Stomach cancer is the 5th most commonly diagnosed cancer worldwide and the 5th leading cause of cancer related mortality [1]. It has a cumulative risk of 1.53 in men and 0.67 in women [2]. In India, it is currently the 7th most common cancer and the 6th most common cause of cancer related mortality [2]. It is the 5th most common cancer among males in India and the projected number of cases in 2025 is set to increase by another 3rd [3]. Tamil Nadu contributes significantly to the gastric cancer patient population with an incidence of 12.2/100,000 in men [4]. A significant proportion of gastric cancer patients in India present at an advanced stage with associated gastric outlet obstruction, cancer cachexia and other complications [5]. This in turn adversely affects their ability to undergo multimodality treatment effectively. Despite effective treatments, a large number of completely resected gastric cancers with adequate lymphadenectomy tend to relapse, often at distant sites, suggesting that gastric cancer tends to metastasize early in the course of the disease [5]. Chemotherapy can be given prior to surgery to downstage the tumour and also to treat micro-metastases early. Ever since the MAGIC trial demonstrated the efficacy of perioperative chemotherapy [6], there has been much interest in using neo-adjuvant chemotherapy for the treatment of gastric cancer. The potential advantages of neoadjuvant chemotherapy include increasing the likelihood of curative resection by downstaging the tumour, eliminating micro-metastases, rapidly improving tumour related symptoms, and determining whether the tumour is sensitive to the chemotherapy [6]. There are not yet much Indian studies published regarding the safety and efficacy of chemotherapy for carcinoma stomach. EPIDEMIOLOGY AND PECULIARITIES OF GASTRIC CANCER IN INDIA Worldwide, there is a slow but steady decline in the incidence of gastric cancer which has been attributed to improved food hygiene, sanitation and food preservation processes. But this has not been observed in India [5]. The regional variation in incidence and presentation can be ascertained by the fact that gastric cancer in South Indian males has been reported to be more common and occurring a decade before their North Indian counterparts [7]. Differences in some dietary pattern and use of tobacco and alcohol have been considered as potential risk factors. In a case–control study from Trivandrum, a high consumption of rice and chili, and consumption of high temperature food were found to be independent risk factors for gastric cancer in multivariate analysis [8]. In a study from Hyderabad comparing 94 gastric cancer patients and 100 normal age- and sex matched controls, smoking (P<0.01) and alcohol (P<0.05) were significantly associated with gastric cancer [9]. In another report from Chennai, alcohol consumption and use of pickled food were found independent risk factors for gastric cancer [10]. On the other hand, use of pulses was found to be offering a protective effect. The incidence of gastric cancer in Mizoram has been reported to be the highest in India. The AAR in males and females has been reported at 50.6 and 23.3, respectively [11]. The male-to-female ratio was 2.3:1; the median age for males was 58 years and that for female was 57 years [12]. The high prevalence of gastric cancer in Mizoram has been attributed to dietary and possibly some unknown genetic differences. In another hospital-based study from Kashmir, similar to Mizoram, the incidence was higher in males and the cancer occurred most commonly in the fifth decade of life. The most common site of tumour was the body of stomach (40.7%) followed by the pylorus (35.5%). Salted tea consumption was found to be associated with gastric cancer [17]. Pickled food, high rice intake, spicy food, excess chilly consumption, consumption of high-temperature foods, smoked dried salted meat, use of soda and consumption of dried salted fish have emerged as significant dietary risk factors in various parts of India. These practices are prevalent in Southern and Eastern