Docetaxel, Oxaliplatin with Capecitabine (TEX Regimen) in Metastatic Gastric and Gastroesophageal Adenocarcinoma: A Prospective Single-Arm Observational Study from a Tertiary Cancer Center in Kashmir

Abstract Background  Metastatic gastric and gastroesophageal adenocarcinoma (MGGEAC) is a challenging disease with limited treatment options. The Taxotere, Eloxatin, and Xeloda (TEX) regimen has shown promising results in several clinical trials. There exists a dearth of data pertaining to the efficacy and tolerance of the treatment approach in the populace of Kashmir. Methods  This study was performed at the Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir. Patients with MGGEAC received treatment with biweekly TEX regimen that included docetaxel 50 mg/m 2 -D1, oxaliplatin 85 mg/m2-D1, and capecitabine 1250 mg/m 2 /day, twice daily orally, for 14 days. The effectiveness of the regimen was assessed based on the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), along with the prognostic factors, safety, and tolerability of the regimen. Results  The ORR was 63.5% after four cycles. The median PFS and OS were 9.1 and 13 months, respectively. Univariate and multivariate analysis showed that a higher number of sites of metastases is associated with poor PFS. The TEX regimen was well tolerated. The most observed grade 3 to 4 toxicities were neutropenia (36.7%), anemia (20%), fatigue (20%), and febrile neutropenia (16.7%). Conclusion  Using the TEX regimen in MGGEAC showed better response rates and a slightly longer PFS. A higher number of sites of metastases is a poor prognostic factor in MGGEAC, as seen in our study. The toxicity profile shows that the regimen is tolerable. We recommend a randomized controlled study comparing CapeOx with TEX to test this regimen further.


Introduction
Globally, gastric cancer accounts for 5.7% of new cases (5th most common) and 8.7% of deaths due to cancer per year (3rd most common). 1 Nonmetastatic gastric and gastroesophageal junction adenocarcinoma are managed by combined therapeutic modality (surgery, chemotherapy, and radiotherapy). 2 The 5-year overall survival (OS) of localized gastric cancer is 31% that has remained stable over the last three to four decades. 3Metastatic disease has an extremely poor prognosis with a 5-year OS of less than 5%. 2 According to Globocan 2020, gastric cancer is the sixth most common cancer in India.India has a yearly estimate of 68,000 new cases of gastric cancer, which leads to around 50,000 deaths. 4,5Kashmir has a high incidence of gastric cancer (4th most common), accounting for 7.6% of all cancers and it exceeds the national average in India. 6,7The metastatic disease is managed primarily by palliative intent chemotherapy with surgery and radiotherapy reserved for selected indications.Systemic chemotherapy results in better response rates, slightly prolonged survival, and improved quality of life. 8][11] However, due to its high cost, chemotherapy remains the standard of care for patients in low-middle income countries like India.Platinum and 5-fluorouracil (5-FU)/analogue combination is considered the gold standard first-line regimen in this setting.The DCF regimen (docetaxel, cisplatin, 5-FU) slightly improves response rate and survival, but with higher toxicity, it provides an additional option for physically fit patients. 12,13To reduce the toxicity, while maintaining the efficacy, different regimens were tried.5][16] The modification of this regimen with the substitution of 5-FU with capecitabine (Taxotere, Eloxatin, and Xeloda [TEX] regimen) has been tested by many investigators. 8,14,17,18n Kashmir, the diagnosis and treatment of MGGEAC are often challenging due to limited healthcare resources; however, efforts are being made to improve the management of these cancers in the region, including the development of specialized cancer centers and increased access to screening and diagnostic services. 6Overall, MGGEAC represents a significant burden of disease in Kashmir, and improving awareness, prevention, and treatment strategies for these cancers in the region is a critical public health priority.
The aim of our prospective observational study is to assess the effectiveness, safety, and tolerability of the TEX regimen in treating MGGEAC in the Kashmir region.The study seeks to assess the ORR, PFS, and OS of patients with MGGEACtreated with this regimen.This information can guide clinical practice and contribute to evidence-based treatment guidelines for patients with MGGEAC.

Patient Selection
This prospective observational study was conducted in MGGEAC patients registered at Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu & Kashmir from November 2017 to December 2018.Patients who had been newly diagnosed with MGGEAC or were developing metastatic disease after receiving definitive treatment with radical surgery and chemoradiation, and who fulfill the following inclusion criteria, were included in the study.Inclusion criteria were (1) age more than 18 years and less than 70 years, (2) Eastern Cooperative Oncology Group (ECOG) performance status less than 2, (3) no prior palliative chemotherapy, and (4) measurable disease and sufficient renal, hepatic, and bone marrow function.However, patients with uncontrolled medical illness, psychiatric illness, and pregnant or lactating women were excluded from the study.

