1 Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo; 2 Division of Gastrointestinal Oncology/Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa; 3 Department of Medical Oncology, Cancer Institute Hospital, Tokyo; 4 Department of Internal Medicine, National Shikoku Cancer Center Hospital, Matsuyama; 5 Department of Surgery, Kurume University School of Medicine, Kurume; 6 Department of Surgery, Hiroshima City Asa Hospital, Hiroshima; 7 Aventis Pharma Ltd, Tokyo, Japan
Received 22 December 2003; revised 8 February 2004; accepted 17 February 2004
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ABSTRACT |
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To evaluate the activity and toxicity of docetaxel in patients with metastatic esophageal cancer.
Patients and methods:
Eligible patients had histologically confirmed carcinoma of the esophagus with measurable metastatic sites according to Response Evaluation Criteria in Solid Tumors (RECIST). Patients were either chemotherapy-naïve or previously treated with one regimen of chemotherapy. Docetaxel 70 mg/m2 was administered intravenously over 12 h, every 21 days.
Results:
Of 52 patients enrolled in this study, three were excluded because they did not receive docetaxel due to worsening condition after enrollment. Thirty-six patients had received prior platinum-based chemotherapy. The majority of patients (94%) had squamous cell carcinoma. Ten of 49 evaluable patients [20%; 95% confidence interval (CI) 1034%] showed a partial response. Of the 10 partial responses, six patients had received prior platinum-based chemotherapy. Grade 3 or 4 neutropenia was noted in 43 of 49 patients (88%), and nine of 49 patients (18%) developed febrile neutropenia. Twenty-eight of 49 patients (57%) required lenograstim. Grade 3 anorexia and fatigue occurred in nine (18%) and six (12%) patients, respectively. Median survival time was 8.1 months (95% CI 6.611.3) and the 1-year survival rate was 35% (95% CI 2148%).
Conclusions:
Docetaxel as a single agent is effective in esophageal cancer, but careful management of neutropenia is needed.
Key words: docetaxel, esophageal cancer, phase II study, RECIST, single agent
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Introduction |
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Surgery alone as the standard treatment in the management of locally advanced esophageal cancer shows a poor prognosis, with 5-year survival rates of 530% [4]. The prognosis is extremely poor, despite treatments with curative intent, because esophageal cancer spreads very quickly to adjacent structures such as the aorta, the trachea and the left main bronchus, and frequently results in lymph node metastases. Therefore, there is a high incidence of residual tumor or recurrence after potentially curative local therapy.
Non-surgical therapies for esophageal cancer include cisplatin, 5-fluorouracil (5-FU), mitomycin C, vindesine [5, 6], paclitaxel [7, 8] and vinorelbine [9]. The combination of cisplatin and continuous-infusion 5-FU is regarded as the standard regimen for both squamous cell carcinoma and adenocarcinoma of the esophagus, with a 2535% response rate in metastatic disease. However, complete responses are rare, median duration of response is generally short, median survival is only 610 months [5, 1012] and toxicity of cisplatin-based chemotherapy is often substantial. New combination regimens such as paclitaxelcisplatin5-FU [8, 13] and irinotecancisplatin [14] have not shown improvement in terms of response and survival compared with cisplatin plus 5-FU. A 5-year survival rate of 27% has been reported with chemoradiotherapy [15]. New agents and therapeutic strategies for esophageal cancer are needed urgently.
Docetaxel has shown extensive cytotoxic activity in animal models, as well as antitumor activity against various common cancers in clinical studies [16]. Clinical trials of single-agent docetaxel have been reported in patients with esophageal cancer [17, 18]; however, these single-agent trials had small sample sizes and the results remain controversial. The present phase II clinical trial investigates the clinical activity and tolerability of docetaxel as a single agent in Japanese patients with metastatic esophageal cancer. The dose of docetaxel used, 70 mg/m2 every 3 weeks, was based on the results of a previous Japanese study [19].
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Patients and methods |
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Exclusion criteria
Exclusion criteria included: active infection; serious complications (severe heart disease, pulmonary fibrosis, interstitial pneumonitis and tendency to bleeding); neuropathy grade 2 by National Cancer Institutecommon toxicity criteria (NCICTC) version 2.0 [21]; edema grade
2 (NCICTC); active concomitant malignancy; symptomatic metastases of the central nervous system; pleural or pericardial effusion or ascites that required drainage; history of drug hypersensitivity; pregnant and lactating females; females of childbearing age, unless using effective contraception; concurrent treatment with corticosteroids; and other serious medical conditions.
Before being enrolled in the study, all patients underwent a physical examination and a complete blood cell count with differential serum chemistry analysis, arterial blood sampling, chest X-ray, ECG and computed tomography scan of the abdomen and other target sites.
Treatment plan
Docetaxel 70 mg/m2 (Taxotere; Aventis Pharma Ltd, Tokyo, Japan) was infused over 12 h. Treatment was repeated every 3 weeks and continued unless there was evidence of disease progression or unacceptable toxicity.
