Gastric cancer is one of the leading digestive cancers concerning incidence and mortality rate. Surgery plays the main role of a multimodal approach to treatment. This research was to evaluate the early results of surgery with perioperative chemotherapy in the treatment of gastric cancer.
JOURNAL OF MEDICAL RESEARCH EARLY OUTCOMES OF SURGICAL TREATMENT WITH PERIOPERATIVE CHEMOTHERAPY FOR GASTRIC CANCER Bui Trung Nghia, Trinh Hong Son Oncology Department, Viet Duc University Hospital Gastric cancer is one of the leading digestive cancers concerning incidence and mortality rate Surgery plays the main role of a multimodal approach to treatment This research was to evaluate the early results of surgery with perioperative chemotherapy in the treatment of gastric cancer Methods: descriptive, uncontrolled case series Results: n = including males: females Neo-adjuvant chemotherapy indications included local invasion, lymph node metastasis and liver metastasis One patient had progression during treatment Toxicity was mostly of grade I or II Surgery included total (5 patients) and partial gastrectomy (4 patients) with resection of neighboring organs (6 patients) Standard lymphadenectomy was D2 up to D4 Average operating time was 287 ± 92.4 minutes [180:480] Pathology was mostly poorly differentiated adenocarcinomas or ringcell carcinomas There was no perioperative morbidity and mortality Average postoperative stay was ± days [6:17] After year of following up, all patients had adjuvant chemotherapy Among them, two patients had progression, one of whom died as a result Conclusion: Multimodal treatment with the combination of surgery and chemotherapy is feasible with acceptable results and could help to improve the possibility of curative treatment Keywords: gastric cancer, perioperative chemotherapy, surgery I INTRODUCTION Gastric cancer ranks fourth in incidence with about million newly - diagnosed cases annually and third for cancer – related deaths worldwide with about 723,000 cases in 2012 [1] Vietnam leads Southeast Asia countries concerning prevalence (24.4 in males and 14.6 in females) as well as mortality (14.0 per 100,000 of population) [2] The 5-year survival rate for gastric cancer is only around 2030% worldwide, with the exception of Japan with 68.2%, thanks to an effective screening Corresponding author: Bui Trung Nghia, Oncology Department, Viet Duc University Hospital Email: btnghia84@gmail.com Received: 27/11/2018 Accepted: 12/03/2019 JMR 118 E4 (2) - 2019 program for early diagnosis and curative surgery with standard D2 lymphadenectomy [3; 4] Gastrectomy with D2 lymphadenectomy has been considered the primary treatment for gastric cancer worldwide from Japan [5] to European countries (ESMO) [6] and the United States of America (NCCN) [7] In the era of multi-modal treatment, neo-adjuvant and adjuvant chemotherapy is increasingly recognized as a best choice in the combination with surgery for advanced, locally invasive or metastatic gastric cancer with proven efficacy in comparison with the surgical alone group [8] This article aims to evaluate the early results of surgical treatment with perioperative chemotherapy in a clinical cases series of 55 JOURNAL OF MEDICAL RESEARCH gastric cancer in the Oncology Department, Viet Duc University Hospital II METHODS Subjects Gastric adenocarcinoma cases were operated after neoadjuvant chemotherapy at the Oncology Department, Viet Duc University Hospital from 01/6/2017 to 31/7/2018 Methodology Descriptive study with uncontrolled cases series The patient was diagnosed as gastric adenocarcinoma and treated by neoadjuvant chemotherapy at the Oncology Department, Viet Duc University Hospital or other medical facilities but transferred to the department for surgery The collected data included administrative information, signs and symptoms, characteristics of lesions in gastroscopy, CT scanner, neoadjuvant chemotherapy regimens including EOX (Epirubicine 50mg/ m2, Oxaliplatine 130 mg/m2, Capecitabine 1250mg/m2 bpd, 21 days per cycle) and FLOT (Oxaliplatine 85 mg/m2, Calcium folinate 200 mg/m2, 5-FU 2600 mg/m2, Docetaxel 50 mg/m2, 14 days per cycle) and their indications (local invasion, distant metastasis, significant lymph node metastasis found during preoperative examination, assessment