|Year : 2020 | Volume
| Issue : 3 | Page : 110-114
Survival outcomes with docetaxel, oxaliplatin, and fluorouracil regimen for the treatment of metastatic gastric adenocarcinoma: A single-center experience
Pratik Patil1, Vineet Govinda Gupta1, Ranga Rao Rangaraju1, Waseem Abbas1, Rudra Prasad Acharya2, Archit Pandit2
1 Department of Medical Oncology, Max Super Speciality Hospital, New Delhi, India
2 Department of Surgical Oncology, Max Super Speciality Hospital, New Delhi, India
|Date of Submission||17-Feb-2020|
|Date of Decision||26-Sep-2020|
|Date of Acceptance||05-Oct-2020|
|Date of Web Publication||26-Nov-2020|
Department of Medical Oncology, Max Super Speciality Hospital, Shalimar Bagh, New Delhi - 110 088
Source of Support: None, Conflict of Interest: None
Background: Patients with metastatic gastric adenocarcinoma have a relatively poor prognosis with a median survival of 6 months. The three-drug regimen of docetaxel, oxaliplatin, and fluorouracil (DOF) has been shown to improve survival compared to the two-drug regimen of docetaxel and oxaliplatin with similar toxicity. However, there is no published Indian experience with this regimen. Aim: The aim of this study was to evaluate the efficacy in terms of progression-free survival (PFS) and overall survival (OS) of DOF regimen for metastatic gastric adenocarcinoma patients in Indian settings. Materials and Methods: All patients with metastatic gastric adenocarcinoma who were treated with DOF regimen chemotherapy at our tertiary care center in North India from 2014 to 2018 were retrospectively reviewed. The DOF regimen consisted of docetaxel 50 mg/m2 on day 1, followed by oxaliplatin 85 mg/m2 on day 1, and 5-FU 2400 mg/m2 continuous intravenous infusion over 46 h; (cycle repeated at two weekly intervals until progression or unacceptable toxicity). The endpoints were overall response rate (ORR), PFS, and OS, which were evaluated using Kaplan–Meier analysis. Results: Fifteen patients with a median age of 52 years were identified; 73% were male. ORR was seen in 86.7% of patients (complete response: 20%, partial response: 60%, and stable disease: 6.7%) and progressive disease was seen in 13.3% of patients. With a median follow-up of 14 months, the median PFS was 7 months and the median OS was 16 months from the start of therapy. One-year PFS was 22% and 1- and 2-year OS was 79% and 26%, respectively. The most frequent Grades 3–4 adverse events in our patients being mucositis (33.3%), neutropenia (26.7%), and diarrhea (20%). Conclusion: DOF regimen is an effective and feasible regimen in patients with metastatic gastric cancer.
Keywords: Docetaxel, oxaliplatin, and fluorouracil regimen, metastatic gastric carcinoma, overall survival, progression-free survival
|How to cite this article:|
Patil P, Gupta VG, Rangaraju RR, Abbas W, Acharya RP, Pandit A. Survival outcomes with docetaxel, oxaliplatin, and fluorouracil regimen for the treatment of metastatic gastric adenocarcinoma: A single-center experience. Oncol J India 2020;4:110-4
|How to cite this URL:|
Patil P, Gupta VG, Rangaraju RR, Abbas W, Acharya RP, Pandit A. Survival outcomes with docetaxel, oxaliplatin, and fluorouracil regimen for the treatment of metastatic gastric adenocarcinoma: A single-center experience. Oncol J India [serial online] 2020 [cited 2021 Jan 20];4:110-4. Available from: https://www.ojionline.org/text.asp?2020/4/3/110/301590
| Introduction|| |
Gastric cancer is among the most common causes of cancer-related deaths throughout the world and ranked as the third and fifth causes of deaths due to cancer in men and women, respectively. The highest rate of gastric cancer has been reported in Eastern Europe, Eastern Asia, and South America., The overall survival (OS) remains poor in cases of advanced gastric cancer; the median OS has been reported as approximately 7.5–12 months versus 3–5 months among patients receiving chemotherapy compared with the patients considering the best supportive care alone. Although the results have not been very optimistic, systemic chemotherapy is associated with substantially superior survival and high quality of life compared with supportive care alone.,,
In India, gastric cancer constitutes a major health disease burden and is one of the most common causes of cancer deaths., Although there are advancements in the treatment of gastric cancer worldwide, the advanced disease has a relatively poorer prognosis with a 5-year OS of 14%. The introduction of combination chemotherapeutic regimens, including 5-fluorouracil (5-FU) and platinum has had a survival advantage over the best supportive care. Although optimistic responses have not been proved, a superior OS and better quality of life have been observed with systemic chemotherapy compared to supportive care.
