Epirubicin, cisplatin and docetaxel combination therapy for metastatic gastric cancer

L. Di Lauro1,*, F. Belli2, M. G. Arena3, S. Carpano1, G. Paoletti1, D. Giannarelli4 and M. Lopez1

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


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Docetaxel is a new agent with activity in metastatic gastric cancer. This phase II study was designed to evaluate the activity and safety of an epirubicin, cisplatin and docetaxel combination in patients with this disease.

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 5–7) and the median overall survival was 11.2 months (95% CI 8.5–13.9). 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


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Despite the decline in the incidence of gastric cancer observed in Western industrialized countries over the past few decades, this tumor remains the fourth most common cancer worldwide and the second leading cause of cancer-related death [1Go]. The only potentially curative treatment for localized gastric cancer is surgery. Unfortunately, the majority of patients have locally advanced or metastatic disease at presentation, which precludes resection. Systemic chemotherapy is often used in these patients, since it has been associated with a significantly superior median survival and a better quality of life in comparison with best supportive care alone [2Go].

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 [2Go]. Thus, new chemotherapy protocols are needed in order to achieve better treatment results.

Several new drugs including irinotecan [3Go, 4Go], oxaliplatin [5Go, 6Go], capecitabine [7Go] and taxanes [8Go] 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 [9Go]. In several phase II studies in patients with advanced gastric cancer, docetaxel as single agent has produced response rates ranging from 17% to 24% [10Go], and an overall response rate of 37.2% to 56% with a median survival of 9–10.4 months have been achieved when docetaxel is combined with cisplatin (DC) [11Go, 12Go]. Furthermore, a synergic effect has been reported with the combination of docetaxel and epirubicin in both gastric cancer [13Go] and other malignant diseases [14Go]. 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 24–48 h before the expected nadir of docetaxel, according to the kinetics of human granulopoiesis following treatment with G-CSF [15Go].


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
Patients with gastric adenocarcinoma with measurable distant metastasis not previously treated by systemic chemotherapy were enrolled onto the study. Adjuvant chemotherapy without cisplatin or docetaxel was allowed if completed at least 6 months before. The patients were required to have measurable disease according to the RECIST criteria [16Go]. Other eligibility criteria were: Eastern Cooperative Oncology Group performance status ≤2, a life expectancy >3 months, age between 18 and 75 years, adequate bone marrow (absolute neutrophil count ≥1500/µl, platelet count ≥100 000/µl), renal (serum creatinine ≤1.5 mg/dl) and liver (serum bilirubin ≤1.5 mg/dL) functions, a normal cardiac function, absence of second primary tumor other than non-melanoma skin cancer or in situ cervical carcinoma, no CNS involvement, no prior radiotherapy in parameter lesions, and no concurrent uncontrolled medical illness. The protocol was approved and carried out according to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines, and all patients gave their written informed consent to participate in the trial.

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 [16Go]. 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 [17Go]. 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 Kaplan–Meier method, and were updated to 30 April 2005.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients characteristics
From February 2001 to October 2003, 46 patients with metastatic gastric cancer were entered onto this multicenter trial. All patients were evaluable for efficacy and toxicity. The pretreatment characteristics of patients are listed in Table 1. None of the patients had previously received chemotherapy for advanced disease; six patients had received adjuvant chemotherapy without cisplatin or docetaxel several months before they entered this study (median 17 months; range 8–29).


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Table 1. Patient characteristics

 
Response
Among 46 assessable patients, we observed two (4.35%) complete responses (CRs) and 21 (45.65%) partial responses (PRs), for an overall response rate of 50% [95% confidence interval (CI) 36% to 64%]. Disease remained stable in 13 (28.26%) patients (Table 2). Responses according to predominant site of disease were as follows: liver, 17 of 30 patients (57%); nodes/peritoneum, four of 12 patients (33.3%); lung, one of two patients; and bone, one of two patients. Noteworthy is the case of a 66-year-old man with a locally advanced gastric cancer and two secondary hepatic lesions who achieved a clinical CR after six cycles of chemotherapy. At surgery, no tumor was found in the liver by intraoperative ultrasound, and gastrectomy specimen was pathologically free of tumor cells. This patient is now free of disease 34 months after surgery. Response rates did not differ significantly according to number of metastatic sites: one site, seven of 13 patients (54%); two sites, 12 of 23 patients (52%); and three or more sites, four of 10 patients (40%). Responses were seen in two of six patients (33%) who received adjuvant chemotherapy and in 21 of 40 patients (52.5%) who were chemotherapy-naïve. Responses also were detected in 14 of 28 patients (50%) with primary tumor not resected and in nine of 18 patients (50%) with primary tumor resected. Median TTP was 6 months (95% CI 5–7) and median OS was 11.2 months (95% CI 8.5–13.9) (Figure 1). One-, 2- and 3-year survivals were 43.5%, 17.4% and 8.9%, respectively. Forty-two patients had died at the time of the present evaluation. Thirty of the 41 patients (73%) who had tumor-related symptoms before therapy showed an improvement in at least one of their symptoms without worsening of any other symptom.


