A phase II study of single-agent docetaxel in patients with metastatic esophageal cancer

K. Muro1,*, T. Hamaguchi1, A. Ohtsu2, N. Boku2, K. Chin3, I. Hyodo4, H. Fujita5, W. Takiyama6 and T. Ohtsu7

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


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

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 1–2 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) 10–34%] 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 6.6–11.3) and the 1-year survival rate was 35% (95% CI 21–48%).

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


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
In the USA, 13 200 new cases of esophageal cancer were diagnosed in 2001, and >90% of patients (12 500) died of their disease, comprising 2% of all cancer deaths [1]. The incidence of esophageal cancer is on the rise, with more cases of adenocarcinoma of the esophagus being reported as compared with squamous cell carcinoma. This phenomenon is a common trend in most Western countries [2]. In Japan, 9991 patients died of esophageal cancer in 1999, accounting for 3.4% of Japanese cancer deaths, which was the sixth leading cause of death in Japanese males. However, in contrast to the West, squamous cell carcinoma is still the most common histological type of esophageal cancer in Japan [3].

Surgery alone as the standard treatment in the management of locally advanced esophageal cancer shows a poor prognosis, with 5-year survival rates of 5–30% [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 25–35% response rate in metastatic disease. However, complete responses are rare, median duration of response is generally short, median survival is only 6–10 months [5, 1012] and toxicity of cisplatin-based chemotherapy is often substantial. New combination regimens such as paclitaxel–cisplatin–5-FU [8, 13] and irinotecan–cisplatin [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].


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Inclusion criteria
Each patient was required to meet the following eligibility criteria: histologically proven esophageal cancer; measurable metastatic lesions assessed by Response Evaluation Criteria in Solid Tumors (RECIST) [20]; no more than one prior chemotherapy regimen; an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; age 20–74 years; adequate baseline bone marrow function (hemoglobin level ≥9 g/dl, white blood cell count ≥4000/mm3 and ≤10 000/mm3, neutrophil count ≥2000/mm3 and platelet count ≥100 000/mm3); adequate hepatic function (total bilirubin level ≤1.5 mg/dl, and aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase levels ≤2.5x the upper limit of normal); adequate renal function (serum creatinine level ≤1.5 mg/dl); adequate respiratory and cardiac function (PaO2 ≥60 mmHg, normal ECG); a life expectancy of at least 2 months; and written informed consent.

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 Institute–common toxicity criteria (NCI–CTC) version 2.0 [21]; edema grade ≥2 (NCI–CTC); 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 1–2 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 {alpha} 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 20–24 patients were enrolled. If none of the first 20–24 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 20–24 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 Kaplan–Meier method was used to estimate the overall survival curves. Survival time was censored at the last confirmation date if the patients were alive.


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient characteristics
Of the 52 patients enrolled in the study from 14 hospitals in Japan between May 2000 and February 2002, the majority were male. Three patients never received docetaxel due to worsening condition after enrollment, and were excluded from the analysis. Thus, 49 patients with metastatic esophageal cancer were evaluable for both the response and toxicity analyses. Patient baseline characteristics are listed in Table 1. The most common histological type seen was squamous cell carcinoma (94%), with lymph nodes (61%) as the main target site of metastases. Ninety per cent of the patients had undergone at least one prior anticancer treatment modality (surgery, chemotherapy, radiotherapy and/or chemoradiotherapy). Prior chemotherapeutic regimens were mostly comprised of 5-FU and platinum combinations.


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Table 1. Baseline patient characteristics (n = 49)
 
Response and survival
Response results are summarized in Table 2. There were no complete responses and response rates by both RECIST and WHO criteria were comparable. Ten of the 49 evaluable patients [20%; 95% confidence interval (CI) 10–34%] achieved partial responses using RECIST and 12 (24%; 95% CI 13–39%)partial responses by the WHO criteria. Of the 10 partial responses by RECIST, six patients (60%) had prior history of platinum-based treatment. The response rates in patients with prior chemotherapy and with no prior chemotherapy were 16% (six of 38) and 36% (four of 11), respectively. The response rates in target sites of metastases by RECIST were 25% (four of 16) in lung, 18% (two of 11) in liver and 20% (six of 30) in lymph nodes. The duration of response ranged from 1.5 to 14.7 months and the median duration of response was 4.7 months by RECIST. Stable disease and progressive disease were each observed in 19 patients (39%). The survival of 49 evaluable patients is shown in Figure 1. With a median follow-up duration of 7.8 months, the median survival time was 8.1 months (95% CI 6.6–11.3) and the 1-year survival rate was 35% (95% CI 21–48%).


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Table 2. Response in assessable patients (n = 49)
 


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Figure 1. Overall survival for all 49 patients eligible for the study.

 
Toxicity
Docetaxel was generally well tolerated. Hematological and non-hematological toxicities are summarized in Table 3. The most common and severe, but reversible, toxicity of docetaxel on this schedule was neutropenia. Leucocytopenia (grade 3 and 4) and neutropenia (grade 3 and 4) occurred in 36 (73%) and 43 (88%) patients, respectively. Grade 4 leukopenia and grade 4 neutropenia occurred in 12 (24%) and 36 (73%) patients, respectively. Nine patients (18%) developed febrile neutropenia. Dose reductions occurred in 18 of 49 patients (37%) and 53 of 171 courses (31%). The relative dose intensity was 0.893. Lenograstim was given to 28 of 49 patients (57%) and in 99 of entire 171 courses (58%). The median time to the nadir of the neutropenia was 9 days. The median time from the nadir to recovery (≥2000/mm3) was 6 days when using lenograstim, as compared with 10 days without lenograstim. Anemia and thrombocytopenia were infrequent and mild.


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Table 3. Toxicity in assessable patients
 
The non-hematological toxicities were generally mild. Anorexia and fatigue were the most common non-hematological toxicities. Grade 3 anorexia and fatigue occurred in nine (18%) and six (12%) patients, respectively.


    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The present investigation was undertaken to assess the activity and tolerability of docetaxel, administered once every 3 weeks at a dose of 70 mg/m2, in metastatic esophageal cancer. Single-agent docetaxel in this group of patients demonstrated a response rate of 20–24%, with stable disease observed in 31–39% of patients using the RECIST and WHO criteria. Neutropenia was the most common adverse event, but was well managed with lenograstim.

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 75–100 mg/m2 in second-line treatment of esophageal cancer has demonstrated overall response rates of 18–28% [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 70–90 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 75–100 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.


    Acknowledgements
 
This study was supported by a grant from Aventis Pharma Ltd.


    FOOTNOTES
 
* Correspondence to: Dr K. Muro, Division of Gastrointestinal Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Tel: +81-3-3542-2511; Fax: +81-3-3542-3815; E-mail: kmuro{at}ncc.go.jp Back


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 Results
 Discussion
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