Japanese Journal of Clinical Oncology 31:275-278 (2001)
© 2001 Foundation for Promotion of Cancer Research
Phase II Trial of Outpatient Schedule of Paclitaxel in Patients with Previously Untreated Metastatic, Measurable Adenocarcinoma of the Stomach
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Chemotherapy represents the standard treatment for patients with metastatic stomach cancer. Conflicting results have been published regarding the activity of paclitaxel in this setting. Therefore, we developed a phase II study to evaluate an outpatient 3 h infusion of paclitaxel.
Methods: Patients with chemonaive metastatic stomach cancer received paclitaxel 210 mg/m2 every 3 weeks. Patients with esophageal cancer were not eligible.
Results: Twenty-one patients were enrolled. The median age was 55.5 years (range 37–81 years). Two partial responses were observed among the 18 patients evaluable for response and toxicity (response rate 11%, 95% CI: 2–33%). The median time to progression was 10.5 weeks and median survival 23 weeks. There was only one episode of grade IV neutropenia and no episodes of grade 3–4 non-hematological toxicity were observed.
Conclusion: Paclitaxel exhibited minimal activity in this patient population.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Gastric cancer represents a major cause of cancer death worldwide (1). The prognosis of patients with metastatic disease is poor, with 5-year survival of <5% (1). Chemotherapy represents the standard treatment for these patients (2). The activity of various single agents such as 5-fluorouracil, cisplatin, doxorubicin and mitomycin is ~20% (3–6). In general, combination therapy has been associated with higher response rates than single agents; however, a recently reported prospectively randomized comparison of three frequently used regimens in metastatic gastric cancer did not find any with a response rate >20% (7). New agents and new treatment strategies must be evaluated (8).
The taxane docetaxel has been reported to have activity in advanced gastric cancer (9,10), but paclitaxel has not been thoroughly evaluated in the phase II setting against measurable gastric cancer. Indeed, paclitaxel has significant activity in diverse tumors (11–14). However, its role in gastrointestinal malignancies has not been well defined. We therefore developed a phase II trial to determine the response rate to an outpatient schedule of paclitaxel in patients with stage IV gastric carcinoma. We chose to study a 3 h infusion of paclitaxel because of its ease of administration, patient convenience and data from randomized studies in breast and ovarian cancer which failed to show significant differences in clinical activity between a 3 and 24 h infusion (15,16)
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
Patients eligible for this trial had to have cancer of the fundus and/or body and/or the pre-pyloric regions of the stomach. Patients with esophageal cancers were not eligible. Patients were required to have histologically confirmed metastatic gastric carcinoma and provide written informed consent. In addition, measurable disease was required and patients had to be
18 years of age, have a SWOG performance status 
2 and a life expectancy of at least 12 weeks. Laboratory criteria included an absolute granulocyte count 1500 cells/mm3, platelets 100 000 cells/mm3, hemoglobin 9 g/dl, serum creatinine 2 mg/dl, bilirubin 1.5 mg/dl and transaminases 4 times the upper limit of normal. No prior chemotherapy was allowed. This study was approved by the Institutional Review Board of the University of Southern California.
Treatment Plan
All treatment was administered on an outpatient basis, using standard premedication. Paclitaxel was administered at a dose of 210 mg/m2 infused over 3 h every 3 weeks. Patients were premedicated with dexamethasone 20 mg (orally or intravenous) administered 12 and 6 h prior to treatment, diphenhydramine 50 mg i.v. and cimetidine 300 mg i.v. 30 min prior to therapy. Subsequent doses were modified according to the NCI Common Toxicity Criteria. Briefly, no modification was done for absolute granulocyte count (AGC) 500. In the event of a nadir 500 or neutropenic fever, G-CSF was employed in an attempt to maintain dose intensity. If this degree of neutropenia persisted for more than 7 days or neutropenic fever developed while on G-CSF subsequent doses were reduced to 175 mg/m2. In case of platelet nadir of 25 000–50 000 subsequent doses were reduced to 175 mg/m2, if the platelet nadir was 25 000 or bleeding occurred, the dose was reduced to 150 mg/m2. Changes in dose were not required for non-hematologic (clinical) toxicity grade 0–2. In the event of grade 3 clinical toxicity the dose was reduced one level and in case of grade 4 dose was reduced two levels. Dose escalation to 250 mg/m2 was allowed if the patient experienced no grade 2 or greater toxicity.
Standard response criteria were employed. Objective response was assessed every 4 weeks. A complete response (CR) was defined as complete resolution of disease by physical and radiographic examination, no new lesions and no disease related symptoms. A partial response (PR) was defined as a 50% reduction in the sum of the products of perpendicular measurements of all sites of measurable disease, and progressive disease (PD) as a 25% increase in the sum of the products of the perpendicular diameters of all measurable lesions. Stable disease (SD) was defined as any condition other than objective response or progressive disease. A 6-week duration of response was required to qualify as a responder.
