|Year : 2017 | Volume
| Issue : 1 | Page : 47-51
Efficacy and safety of first-line systemic chemotherapy with epirubicin, cisplatin plus 5-fluorouracil and docetaxel, cisplatin plus 5-fluorouracil regimens in locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma: A prospective phase II study from South India
KG Babu, T Chaudhuri, KC Lakshmaiah, L Dasappa, LA Jacob, MCS Babu, AH Rudresha, KN Lokesh, LK Rajeev
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
|Date of Web Publication||1-Dec-2017|
Dr. T Chaudhuri
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
BACKGROUND: Patients with locally advanced inoperable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma have a poor prognosis. The maximum benefit of systemic chemotherapy is usually achieved in the first-line setting. Even though systemic chemotherapy has been used for long time, in view of unsatisfactory results, no standard regimen has been emerged. Unfortunately, till date, there is no published prospective data from India, comparing the two most commonly used triplet regimens, epirubicin, cisplatin plus 5-fluorouracil (ECF) and docetaxel, cisplatin plus 5-fluorouracil (DCF), in this patient population. MATERIALS AND METHODS: The present study aimed to compare the efficacy and safety of the first-line systemic chemotherapy with ECF and DCF regimens in locally advanced inoperable or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was overall survival (OS). The secondary endpoints were overall response rate, progression-free survival (PFS), and toxicity profile. RESULTS: Between January 2015 and December 2016, 58 patients were assigned and treated with ECF (n = 30) or DCF (n = 28) regimens. The median OS was 9.4 months with ECF and 12.5 months with DCF regimen (log-rank, P = 0.000), while median PFS was 5.8 and 7.5 months, respectively (log-rank, P = 0.002). Patients in the DCF arm had more frequent reductions in chemotherapy doses than those of the ECF arm (28.6% vs. 16.7%; P = 0.54). As compared with the ECF, the DCF regimen was associated with more frequent Grades 3–4 toxicities-neutropenia (16.7% vs. 39.3%, P = 0.17), febrile neutropenia (13.3% vs. 25%, P = 0.52), mucositis (6.7% vs. 17.8%, P = 0.43), and diarrhea (6.7% vs. 14.3%, P = 0.67). CONCLUSIONS: In comparison to ECF, the DCF regimen was associated with a statistically significant 3.1 months longer median OS without any significant increase in Grades 3–4 toxicities. DCF can be considered as one of the reference regimens, in properly selected patients with advanced/metastatic gastric or GEJ adenocarcinoma.
Keywords: Docetaxel, cisplatin plus 5-fluorouracil regimen, epirubicin, cisplatin plus 5-fluorouracil regimen, gastric cancer, systemic chemotherapy
|How to cite this article:|
Babu K G, Chaudhuri T, Lakshmaiah K C, Dasappa L, Jacob L A, Babu M, Rudresha A H, Lokesh K N, Rajeev L K. Efficacy and safety of first-line systemic chemotherapy with epirubicin, cisplatin plus 5-fluorouracil and docetaxel, cisplatin plus 5-fluorouracil regimens in locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma: A prospective phase II study from South India. Indian J Cancer 2017;54:47-51
|How to cite this URL:|
Babu K G, Chaudhuri T, Lakshmaiah K C, Dasappa L, Jacob L A, Babu M, Rudresha A H, Lokesh K N, Rajeev L K. Efficacy and safety of first-line systemic chemotherapy with epirubicin, cisplatin plus 5-fluorouracil and docetaxel, cisplatin plus 5-fluorouracil regimens in locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma: A prospective phase II study from South India. Indian J Cancer [serial online] 2017 [cited 2020 Mar 29];54:47-51. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/47/219550
| » Introduction|| |
Gastric cancer is the fourth most common type of cancer worldwide, and despite advances in the treatment, it remains the world's second highest cause of cancer-related death. It is often diagnosed at an advanced stage and is a major health problem in many parts of the world. Patients with metastatic disease have a poor prognosis, with a median survival time, if untreated, of 3–5 months., In several randomized trials of best supportive care (BSC) versus chemotherapy, BSC results in median survival of only 3–5 months versus 7–9 months for chemotherapy., Systemic chemotherapy is the mainstay of treatment for these patients, and many drugs are active in the first-line chemotherapy of advanced or metastatic gastric cancer, such as fluoropyrimidines, platinum agents, epirubicin, taxanes, and irinotecan.,, Although the array of chemotherapy agents available for treating gastric cancer is increasing, in view of unsatisfactory results, no consensus has emerged regarding the optimal first-line systemic chemotherapy for advanced disease. In light of the data from different trials, cisplatin and 5-fluorouracil (CF) -based regimens are considered as reference standards.,,, The incremental gain, which could be achieved by addition of a third chemotherapy agent (e.g., epirubicin and docetaxel) with this reference regimen (CF), has been investigated in various studies.,,,
Till date, there is no published prospective study from India, comparing epirubicin, cisplatin plus 5-fluorouracil (ECF) versus docetaxel, cisplatin plus 5-fluorouracil (DCF) regimen in locally advanced inoperable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Clearly, there is a need to compare the efficacy and safety of these two commonly used triplet regimens (ECF and DCF), prospectively in Indian patients with advanced/metastatic gastric or GEJ adenocarcinoma.
