for the single-agent arms and an 11% RR with 8.5 months median survival for the combined arm.16

The rationale for the use of a gemcitabine/oxaliplatin combination has a strong preclinical basis. A supra-additive effect was observed in human leukemia and colorectal cancer cell lines, with an optimal sequence-dependent synergy when tumor cells were exposed to gemcitabine first and then to oxaliplatin 24 hours later. Furthermore, the gemcitabine-oxaliplatin combination was shown to be more potent in vitro than the gemcitabine-cisplatin combination in the mismatch repair-deficient HCT 116 colon cancer cell line.17

Based on the above data, this study was designed to evaluate the activity and tolerance of the gemcitabine/oxaliplatin combination (GEMOX) in patients with locally advanced (LA) and metastatic pancreatic cancer.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility Criteria
Eligible patients had histologically confirmed nonresectable pancreatic adenocarcinoma (ie, locally advanced or metastatic disease); however, patients with Vater’s ampulloma and adenocarcinoma of the biliary tract were not eligible. Eligible patients had not received prior chemotherapy or radiotherapy, had a Karnofsky performance status of 60 or greater, were 18 to 75 years of age, had no CNS metastases, had no uncontrolled infection, had a life expectancy of longer than 3 months, and were required to have adequate hematologic (neutrophil count > 1,500/mL; platelet count > 100,000/mL), renal (serum creatinine < 1.5 x the upper limit of normal value [ULN]), and hepatic (alkaline phosphatase < 3 x ULN and bilirubin < 1.5 x ULN) functions. Pain and biliary obstruction had to be controlled in all patients before inclusion in the study. The protocol was approved by the institutional ethics committee, and written informed consent was obtained from each patient.

Treatment Plan
GEMOX consisted of gemcitabine 1,000 mg/m2 in a 10-mg/m2/min (100-minute) infusion on day 1, followed on day 2 by oxaliplatin 100 mg/m2 in a 2-hour infusion. Treatment was repeated every 2 weeks. If nonneurologic toxicity greater than National Cancer Institute common toxicity criteria (NCI-CTC) grade 2 occurred, the subsequent cycle was only administered after recovery, with a gemcitabine dose reduction to 800 mg/m2 (in an 80-minute infusion) and an oxaliplatin dose reduction to 85 mg/m2. When grade 3 characteristic cumulative sensitive peripheral neuropathy NCI-CTC occurred, oxaliplatin was discontinued and gemcitabine alone was administered according to the above schedule. In cases of laryngopharyngeal dysesthesia, oxaliplatin infusion was prolonged to 6 hours and eventually stopped if additional symptoms occurred during the following cycles. Patients with metastatic disease received GEMOX until evidence of disease progression, patient refusal, or unacceptable toxicity. Patients with LA disease received at least six cycles of study treatment. It has been shown that concomitant radiochemotherapy (CRCT) with 5FU provides effective and prolonged pain relief in LA patients.18,19 Thus CRCT (45 Gy in 25 fractions over 5 weeks, associated with a daily continuous infusion of 250 mg/m2 5FU, and a boost of 10 Gy in eight fractions restricted to the initial tumor volume, administered as a second daily fraction during the last 2 weeks of treatment) was then allowed in the absence of progression to metastatic disease, according to the patient’s general condition and the investigator’s decision.

Treatment Evaluations
Baseline biologic analyses (blood cell count, serum creatinine, bilirubin, AST, ALT, alkaline phosphatase, and CA 19.9 levels) were performed within the week preceding treatment initiation, and tumor measurement (computed tomography scan) was performed within 21 days of treatment start. Within the 3 days preceding each cycle, a physical examination and complete blood cell count were performed, whereas performance status, weight, pain assessment using a visual analog scale, and analgesic consumption were recorded at each cycle to evaluate the clinical benefit.