Many new chemotherapeutic regimens have proven efficacy in advanced gastric cancer such as oxaliplatin plus 5-FU and leucovorin, as FOLFOX regimen giving 40%–50% response rate and 10–12 months median OS. Furthermore, docetaxel, cisplatin, and infused 5-FU (DCF) have shown to be more efficacious than historical standard cisplatin and infused 5-FU regimen (CF), but, Grades 3–4 treatment-emergent adverse events have been shown comparatively higher with DCF. The follow-up reports showed a better quality of life and clinical benefit with the DCF regimen., But still, there is a requirement to find effective regimens with reduced toxicity. In combination protocols for advanced gastric cancer, oxaliplatin has shown higher progression-free survival (PFS) rate than cisplatin, with significantly lower incidences of most of the adverse events. In the elderly subset of patients, oxaliplatin showed superior response rate, time to treatment failure, PFS, and better tolerability than cisplatin. This combination of 5-FU and oxaliplatin is studied in several Phase II studies with different doses, schedules, with all having outcomes that were significant and satisfactory., Docetaxel, oxaliplatin, and capecitabine (DOX) regimen has been proved as superior alternative regimen for first-line treatment of advanced gastric cancer compared to DCF regimen. Docetaxel, oxaliplatin, and fluorouracil (DOF) regimen has been shown higher overall response rates (ORRs), disease control rate (DCR), PFS, and OS as compared to FOLFOX regimen with no significant difference in toxicity.
Positive outcomes of most of the DOF regimen-based trials are from Western countries and China. These results cannot be generalized for Indian populations due to population heterogeneity, difference in tumor characteristics, and guidelines., Moreover, DOF regimen chemotherapy is no published Indian experience with this regimen. Hence, further evaluation of efficacy and safety of DOF regimen in the Indian population would aid in optimizing treatment guidelines for advanced gastric cancer. With this background, the present study was conducted to assess the safety and efficacy of DOF regimen in the treatment of metastatic gastric cancers in Indian patients.
| Materials and Methods|| |
All patients with metastatic gastric cancer who underwent treatment at our tertiary care center in North India from 2014 to 2018 were reviewed retrospectively. The patients were included if they met all of the following inclusion criteria: (1) had an age between 18 and 75 years at diagnosis; (2) had histology proven gastric cancer; (3) had metastatic disease; and (4) received treatment with DOF regimen for ≥2 cycles. The patients who had received DOF for <2 cycles were not included in this retrospective analysis.
All of these patients received DOF regimen as docetaxel 50 mg/m2 on day 1, followed by oxaliplatin 85 mg/m2 on day 1, and 5-FU 2400 mg/m2 continuous intravenous infusion over 46 h, with pegylated granulocyte colony-stimulating factor support. The cycle was repeated at every 2 weeks until progression or unacceptable toxicity. Information regarding demographic characteristics, prior treatment, and adverse events was retrieved from the available data. The endpoints were ORR, PFS, and OS. The response was assessed after the fourth cycle and then after every four to six cycles. Therapy was given until progression or unacceptable toxicity.
IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, N.Y., USA) was used for the statistical analyses. OS was defined as a period from the date of the start of chemotherapy to the date of death from any cause. PFS was defined as the time period from the date of the start of chemotherapy to the date of the radiological/clinical progression of disease or death due to any cause. Kaplan–Meier analysis was performed to evaluate OS and PFS. Categorical variables were compared using the Chi-square test or Fisher's exact test when indicated. Predictive factors for OS or PFS were analyzed through Cox regression analysis. All analyses were censored on September 1, 2018.
| Results|| |
Records of 17 patients who met the inclusion criteria were retrieved. From this cohort, two patients violated the inclusion criteria as they had received DOF therapy for <2 cycles; therefore, they were excluded from the study. The remaining 15 patients constituted the study group. The baseline characteristics of these 15 patients are described in [Table 1]. The median age was 52 years within the range of 26–63 years. A majority of patients were male 10 (73.3%). Six (40%) patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) between 0 and 1, 5 patients (33.3%) had ECOG PS 2, and 4 patients (26.7%) had a PS 3. Of the two patients who had received prior chemotherapy, one patient had received capecitabine, and one patient had received capecitabine and oxaliplatin.
Among the 15 patients evaluable for response, 3 patients had complete response, 9 had partial response, 1 patient had stable disease, and the remaining 2 had progressive disease [Table 2].
The median follow-up of the cohort was 14 months. The median PFS was 7 months [Figure 1] and the median OS was 16 months from the start of therapy [Figure 2]. One-year PFS was 22%, and 1- and 2-year OS was 79% and 26%, respectively.