| » Materials and Methods|| |
Patients older than 18 years of age were eligible for inclusion in this prospective single-center study if they had histologically confirmed locally advanced inoperable or metastatic adenocarcinoma of the stomach or GEJ; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2; adequate renal, hepatic and hematologic function; and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST). Patients with intraoperatively confirmed intraperitoneal metastases but without detectable disease in radiological studies were also eligible. Major exclusion criteria were previous chemotherapy for metastatic or locally advanced disease, congestive heart failure, concurrent second malignancy, and evidence of brain metastases.
Patients who fulfilled all the eligibility criteria were allocated (1:1) to either ECF or DCF chemotherapy regimen, by alternating assignment. Both the regimens were given every 3 weekly. The ECF regimen consisted of epirubicin 50 mg/m 2 (1-h intravenous infusion) plus cisplatin 60 mg/m 2 (1–2 h intravenous infusion) on day 1, followed by 5-fluorouracil (5-FU) 750 mg/m 2/day (continuous intravenous infusion over 6 h) for 5 days; and the DCF regimen consisted of docetaxel 75 mg/m 2 (1-h intravenous infusion) on day 1, along with CF doses, same as that of the ECF regimen. All the patients also received appropriate hydration, premedication, and primary prophylactic granulocyte-colony stimulating factor (5 μg/kg/day, subcutaneously for 5 days, starting from day 6). Chemotherapy dose adjustments and treatment delays were allowed and were at the discretion of the treating physician. A 25% dose reduction in subsequent cycles was done in patients developing any Grade 4 or life-threatening toxicity. Treatment was continued until disease progression, unacceptable toxicity, death, or patient withdrawal. After the first-line chemotherapy had failed, the second-line chemotherapy was recommended to all the patients if their PS was preserved.
Evaluation and outcomes
Before treatment assignment, a complete evaluation was carried out, including full medical history, physical examination, complete blood count, serum biochemical analysis, electrocardiography, and two-dimensional echocardiography. Baseline tumor assessments, including upper gastrointestinal endoscopy and contrast-enhanced computed tomography (CECT) of the thorax, abdomen and pelvis, were performed within 28 days before treatment initiation. CECT scans were repeated after three and six cycles of primary chemotherapy as a routine departmental strategy. In case of clinical suspicion of disease progression, urgent CECT scans were requested whenever needed and were at the discretion of treating physician. After the active treatment phase of the study, subsequent computed tomography scans have been performed every 12 weeks (± 2 weeks) or whenever needed depending on the symptoms. Responses to chemotherapy were reported according to the RECIST 1.1. The adverse events were classified based on the National Cancer Institute of Canada Common Terminology Criteria for Adverse Events version 4.0. The primary endpoint was overall survival (OS). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and toxicity profile.
Continuous variables were presented as medians and range; categorical variables were presented as counts and percentages. Statistical significance of differences between two independent groups was assessed using t-test for continuous variables and the Fisher's exact test for categorical variables. The Kaplan–Meier method was used to estimate the survival distributions, and survival of two treatment groups was compared using the log-rank test. All statistical analyses have been performed using IBM SPSS version 17.0.
| » Results|| |
Between January 2015 and December 2016, 58 patients were assigned to the first-line triplet chemotherapy (30 in the ECF arm and 28 in the DCF arm), at the Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India. Both the treatment groups were well balanced for baseline characteristics [Table 1]. The median age was 52 years and majority of the patients (63.8%) were male. ECOG PS was determined as ≤1 in most (96.5%) of the patients. Fifty-four patients (93.1%) had metastatic disease at baseline. The most common site of metastases was liver (63.8%) followed by peritoneum (29.3%). Approximately, three-fourth of the patients had ≥2 metastatic disease sites involvement at baseline, mostly involving the liver and peritoneum.
The median number of the first-line chemotherapy cycles received were 5 (range: 3–7) and 6 (range: 3–9) for ECF and DCF regimens, respectively. Dose reductions due to toxicity were more frequent in the DCF arm in comparison to the ECF arm (28.6% vs. 16.7%; P = 0.54), but this difference did not reach statistical significance. The most common adverse events leading to dose reductions and treatment delays were febrile neutropenia, mucositis, and diarrhea. The second-line treatment with docetaxel was given in eight patients (26.7%) of the ECF arm; and irinotecan was administered to three patients (10%) in the ECF arm and five patients (17.8%) in the DCF arm. Overall, five patients (two patients of ECF arm and three patients of DCF arm) received third-line chemotherapy with capecitabine.
