1 Division of Medical Oncology B and 4 Biostatistics Unit, Regina Elena Institute for Cancer Research, Rome 2 Oncology Service, San Giuseppe Hospital, Albano Laziale 3 Oncology Service, Toraldo Hospital, Tropea, Italy
* Correspondence to: Dr L. Di Lauro, Division of Medical Oncology B, Regina Elena Institute for Cancer Research, Via Elio Chianesi, 53, 00144 Rome, Italy. Tel: +39-06-52666762; Fax: +39-06-52665075; Email: dilauro{at}ifo.it
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Abstract |
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Patients and methods: Forty-six patients with gastric adenocarcinoma with measurable distant metastasis were eligible for the study. Patients received epirubicin 50 mg/m2 and docetaxel 60 mg/m2, on day 1, and cisplatin 60 mg/m2 on day 2. Granulocyte colony-stimulating factor 300 µg/day subcutaneously was given on days 5 and 6. Cycles were repeated every 3 weeks for a maximum of eight courses.
Results: All patients were evaluable for response and toxicity. Two complete and 21 partial responses were observed, with an overall response rate of 50% [95% confidence interval (CI) 36% to 64%]. Stable disease was observed in 13 patients (28%) and progressive disease in 10 patients (22%). The median time to progression was 6 months (95% CI 57) and the median overall survival was 11.2 months (95% CI 8.513.9). Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 46%, 7% and 13% of patients, respectively. There were five episodes of febrile neutropenia in four patients. Other grade 3 toxicities included mucositis in three patients (6.5%), vomiting in four patients (8.7%) and diarrhea in one patient (2%). There were no cardiac toxicity, severe neurotoxicity or treatment-related deaths.
Conclusions: The epirubicin, cisplatin and docetaxel combination is an active and well tolerated novel chemotherapy regimen for treating metastatic gastric cancer and deserves further evaluation in randomized studies.
Key words: cisplatin, docetaxel, epirubicin, metastatic gastric cancer
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Introduction |
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Overall, although gastric cancer is a relatively chemosensitive disease with response rates of 30% to 40%, results of most combination regimens have been unsatisfactory in terms of survival in the advanced setting, and no regimen has emerged as standard in the last few years [2]. Thus, new chemotherapy protocols are needed in order to achieve better treatment results.
Several new drugs including irinotecan [3, 4
], oxaliplatin [5
, 6
], capecitabine [7
] and taxanes [8
] have been demonstrated to be active in this disease. Although taxanes have similar mechanisms of action as antimicrotubule agents and share a number of pharmacologic properties, docetaxel has demonstrated a greater affinity for tubulin and a longer intracellular retention time in comparison with paclitaxel [9
]. In several phase II studies in patients with advanced gastric cancer, docetaxel as single agent has produced response rates ranging from 17% to 24% [10
], and an overall response rate of 37.2% to 56% with a median survival of 910.4 months have been achieved when docetaxel is combined with cisplatin (DC) [11
, 12
]. Furthermore, a synergic effect has been reported with the combination of docetaxel and epirubicin in both gastric cancer [13
] and other malignant diseases [14
]. It seemed thus appropriate to test the activity and toxicity of the combination of epirubicin, cisplatin and docetaxel (ECD) in patients with metastatic gastric cancer. To this purpose, we first performed a phase I study of this combination. The recommended phase II doses were as follows: epirubicin 50 mg/m2 and docetaxel 60 mg/m2 on day 1, cisplatin 60 mg/m2 on day 2 with granulocyte colony-stimulating factor (G-CSF) support on days 5 and 6, with cycles repeated every 3 weeks. The choice of administering G-CSF on days 5 and 6 was to give this agent 2448 h before the expected nadir of docetaxel, according to the kinetics of human granulopoiesis following treatment with G-CSF [15
].
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Patients and methods |
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Treatment
Treatment consisted of epirubicin 50 mg/m2 by intravenous bolus followed, 15 min later, by docetaxel 60 mg/m2 in 500 ml of normal saline as a 1 h infusion on day 1, and cisplatin 60 mg/m2 intravenous with adequate pre- and post-hydration on day 2. Cycles were repeated every 3 weeks. Antiemetic treatment consisted of an antiserotonin agent plus dexamethasone in a 15 min infusion before starting chemotherapy. In addition, oral prednisone premedication was used for prophylaxis of docetaxel-induced hypersensitivity and fluid retention. G-CSF 300 µg subcutaneously was given on days 5 and 6 of each cycle. Treatment was postponed by a maximum of 2 weeks if the absolute neutrophil count was <1500/µl or the platelet count was <100 000/µl. A 25% drug dose reduction was planned in case of grade 4 neutropenic fever (absolute granulocyte count <500/µl at the time of a documented temperature of 38°C or higher), as well as in case of grade 4 mucositis or grade 3 neurotoxicity. Chemotherapy was generally administered on an outpatient basis for a maximum of eight cycles and was discontinued in case of unacceptable toxicity, treatment delay longer than 2 weeks, disease progression or patient refusal.
