Gastric cancer (GC) is the fifth most common malignancy and third leading cause of cancer related deaths worldwide. Highest rates of incidence are seen in Eastern Asia, Eastern Europe and South America. In Asia the highest incidences are seen in China, Japan and Korea [1] [2]. In India, the north eastern region of Mizoram has the highest rates followed by Chennai, Bangalore and Hyderabad. The Incidence is lesser in Northern Indian as compared to the South [3]. Gastric cancer demonstrates familial aggregation in approximately 10% of cases and an inherited genetic predisposition in a small proportion (approximately 1% - 3%) [2] [3] [4]. Locally advanced gastric cancer (LAGC) includes AJCC/UICC stage II and stage III patients. About two-thirds of patients are diagnosed with LAGC at diagnosis which leads to significant morbidity and mortality [5] [6].

The role of chemotherapy in gastric cancer (GC) is constantly evolving to improve outcomes and reduce toxicity. Currently several acceptable chemotherapy approaches are available for management of LAGCs namely adjuvant (post-operative chemotherapy), peri-operative (pre and post-operative) and the most recent being neo-adjuvant chemotherapy (pre-operative chemotherapy). Several chemotherapeutic agents are used in treatment of GC namely platinum based compounds (Cisplatin, Oxaliplatin), fluoropyrimidines like 5-Flurouracil (5-FU) and Capecitabine, taxanes (Docetaxel) and anthracyclines (Epirubicin). Triplet regimens are more effective than doublet regimens for LAGCs. Some of the most commonly used triplet regimens are Epirubicin and Docetaxel based regimens The landmark FLOT-4 trial, a multi-centric randomized phase-3 trial conducted by Al Batran et al. compared docetaxel-based triplet FLOT (modified DOF) with Anthracycline-based triplet Epirubicin, Cisplatin, and 5-Fluorouracil or Capecitabine (ECF/ECX) as perioperative treatment for patients with resectable gastric or GEJ cancers. Perioperative chemotherapy with Docetaxel, Oxaliplatin, and 5-Fluorouracil (FLOT) significantly improved Progression-Free Survival (PFS) and Overall Survival (OS) among patients with resectable gastric cancers compared with ECF/ECX. Of 716 patients enrolled, 360 patients received ECF/ECX and 356 patients received FLOT. After a median follow up of 43 months, median OS was 35 months with ECF/ECX and 50 months with FLOT (hazard ratio, 0.77; P = 0.012). Perioperative complications were similar across the 2 arms: 50% with ECF/ECX and 51% with FLOT. More cases of grade 3/4 nausea and vomiting were seen with ECF/ECX and more cases of grade 3/4 neutropenia were seen with FLOT [7].

Despite data on improved overall survival and better compliance, DOF as NACT remains an experimental approach in India owing to limited number of studies conducted in India. As most DOF based trials have shown positive outcomes in the West and China, these results cannot be generalized due to population heterogeneity, difference in tumor characteristics and guidelines [8] [9]. Hence further evaluation of efficacy and safety of Neoadjuvant DOF regimen in Indian population would aid in optimizing treatment guidelines for LAGC. The present study was done to assess safety and efficacy of DOF regimen as Neoadjuvant chemotherapy in Locally Advanced Gastric Cancers.

This was a prospective, observational study. 50 newly diagnosed patients of Locally Advanced Gastric Cancer (stage II or III) assessed in our hospital from September 2016 to September 2017 deemed fit to receive chemotherapy were included in the study after taking prior informed consent. Fitness was determined by ECOG (Eastern Co-operative Oncology Group) Performance Status. Only those patients with ECOG ≤ 2 were enrolled in the study. Patients with an ECOG > 2, early or metastatic disease and those who underwent upfront surgery were excluded. A baseline PET-CT scans/CT scan was done for all the patients. Clinical Staging was recorded at baseline based on radiology reports.

Neoadjuvant chemotherapy (NACT) is now used worldwide as initial therapy for treating LAGC and operable gastric cancer. It has shown improvement in survival when compared to surgery alone [10] [11]. In our study we evaluated the efficacy and safety profile of patients who received neo-adjuvant chemotherapy with DOF regimen. We broadly categorized the toxicities into hematological, gastrointestinal and others.

The most common hematological toxicities observed in our study included

anemia (cycle 1: 58% cycle 2: 60%; cycle 3: 66% Overall: 61.2%), neutropenia (cycle 1: 22% cycle 2: 50%; cycle 3: 56% Overall 42.6%,), thrombocytopenia (cycle 1: 8%, cycle 2: 10%; cycle 3: 20% Overall: 13.2%) and febrile neutropenia (cycle 1: 0%, cycle 2: 8%, cycle 3: 10% Overall: 6%). The hematological toxicity profile of DOF regimen reported by Liu M et al. included anemia (50%), neutropenia (44.8%), thrombocytopenia (36.2%) and febrile neutropenia (10.3%). This was comparable to our study except a lower incidence of thrombocytopenia and febrile neutropenia [12]. The slightly higher percentage of anemia in our study can be partly attributed to lower baseline hemoglobin levels [13]. The hematological toxicity profile of DOF regimen reported by Yao Z et al. included anemia (80%), neutropenia (84%), thrombocytopenia (22%) and febrile neutropenia (18%) [8]. The lower percentage of anemia, neutropenia and febrile neutropenia in our study could be due to lower doses of Docetaxel and Oxaliplatin used in our study. The most common Gastro-Intestinal [GI] toxicities observed in our study included nausea (cycle 1: 62% cycle 2: 76%; cycle 3: 70% Overall: 69.2%), vomiting (cycle 1: 22% cycle 2: 44%; cycle 3: 28% Overall 31.2%), diarrhea (cycle 1: 38% cycle 2: 34%; cycle 3: 30% Overall: 34%), abdominal pain (cycle 1: 28%, cycle 2: 26%, cycle 3: 30% Overall: 28% ) and oral mucositis (cycle 1: 14%, cycle 2: 18% cycle 3: 12% Overall: 14%). A study done by Van Cutsem E et al. showed GI toxicities as follows: nausea (59%), vomiting (35%), diarrhea (67%), abdominal pain (22%), and oral mucositis (33%) [14]. These findings suggest that our study had lesser incidence of diarrhea, oral mucositis and constipation.