states of India where a higher frequency of gastric cases are also observed [18-20]. ASSOCIATION WITH H. pylori H. pylori, a Gram-negative bacteria, is associated with gastric mucosal infection. In underdeveloped countries with poor hygienic conditions, 50–90% of the population is infected asymptomatically in childhood. H. pylori has been attributed to cause distal gastric cancers and it is believed that the overall decline in gastric cancers and more so distal cancers worldwide is due to reduction and eradication of H. pylori infection with improved sanitation [14]. In the previous study mentioned from Kashmir, there was no significant association between H.pylori and gastric cancer[13]. A study from North India reported the prevalence of H. pylori infection to be 56.5% in gastric cancer patients [15]. The frequency of Cag-A IgG was found to be more common in the healthy controls (89%) compared to gastric cancer patients (76%) [16]. GENETIC POLYMORPHISMS IN INDIA The traditional molecular genetics and genetic mutations for gastric cancer doesn’t seem to hold good for Indian population. Various epidemiological studies have identified the following genetic polymorphisms to be associated with gastric cancer in India - GSTM1null and CYP2E1c1c2 genotypes, GSTT1 null genotype, C carrier and H. pylori infection. Single nucleotide polymorphism (SNP) in genes NAT2 (N-acetyl transferase), Interlukin-1B, GSTM1 and GSTT1 (Glutathione S-transferase), Pro12Ala Peroxisome proliferator-activated receptor γ, COX (Cyclooxygenase) have reported significant association in the development of gastric cancer [21-26]. With this background, it can be assumed that the etiopathogenesis of gastric cancer depends on a complex inter-play between genetic, socio-cultural and environmental risk factors in a particular region, and hence the treatment planning/sequencing also will be different. NEO-ADJUVANT CHEMOTHERAPY FOR GASTRIC CANCER Since the 1990s, neo-adjuvant chemotherapy for advanced gastric cancer has been in use. A number of studies have evaluated the efficacy of neo-adjuvant chemotherapy for gastric cancer.(Table -1). TABLE -1: SUMMARY OF CLINICAL TRIALS INVESTIGATING THE IMPACT OF NEOADJUVANT CHEMOTHERAPY FOR LOCALLY ADVANCED GASTRIC CANCER [27-36] Author Studies Year Inclusion criteria Group Patients R0 rate (%) CR rate (%) OS or median survival time Ajani et al 1991 Resectable gastric M0 + EGJ cancer EFP × 2 + surgery + EFP × 3 25 72 0 15 months Ajani et al 1993 Resectable gastric M0 cancer EAP × 3 + surgery + EAP × 2 48 90 0 16 months Rougier et al 1994 Locally advanced gastric cancer M0 + EGJ FP × 6 + surgery 30 78 0 16 months Songun et al 1999 T2–4M0 1.FAMTX × 3 + surgery/2.surgery 27/29 75/75 NS 18/30 months Schuhmacher et al 2001 Locally advanced gastric cancer III–IV (M0) + EGJ EAP + surgery 42 86 0 19 months D'Ugo et al 2006 T3–4 Nx M0 or T ≤ 2N + M0 EEP × 3/ECF × 3 + surgery + EEP × 3/ECF × 3 34 82 3 >28 months Cunningham et al MAGIC 2006 Resectable gastric + EGJ cancer 1. ECF × 3 + surgery + ECF × 3/2. surgery 250/253 74/68 NS 5 years, 36.3% vs. 23.0%, P = 0.009 Tsuburaya et al JCOG0405 2007 Bulky N2/3 S-1/CDDP × 2–3 + surgery + D2 + PAND 53 82.4 NS 5 years, 53% Ychou et al FNLCC and FFCD 2011 Resectable gastric + EGJ cancer 1. FP × 2–3 + surgery + FP × 3–4/2. surgery 113/111 84/73 NS 5 years 38% vs. 24%, P = 0.02 Schuhmacher et al EORTC 2010 T3–4NxM0 1. PFL × 2/2. surgery 72/72 81.9/66.7 NS 64.62/52.53 months Kinoshita et al 2009 T2–3/N+ or T4aN0 S-1 × 2 + surgery 55 80.8 0 NS Biffi et al 2010 T3–4 Nx or Tx N1–3 M0 + EGJ 1. TCF × 4 + surgery/2. surgery 34/35 85 11.7/- NS Iwasaki et al JCOG0210 2013 Resectable gastric cancer SC × 2 + surgery 36 73.5 NS 17.3 months, 3 years, 24.5% Yoshikawa et al COMPASS 2014 T2–3/N+ or T4aN0 + EGJ 1. SC × 2 + surgery/2. SC × 4 + surgery 21/20 NS NS NS Cunningham et al ST03 2017 Resectable gastric + EGJ + esophageal cancer 1. Bevacizumab + ECX + surgery/2. ECX + surgery 530/533 64/61 NS 33.97 vs. 34.46 months, 3 years, 48.9% vs. 47.6% Katayama et al JCOG1002 2013 Bulky N2/3 CDDP/S-1 × 2–3 + surgery + D2 + PAND 53 84.6 NS 5 years, 55% Al-Batran et al FLOT-AIO 2017 cT2-4/cN-any/cM0 or cT-any/cN+/cM0 1. ECF/ECX + surgery/2. FLOT + surgery 360/356 78/85 NS 35/50 months, P = 0.012 Terashima et al JCOG0501 2019 Resectable gastric cancer 1. Surgery + S1/2. SC × 2 + surgery + S-1 149/151 NS NS 3 years, 62.4% vs. 60.9%, P = 0.916 The above mentioned studies confirmed that neoadjuvant chemotherapy has a significant downstaging pathological effect, increasing the R0 resection rate and improving the 5-year OS rate. Moreover, there was no significant difference between the neoadjuvant chemotherapy group and surgery alone group with regard to postoperative complications, mortality, and length of hospital stay. Recently, meta-analysis and systematic reviews of neoadjuvant chemotherapy have also shown that neoadjuvant chemotherapy can significantly improve the survival and R0 resection rates of patients. Compared with ECF or Epirubicin, Cisplatin, and Capecitabine (ECX), the FLOT regimen increased the R0 resection rate and improved OS and DFS. These results confirmed that FLOT is efficacious as a novel standard treatment for perioperative therapy of gastric or esophagogastric junction adenocarcinoma and is the current standard of care. NCCN recommends FLOT as the preferred regimen during perioperative chemotherapy. The recently released Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition), recommends to consider Neo-adjuvant chemotherapy followed by D2 gastrectomy in clinically T2-T4 gastric cancers with bulky nodal disease(N+) [37] . Our study was performed as a retrospective institutional audit to compare the outcomes of the patients with gastric cancer who underwent upfront surgery with those who underwent surgery after neo-adjuvant chemotherapy.

• All patients who underwent curative Radical Gastrectomy for Carcinoma Stomach either upfront (or) after Neo-Adjuvant Chemotherapy with treatment policy taken in the Multi-Disciplinary Tumour Board were included in the audit. • All patients undergoing upfront surgery underwent a Staging Laparoscopy before surgery to rule out undiagnosed/occult peritoneal disease (or) liver metastases. All patients also received adjuvant CAPE-OX based chemotherapy. • Post-operative radiotherapy was given to some patients with high-risk features like close margins, extra-nodal extension etc. • Neo-adjuvant Chemotherapy was divided into 2 arms – ECF regime(Epirubicin, Cisplatin, 5-FU) and EOX regime(Epirubicin, Oxaliplatin and Capecitabine) • Time period of study – from June 2020 to June 2023; all patients who completed treatment from June 2020 onwards were included in the study.

GROUP I - UPFRONT SURGERY: • The Total number of patients included in this group was 93. • The most common grade of cancer was Grade II – Moderately differentiated Adenocarcinoma (Table-2). TABLE – 2: GRADE OF TUMOR SNO GRADE NUMBER OF PATIENTS 1 WELL – DIFFERENTIATED 13(13.97%) 2 MODERATELY DIFFERENTIATED 61(65.59%) 3 POORLY DIFFERENTIATED / SIGNET RING CELLS 19(20.43%) • The most common site of tumour was Antro-Pyloric region. Other sites include Body, Fundus and Cardia. • Table – 3 gives the Post operative HPE staging of the patients who underwent upfront surgery. TABLE – 3: POST OPERATIVE HPE STAGING SNO PATHOLOGY REPORT NUMBER OF PATIENTS 1 pT1bN0 1 2 pT2No 1 3 pT2N2 1 4 pT3No 11(11.82%) 5 pT3N1 13(13.97%) 6 pT3N2 17(18.27%) 7 pT3N3 9 8 pT4aN0 1 9 pT4aN1 7 10 pT4aN2 16(17.20%) 11 pT4aN3 15(16.12%) 12 pT4b2 1 • A total of 22 patients (23.66%) did not receive Adjuvant Chemotherapy after surgery (Table -4). • Of the 22 patients, 3 patients died due to surgical complications and the other 19 patients defaulted for treatment (Table – 5). • The average time to start Adjuvant Chemotherapy was 1 month after surgery. • In a total of 20 patients (21.50%), Chemotherapy was delayed beyond 1 month. TABLE – 4: ADJUVANT CHEMOTHERAPY SNO CATEGORIES NUMBER OF PATIENTS 1 RECEIVED ADJUVANT CHEMOTHERAPY 71(76.34%) 2 DID NOT RECEIVE ADJUVANT CHEMOTHERAPY 22(23.66%) TABLE -5: REASONS FOR NOT RECEIVING ADJUVANT CHEMOTHERAPY SNO REASONS NUMBER