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Table 2. Objective response in 46 patients

 


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Figure 1. Overall survival for all patients, and 1-, 2- and 3-year survival.

 
Toxicity
Hematological toxicity data are listed in Table 3. A total of 252 cycles of ECD regimen were analyzed in 46 patients, with a median of six cycles administered per patient (range one to eight). The most important toxicity was myelosuppression, which occurred almost always on day 7 (docetaxel nadir), including grade 4 neutropenia in 13% of patients and in 7% of cycles; grade 3 neutropenia was observed in 33% of patients and in 20% of cycles. Five episodes of febrile neutropenia occurred in four (8.7%) patients. In these patients a 25% dose reduction of docetaxel was required, whereas treatment was postponed in three (6.5%) patients and in eight (3%) cycles because of a delay in bone marrow recovery. Mean epirubicin, cisplatin and docetaxel dose intensities were 16.13, 19.36 and 18.41 mg/m2/week, respectively, which are equivalent at 96.8%, 96.8% and 92.1% of the planned dose intensities for all drugs. Grade 3 thrombocytopenia was observed in 7% of the patients, and grade 3 anemia occurred in 13% of the patients. Non-hematological toxicities are listed in Table 4. Alopecia was universal. Mild nausea and vomiting was encountered in 52% of the patients, and was severe in four (9%) patients. Mucositis was of grade 3 in three (6.5%) patients. Grade 3 diarrhea was detected in one patient. Mild and transient peripheral neurotoxicity was recorded in 39% of the patients. Mild fluid retention due to docetaxel administration was seen in 24% of the patients. Hypersensitivity reactions, which did not preclude chemotherapy continuation, were recorded in 6% of patients. No cardiotoxicity or treatment-related deaths were observed.


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Table 3. Grade 3/4 hematotoxicity per cycle and per patient

 

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Table 4. Non-hematological toxicity in 46 patients

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of this study show that the combination of epirubicin, cisplatin and docetaxel is an active and well tolerated regimen as first-line chemotherapy for metastatic gastric cancer. Treatment results are particularly important considering that 65% of the patients had liver involvement, and primary tumor was not resected in 61% of the patients. The overall response rate of 50% with a median TTP of 6 months and an OS of 11.2 months are in agreement with those reported in a smaller Korean study using the same drugs in this tumor type [18Go]. Nevertheless, it should be considered that more patients in our study had liver involvement (65% versus 37%), whereas hematological toxicity was more frequently encountered in the Korean study, requiring a reduction of epirubicin dose.

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 [19Go, 20Go]. 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 [21Go, 22Go].

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 [23Go]. Recently, preliminary results of a phase II randomized study evaluating the activity of the DCF, DC and ECF regimens have been reported [24Go]. 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.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74–108.[Abstract/Free Full Text]

2. Wöhrer SS, Raderer M, Hejna M. Palliative chemotherapy for advanced gastric cancer. Ann Oncol 2004; 15: 1585–1595.[Abstract/Free Full Text]

3. Bleiberg H. CPT-11 in gastrointestinal cancer. Eur J Cancer 1999; 35: 371–379.[CrossRef][ISI][Medline]

4. Kohne CH, Thuss-Patience P, Catane R et al. Final results of a phase II trial of CPT-11 in patients with advanced gastric cancer. Proc Am Soc Clin Oncol 1999; 18: 258a (Abstr 993).

