Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study

T. André1,*, C. Tournigand2, O. Rosmorduc3, S. Provent1, F. Maindrault-Goebel2, D. Avenin1, F. Selle1, F. Paye4, L. Hannoun5, S. Houry1, B. Gayet6, J. P. Lotz1, A. de Gramont2 and C. Louvet2 On behalf of the GERCOR group

1 Oncology Department and Digestive Surgery Department, Tenon Hospital, Paris; 2 Internal Medicine and Oncology Department, 3 Gastroenterology Department and 4 Digestive Surgery Department, Saint-Antoine Hospital, Paris; 5 Digestive Surgery Department, Pitié-Salpétrière Hospital, Paris; 6 Digestive Surgery Department, Institut Mutualiste Montsouris, Paris, France

* Correspondence to: Dr T. André, Service d'Oncologie Médicale, Hôpital Tenon, 4 rue de la Chine, 75970 Paris cedex 20, France. Tel: +33-1-56-01-60-21; Fax: +33-1-56-01-73-04; Email: thierry.andre{at}tnn.ap-hop-paris.fr


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Since gemcitabine–oxaliplatin (GEMOX) has been used in pancreatic adenocarcinoma, we studied its activity and tolerability in advanced biliary tract adenocarcinoma (ABTA).

Patients and methods: Consecutive adult patients with confirmed ABTA were recruited from four centers. Those in group A had performance status (PS) 0–2, bilirubin <2.5x normal and received GEMOX as first-line chemotherapy. Those in group B had PS >2 and/or bilirubin >2.5x normal and/or prior chemotherapy. All received gemcitabine 1000 mg/m2 as a 10 mg/m2/min infusion on day 1, followed by oxaliplatin 100 mg/m2 as a 2-h infusion on day 2, every 2 weeks.

Results: Tumor sites were gallbladder (19), extrahepatic bile ducts (5), ampulla of vater (3) and intrahepatic bile ducts (29). Results for group A (n=33) were: objective response 36% [95% confidence interval (CI) 18.7% to 52.3%], stable disease 26%, progressive disease 39%, median progression-free survival (PFS) 5.7 months and overall survival (OS) 15.4 months. Results for group B (n=23) were: objective response 22% (95% CI 6.5% to 37.4%), stable disease 30%, progressive disease 48%, PFS 3.9 months and OS 7.6 months. National Cancer Institute Common Toxicity Criteria grade 3–4 toxicities were neutropenia 14% of patients, thrombocytopenia 9%, nausea/vomiting 5% and peripheral neuropathy 7%.

Conclusion: The GEMOX combination is active and well tolerated in ABTA.

Key words: advanced biliary tract adenocarcinoma, chemotherapy, gemcitabine, oxaliplatin


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Biliary tract adenocarcinomas are often diagnosed at an advanced/metastatic stage. To date, there are few data comparing chemotherapy versus best supportive care. The study by Glimelius et al. [1Go] in advanced pancreatic and biliary cancer showed a significant advantage for chemotherapy over best supportive care in terms of survival and quality of life. Despite these data, no standard chemotherapy regimen for advanced disease has been established. Phase II survival data are difficult to interpret due to the small numbers and the considerable variability of enrolled patients.

Single-agent systemic chemotherapy such as 5-fluorouracil (5-FU) or mitomycin C achieves objective response rates ranging from 10% to 25% [2Go–4Go]. Systemic polychemotherapies achieve variable response rates, but with consistent toxicity. The more commonly used combined regimens such as FAM (5-FU, adriamycin, mitomycin C) [5Go] or 5-FU and cisplatin have provided overall survival (OS) of <1 year [6Go–8Go]. Table 1 summarizes the most relevant results in palliative chemotherapy of advanced biliary tract adenocarcinoma (ABTA) [1Go, 3Go, 5Go, 7Go–23Go].


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Table 1. Summary of previous phase II chemotherapy studies in advanced biliary tract adenocarcinoma (studies selected included at least 10 patients)

 
The nucleoside analog gemcitabine has been reported to be active against pancreatic adenocarcinoma and in ABTA, to be able to induce an 8–60% objective response rate (RR) [24Go]. It has become the standard for pancreatic cancer treatment, and is now commonly used in ABTA. However, clinical efficacy with gemcitabine as a single agent remains poor, and gemcitabine-based combinations are needed to improve outcomes. There is a strong preclinical rationale to support the combination of gemcitabine and oxaliplatin. 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 to oxaliplatin 24 h later. Furthermore, the gemcitabine–oxaliplatin combination has been shown to be more potent in vitro than the gemcitabine–cisplatin combination in the mismatch repair-deficient HCT 116 colon cancer cell line [25Go].