Assessment of Efficacy
The objective tumor response, defined according to the World Health Organization, was assessed every 2 months or earlier if clinically indicated. Objective responses had to be confirmed by imaging at least 1 month later. Clinical benefit was evaluated according to Andersen’s definition8: patients with less pain (at least >= 50% improvement from baseline) on the Memorial Pain Assessment Card visual analog scale, decreased analgesic consumption (>= 50% reduction compared with baseline consumption), or improved Karnofsky performance status (>= 20 points compared with baseline evaluation) for at least 4 consecutive weeks without any degradation of any of these parameters were considered as having a clinical benefit. If a patient was stable on both primary measures of clinical benefit (pain and performance status), he or she was then classified for clinical benefit as either a responder (weight gain of >= 7% from baseline, sustained for >= 4 weeks) or a nonresponder. Of note, performance status was only determined by the treating physician. Toxicity was evaluated at each cycle according to NCI-CTC. An external panel of radiologists separately analyzed all radiologic examinations of patients reported as responding or with stable disease. Progression-free survival (PFS) was calculated from the first day of treatment until evidence of clinical progression or tumor progression assessed by computed tomography scan measurement. Overall survival (OS) was calculated from the first day of treatment until the date of death. PFS and OS data were analyzed according to the Kaplan-Meier method.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Sixty-six patients were enrolled in eight institutions between September 1999 and July 2000. Two patients (3%) were considered to be ineligible, one with a bilirubin value 10-fold the ULN and the other with a performance status of three. The demographic and clinical characteristics of the 64 eligible patients are reported in Table 1. The primary tumor was present in all but two patients who had previously undergone surgery and subsequently developed metastatic relapse. Of the 34 patients with metastatic disease, 74% had liver involvement. Thirty-two of these metastatic patients had one involved organ, and the other two patients had two or more. Thirty patients (45%) had nonmetastatic LA disease.


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  		Table 1.  Patient Characteristics at Baseline (N = 64)
 
Toxicity
Five hundred seventy-four cycles were administered every 2 weeks (median, nine cycles per patient; range, zero to 27), for a median duration of treatment of 18 weeks. All 64 treated patients were assessed for safety according to version 1.0 of the NCI-CTC, and grade 3 or 4 toxicities per patient and per cycle are summarized in Table 2. Grade 3 or 4 neutropenia, assessed at the previous cycle nadir, occurred in 11% of patients in only 1.7% of cycles, with a single episode of febrile neutropenia. Grade 3 or 4 thrombocytopenia occurred in 11% of patients in 1.3% of cycles, and no patients experienced severe anemia. Grade 3 peripheral neuropathy occurred in seven patients (11%) at cycles 8, 10, 10, 11, 13, 13, and 15. Maximal toxicity per patient was NCI-CTC grade 0, 1, 2, 3, and 4 in 1.6%, 25%, 39%, 25%, and 9.4% of patients, respectively. The most prevalent nonhematologic toxicities reported were digestive, with 14% of patients reporting grade 3 or 4 nausea or vomiting and 6.2% experiencing diarrhea. Grade 2 alopecia occurred in only two patients (3.1%). No toxic deaths were observed in this study.


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  		Table 2.  NCI-CTC Grade 3/4 Toxicities per Cycle (N = 574) and per Patient (N = 64)
 
Dose-Intensity
Planned gemcitabine and oxaliplatin dose-intensities were 500 mg/m2/wk and 50 mg/m2/wk, respectively. The administered dose-intensities of gemcitabine and oxaliplatin for all cycles were 86% and 81% of the planned dose-intensity, respectively. When only the first six cycles are considered, administered dose-intensities were 88% for both agents. Seven patients discontinued oxaliplatin treatment without evidence of disease progression as a result of peripheral neuropathy. These patients had a median cumulative oxaliplatin dose of 1,100 mg/m2 (range, 800 to 1,500) and continued receiving gemcitabine alone.

