1 University of Chicago Section of Hematology/Oncology and University of Chicago Cancer Research Center, Chicago, IL; 2 The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
Correspondence to: Dr A. M. Mauer, University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA. Email: amauer{at}medicine.bsd.uchicago.edu
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Abstract |
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Patients and methods: Thirty-five patients with recurrent or metastatic esophageal adenocarcinoma or squamous cell carcinoma were enrolled. Up to one prior chemotherapy regimen was allowed. All patients had bi-dimensionally measurable disease. Patients received oxaliplatin 85 mg/m2 as a 2-h infusion on day 1. Leucovorin (500 mg/m2) followed by fluorouracil bolus (400 mg/m2) and 22-h continuous infusion fluorouracil (600 mg/m2) was administered on days 1 and 2. Granulocyte colony stimulating factor was not routinely administered unless the patient developed febrile neutropenia or prolonged neutropenia. Treatment was repeated every 14 days.
Results: Of the thirty-five patients enrolled, all were evaluated for toxicity and 34 were evaluated for response. The overall response rate was 40% (95% confidence interval, 24% to 57%) with complete and partial response rates of 3% and 37%, respectively. The median response duration was 4.6 months, and the median overall survival was 7.1 months. One-year survival was 31%. The major toxicity noted was cumulative neutropenia, with 29% developing grade 4 toxicity. There was one treatment-related death secondary to neutropenic sepsis. The most common non-hematologic toxicity encountered with this regimen was cumulative peripheral neuropathy, with 26% experiencing grade 2 or 3 toxicity.
Conclusions: The combination of oxaliplatin, leucovorin, and fluorouracil shows significant anti-tumor activity and a favorable toxicity profile in patients with metastatic carcinoma of the esophagus.
Key words: oxaliplatin, fluorouracil, leucovorin, esophagus cancer
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Introduction |
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Oxaliplatin is a novel antineoplastic platinum derivative that has a more favorable toxicity profile than cisplatin [7]. At therapeutic doses, it is less emetogenic, nephrotoxic, ototoxic and myelosuppressive than cisplatin. In phase I trials, the dose-limiting toxicity of oxaliplatin was a cumulative sensory peripheral neuropathy. Oxaliplatin also produced an acute neurotoxicity distinct from the neuropathy noted with other platinum compounds. This unique neurotoxicity was characterized by a rapid onset that is precipitated by exposure to cold with regression between treatment cycles [8
].
In preclinical studies, oxaliplatin demonstrated antitumor activity against multiple tumor cell lines [913
] including some that are resistant to cisplatin and fluorouracil [9
13
]. Oxaliplatin has also shown clinical activity in several solid tumors, including colorectal [14
16
], lung [17
], ovarian [18
], pancreatic, and head and neck cancer [19
]. Based on preclinical studies indicating that the combination of oxaliplatin and 5-fluorouracil exhibits synergy, clinical trials were undertaken to investigate the combination in colorectal [13
], gastric [20
], and breast cancer [21
]. In phase II trials exploring various doses and schedules of oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin [22
27
], the regimen demonstrated significant activity and good tolerability, where the predominant toxicities were neutropenia and peripheral neuropathy. We report results of a multi-institutional phase II study to test the efficacy of oxaliplatin and fluorouracil/leucovorin in patients with metastatic carcinoma of the esophagus and gastric cardia. The regimen utilized was based on the FOLFOX4 regimen [27
, 28
].
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Patients and methods |
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Treatment
Protocol treatment was delivered in the outpatient setting. Oxaliplatin 85 mg/m2 was administered as a 2-h intravenous (i.v.) infusion on day 1. Leucovorin 500 mg/m2 i.v. was administered as a 2-h infusion followed by fluorouracil (400 mg/m2) as an i.v. bolus immediately followed by fluorouracil (600 mg/m2) as a 22-h continuous infusion on days 1 and 2. Prophylactic antiemetic support with ondansetron 24 mg and dexamethasone 20 mg was administered prior to each oxaliplatin dose. Prophylactic granulocyte colony stimulating factor was not routinely administered unless the patient developed febrile or prolonged neutropenia. Treatment cycles were administered every 14 days. Patients were counseled to avoid exposure to cold liquids or air because the acute neurotoxicity encountered with oxaliplatin appears to be exacerbated by exposure to cold.
Dose modifications
Dose modification of the oxaliplatin, leucovorin and fluorouracil was specified for myelosuppression, nephrotoxicity, neurotoxicity and hepatic dysfunction. Dose modification for toxicity was based on the worst toxicity observed during the previous course. Therapy was delayed 1 week for inadequate hematologic recovery (absolute neutrophil count <1500/µl or platelet count <100 000/µl) by day 15. For grade 4 neutropenia or thrombocytopenia, the oxaliplatin and fluorouracil doses were reduced 25% in the subsequent cycle. For grade 3 or 4 stomatitis or diarrhea, the doses of oxaliplatin and fluorouracil were reduced by 25% in the subsequent cycle after recovery to baseline. Oxaliplatin doses were reduced by 25% for significant neurotoxicity defined as persistent grade 2 neuropathy or any grade 3 neuropathy.