Efficacy and survival
The ORR in the ECF group was 26.7% (0% complete response [CR] and 26.7% partial response [PR]) versus 46.4% (3.6% CR and 42.8% PR) in the DCF group (P = 0.31). Stable disease rates were 36.7% and 32.1%, respectively (P = 0.99). The median PFS was 5.8 months (95% confidence interval [CI]: 4.7–6.8) with ECF and 7.5 months (95% CI: 6.2–9.7) with DCF regimen (log-rank, P = 0.002) [Figure 1], while median OS was 9.4 (95% CI: 7.9–10.7) and 12.5 (95% CI: 11.2–15.8) months, respectively (log-rank, P = 0.000) [Figure 2]. Multivariate analysis showed that patient characteristics including gender, site of primary tumor, and site and number of metastatic sites had no significant impact on survival or response to chemotherapy.
|Figure 1: Kaplan–Meier estimates of progression-free survival (in months) of the patients treated with epirubicin, cisplatin plus 5-fluorouracil and docetaxel, cisplatin plus 5-fluorouracil regimens|
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|Figure 2: Kaplan–Meier estimates of overall survival (in months) of the patients treated with epirubicin, cisplatin plus 5-fluorouracil and docetaxel, cisplatin plus 5-fluorouracil regimens|
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The majority of hematological and nonhematological adverse events were of Grades 1 and 2 [Table 2]. The most frequent Grades 3–4 adverse events in both the groups were neutropenia, febrile neutropenia, mucositis, and diarrhea. As compared with the ECF, the DCF regimen was associated with more frequent Grades 3–4 toxicities - neutropenia (16.7% vs. 39.3%, P = 0.17), febrile neutropenia (13.3% vs. 25%, P = 0.52), mucositis (6.7% vs. 17.8%, P = 0.43), and diarrhea (6.7% vs. 14.3%, P = 0.67); however, none of the differences were statistically significant.
| » Discussion|| |
In the early 1980s, the FU, doxorubicin, and mitomycin regimens were accepted as the gold standard regimen for patients with metastatic gastric cancer. Subsequently, in a study carried out by Webb et al., 274 patients with metastatic esophagogastric cancer were randomly assigned to receive either ECF or fluorouracil, doxorubicin, and methotrexate (FAMTX). The patients treated with ECF had a significantly longer median OS (8.9 months vs. 5.7 months, P = 0.0009), superior ORR (21% vs. 45%, respectively), and superior median time to progression (TTP) (3.4 vs. 7.4 months, respectively) than the FAMTX group, leading the investigators to propose ECF as a standard chemotherapy regimen. This was the first phase III trial, which established the efficacy and safety of ECF regimen in metastatic gastric cancer. Subsequently, multiple randomized studies have compared various FU-based regimens and of all the combination regimens, ECF is probably the most widely used and the best validated regimen.,, In a meta-analysis, Wagner et al. showed an improvement in weighted average survival of approximately 2 months with addition of anthracycline to CF regimen.
Among the newer cytotoxic agents with potential activity in advanced and/or metastatic gastric cancer, docetaxel has been of considerable interest. It has been shown to be active alone ,, and in combination with other agents.,,,, In a randomized phase II trial, Roth et al. evaluated two docetaxel-based regimens (DC and DCF) to see which would be most promising according to ORR for comparison in a phase III trial with ECF as first-line advanced gastric cancer therapy. In that study, ORR favored DCF over DC for further evaluation, and a trend toward increased myelosuppression and infectious complications with DCF versus DC was observed.
The addition of DCF regimen improved survival of gastric cancer patients compared to CF alone in V325 trial. This multinational phase III trial randomized 445 patients with untreated advanced gastric cancer to receive either DCF or CF. TTP for patients who received DCF was significantly longer than that of patients treated with CF (5.6 months vs. 3.7 months; P < 0.001). Moreover, the median OS was also longer with DCF versus CF (9.2 months vs. 8.6 months; P = 0.02; 23% risk reduction). High toxicity rates were reported in this trial, especially involving febrile neutropenia, which was more common in patients who received DCF (29% vs. 12%).
Our study comparing two three-drug combination systemic chemotherapy regimens in advanced/metastatic gastric or GEJ adenocarcinoma showed that DCF chemotherapy compared to ECF was associated with a 1.7-month longer median PFS and 3.1-month longer median OS, which were statistically significant. There were no statistically significant differences in Grades 3–4 toxicity between the study arms; however, this lack of significance might be resulted from the small number of patients. This study has several other limitations also. First of all, this was a single-center nonrandomized study restricted to patients treated only in our department. Second, because of logistic issues, reassessment CECT studies were performed every 2–3 months in accordance with our routine departmental strategy; therefore, there might be bias in the PFS assessment.
| » Conclusions|| |
At present, there is no one universal first-line systemic chemotherapy regimen for the treatment of patients with advanced/metastatic gastric and GEJ carcinoma. This prospective study comparing two triplet chemotherapy regimens in locally advanced inoperable or metastatic gastric or GEJ adenocarcinoma showed that DCF chemotherapy compared to ECF was associated with a 3.1-month longer median OS, without any significant increase in Grades 3–4 toxicity. In our opinion, DCF can be considered as one of the reference regimens, in properly selected patients with advanced/metastatic gastric or GEJ adenocarcinoma. Clearly, these findings need further validation through large prospective randomized trials from other centers, comparing these two triplet regimens.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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