Study Design and Treatment Protocol
Eighty-five patients were enrolled in the study.History with clinical examination was performed before enrolment.Baseline complete blood count, blood chemistries, electrocardiogram, and serum tumor markers (Carcinoembryonic antigen (CEA), CA19-9) were analyzed.All the enrolled patients underwent Oesophagogastroduodenoscopy (OGD) scopy and histopathological confirmation of disease.A contrast-enhanced computed tomography (CECT) scan of the thorax, abdomen, and pelvis was performed 2 weeks before starting the treatment.After enrolment, patients received the TEX regimen as follows: docetaxel 50 mg/m 2 (1 hour infusion), followed by oxaliplatin 85 mg/m 2 (2 hours infusion) on day 1, and capecitabine 1250mg/m 2 /day twice daily for 14 days by oral route.The cycle was repeated every 14 days.Administration of prophylactic treatments, such as antiemetics and corticosteroids, was based on standard recommendations and physician assessment.Granulocyte colony-stimulating factor was used for secondary prophylaxis.Treatment continued as long as the disease progressed, there was unacceptable toxicity, or the patient refused treatment.Dose modifications were performed according to published guidelines.

Assessment of Response and Tolerability
The patients were evaluated for their response to chemotherapy after each treatment cycle.They underwent a CECT scan after completing four cycles of chemotherapy or earlier if the physician deemed it necessary.The scans were evaluated by at least two observers and confirmed by an independent radiologist.The assessment of radiological response was determined using the RECIST 1.1 criteria. 19esults were stratified as complete response (CR), partial response (PR), stable disease, or progressive disease.The period of PFS was calculated from the commencement of chemotherapy until the first indication of disease progression or death.In the absence of any such events, the last follow-up date was considered as the end-point for PFS measurement.The OS period was calculated from the beginning of chemotherapy until the patient's death due to any cause, or until the last follow-up date if the patient was still alive.Toxicity assessments were conducted in each cycle using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0.OS and PFS were further evaluated with univariate and multivariate analyses.A prognostic score proposed by Chau et al, which includes ECOG performance status more than or equal to 2, SAP levels more than 100, presence of peritoneal metastases, and presence of liver metastases were calculated and patients were divided into three groups (no risk factors, one or two risk factors, 3 risk factors). 20

Statistical Analysis
The utilization of descriptive statistics, such as median, frequency, and percentage, was employed to depict categorical variables encompassing age, gender distribution, treatment, and response to treatment.All patients were assessed for the ORR, which was expressed as a percentage and considered as the primary end-point.The secondary endpoints were PFS, OS, and safety.PFS and OS were evaluated using Kaplan-Meier survival methods, whereas univariate and multivariate comparisons analysis was done by log-rank test.IBM SPSS version 20.0 (SPSS Inc.Chicago, Illinois, United States) was used for statistical analyses.

Patient Demographics
The study enrolled a total of 85 patients between November 2017 and December 2018.The data from 85 patients diagnosed with gastric (n ¼ 61) and gastroesophageal junction (n ¼ 24) adenocarcinomas who underwent treatment with the TEX regimen was analyzed.Her2 neu tested positive in 8 out of 38 biopsy samples (►Table 1).

Efficacy
Median number of chemotherapy cycles delivered was eight cycles (1-15).After completion of four cycles of the TEX regimen, we evaluated a total of 85 patients and found that one of them achieved a CR, which corresponds to a percentage of 1.2%.Additionally, 53 patients showed a PR, representing a percentage of 62.4%.Thus, ORR was 63.5% (54/85).In 21 patients (24.7%), the disease remained stable.In addition, only 10 patients (11.8%) showed progressive disease (►Table 2).Maintenance capecitabine was received by 32 patients (37%) after getting a favorable response on the TEX regimen.Upon progression, 62% of patients (33/53) received second-line chemotherapy.The most common second-line chemotherapy used was single-agent irinotecan (70%).
Having observed clinical responses of the tumor against the TEX regimen after four cycles, next, we evaluated PFS and OS as secondary end-points of our study.The median followup period was 10.5 (3-27) months.The duration of median PFS was noted to be 9.1 months (standard error: 1.15, 95% confidence interval [CI]: 6.84-11.23 months).Similarly, the median OS noted was 13 months (standard error: 1.53; 95% CI: 10.01-15.99months; ►Fig. 1).A Prospective Observational Study of TEX Regimen in Metastatic Gastric and Gastroesophageal Adenocarcinoma Puthiyottil et al.

Univariate Analysis of OS and PFS with Prognostic Factor Score
In the univariate analysis, a single metastatic site had shown better progression-free survival (PFS), which retained significance in multivariate analysis (8.5 vs. 2.7 months; p-value 0.035).ECOG performance status, presence of nonregional lymph nodal disease, and capecitabine maintenance had significant effects on PFS in univariate analysis, whereas none of these factors showed significance in multivariate analysis.For OS, capecitabine maintenance had shown significance in univariate analysis, but not shown significance in multivariate analysis (►Tables 3 and 4).

