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

Background: The role of chemotherapy in Gastric Cancer is constantly evolving with various neoadjuvant and adjuvant strategies. Several chemotherapeutic agents are used in the treatment of locally advanced gastric cancer (LAGC) namely Platinum based compounds (Cisplatin, Oxaliplatin), Fluoropyrimidines like 5-Flurouracil [(5-FU), Capecitabine)], Taxanes (Docetax-el) and Anthracyclines (Epirubicin). Various doublet and triplet combination chemotherapy regimens have been used for neo-adjuvant chemotherapy (NACT) in LAGCs. In this study we evaluated the safety and efficacy of docetaxel based triplet regimen DOF [Docetaxel, Oxaliplatin, 5-Fluorouracil] in LAGC. Material and methods: 50 Newly diagnosed patients of Locally Advanced Gastric Cancer (stage II or III) deemed fit to receive chemotherapy were included in our study. After 3 cycles of neoadjuvant chemotherapy, patients were assessed based on radiological and pathological response. Results: 50 Patients were included in our study of which majority were male (32), median age at presentation was 55 years and 24 patients presented with a history of gastrointestinal constipation (6.6%). We found that safety profile of DOF regimen was favorable with majority of patients tolerating the regimen well. The Overall Response Rate (68%), Disease Control Rate (96%) and Resectability Rate (80%) were higher compared to western studies. Pathological CR (17.5%), ypN 0 disease status (42.5%) and nodal down staging (52%), all showed positive corre-lations with survival outcomes. Conclusion: DOF regimen is an effective and feasible option for neoadjuvant treatment of LAGC in an Indian population.


Introduction
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 (postoperative 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.

Materials and Methods
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.

Statistical Methods
The information collected was recorded on a master chart. The Statistical analysis was performed on a computer using SPSS 23.0. In Descriptive statistics, the continuous variables were expressed as Mean and Standard deviation for normally distributed data and median and range for skewed data. Categorical variables were expressed as frequency and percentage. Based on the normality of data, Chi-square was used to find association between the categorical variables and Pearson Co-relation Test was used to find the relationship between two variables. Independent Student t Test was used to find the difference between two groups. One way ANOVA test was used to find the difference between multiple groups. Results were graphically represented where deemed necessary. P < 0.05 was considered as statistically significant. D3] IV infusion over 6 hours. Each patient received 3 cycles of chemotherapy with DOF regimen as mentioned above. In each cycle patients were administered growth factor [Inj Pegylated GCSF 6 mg SC], 24 hours after the end of chemotherapy. Detailed history, physical examination and investigations were done before each cycle. Laboratory results were recorded and the various hematological side effects of chemotherapeutic agents were analyzed. Patients were administered chemotherapy only if considered fit by the treating Medical Oncologist.

Evaluation of the Safety Profile
The grading used was according to CTCAE 4.03 criteria. Adverse effects were assessed before each cycle of chemotherapy and in the event of any patient reported issue.

Dose Modifications
Dose modifications were carried out based on the presence of any grade 3 or grade 4 side effects. 20% dose reductions were made for any grade 3/grade 4 toxicity. If the patient required more than two dose reductions, treatment was discontinued.

Evaluation of Efficacy
At the end of three cycles the patients underwent a PET CT scan/CT scan to assess the response. The response assessment was based on the RECIST 1.1 criteria.

Patient Characteristics
Fifty patients of newly diagnosed locally advanced gastric cancer were administered DOF regimen. The mean age was 55 ± 7.97 years. The number of male patients (n = 32) [64%] was higher compared to females (n = 18, 36%). Number of patients with history of GERD (Gastro-Esophageal Reflux Disease) (n = 24, 48%) was almost similar to those without GERD (n = 26, 52%).
The most common hematological toxicity in 3 rd cycle was anemia seen in 66%  (Table 3).
Dose modifications were required only in 14 (28%) patients. These modifications were done for Grade 3/4 toxicity.

Efficacy Responses as Assessed by PET-CT Scan 1) ORR [Overall Response Rate] and DCR [Disease Control Rate]
In this study we observed an ORR [CR + PR] of 68% and DCR [CR + PR + SD] of 96% which indicated the effectiveness of DOF regimen (Figure 1).

2) Overall Survival (OS) Rate at One Year
The overall survival rate at one year was 88% ( Figure 2). The mean DFS [in months] in patients with or without pCR was 11.46 ± 1.35 and 8.53 ± 2.21 respectively [P = 0.002]. This indicated that patients achieving pCR had better DFS than patients who did not achieve pCR (Table 5).

Discussion
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 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]. 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 neutro-  [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 ypN 0 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 ypN 0 status and these patients had better survival than those with ypN + status [24] [25] [26]. In our study ypN 0 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.

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

Conclusion
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 Resec-tability Rates were higher compared to western studies. Pathological CR, ypN 0 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
Ethical approval was obtained from the institution ethics committee.