of treatment response based on diagnostic imaging devices such as computerized tomography, PET, tumor response, surgical treatment including type of surgery: partial or total gastrectomy, resection of invaded or metastatic organs, lymphadenectomy level, 56 radical level (R0: clean resection margin in both gross and microscopic view; R1: clean in gross but residual in microscopic view; R2: residual in gross view) and postoperative complications (surgical site infection – red, hot, swollen wound with dirty discharge, fever or other sign of local and systemic infection; bleeding – both intra-abdominal and at the surgical sites with or without change in blood test; pancreatic leakage – amylase test of drainage discharge at 3rd day after operation was times more than amylase level in the blood following criteria of International Study Group of Pancreatic Fistula; lymphatic leakage – drainage discharge more than 300 ml / day in consecutive days with or without quantitative test of lipid over 110 mg/dL) as well as recorded treatment and results, recovery time of bowel movements (gaz) and postoperative hospital stay, pathology The patient was re-examined at the time of weeks after hospital discharge to decide on the next treatment and to be monitored periodically every 1-3 months to record related events RECIST (Response Evaluation Criteria In Solid Tumors) [9] At the time of surgical decision, tumor response with preoperative chemotherapy was assessed using the RECIST standard 2009 that is based on target lesions, clinical examination and imaging tests (ultrasonography, computerized tomography, endoscopy ) Target lesions are measurable lesions, up to (max lesions per organ) The sum of highest diameters of lesions is used as the basis for the assessment response JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH Table Evaluation of solid tumor response according to RECIST Evaluation RECIST guideline, version 1.1 CR (complete response) Disappearance of all targeted lesions and reduction of short diameter of metastatic lymph nodes below 10 mm PR (partial response) Reduction ≥30% of total highest diameters of targeted lesions in comparison with original one Augmentation ≥20% or at least mm of total highest diameters in the comparison with smallest size of total highest measurable diameters Or appearance of new lesions including ones detected by PET – CT PD (progressive disease) SD (stabilized disease) Without criteria of PR and PD Assessment of toxicity and side effects of chemotherapy regimens following WHO standards Table2 Toxicity in hematopoietic system Toxicity Unit Grade Grade Grade Grade Grade Leukopenia 103/ml ≥ 4,0 3,0 - 3,9 2,0-2,9 1,0 - 1,9 < 1,0 Neutropenia 103/ml ≥ 2,0 1,5 - 1,9 1,0-1,4 0,5 - 0,9 < 0,5 Anemia (Hb) g/l N 100 - N 80 - 100 65 - 79 < 65 Thrombocytopenia 103/ml N 75 - N 50 - 74.9 25 - 49.9 < 25 Table3 Toxicity in liver and kidney function Toxicity Unit Grade Grade Creatinine µmol/l N < 1,5xN Urea mmol/l < 1,5xN Bilirubin mmol/l Transaminase Glucose Grade Grade Grade 1,5 - 3,0xN 3,1 - 6,0xN > 6,0xN 1,5 - 2,5xN 2,6 - 5,0xN 5,1 - 10xN > 10xN N - < 1,5xN 1,5 - 3,0xN > 3,0xN UI/ml N ≤ 2,5xN 2,6 - 5,0xN 5,1 - 20xN > 20xN mmol/l < 6,5 6,5 - 8,9 9,0 - 13,9 14 - 27,9 ≥ 30 or ketoacidosis N: normal range Collected data was entered and analyzed in SPSS 18.0 with statistical algorithm Ethical Considerations All patients’ data was collected and kept for only authorized personnel No private information was provided to any third party or person without written agreement JMR 118 E4 (2) - 2019 of the patients, themselves or their legal representatives III RESULTS Characteristics of research group 57 JOURNAL OF MEDICAL RESEARCH - Sexuality: males (77.8%) / females (22.2%) - Age: 57 ± 11.3 [33:66] Our study group had the superiority in males and mostly middle aged Neo-adjuvant chemotherapy indications Table Indicatins of neo-adjuvant chemotherapy Indications n Ratio % Local invasion 33.3 Liver metastasis 22.2 Lymph node metastasis 44.5 Total 100 Neoadjuvant regimens: EOX – cases and FLOT – case Tumor response with preoperative chemotherapy Of the cases of the study group, there were only three cases of partial response (PR) and five cases of stable, non-progressive (SD) disease There were no cases of complete response (CR) and