The DOF regimen-induced adverse events are mentioned in [Table 3]. The majority of hematological and nonhematological adverse events were of Grades 1 and 2. The most frequent Grades 3–4 adverse events in our patients were mucositis (33.3%), neutropenia (26.7%), and diarrhea (20%) which is comparable from the studies previously done. All the adverse events were managed with adequate supportive care and no adverse event-related mortality was seen.
| Discussion|| |
Gastric cancer is one of the common malignancies in the Indian population and 40% of the patients are diagnosed at the advanced stage despite the decline rates of incidence and mortality over the past two decades. The prognosis for advanced gastric cancer is not satisfactory, with a 5-year survival rate of <10% and a median OS of <1 year. For patients with metastatic gastric cancer, not suitable for surgery or developed postoperative extensive metastasis, chemotherapy remains the standard of care. The research on advanced gastric cancer has been focused on finding better combination regimens that shall improve the outcomes with the least possible toxicities. This study was conducted to evaluate the efficacy of DOF regimen in Indian patients; DOF regimen data have been published only for other countries' patients before this.
Docetaxel has been proved as an efficacious agent, and in TAX325 study, it has been dictated as a novel option for treating advanced stage gastric cancer with significant efficacy. DCF combination regimen versus CF regimen in the V325 trial, a randomized multinational Phase II/III trial of untreated advanced gastric cancer patients, gave a median time to progression of 2.2 months that were significantly longer than the control arm (P <0.001) and OS advantage of 2 months, with 1-year survival of 40% versus 32%. Although DCF has shown to be more efficacious than CF, Grades 3 and 4 treatment-emergent adverse events have been shown comparatively higher with DCF. A Phase II study of 5-FU, leucovorin, oxaliplatin, and docetaxel regimen reported an improved median PFS of 9 months and OS (median) of 17.3 months in older adults with locally advanced or metastatic stomach or esophagogastric junction cancer. One more Phase II study in advanced gastric cancer patients treated with DOF regimen reported the median OS of >14 months and the duration was substantially higher than to 8–9 months of OS, as reported in previous international multicenter studies. In the combination protocols for advanced gastric cancer, oxaliplatin (+leucovorin and 5-FU) has shown significantly higher 6-month PFS rate than cisplatin (leucovorin + 5-FU; P = 0.024) with significantly lower incidences of most of the adverse events. In the elderly subset of patients, oxaliplatin showed significantly superior response rate, time to treatment failure, PFS, and better tolerability than cisplatin.
To the best of our knowledge, though some studies have been conducted on DOF regimen before the present study, these were conducted in the countries outside India. It is not known whether the DOF regimen is suitable for Indian patients or not. This was the reason to perform this study. This study was conducted in 15 patients with the aim of evaluating the efficacy of DOF regimen in Indian patients with metastatic gastric adenocarcinoma. Among the 15 patients evaluable for response, 20% had complete response, 60% had partial response, 6.7% had stabilized disease, and the remaining 13.3% had progressive disease. The corresponding values in a previous study were 5%, 45%, 41%, and 9%, in which the number of patients was 58 in the DOF group. The variation in the rate of incidences seems due to the small number of patients in the present study.
A study of 97 consecutive advanced gastric cancer patient compared DCF (n = 53) and three modified regimens of DOX (n = 14), DOF (n = 13), and PDF (n = 17). The study reveals no statistical difference among the different treatment groups. Furthermore, a study comparing DOF and FOLFOX in 118 randomized patients showed higher ORRs, DCR, PFS, and OS for DOF as compared to FOLFOX with no significant difference in toxicity. The median OS and PFS in the DOF group were significantly higher than in the FOLFOX group (16.3 vs. 11.2 months and 8.2 vs. 6.4 months; P < 0.001) with acceptable toxicities in both groups. The results in the DOF group are consistent with the results observed in the present study where the median OS was 16 months and PFS was 7 months. Another retrospective analysis of 88 patients comparing DOF (n = 45) and epirubicin, cisplatin, and 5-FU (ECF) regimen (n = 43) showed higher ORR (42.2% vs. 37.3%), tumor control rate (80% vs. 60.6%), median PFS (6.7 vs. 5.0 months), and OS (11.4 vs. 9.8 months) in the DOF group than in the ECF group.
In the above review analysis of all the studies, DOF regimen appears to be an efficacious and safe therapy for advanced/metastatic gastric carcinomas. However, these studies have been performed in the Western population and no Indian data are available till now to conclude the same. It is well known that patients in India have a poorer nutrition profile and chemotherapy tolerance than Western patients. Therefore, we present this study that investigated the efficacy of DOF regimen in the Indian population, which gave a median PFS of 7 months and a median OS of 16 months, which correlates well with the available data on DOF from the international trials as discussed above.
The present study has some limitations such as retrospective study design from a single-center and small number of sample size to draw a significant result.
| Conclusion|| |
The efficacy of the DOF regimen in Indian patients is comparable to that seen in international studies. To conclude, the DOF regimen can be effectively used in Indian patients for the treatment of metastatic gastric adenocarcinoma with good results and may be considered a first-line regimen for this indication. However, our study had small size to draw a significant attention for which further prospective studies with a large sample size are necessary.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]