Gemcitabine administered at a fixed-dose infusion rate of 10 mg/m2/min could be more potent than a traditional 30-min infusion in pancreatic cancer, as suggested by Tempero et al. [26Go]. This method of administration allows an increase of the active triphosphorylated gemcitabine in mononuclear cells, which could translate into a survival advantage for patients. A multicenter phase II study of the gemcitabine–oxaliplatin combination (GEMOX: gemcitabine 1000 mg/m2 as a 100-min infusion on day 1, followed by oxaliplatin 100 mg/m2 as a 2-h infusion on day 2, repeated every 2 weeks) in advanced pancreatic cancer patients showed promising results [27Go], and was thus further explored in a randomized phase III study. Three hundred and twenty-six patients have been enrolled. Preliminary results showed a significant improvement for the GEMOX arm in terms of RR (28.7% versus 16.7%; P=0.02), median progression free survival (PFS) (24 weeks versus 16 weeks; P=0.04) and clinical benefit (38.9% versus 29.2%; P=0.05), with good tolerance of the GEMOX combination [28Go]. On the basis of these findings, we designed the present study to evaluate GEMOX activity and tolerability in patients with ABTA.


    Patients and methods
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 Introduction
 Patients and methods
 Results
 Discussion
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Eligibility criteria
In order to enter the study, adult patients (aged 18–80 years) had to have histologically confirmed, non-resectable adenocarcinoma of the biliary tract (i.e. locally advanced or metastatic disease), with pain and biliary obstruction controlled. Two groups were defined. Patients in group A had not received prior chemotherapy or radiotherapy, had a performance status (PS) 0–2 [World Health Organization (WHO)], no central nervous system metastases or uncontrolled infection, a life expectancy >3 months, adequate hematological parameters (neutrophils ≥1500/mm3, platelets ≥100 000/mm3), and adequate renal and liver functions [serum creatinine <1.5 x upper limit of normal (ULN) and bilirubin <2.5 x ULN]. Patients in group B had PS >2 and/or bilirubin >2.5 x normal value, and/or prior chemotherapy for advanced disease. Written informed consent was obtained from all patients. The study was carried out according to the Declaration of Helsinski.

Pretreatment evaluation
Baseline biological analyses (blood cell count, serum creatinine, bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and CA 19.9 levels) were performed within 1 week, and tumor size was assessed [by computed tomography (CT) scan] within 3 weeks of the start of the first cycle. A physical examination and complete blood cell count were performed up to 3 days before each cycle.

Treatment
All patients received GEMOX comprising: gemcitabine 1000 mg/m2 as a 10 mg/m2/min (100 min) infusion on day 1, followed by oxaliplatin 100 mg/m2 as a 2-h infusion on day 2. Treatment was repeated every 2 weeks. If non-neurological toxicity occurred with severity greater than National Cancer Intitute Common Toxicity Criteria (NCI CTC) (version 2.0) grade 2, the subsequent cycle was administered after recovery, the gemcitabine dose was decreased to 800 mg/m2 (given in an 80-min infusion) and the oxaliplatin dose was decreased to 85 mg/m2. Oxaliplatin was discontinued if specific cumulative peripheral sensory neuropathy of NCI CTC grade 3 occurred, and these patients received only gemcitabine according to the same schedule. If laryngopharyngeal dysesthesia occurred, the oxaliplatin infusion was prolonged to 6 h, and was stopped if symptoms recurred during subsequent cycles. Patients received GEMOX until there was evidence of disease progression or unacceptable toxicity, or they refused further treatment.

Assessment of efficacy
Tumor evaluation was performed every 2 months (four cycles) during therapy, or earlier when clinically indicated, using World Health Organization (WHO) criteria [29Go]. Toxicity was evaluated at each cycle according to NCI CTC version 2.0. PFS was determined from the first day of treatment until evidence of clinical progression or tumor progression assessed by CT scan measurement. OS was determined from the first day of treatment until the date of death. PFS and OS data were analyzed using the Kaplan–Meier method.


    Results
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 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Fifty-six consecutive patients enrolled in the study between April 2000 and August 2002. Patient characteristics are shown in Table 2. Thirty-three patients met the usual criteria for phase II studies and were allocated to group A, while 23 met the criteria for group B. Of the patients in group B, 13 (57%) received GEMOX as first-line chemotherapy, six (26%) as second-line and four (18%) as third-line; one patient had PS >2 and 13 (57%) patients had bilirubin ≥2.5 x normal value.


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Table 2. Patient characteristics

 
Toxicity
A total of 490 cycles were administered (median eight per patient; range 1–28). NCI CTC grade 3–4 toxicities are summarized in Table 3. Grade 3–4 neutropenia occurred in 1.5% of cycles, with four febrile episodes. Grade 2 alopecia occurred in three patients (5%). Grade 3 peripheral neuropathy occurred in four patients (7%) at cycle 11 (two patients), 10 or 15. Grade 3–4 toxicities per patient for neutropenia, thrombocytopenia, nausea/vomiting and diarrhea were 14%, 9%, 5% and 0%, respectively. No deaths attributed to toxicity occurred during the study.