one case of progressive disease (PD) Toxicity on the hematopoietic system was mostly at grade II with the most common was anemia (6 out of cases accounted for 66.67%) Toxicity on liver and kidney function was common at grade and I (8/9 cases accounted for 88.89%) Surgical treatment 58 Surgical procedures: There were five cases of total gastrectomy (55.56%) and cases of partial gastrectomy (44.44%) Six out of nine cases (66.67%) were associated with resection of surrounding organs, most common is liver metastasectomy (including segmentectomy, left lobectomy and RF – 3/6 ~ 50%) and splenopancreatectomy (2/6 ~ 33%) All of the cases were with standard lymphadenectomy D2 (dissection of lymph nodes around the liver pedicle and celiac trunk) to D4 (dissection of lymph nodes of group 16) Average operating time was 287 ± 92.4 minutes [180:480] No intra-operative complication was recorded Two cases (22.22%) needed blood transfusion with – packed red blood cells unit JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH Figure Radical level of surgery In the study group, 2/9 cases (22.2%) were not considered radical operation because of unresectable liver and peritoneal metastasis Table Post-operative complication (N=9) Post-operative complication n Ratio % Surgical site infection 33.3 Lymphatic leakage 11.1 Intra-abdominal hemorrhage 11.1 Pancreatic leakage 11.1 No complication 65.6 Among them, antibiotic treatment was indicated in days after operation in normal cases but days with presence of surgical site infection even though a regular dressing changes was required every day during hospitalized period and at home until full wound healing There was one case of lymphatic leakage with surcharged abdominal drainage of more than 300 ml / day in days but it was well controlled by letting patient fast in days with subcutaneous octreotide of 0.1 mg/ml x times a day There was one case of pancreatic leakage starting on 5th day after operation after intraabdominal hemorrhage on 2nd day requiring a transfusion of units of blood Without JMR 118 E4 (2) - 2019 presence of general peritonitis, conservative treatment was indicated and patient could discharge at 15th day after operation with drainage that was removed weeks after at his visit in the consultation of the department In our group, no re-operation was needed Average time of bowel peristaltic recovery: ± days [2:5] Average post-operative stay: ± days [6:17] Pathology One-hundred percent of the cases were confirmed as gastric adenocarcinomas Among them, 6/9 cases (66.67%) were poorly differentiate or of ring – cell 59 JOURNAL OF MEDICAL RESEARCH Figure Differentiation leve 6/9 cases (66.67%) were with lymph nodes metastasis Follow – up results Re-examination at the time of 1, 3, 6, and 12 months after discharging from hospital showed that all cases were treated with adjuvant chemotherapy; 2/9 cases (22.2%) showed progression including case of axillary lymph nodes at months and liver metastasis causing jaundice at month One death was recorded months after operation and cases are still being followed IV DISCUSSION Neo-adjuvant chemotherapy is indicated as a "down-staging" approach to advanced gastric cancer that aims to increase the ability to perform radical surgery For high-risk cases of distal metastases such as T3 / T4 tumors, metastatic lymph nodes were observed on imaging diagnostic devices with characteristics such as loss of normal structure, diameter > cm or linitis plastic, an unnecessary surgery could be avoidable if distant metastatic lesions develop during chemotherapy In three large clinical trials with direct confrontation between the surgical group and the neoadjuvant chemotherapeutic group, two trials showed superior survival benefit in the cohort The 60 MAGIC trial was conducted in the United Kingdom on 503 resectable gastric cancer cases, which showed that combination group (3 preoperative and postoperative) had a higher rate of curative surgical intervention (79 vs 70%), higher 5-year survival rates (36 vs 23%) as well as overall survival and diseasefree survival compared to surgery alone group while tolerance is acceptable with toxicity of grade or less than 12% [10] Similar results were reported in the FNCLCC / FFCD trial in France with 224 cases of gastric cancer of stage