OF PATIENTS 1 DEFAULTED TREATMENT 19 (20.43%) 2 DIED DUE TO SURGICAL COMPLICATIONS 3 (3.22%) • A total of 12 patients had less than 1 year Disease Free Survival even after receiving Adjuvant Chemotherapy. • All the patients who did not receive Adjuvant Chemotherapy developed recurrent disease within 1 year of completion of surgery. • Table -6 shows the Overall Survival (OS) after 4 years for patients treated with upfront surgery for carcinoma stomach. TABLE -6: OVERALL SURVIVAL OF PATIENTS UNDERGOING UPFRONT SURGERY SNO YEARS OF SURVIVAL TOTAL NUMBER OF PATIENTS IN COHORT ACTUAL NO. OF PATIENTS SURVIVING 1 4 YEARS 20 4 (20%) 2 3 YEARS 46 18 (39.13%) 3 2 YEARS 70 36 (51.42%) 4 1 YEAR 93 59 (63.44%) Table – 7 shows the most common patterns and sites of recurrence in patients undergoing upfront surgery. TABLE -7: RECURRENCE PATTERNS AND SITES OF RECURRENCE SITES MC SITE OF RECURRENT DISEASE -DISTANT METASTASIS/PERITONEAL DISEASE>>NONREGIONAL NODAL METS>>ANASTOMOTIC SITE>>SPINE GROUP II – SURGERY AFTER NEO-ADJUVANT CHEMOTHERAPY: • The Total number of patients included in this group was 40. • The most common reason for starting Neo-adjuvant chemotherapy in our institute was Effaced fat planes. • The most common grade of cancer was Grade II – Moderately differentiated Adenocarcinoma. • The most common site of tumour was Antro-Pyloric region. Other sites include Body, Fundus and Cardia. • Table – 8 gives the Post operative HPE staging of the patients who underwent surgery following Neo-adjuvant Chemotherapy. TABLE – 8: POST OPERATIVE HPE STAGING SNO PATHOLOGY REPORT NUMBER OF PATIENTS 1 ypTisNo 3 2 ypT1N0 6 3 ypT2No 7(20.58%) 4 ypT2N1 5 5 ypT3N1 5 6 ypT3N2 5 7 ypT3N3 4 8 ypT4aN0 1 9 ypT4aN1 1 10 ypT4aN2 0 11 ypT4aN3 3(8.82%) 12 ypT4b2 0 • A total of 5 patients (9.8%), discontinued and defaulted neo-adjuvant chemotherapy due to toxicity. • A total of 6 patients (11.76%) developed progressive disease on neo-adjuvant chemotherapy. • Table -9 shows the Overall Survival (OS) after 4 years for patients treated with upfront surgery for carcinoma stomach. TABLE -9: OVERALL SURVIVAL OF PATIENTS UNDERGOING SURGERY AFTER NEO-ADJUVANT CHEMOTHERAPY SNO YEARS OF SURVIVAL TOTAL NUMBER OF PATIENTS IN COHORT REGIMEN ACTUAL NO. OF PATIENTS SURVIVING 1 4 YEARS 4 ECF 1 (25%) NIL EOX -- 2 3 YEARS 16 ECF 7 (43.75%) NIL EOX -- 3 2 YEARS 24 ECF 14 (58.33%) 5 EOX 3 (60%) 4 1 YEAR 31 ECF 22 (70.96%) 9 EOX 7 (77.77 %) • Like in Group I, the MC site of recurrence was Distant /Peritoneal. OTHER OBSERVATIONS A total of 27 patients in the given study period were taken up for curative radical gastrectomy upfront – but radical surgery was not performed due to inoperability/ unresectability detected in Staging Laparoscopy or after Laparotomy. (Table -10). All of these patients eventually progressed and had invariably poor survival and were not included in the study. TABLE 10 – UNRESECTABLE/INOPERABLE PATIENTS SNO FINDINGS NUMBER OF PATIENTS 1 PANCREAS INFILTRATION 16 (59.25%) 2 TRANSVERSE MESO- COLON INFILTRATION 3 (11.1%) 3 BULKY PARA-AORTIC NODES 3 (11.1%) 4 PRE-OPERATIVELY UNDETECTED LIVER METASTASES 5 (18.51%)

The most common site of tumour in our audit was the Antro-pyloric region, reflecting association with Helicobacter pylori. As discussed in Table 10, a separate subgroup of patients were initially planned for upfront radical surgery, but due to either unresectability or inoperability – the planned procedure was not carried out and they underwent only Gastric Bypass (or) Feeding Jejunostomy. When taken as a proportion of the total number of cases who underwent upfront surgery- it comes to around 22.5%. Proper Image Standardization (Contrast Enhanced CT scans- Gastric Protocol) and accurate Staging Laparoscopy is currently recommended in all cases of carcinoma stomach > T1. It could avoid unnecessary laparotomies in upto 50% of cases [38,39]. Most of the patients who underwent upfront surgery had higher stages of disease in their final HPE report. This indicates two inferences – a) Most patients in India present with advanced gastric cancer partly due to