Statistics
A two-stage Simon design was used for patient accrual, in which the accrual would be terminated if the response rate was 2 of 18 patients. A response rate of >2 of 18 patients would extend the accrual to 35 patients. This design has an 
error 0.05 and ß 0.10.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Twenty-one patients were enrolled in this study. One patient was enrolled but did not receive any paclitaxel because her performance status decreased to SWOG 3 prior to the first dose of paclitaxel; two patients were lost to follow-up after receiving only one dose of paclitaxel. Thus, 18 patients were evaluable for toxicity and response.
Patients’ characteristics are presented in Table 1. All the patients were either Hispanic or Asian. The majority were male. The median age was 55.5 years. Most patients had a performance status of 1.
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The total number of administered courses was 78. The median number of courses per patient was 3 (range, 1–14). No patient had a complete response; two patients achieved a partial response (PR) for a response rate of 11% (CI: 2–33%). One of these responders had a proximal gastric tumor and the other had an antral cancer. In addition, five patients achieved stable disease of 3, 3, 4, 4 and 5 months duration. Median time to progression was 10.5 weeks (range, 5–43 weeks) and median survival was 23 weeks (range, 10–74 weeks).
Toxicity
Treatment was well tolerated. No treatment-related deaths occurred. Hematological toxicity was mild. Only one case of grade 4 neutropenia was observed; no episodes of neutropenic fever were recorded. The mean AGC nadir was 2358 (range, 485–5180 ). No patient had thrombocytopenia.
Common clinical (non-hematological) toxicities were alopecia (all patients), peripheral neuropathy, arthralgia/myalgia and nausea or vomiting (Table 2). However, no patients experienced any grade 3 or 4 non-hematological toxicity.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Deciding upon a standard chemotherapy regimen for patients with disseminated gastric cancer has been a difficult exercise. Although randomized studies have shown an improvement in survival when combination chemotherapy is compared with best supportive care (17,18), it has not been possible to define a specific regimen that leads to enhanced overall survival or advances the prognosis of patients with disseminated gastric cancer. Therefore, it seemed appropriate to test a relatively high-dose, every 3-week schedule of paclitaxel for patients with disseminated, measurable gastric cancer. The importance of the duration of infusion was suggested by a non-randomized study reported by Ajani et al. (19). In this trial the first 15 patients were treated with a 3 h infusion regimen. The response rate was only 8%. The 18 subsequent patients were treated with a 24 h infusion and the response rate was 23% (19).
The precise role of paclitaxel in gastrointestinal tumors is still uncertain. Indeed, paclitaxel has apparent activity in patients with esophageal carcinoma where a response rate of 23% was observed using a 24 h infusion (20). However, studies in colorectal (21), pancreatic (22) and biliary (23) carcinomas showed disappointing results.
Some studies have reported that paclitaxel, as a single agent, has modest clinical activity against disseminated, gastric cancer (19,24), while another study showed no activity (25). As mentioned, the study by Ajani et al. (19) suggested that the duration of infusion was important in determining activity in stomach cancer. However, the ECOG study showed a lack of activity when using a 24 h infusion. Despite these conflicting data, paclitaxel is frequently employed as part of multiagent chemotherapy regimens or in combination with radiation (26–28). These reports may be overestimating the contribution of paclitaxel to the reported response rates. Docetaxel, however, may be a more active taxane against disseminated gastric cancer than paclitaxel. Docetaxel shares a common mechanism of action with paclitaxel. However, preclinical data suggests more activity compared with paclitaxel (29) and available clinical data suggest incomplete cross-resistance between these taxanes (30).
While it is possible that our results were influenced by the specific gastric cancer histology and/or molecular biology that is exhibited by Asian and Hispanic patients, our report on gastric cancer preoperative chemotherapy for patients of similar ethnic background indicated that 5-fluorouracil and cisplatin were relatively effective in causing primary tumor response (31). In conclusion, our study shows that at this dose and schedule, paclitaxel has minimal activity against disseminated gastric carcinoma. Because of this limited activity, the risk and benefits of paclitaxel should be carefully addressed in the management of stomach cancer. Furthermore, these results suggest that combining paclitaxel with other agents in the treatment of disseminated gastric cancer is not likely to be a fruitful exercise.
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FOOTNOTES |
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+ For reprints and all correspondence: Agustin A. Garcia, Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, MS 34, Los Angeles, CA 90089-9173, USA. E-mail: aagarcia@hsc.usc.edu
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Received November 6, 2000; accepted February 23, 2001.
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