Assessment of response and toxicity
Patients were monitored biweekly throughout treatment by physical examination and recording of toxic effects. Toxicities were graded according to the NCI Common Toxicity Criteria (CTC) 2.0. A modified CTC sensory neuropathy grading scale and neurologic toxicity grading scale was used for the evaluation of oxaliplatin-associated sensory neuropathies to account for the unique, cold sensitive neuropathy noted with the drug, and for the determination of dose modifications (Table 1). Complete blood counts were performed at least weekly. Serum chemistry and liver function tests were obtained before each cycle of chemotherapy.
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Those patients who achieved stable disease or response after four cycles of therapy continued to receive protocol-specified therapy until disease progression, unacceptable toxicity, or the patient's desire to discontinue therapy. The relative dose intensity was defined as the total dose administered for all cycles divided by the product of the dose administered in cycle 1 and the total number of treatment cycles.
Statistical analysis
The overall response rate (combining CR and PR) was computed using all enrolled patients, and a 95% confidence interval (CI) was constructed based on the binomial distribution but ignoring the multistage nature of the design. Progression-free survival (defined as the time from registration until progression or death from any cause) and survival (also from date of registration) curves were estimated for all enrolled patients using the KaplanMeier method, and approximate 95% CI were computed using the method described by Kalbfleisch and Prentice [29]. Confidence intervals for the median survival times were obtained as described in Brookmeyer and Crowley [30
].
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Results |
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Response
The responses for all patients treated are shown in Table 3. Thirty-two patients completed at least four cycles of therapy and were evaluated using the radiologic parameters described above. Two patients were deemed to have clinical disease progression after less than four cycles of therapy and died while on study. One patient had a treatment-related death before radiologic evaluation. The overall response rate for all 35 patients was 40% (95% CI 24% to 58%). The overall response rate for the patients who were chemotherapy-naïve was 45% (95% CI 27% to 64%). No responses were noted in patients who had received chemotherapy prior to enrollment. Thirteen of the responding patients had tumors with adenocarcinoma and one had adenosquamous histology. One patient with a gastric cardia tumor achieved a partial response. Twenty-six patients (40%) had stable disease as the best response after four or more cycles of chemotherapy.
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The maximum hematologic toxicity experienced by patient is listed by grade of severity for each parameter in Table 4. Overall the hematologic toxicity encountered in patients treated at the recommended phase II dose was tolerable with 29% experiencing grade 4 neutropenia of any duration. One patient developed fatal sepsis while neutropenic. Cumulative thrombocytopenia was noted with this regimen with typical onset after four cycles of therapy. Seven patients developed cumulative myelosuppression that required a dose modification of the oxaliplatin dose.
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Discussion |
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Our phase II experience with oxaliplatin, fluorouracil and leucovorin confirms the feasibility of delivering these drugs at doses that are active in esophageal cancer, with an acceptable level of toxicity. In our trial neutropenia was designated as grade 4 in 29%. In most patients the neutropenia was of no clinical significance; the rate of febrile neutropenia was low at 6%. Of note, the incidence of severe neutropenia was higher than the rates reported for other trials studying the FOLFOX regimens. This difference may be secondary to the higher dose of leucovorin that was utilized in our trial. In addition, the incidence of neutropenia is generally lower for FOLFOX regimens that include infusional fluorouracil without bolus fluorouracil. Remarkable in this trial was the lack of grade 3 or 4 toxicity other than myelosuppression. The predominant non-hematologic toxicity of the regimen, peripheral neuropathy, was moderate in 25% of patients. This low rate of peripheral neuropathy may be due to the limited duration of therapy and short survival times.
This combination regimen demonstrates significant antitumor activity in advanced esophageal cancer and produced an overall response rate of 40% and a median survival time of 7.1 months. The response rate for patients with adenocarcinoma or mixed histology was 44%. The proportion of patients with squamous cell carcinomas enrolled in this trial was low, and this experience is not sufficient to conclude the activity of the regimen in that disease histology. The efficacy of this oxaliplatin, fluorouracil and leucovorin regimen compares favorably with results reported for other cisplatin-based therapies in adenocarcinomas of the esophagus and gasto-esophageal junction [3234
]. Based on the activity and tolerability of this regimen, further investigation of the combination in esophageal cancer is warranted. The combination of oxaliplatin, fluorouracil and leucovorin with a targeted therapy would be of interest. The investigation of oxaliplatin, fluorouracil and leucovorin-based approaches in the preoperative setting should also be undertaken now that there is support for this approach [35
]. Khushalani and colleagues [36
] have demonstrated the feasibility of combining oxaliplatin and fluorouracil with thoracic radiotherapy for advanced esophagus cancer.
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Acknowledgements |
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Received for publication March 4, 2004. Revision received March 21, 2005. Accepted for publication March 22, 2005.
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