5. Louvet C, André T, Tigaud JM et al. Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol 2002; 20: 4543–4548.[Abstract/Free Full Text]

6. Al-Batran SE, Atmaca A, Hegewisch-Becker S et al. Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol 2004; 22: 658–663.[Abstract/Free Full Text]

7. Koizumi W, Saigenji K, Ujiie S et al. A pilot phase II study of capecitabine in advanced or recurrent gastric cancer. Oncology 2003; 64: 232–236.[CrossRef][ISI][Medline]

8. Van Cutsem E. The treatment of advanced gastric cancer: new findings on the activity of taxanes. Oncologist 2004; 9 (Suppl 2): 9–15.[Abstract/Free Full Text]

9. Crown J, O'Leary M. The taxanes: an update. Lancet 2000; 355: 1176–1178.[CrossRef][ISI][Medline]

10. Roth AD, Ajani J. Docetaxel-based chemotherapy in the treatment of gastric cancer. Ann Oncol 2003; 14 (Suppl 2): 41–44.[CrossRef][ISI]

11. Roth AD, Maibach R, Martinelli G et al. Docetaxel (Taxotere®)-cisplatin (TC): an effective drug combination in gastric carcinoma. Ann Oncol 2000; 11: 301–306.[Abstract]

12. Ridwelski K, Gebauer T, Fahlke J et al. Combination chemotherapy with docetaxel and cisplatin for locally advanced and metastatic gastric cancer. Ann Oncol 2001; 12: 47–51.[Abstract]

13. André T, Louvet C, Ychou M et al. Docetaxel–epirubicin as second-line treatment for patient with advanced gastric cancer. Proc Am Soc Clin Oncol 1999; 18: 277a (Abstr 1062).

14. Pagani O, Sessa C, Nolè F et al. Epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer: A multicentric phase I-II study. Ann Oncol 2000; 11: 985–991.[Abstract]

15. Price TH, Chatta GS, Dale DC et al. Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans. Blood 1996; 88: 335–340.[Abstract/Free Full Text]

16. Therasse P, Arbuck SG, Eisenhauer E et al. New guidelines to evaluate the response to treatment in solid tumours. J Natl Cancer Inst 2000; 92: 205–216.[Abstract/Free Full Text]

17. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10.[ISI][Medline]

18. Lee SH, Kang WK, Park J et al. Combination chemotherapy with epirubicin, docetaxel and cisplatin (EDP) in metastatic or recurrent, unresectable gastric cancer. Br J Cancer 2004; 91: 18–22.[CrossRef][ISI][Medline]

19. Webb A, Cunningham D, Scarffe JH et al. Randomized trial comparing epirubicin, cisplatin and fluorouracil versus fluorouracil, doxorubicin and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997; 15: 261–267.[Abstract/Free Full Text]

20. Ross P, Nicolson M, Cunningham D et al. Prospective randomized trial comparing mitomycin, cisplatin and protracted venous-infusion fluorouracil (PVI-5FU) with epirubicin, cisplatin and PVI-FU in advanced esophagogastric cancer. J Clin Oncol 2002; 20: 1996–2004.[Abstract/Free Full Text]

21. Lacave AJ, Baron FJ, Anton LM et al. Combination chemotherapy with cisplatin and 5-fluorouracil 5-day infusion in the therapy of advanced gastric cancer: a phase II trial. Ann Oncol 1991; 2: 751–754.[Abstract]

22. Rougier P, Ducreux M, Mahjoubi M et al. Efficacy of combined 5-fluorouracil and cisplatinum in advanced gastric carcinomas. A phase II trial with prognostic factor analysis. Eur J Cancer 1994; 30A: 1263–1269.[CrossRef]

23. Moiseyenko V, Ajani JA, Tjulandin SA et al. Final results of a randomized controlled phase III trial (TAX 325) comparing docetaxel (T) combined with cisplatin (C) and 5-fluorouracil (F) to CF in patients (pts) with metastatic gastric adenocarcinoma (MGC). J Clin Oncol 2005; 23 (16S): 308s (Abstr 4002).

24. Roth DA, Maibach R, Falk S et al. Docetaxel-cisplatin-5FU (TCF) versus docetaxel-cisplatin (TC) versus epirubicin-cisplatin-5FU (ECF) in systemic treatment for advanced gastric carcinoma (AGC): A randomized phase II trial of the Swiss Group for Clinical Cancer Research (SAKK). Proc Am Soc Clin Oncol 2004; 23: 317 (Abstr 4020).





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