Assessment of Safety Profile
Next, we checked for TEX regimen safety and tolerability.Neutropenia was the most observed grade ¾ toxicity (36.7%).Anemia and fatigue were the second most common toxicity, affecting 20% of the participants.Febrile neutropenia and

Discussion
Systemic treatment in MGGEAC aimed to improve survival, pain control, quality of life, and nutritional intake.The Cochrane meta-analysis 13 showed that systemic chemotherapy improves median survival and response rate compared with placebo.The combination chemotherapy regimen is superior to single-agent chemotherapy in terms of survival and response rate with slightly increased toxicity. 21There is no ideal first-line chemotherapy regimen, which could be either a doublet of a platinum agent with 5-FU/analogue, or a triplet of docetaxel combined with platinum and 5-FU/analogue.The selection is based on patient performance status, general health, comorbid illnesses, and patient preference. 22ocetaxel-based triplet regimens for advanced gastric cancer have become more common following the results of the V-325 trial of Van Cutsem et al 2006, which concluded that the use of DCF resulted in improved clinical outcomes and survival compared with only CF regimen, 14 but with higher frequency of adverse events (82% severe neutropenia, A Prospective Observational Study of TEX Regimen in Metastatic Gastric and Gastroesophageal Adenocarcinoma Puthiyottil et al.A Prospective Observational Study of TEX Regimen in Metastatic Gastric and Gastroesophageal Adenocarcinoma Puthiyottil et al. 29% febrile neutropenia and 49% severe gastrointestinal adverse events).
Stein et al 18 conducted a study which revealed that the TEX regimen resulted in an overall response rate (ORR) of 43%.The study also found that the median PFS was 6.9 months, and the OS was 13 months.The most common higher grade toxicities were diarrhea (30%), nausea/vomiting, and infections.
Van Cutsem et al 14 randomly assigned patients with MGGEAC into three arms-TE, TEF, and TEX.ORR, median PFS, and median OS in the TEX arm were 25.6%, 5.55 months, and 11.30 months respectively.Febrile neutropenia was reported in 9% (TEX) of patients.Other toxicities were similar across the arms.
Our study is prospective, and to the best of our knowledge, it is the largest study to feature the TEX regimen in the region of Kashmir.We reported a higher ORR (63.5%) and better median PFS (9.1 months) in comparison with published literature.Median OS (13 months) was comparable. 8,14,15,18,28,29Single site of metastases had shown better PFS in our study.
Neutropenia and anemia of grade ¾ were noticed in 36.7 and 20% of patients, respectively.Additionally, only 16.7% of patients had febrile neutropenia.These toxicities are comparable with other studies of FLOT and TEX regimens and much lesser compared with the DCF regimen.Additionally, the incidence of nonhematological toxicities was lower compared with the modified DCF regimen 23,24 and was comparable with other studies of FLOT and TEX regimen. 8,14,15,18,28,29These findings suggest that the TEX regimen may be associated with a lower risk of certain toxicities, making it a potentially viable treatment option for patients with MGGEAC.
Merits of our study were prospective nature, real-world setting, adequate patient numbers, daycare delivery of chemotherapy, avoidance of peripherally inserted central catheter line and its complications, lesser toxicity, and better response rates.This is the first study from Jammu and Kashmir, supporting the use of the TEX regimen.
The limitations of the study were primarily observational nature, shorter follow-up, and no comparison arm.We did not use trastuzumab in this study because it is not combined with three-drug regimens in other trials.

Conclusion
In MGGEAC, the TEX regimen gives superior response rates and numerically higher PFS.A higher number of sites of metastases is a poor prognostic factor in MGGEAC, which has been seen in our study.The trial needs a longer follow-up for updated results, and we recommend a randomized controlled study comparing CapeOx with TEX to test this regimen further.

Ethics
The Ethical Standards by the Institutions and National Research Committee, Helsinki Declaration of 1964, and subsequent amendments or equivalent standards have been complied with for all procedures undertaken in this study.The study was approved by the Institutional Ethics Committee of SKIMS, Soura, Jammu & Kashmir (Protocol number 65/2018 dated 07.07.2018), and conducted in compliance with protocol after written informed consent to participate in the study was taken from all patients before enrolment.

Funding
This work had no specific funding.A Prospective Observational Study of TEX Regimen in Metastatic Gastric and Gastroesophageal Adenocarcinoma Puthiyottil et al.

Table 1
Patient dispositions and demographics Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.

Table 2
Tumor response to Taxotere, Eloxatin, and Xeloda (TEX) regimen after completion of four cycles Indian Journal of Medical and Paediatric Oncology © 2024.The Author(s).

Table 3
Univariate and multivariate analyses of PFS

Table 5
Adverse events Indian Journal of Medical and Paediatric Oncology © 2024.The Author(s).