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Table 3. Grade 3–4 NCI CTC toxicities per cycle (n=490) and per patient (n=56)

 
Efficacy
In group A, two patients had non-measurable disease. According to the investigators' assessment 11 patients had a partial response, eight had stable disease and 12 had disease progression, giving a response rate in evaluable patients of 35.5% [95% confidence interval (CI) 18.7–52.3%]. Median PFS and OS were 5.7 and 15.4 months, respectively. The 1-year actuarial survival rate was 57%. Efficacy data are shown in Table 4. For patients with gallbladder carcinoma (n=11), the response rate was 54.4%, and median PFS and OS were 6 and 16 months, respectively. For patients with intrahepatic bile duct tumors (n=16), the response rate was 21.4%, and median PFS and OS were 2.5 and 14.5 months, respectively.


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Table 4. Best response and survival data

 
In group B, all patients had measurable disease. According to the investigators' assessment, one patient had a complete response, four had a partial response, seven had stable disease and 11 had disease progression, giving a response rate of 22% (95% CI 6.5–37.4%). Median PFS and OS were 3.9 and 7.6 months, respectively. The 1-year actuarial survival rate was 31%. Efficacy data are shown in Table 4.


    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study examined a cohort of 56 consecutive patients with advanced or metastatic biliary tract carcinoma. They were divided into two subgroups: group A had the usual inclusion criteria for phase II studies, while group B included patients who would normally be excluded from such studies. Response rates and survival times obtained in group A patients compare favorably with previous results for phase II ABTA with other chemotherapeutic regimens. Table 1 summarizes published data from clinical trials including at least 10 patients.

However, caution must be exercised when comparing results from different studies, since clinical prognostic parameters may be more important in ABTA than differences between therapeutic regimens. In phase II ABTA studies, inclusion criteria are very heterogeneous and comparison of results may therefore be inappropriate. ABTA includes a heterogeneous group of patients with primary tumors in the gallbladder, intrahepatic bile ducts, extrahepatic bile ducts and ampulla, and also patients with liver metastases from an unknown primary site. Indeed, for tumors in the intrahepatic bile ducts, diagnosis of primary biliary tract origin cannot be made by imaging or surgical exploration. After an exhaustive and negative search for the primary site (using chest radiography, thoracic and abdominopelvic CT scan, colonoscopy, oesophageo-gastroduodenal endoscopy, prostate-specific antigen determination for men and mammography for women, and a positron emission tomography scan if possible), it is difficult to know whether the primary tumor arose in the intrahepatic bile duct or at some other site. For ABTA, and especially for carcinomas of the intrahepatic bile ducts, immunostaining of cytokeratins 7, 19 and 20 can help histological examination. If cytokeratins are 7 +, 20– and 19 +, this suggests a diagnosis of adenocarcinoma of the bile ducts [30Go]. In our study, response rates seem better for patients with gallbladder tumors than for those with carcinomas of the intrahepatic bile ducts (54.4% versus 21.4% response in group A). This is in accord with data from other studies, and underlines the difficulty of interpreting ABTA results from small studies. Future studies should include a precise description of results by tumor site, to determine whether this affects the outcome for patients with ABTA.

Results from group B indicate that GEMOX has some activity even in patients with a poor prognosis who have received previous chemotherapy. Tolerability of GEMOX in group B did not differ significantly from that in group A patients, indicating that this combination is safe in patients with a poor prognosis or pretreated by chemotherapy.

The best available chemotherapy for ABTA remains to be determined. Data from small, phase II studies suggest that gemcitabine monotherapy represents an active and well tolerated treatment option [24Go]. However, others use 5-FU and leucovorin with or without cisplatin [1Go, 6Go–8Go]. A European Organization Research for Treatment of Cancer phase III study comparing 5-FU and leucovorin with or without oxaliplatin is planned.

We conclude that, while we still need to elucidate the respective contributions of oxaliplatin and gemcitabine when given as a fixed-rate infusion, the GEMOX combination is active in patients with ABTA. In this population, a favorable toxicity profile is of great importance, and our study also indicated that GEMOX was safe and well tolerated. An international, confirmatory phase II study is ongoing.


    Acknowledgements
 
Oxaliplatin was supplied by Sanofi-Synthelabo. Preliminary results were presented as a poster during the 2003 meeting of the American Society of Clinical Oncology [31Go].

Received for publication March 31, 2004. Revision received May 2, 2004. Accepted for publication May 5, 2004.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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