Efficacy
Efficacy was assessed according to tumoral response, clinical benefit, and time-related parameters, and data are listed in Table 3. Of the 64 treated patients, two had nonmeasurable disease and thus were not assessable for efficacy. According to investigator assessment, 19 patients had a partial response, 28 had disease stabilization, and 16 had disease progression, giving a response rate of 19 (30.6%) of 62 (95% confidence interval, 19.7 to 42.3). The 19 partial responses were confirmed by an external panel of radiologists. The response rates in LA and metastatic patients were 31.0% and 30.3%, respectively.


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  		Table 3.  Response Rate, Clinical Benefit Response, and Survival Data
 
Clinical benefit could not be evaluated in six patients, all of whom had a baseline performance status of at least 90 without pain or analgesic consumption. Twenty-three (40%) of the 58 assessable patients reported a clinical benefit. Among the 30 patients with LA disease, 12 (40%) received a CRCT after six cycles and 12 (40%) presented metastatic progression within the first six cycles, and for the remaining six (20%) who had controlled disease and no pain, the investigator decided not to administer CRCT and to continue the GEMOX treatment.

With a median follow-up of 14 months, median PFS and median OS in the treated population were 5.3 and 9.2 months, respectively. Median OS in patients with LA and metastatic disease were 11.5 and 8.7 months, respectively. The 1-year actuarial survival rate was 36% for all treated patients, 47% for patients with LA disease, and 26% for patients with metastatic disease. Efficacy data are listed in Table 3.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Single-agent gemcitabine administered at the dose of 1,000 mg/m2 in a weekly 30-minute infusion is more active in terms of palliative effects and survival than 5FU, and as such, it is considered the standard treatment in pancreatic adenocarcinoma.5 However, treatment of pancreatic cancer patients with gemcitabine has provided limited benefit, motivating many attempts to provide better palliative treatment in this indication. Several new drugs, including oxaliplatin, are presently being tested, either alone or in combination with gemcitabine. The superior preclinical synergistic profile of the gemcitabine/oxaliplatin combination17 can in part be attributed to the fact that in comparison to cisplatin, oxaliplatin forms more stable platinum adducts because of its diaminocyclohexane moiety.20 Furthermore, oxaliplatin is active in tumor cells with a high expression of microsatellite instability, a characteristic of mismatch repair deficient cells,20 and frequently observed in pancreatic tumor cells.21

Several schedules are potentially available for administration of gemcitabine/oxaliplatin combinations. The bimonthly schedule used in this study comes from our oxaliplatin-based studies in colorectal cancer.14,22 A 100 mg/m2 oxaliplatin dose every 2 weeks achieves a high dose-intensity, which in our experience correlates significantly with the antitumor activity of the FOLFOX regimens.22 Furthermore, a combination of gemcitabine and 5FU every 2 weeks was found to be active in advanced pancreatic adenocarcinoma, with a 25.9% response rate, although this combination had a high rate of limiting hematologic toxicity.23 A 10 mg/m2/min gemcitabine schedule was chosen based on its more potent activity compared with 30-minute infusion of gemcitabine.9 A day 1 gemcitabine/day 2 oxaliplatin schedule was retained because of the optimal sequence-dependent synergy observed in vitro17 and because the influence of the schedule administration sequence on response and survival has been well demonstrated with the gemcitabine/cisplatin regimens in advanced non–small-cell lung cancer.24 In the latter retrospective analysis of six phase II studies combining these two drugs, the best therapeutic index was achieved when cisplatin was administered after gemcitabine, this parameter being an independent prognostic factor for both response and survival in a Cox regression analysis.

It is possible that the promising RR observed in this study (30.6% RR, 9.2-month median OS) is in part attributable to a relatively good prognostic population, with 47% of patients having LA disease and 39% of patients having a favorable performance status. Nonetheless, the results of the subgroup of patients with metastatic disease who showed an identical RR (30.3%) and a median OS of 8.7 months indicate that the GEMOX combination is definitively active.