II or higher with a higher rate of radical surgery (R0), lower lymph node metastasis recurrence rate (5-year survival rate of 34% vs 19%) and lower mortality (5-year survival rate of 38% vs 24%) in the combination chemotherapy group (2 - preoperative cycles and - postoperative cycles) vs surgical alone group [11] The EORTC (European Organization for Research and Treatment of Cancer) trial had a higher rate of radical surgery (82% vs 67%) but did not show improvements in overall survival and disease-free survival rate of combination group versus surgical group [12] In our study group, although there was not a long enough follow-up period for accurate evaluation, a JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH high rate of radical surgery (77.78%) and one-year mortality was low with one in nine because of early progression This was a case of progressive disease with the presence of hepatic multi-focal metastases leading to nonradical surgery (R2) Although no recommendations have been made regarding the choice of chemotherapy regimens, many clinicians have selected Epirubicine – based regimens with three preoperative and three postoperative cycles in the MAGIC study However, as the disease progresses, some clinicians tend to prolong neoadjuvant chemotherapy up to a maximum of cycles due to a high risk of surgical intervention In our study, of cases were treated with EOX protocol including Epirubicine, Oxaliplatine and Capecitabine Recently, with positive results from Phase II and III trials in response rates versus Epirubicine, FLOT (Docetaxel, Oxaliplatine, Leuvocorin and - FU) were preferred for resectable local advanced gastric cancer [13] In our study, case was treated with this protocol (4 preoperative and postoperative cycles) with good results The most common toxicity was febrile leukkopenia of grade II, nausea, vomiting and headache surgical treatment was given as an opportunity to approach the radical treatment of the patient or what called “salvage solution” 100% of cases in the study were indicated postoperative chemotherapy with same regimens as preoperative protocol However, some authors argue that if preoperative regimens not work, it might not be effective after surgical intervention [15] In terms of surgery, most authors agree that radical surgery offers the best long-term survival for gastric cancer patients, especially when combined with neo-adjuvant and adjuvant therapy [10; 16] However, the biggest problem is to diagnose patients at the focal stage In the United States of America, up to two thirds of cases were diagnosed in stage III or IV, while only 10% were in stage I according to TNM classification [17] It is highly dependent on screening programs where Japan has become a worldwide particularity, with more than half the cases diagnosed at early stage [18] Surgical indication is considered after neoadjuvant chemotherapy with EOX cycles or FLOT cycles For those who respond fully or partially, the intervention is quite clear and easily accepted by the surgeon and the patient However, for non-responders, especially for lymph node as well as distant metastases, To assess the preoperative stage for treatment indications, clinicians often rely on imaging diagnostic tools such as computer tomography, endoscopic ultrasonography to assess on-site invasiveness, such as nodal metastasis and distant metastases The ability to resect thoroughly depends on the subjective assessment, level and experience of the surgeon but is generally consistent in the following points: distant metastasis, invasive blood vessels such as aorta, celiac trunk, hepatic arteries, mediastinal nodal metastases optimal option remains unclear due to poor prognosis [14] In our study, only out of cases followed the recommended protocol (3 EOX cycles or FLOT cycles) and 4/9 cases extended neoadjuvant chemotherapy to 4, or cycles due to an inadequate treatment response At this point, the indication for (out of surgical area), local invasion, especially in the pancreas Although not absolute, but Whipple surgery for treatment of gastric cancer is very rare Surgical abdominal exploration should be performed unless there is evidence of progressive disease, major invasive blood vessels or contraindications to surgery due to JMR 118 E4 (2) - 2019 