lack of efficient screening programmes in India [40] and partly due to the inherent disease biology, b) Higher stage disease often has micro-metastases leading to poor survival even after curative radical surgery. Two significant downsides exist in upfront surgery. A) The patients with carcinoma stomach are often nutritionally depleted and this prevents them from turning up for adjuvant chemotherapy after a radical curative surgery. Sometimes, even if the patient is willing for adjuvant chemotherapy, the complications and morbidities following gastric surgery resulting either directly or indirectly from nutritional deprivation prevents them from receiving adjuvant chemotherapy on time or not at all. In our study all the patients who defaulted adjuvant chemotherapy had less than 1 year disease free survival. This reflects the importance of adjuvant chemotherapy in increasing the overall survival of gastric cancer patients as already established by the CLASSIC and ACTS-GC study [41-43]. But upfront surgery is sometimes needed to improve the nutritional status of patients and it becomes radical surgery at times. This is one confounding factor which comes into play while considering Neo-Adjuvant chemotherapy for all patients with carcinoma stomach. In such scenarios, the ideal treatment would be to perform a Gastro-Jejunostomy first and then take up the patient for chemotherapy as soon as possible [44]. The most common site for recurrence after curative radical surgery and adjuvant chemotherapy is Distant / Peritoneal, further highlighting the importance of chemotherapy in the management of Adenocarcinoma stomach. After Neo-adjuvant chemotherapy followed by surgery, the post-operative HPE report tend to be at a lower stage than those in patients undergoing upfront surgery. This proves the role of chemotherapy in downstaging the disease. All of the patients in this group were able to receive Adjuvant Chemotherapy. EOX regimen tends to offer better survival than ECF regime, though subgroup analysis has not been done. This can also help in assessing the in-vivo sensitivity of the tumour to chemotherapy. Indeed 11.76% of our patients progressed while on neo-adjuvant chemotherapy. Gastric cancer, being a biologically aggressive tumour, leaves little chance to explore 2nd line treatment options for such patients. Also, toxicities of various chemotherapy regimens need to be taken into account. When compared, patients who underwent surgery after Neo-Adjuvant Chemotherapy tend to do well with an increased Overall Survival (OS) than patients who underwent upfront surgery (Table 10) TABLE 10 – HEAD TO HEAD COMPARISON OF OVERALL SURVIVAL SNO OVERALL SURVIVAL UPFRONT SURGERY SURGERY AFTER NEO- ADJUVANT CHEMOTHERAPY 1 4 YEAR SURVIVAL 20 % 25 % 2 3 YEAR SURVIVAL 39.13 % 43.75 % 3 2 YEAR SURVIVAL 51.42 % 59.16 % 4 1 YEAR SURVIVAL 63.44 % 74.35 % FIGURE -1 : KAPLAN – MEIER CURVES UPFRONT SURGERY SURGERY AFTER NEO-ADJUVANT CHEMOTHERAPY LIMITATIONS • Statistical Analysis is not done for Overall Survival as it is not a head to head Randomized controlled study. • The effect of Post-operative Radiotherapy has not been taken into account while calculating Overall survival. • Full subgroup analysis has not been done between ECF and EOX regimes. • FLOT-4 represents the latest standard of care for NACT in carcinoma stomach. Since, it has been started only recently in our institute, it has not been included in the audit. • Being a public sector institute, imaging parameters and acquisition protocols could not be standardized as patients present to us from elsewhere with their imaging workup already done.

Neo-Adjuvant chemotherapy for all cases of gastric adenocarcinoma except Early Gastric Cancer, offers the potential for improved survival after surgery, especially in the Indian population. Further powered studies are necessary to validate this hypothesis. The prospective addition of S1 in the future to the Neo-Adjuvant chemotherapy regimens in India adds further exciting dimensions to this hypothesis.

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