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
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Abstract |
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Patients and methods: Consecutive adult patients with confirmed ABTA were recruited from four centers. Those in group A had performance status (PS) 02, 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 34 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
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Introduction |
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Single-agent systemic chemotherapy such as 5-fluorouracil (5-FU) or mitomycin C achieves objective response rates ranging from 10% to 25% [24
]. Systemic polychemotherapies achieve variable response rates, but with consistent toxicity. The more commonly used combined regimens such as FAM (5-FU, adriamycin, mitomycin C) [5
] or 5-FU and cisplatin have provided overall survival (OS) of <1 year [6
8
]. Table 1 summarizes the most relevant results in palliative chemotherapy of advanced biliary tract adenocarcinoma (ABTA) [1
, 3
, 5
, 7
23
].
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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. [26]. 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 gemcitabineoxaliplatin 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 [27
], 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 [28
]. On the basis of these findings, we designed the present study to evaluate GEMOX activity and tolerability in patients with ABTA.
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Patients and methods |
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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 [29]. 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 KaplanMeier method.
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Results |
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Discussion |
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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 [30]. 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 [24]. However, others use 5-FU and leucovorin with or without cisplatin [1
, 6
8
]. 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.
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Acknowledgements |
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Received for publication March 31, 2004. Revision received May 2, 2004. Accepted for publication May 5, 2004.
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References |
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