61 JOURNAL OF MEDICAL RESEARCH medical conditions attached In our study, three out of nine cases had surgical exploration, lymph node biopsy and injury assessment, of which one had emergency surgery due to perforation and bleeding In the study group, there were cases of total gastrectomy and cases of partial gastrectomy While indications are quite clear with partial distal gastrectomy due to cancer at the antrum and pylorus [19], the indication for total gastrectomy was considered preferable to proximal gastrectomy due to similar 5-year survival rate (64% vs 61%) but lower recurrent rate (24 vs 39%) and less complications such as anastomotic stricture (7 vs 27%) or reflux (2 vs 20%) [20] Laparoscopic surgery is indicated only in cases of early gastric cancer, which is not included in the study group In the study group, only one case of patients underwent laparoscopic surgery for lymph node biopsy where gastric lesions were unclear but suspected lymph node metastasis Spleno-pancreatectomy is not recommended unless there is direct invasion of the tumor [23] In our study group, 100% of the cases were with standard lymph nodes dissection D2 to D4 with low incidence of complications: one case of lymphatic leakage and one case of leukemia that responded well to medical treatment No surgical intervention was required In a different study, the rate of intra-abdominal hemorrhage was 0.33%, hemorrhage at the surgical site infection was 5.23% [24] Regarding anato-pathological findings, the majority of cases in the study group were poorly differentiated adenocarcinoma or ring cell (very poorly differentiated) This is also consistent with the degree of malignancy progression and neoadjuvant treatment indication Trinh Hong Son summarized 537 cases of gastrectomy for cancer in Viet Duc University Hospital from 1993 to 1997 with mostly (95.7%) of adenocarcinomas [25] Lymphadenectomy is also a controversial topic in the treatment of gastric cancer as Asia-Pacific countries tend to more extensive dissection of lymph nodes than Western countries Lymphadenectomy level are based on the 16 groups of lymph nodes classification of Japanese surgeons D1 consists of lymph nodes surrounding the stomach (1 - 7), D2 consists of D1 and lymph nodes surrounding hepatic pedicle, left gastric artery, splenic artery and celiac trunk (1 - 12a) and D3 - includes D2 and lymph nodes along the aorta In addition, in Postoperative follow-up showed one case of recurrent hepatic metastasis, which occurred very early after surgery This was a progression after cycles of EOX but only detectable during operation with the presence of unresectable multi-focal hepatic lesions Therefore, surgical resection in this case was palliative (R2) In addition, one case of peritoneal metastasis was also considered non-radical surgery (R1) despite removal of all visible peritoneal with clear margin The remaining cases were considered radical surgery with gastrectomy, lymphadenectomy of the standard D2 to D4 the Japanese literature, a D1 + was defined as D1 and 8a, and 11p groups As clinical trials not show the superiority of extensive lymph node dissection (D3, D4) [21; 22], standard D2 lymphadenectomy is recommended for the treatment of advanced gastric cancer but only in big centers and with experienced surgeons and removal of invaded organs into the block such as splenopancreatectomy, removal of peritoneal capsule of pancreas, left liver lobectomy (tumor invaded to Glisson capsule but not into biliary ducts and liver parenchyma – negative resection margin) Besides, two cases with radio-frequency onto single hepatic 62 JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH metastasis in segment and segment were considered radical although there was no international consensus relating to resection of the liver due to metastases from gastric cancer and apparently no statistically significant association with survival time [26; 27] 30(6), 643-9 V CONCLUSION Japanese Gastric Cancer A (2017) Japanese gastric cancer treatment guidelines 2014 (ver 4) Gastric Cancer, 20(1), 1-19 Despite of the small size of study group and lack of long-time follow-up, surgery with perioperative chemotherapy seems to be able to improve the possibility of radical surgery with acceptable morbidity rate and