The respective contributions of oxaliplatin and gemcitabine administered at a fixed infusion rate to the antitumor activity of GEMOX is a subject of speculation. Even though limited data are available, it is probable that single-agent oxaliplatin has only marginal activity in this disease type.16 On the other hand, a weekly schedule of gemcitabine 1,500 mg/m2 at a constant infusion rate (corresponding to a gemcitabine dose-intensity three-fold that in the GEMOX regimen used in this study) achieved a response rate of only 9.1%, with a median PFS of 3.5 months and a median OS of 6.1 months.9 These results are lower than those reported in the present study and argue for a significant contribution by oxaliplatin in this combination. These data strongly support the clinical relevance of the gemcitabine/oxaliplatin synergy observed preclinically.

The results of the efficacy and tolerance assessments of the GEMOX combination are better than those of single-agent gemcitabine administered as a fixed-dose infusion.9 Table 4 summarizes all presently published or reported gemcitabine-based combination studies in LA/metastatic pancreatic adenocarcinoma.25-43 However, several prognostic factors could have influenced the observed results, and Table 4 should be interpreted carefully. Therefore, Table 4 contains, when available, the proportion of patients with locally advanced and metastatic disease and the proportion of patients with a performance status over 70% according to Karnofsky. Nevertheless, the results of the present multicenter study, validated by external review, are clearly in the upper range of reported activity, including for patients with metastatic disease. Furthermore, the favorable toxicity profile we observed is of major value in a palliative situation for fragile patients, a prevalent condition in pancreatic cancer. No limiting toxicity was achieved with the GEMOX regimen; NCI-CTC grade 3 or 4 toxicity per cycle was never greater than 2%. Overall, only 11% of patients experienced a grade 3 or 4 hematologic toxicity, and 14% experienced grade 3 or 4 nausea or vomiting. In addition, the fact that treatment was both prolonged and administered without significant dose adjustments (with the exception of 11% of patients having an interruption attributable to cumulative oxaliplatin neurotoxicity) is a major advantage of this combination.


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  		Table 4.  Summary of Gemcitabine-Based Combination Studies in Pancreatic Adenocarcinoma, by Ascending Response Rate
 
This study demonstrated the efficacy and favorable toxicity profile of this gemcitabine/oxaliplatin combination schedule. While waiting for confirmation of the results of several ongoing studies comparing single-agent gemcitabine to 5FU/gemcitabine or to cisplatin/gemcitabine, single-agent gemcitabine remains the standard treatment for patients with advanced pancreatic cancer. A large multicenter randomized phase III study comparing gemcitabine to GEMOX is now ongoing that may provide an alternative combination regimen for the treatment of advanced and metastatic pancreatic adenocarcinoma.


   ACKNOWLEDGMENTS
 
Supported in part by Sanofi-Synthélabo, Paris, and Eli Lilly, Saint-Cloud, France.

We thank all physicians who participated in this study, the GERCOR team for study management, and Sarah Mackenzie, PhD, for editorial assistance.


   NOTES
 
Preliminary results presented 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
 
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41. Garnier C, Rebischung C, Chirpaz E, et al: Phase II study of a combination with leucovorin (LV), 5 FU bolus and infusion (FU), gemcitabine (GEM) and oxaliplatin (LOHP) (FOLFU GEMOX regimen) in locally advanced (LA) and metastatic (M) pancreatic carcinoma (APC). Proc Am Soc Clin Oncol 20: 156a, 2001 (abstr 620)

42. Brodowicz T, Wolfram RM, Kostler WJ, et al: Phase II study of gemcitabine in combination with cisplatin in patients with locally advanced and/or metastatic pancreatic cancer. Anticancer Drugs 11: 623-628, 2000[CrossRef][Medline]

43. Reni M, Passoni P, Panucci MG, et al: Definitive results of a phase II trial of cisplatin, epirubicin, continuous-infusion fluorouracil and gemcitabine in stage IV pancreatic adenocarcinoma. J Clin Oncol 19: 2679-2686, 2001[Abstract/Free Full Text]

Submitted July 24, 2001; accepted November 1, 2001.


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