There was a steady increase in the number of patients who developed neutropenia and anemia with each cycle of DOF. This could be attributed to dose related cumulative toxicities of the component drugs which gradually increase with each cycle. Unlike hematological toxicities, the gastrointestinal adverse effects did not show an increasing trend with each cycle. This may be due to better GI tolerability of the DOF regimen in Indian patients. GI tolerability is one of the important factors which influence patient compliance to chemotherapeutic regimens and thus influence the effectiveness of therapy [14] [15].

The other common toxicities observed in our study included fatigue (cycle 1: 66% cycle 2: 86%; cycle 3: 90% Overall: 80.6%), alopecia (cycle 1: 26% cycle 2: 72%; cycle 3: 76% Overall 58%) and peripheral neuropathy (cycle 1: 16%, cycle 2: 34 %, cycle 3: 40% Overall: 30%). Retrospective studies show a slightly higher incidence of fatigue, peripheral neuropathy and alopecia in docetaxel based regimens [16]. In a study by Yao Z et al., the frequency of alopecia and peripheral neuropathy was 56% and 58% respectively. The lower incidence of neuropathy in our study can be explained by modified doses of oxaliplatin, lesser number of patients with diabetes and lesser number of chemotherapy cycles used [17]. These adverse effects were managed and did not require dose modifications.

PR was achieved in 68% and SD in 28% of patients. ORR [CR + PR] achieved in our study was 68% which is similar to the ORR achieved in a study by Wang Z et al. at 66.6% [18]. The ORR achieved in our study was higher than most other studies namely Yao Z et al. and Liu M et al. which showed ORR of 42.2% and 50% respectively [8] [12]. Our study had increased Response Rates [ORR and DCR] as compared to other studies. This could be attributed to higher number of patients with good Performance Status in our study [ECOG 1 = 82%] when compared to study by Yao Z et al. [ECOG = 60%], more number of patients < 60 years [60%] resulting in better tolerability of chemotherapy which is reflected by lesser dose modifications [28%] when compared to Yao Z et al. [64%, [8] [19] ].

The DFS and PFS [Disease Free Survival and Progression free survival] in our study were 9.1 months and 14.2 months respectively which is higher compared to other studies. A study done by Satheesh et al. reported a median PFS of 9 months and a similar study done by Liu M reported a median PFS 8.2 months [12] [20]. The patients in our study were entirely LAGC where as other studies included both LAGC and metastatic patients. It is well known that patients with good performance status at baseline [ECOG 0 and 1] have better survival [19]. In our study most of the patients had an ECOG performance status of 1 [82%].

In our study the pathological CR [pCR] rates was 17.5% which is similar to studies by Al Batran et al. who reported a pCR of 18% [7]. Our study found a statistically significant difference in DFS in those who achieved pCR (11.46 months) compared to those who did not (8.53 months), P < 0.05. Several other studies have shown similar positive co-relation between pCR and survival [21] [22] and [23].

Several studies achieving ypN₀ disease status showed an improved survival when compared to residual lymph node disease. In a study done by Ikoma N et al., 59% of patients achieved ypN₀ status and these patients had better survival than those with ypN + status [24] [25] [26]. In our study ypN₀ status was achieved in 42.5% of patients and they had better DFS [10.27 months] compared to those who did not [8.14 months] which was statistically significant (P value < 0.005).

Studies have shown that patients achieving pathological nodal down staging have better DFS compared to those who did not achieve nodal down staging, whereas pathological tumor down staging does not appear to provide any survival benefit [26] [27]. In our study there was a statistically significant survival benefit [P value < 0.05] in patients achieving nodal down staging [10.02 months] as compared to those who did not [7.23 months]. Survival benefit was not statistically significant with respect to tumor down staging.

Our study was mainly limited due to small sample size and a single arm design.

Our study shows that the DOF regimen can be an effective and feasible option as NACT in the management of patients with LAGC in an Indian population. The safety profile of DOF regimen was favorable with majority of patients tolerating the regimen well. The Overall Response Rates, Disease Control Rates and Resectability Rates were higher compared to western studies. Pathological CR, ypN₀ status and nodal down staging, all showed positive correlation with survival outcomes. Further evaluation of DOF regimen with multi-centric studies involving large population in Indian settings would be needed to validate the outcomes and thus aid in effective management of patients with LAGC.

Ethical approval was obtained from the institution ethics committee.

The authors declare no conflicts of interest regarding the publication of this paper.

Kulkarni, V., Thungappa, S.C., Patil, S., Sarathy, V., Krishnamurthy, K.P., Kumar, R. and Naik, R. (2020) Safety and Efficacy of Neoadjuvant DOF [Docetaxel, Oxaliplatin, 5-Fluorouracil] Chemotherapy Regimen in Patients with Locally Advanced Gastric and Gastro-Esophageal Junction Cancers: A Single Center Experience from India. Journal of Cancer Therapy, 11, 237-250. https://doi.org/10.4236/jct.2020.115020