Pretreatment and follow-up studies
Pretreatment evaluation included clinical history and physical examination, automated blood cell count, biochemical profile, computed tomography of thorax and abdomen, ECG and resting left ventricular ejection fraction (LVEF) determination by echocardiography. Endoscopy was performed only in case of complete remission of all measurable lesions. Blood counts were obtained on days 1, 7, 13 and 20; biochemical profile was repeated every 3 weeks. All measurable parameters of disease were reevaluated every 6 weeks, until the tumor progressed. Cardiac monitoring was performed at baseline with ECG repeated every cycle and LVEF after six cycles.
Evaluation of response and toxicity
Patients were evaluated for response to chemotherapy every two cycles of treatment. Responses were assessed by at least two observers, and were confirmed by an expert independent radiologist. The RECIST criteria were used to evaluate clinical response [16]. Time to progression (TTP) and overall survival (OS) were calculated starting from the date of first chemotherapy cycle to the date of disease progression, death or last follow-up evaluation. Toxicity was assessed in each treatment cycle of therapy using the National Cancer Institute Common Toxicity Criteria (version 2.0).
Statistical considerations
The primary end point of this study was to estimate the overall response rate of the regimen. Secondary end points were TTP, OS and safety. The optimal Simon two-stage phase II design was used to determine the sample size [17]. An interim analysis was carried out when the first 15 assessable patients had been recruited. If more than five responses were observed, 31 additional patients were to be recruited; otherwise, the study was to be terminated. If more than 18 responses were observed in the 46 patients (response rate >39.1%), the regimen was considered sufficiently active with a significance level of 5% and power of 80% to be submitted for further evaluation. TTP and OS were analyzed according to the KaplanMeier method, and were updated to 30 April 2005.
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Results |
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Discussion |
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The results of the present study also compare favorably with those achieved in several trials using the most common combinations in gastric cancer. In two randomized studies using the combination of epirubicin, cisplatin and infusional 5-fluorouracil (5-FU) (ECF), response rates of 45% and 42% with median survivals of 8.9 and 9.4 months have been reported [19, 20
]. When the combination of cisplatin and 5-FU (CF) was used in phase II studies, the response rate was 40%, with a median survival of 9 months [21
, 22
].
In a more recent randomized phase III trial involving 457 patients, the combination of docetaxel 75 mg/m2 plus cisplatin 75 mg/m2 on day 1 plus 5-FU 750 mg/m2/day by continuous intravenous infusion over 5 days every 3 weeks (DCF) was compared with cisplatin 100 mg/m2 on day 1 followed by 5-day infusion of 5-FU 1000 mg/m2/day every 4 weeks (CF). Although DCF was superior to CF in terms of response rates (37% versus 25%), TTP (5.6 versus 3.7 months) and 2-year survival (18% versus 9%), grade 3/4 toxicities occurred in 81% of the patients [23]. Recently, preliminary results of a phase II randomized study evaluating the activity of the DCF, DC and ECF regimens have been reported [24
]. Although the response rate and TTP were higher with the DCF combination, grade 3/4 neutropenia was registered in 76% of the patients. Moreover, since in docetaxel arms febrile neutropenia occurred in 10 of the first 21 patients, a docetaxel dose reduction was required in the remaining patients.
Treatment compliance for the ECD regimen, as administered in our study, was good, since the median relative dose intensities for epirubicin, cisplatin and docetaxel were 96.8%, 96.8% and 92.1%, respectively. As expected, the most important toxicity was myelosuppression, but severe neutropenia was less frequent than that observed in studies using similar regimens. Apart from alopecia, which was universal, other severe side-effects were infrequent.
The lower hematological toxicity observed in the present study might be related to the use of G-CSF, as well as to the administration of comparatively lower doses of both cisplatin and docetaxel. Nevertheless, this apparently did not compromise treatment results. Moreover, although quality of life was not assessed in our study, a clear clinical benefit was observed during treatment with the ECD regimen, as evidenced by the relief of tumor-related symptoms in the majority of the patients. It is also noteworthy that these results were obtained with moderate toxicity, and that chemotherapy was almost always administered on an outpatient basis.
With an activity at least comparable to other studies evaluating commonly used regimens or even more innovative combinations, and an acceptable safety profile, the ECD regimen should be considered an useful treatment for patients with advanced or metastatic gastric cancer. However, to better define the role of this combination in the management of gastric cancer, comparative trials with other active regimens (e.g. ECF, DCF) should be carried out.
Received for publication May 6, 2005. Revision received May 12, 2005. Accepted for publication May 13, 2005.
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References |
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