The dose of docetaxel was adjusted according to hematological and other toxicities observed in the previous course. Docetaxel 70 mg/m2 was reduced to 60 mg/m2, if one of the following occurred: grade 4 neutropenia lasting for 5 days or longer; grade 3 neutropenia with fever with a requirement for intravenous antibiotics lasting for 3 days; grade 3 thrombocytopenia lasting
5 days; grade 3 thrombocytopenia with bleeding that required platelet transfusion; and grade 3 non-hematological toxicity other than nausea/vomiting, anorexia, fatigue or hypersensitivity. Lenograstim (Neutrogin; Chugai Pharmaceuticals Co., Ltd, Tokyo, Japan) was administered subcutaneously when grade 4 neutropenia or grade 3 neutropenia with fever occurred. If one of the above toxicities occurred at a dose of 60 mg/m2, docetaxel was discontinued.
No routine premedication for hypersensitivity reactions was given and there was no routine prophylactic administration of antiemetics or granulocyte colony-stimulating factors. When hypersensitivity reactions occurred, docetaxel administration was stopped immediately, and corticosteroids and antihistamines were given. Patients who experienced hypersensitivity reactions were pretreated with these drugs in subsequent courses. Patients who experienced edema or nausea/vomiting were allowed prophylactic administration of corticosteroids or antiemetics, respectively, in subsequent courses.
Criteria for response
Standard clinical measurements and radiological examination were used to assess tumor response according to RECIST. Furthermore, we also used the World Health Organization (WHO) response criteria [22] and a modified criteria of the Japanese Society for Esophageal Diseases [23]. A complete response required disappearance of all evidence of tumor for at least 4 weeks; endoscopic confirmation of no cancer cells was required for patients with primary tumor. A partial response was defined as a >50% reduction in the sum of the longest perpendicular diameters of indicator lesions in WHO criteria, and as a >30% reduction in the sum of the longest diameters of target lesions by RECIST, for a period of at least 4 weeks. Patients were assessed for response every 3 weeks. An independent review committee confirmed the observed responses by radiological and endoscopic examinations.
Statistical methods
The number of patients to be enrolled was planned using a modified multi-stage Fleming design [24] based on an expected docetaxel response rate of 15% and a non-response rate of 5%, with error of 0.05 (one-tailed) and ß error of 0.2. The required number of patients was 44. An interim analysis was planned when 2024 patients were enrolled. If none of the first 2024 patients had a partial or complete response, the trial was to be stopped. If a major objective response was confirmed in any of the first 2024 patients studied, accrual was to be continued to a total of 44.
Overall survival was measured from the start of the treatment to the date of death or the last confirmed date of survival. The KaplanMeier method was used to estimate the overall survival curves. Survival time was censored at the last confirmation date if the patients were alive.
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Results |
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Discussion |
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The response rate of 36% observed in chemotherapy-naïve patients (albeit only 11 patients) is comparable to responses obtained with cisplatin plus 5-FU, the standard treatment in patients with metastatic esophageal cancer. In our study, the response rate of 16% in patients with prior chemotherapy was moderate. Single-agent docetaxel 75100 mg/m2 in second-line treatment of esophageal cancer has demonstrated overall response rates of 1828% [17, 18]. Whereas the phase II trial in France of docetaxel at 100 mg/m2 every 3 weeks as a second-line chemotherapy showed that docetaxel is an effective treatment for metastatic esophageal cancer in pretreated patients, with an overall response rate of 28% [17], the phase II trial in the USA reported that docetaxel at a dose of 75 mg/m2 every 3 weeks was ineffective in pretreated patients with adenocarcinoma of the esophagus [18]. However, these single-agent docetaxel trials were limited by their small sample size (n <25). Most of the patients in the current study had squamous cell carcinoma, whereas, all the patients in other studies had adenocarcinoma [18, 25].
Docetaxel was fairly well tolerated. There were no treatment-related deaths. Grade 3 and 4 neutropenia, which was the most common and severe toxicity, was observed in a majority of the patients, but only one-fifth developed febrile neutropenia. Thirty-seven per cent of patients required dose reductions of docetaxel and 57% were given lenograstim for neutropenia. The median time from the nadir to recovery of neutropenia was reduced to 6 days by using lenograstim, as compared with 10 days without lenograstim.
The present investigation assessed docetaxel at a dose of 70 mg/m2. A previous Japanese phase I trial of docetaxel determined the maximum-tolerated dose to be 7090 mg/m2, with neutropenia as the dose-limiting toxicity [26]. Therefore, the recommended dose of docetaxel for phase II trials in Japan is 60 mg/m2 every 3 weeks, which is lower than the standard dose of 75100 mg/m2 used in Western countries. This difference is based on different criteria for dose-limiting toxicities in clinical phase I trials [27], and not to racial differences in docetaxel pharmacokinetics [28]. The tolerability of docetaxel at a dose of 70 mg/m2 in Japanese population was confirmed by a phase II dose-escalation study in ovarian cancer [19], and consequently the present study was performed at that dose.
The results of this study suggest that single-agent docetaxel 70 mg/m2 every 3 weeks in metastatic esophageal cancer is an effective feasible schedule under careful management of neutropenia. Future studies of docetaxel alone or in combination in locally advanced esophageal cancer are warranted.
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Acknowledgements |
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FOOTNOTES |
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