nonpostoperative mortality However, surgery is still considered the best chance for advanced stomach cancer patients Obviously, multicenter studies with large numbers are needed for more accurate assessment Acknowledgments I would like to express my gratitude and appreciation to Professor Trinh Hong Son, my personal tutor and also to Department of Postgraduate Study, Hanoi Medical University and Viet Duc University Hospital where I have received a lot of support and assistance REFERENCES Ferlay J, Soerjomataram I, Dikshit R, et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer, 136(5), E359-86 Kimman M, Norman R, Jan S, et al (2012) The burden of cancer in member countries of the Association of Southeast Asian Nations (ASEAN) Asian Pac J Cancer Prev, 13(2), 411-20 Hartgrink HH, van de Velde CJ, Putter H, et al (2004) Neo-adjuvant chemotherapy for operable gastric cancer: long term results of the Dutch randomised FAMTX trial Eur J Surg Oncol, JMR 118 E4 (2) - 2019 Japanese Gastric Cancer Association Registration C, Maruyama K, Kaminishi M, et al (2006) Gastric cancer treated in 1991 in Japan: data analysis of nationwide registry Gastric Cancer, 9(2), 51-66 Okines A, Verheij M, Allum W, et al (2010) Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol, 21 Suppl 5, v50-4 Ajani JA, Bentrem DJ, Besh S, et al (2013) Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines J Natl Compr Canc Netw, 11(5), 531-46 Newton AD, Datta J, Loaiza-Bonilla A, et al (2015) Neoadjuvant therapy for gastric cancer: current evidence and future directions J Gastrointest Oncol, 6(5), 534-43 Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer, 45(2), 228-47 10 Cunningham D, Allum WH, Stenning SP, et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer N Engl J Med, 355(1), 11-20 11 Ychou M, Boige V, Pignon JP, et al (2011) Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial J Clin Oncol, 29(13), 1715-21 12 Schuhmacher C, Gretschel S, Lordick F, et al (2010) Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and 63 JOURNAL OF MEDICAL RESEARCH Treatment of Cancer randomized trial 40954 J Clin Oncol, 28(35), 5210-8 13 Al-Batran SE, Hofheinz RD, Pauligk C, et al (2016) Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastrooesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase part of a multicentre, open-label, randomised phase 2/3 trial Lancet Oncol, 17(12), 1697-708 14 Smyth EC, Fassan M, Cunningham D, et al (2016) Effect of Pathologic Tumor Response and Nodal Status on Survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial J Clin Oncol, 34(23), 2721-7 15 Saunders JH, Bowman CR, Reece-Smith AM, et al (2017) The role of adjuvant platinum-based chemotherapy in esophagogastric cancer patients who received neoadjuvant chemotherapy prior to definitive surgery J Surg Oncol, 115(7), 821-29 16 Macdonald JS, Smalley SR, Benedetti J, et al (2001) Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction N Engl J Med, 345(10), 725-30 17 Wanebo HJ, Kennedy BJ, Chmiel J, et al (1993) Cancer of the stomach A patient care study by the American College of Surgeons Ann Surg, 218(5), 583-92 18.Yoshida S, Saito D (1996) Gastric premalignancy and cancer screening in highrisk patients Am J Gastroenterol, 91(5), 83943 19 Gouzi JL, Huguier M, Fagniez PL, et al (1989) Total versus subtotal gastrectomy 64 for adenocarcinoma of the gastric antrum A French prospective controlled study Ann Surg, 209(2), 162-6 20 Pu YW, Gong W, Wu YY, et al (2013) Proximal gastrectomy versus total gastrectomy for proximal gastric carcinoma A meta-analysis on postoperative complications, 5-year survival, and recurrence rate Saudi Med J, 34(12), 1223-8 21 Jiang L, Yang KH, Guan QL, et al (2013) Survival and recurrence free benefits with different lymphadenectomy for resectable gastric cancer: a meta-analysis J Surg Oncol, 107(8), 807-14 22 Mocellin S, McCulloch P, Kazi H, et al (2015) Extent of lymph node dissection for adenocarcinoma of the stomach Cochrane Database Syst Rev, (8), CD001964 23 Csendes A, Burdiles P, Rojas J, et al (2002) A prospective randomized study comparing D2 total gastrectomy versus D2 total gastrectomy plus splenectomy in 187 patients with gastric carcinoma Surgery, 131(4), 401-7 24 Son TH, Nghia NQ, Van DD (1999) Research on some related factor to survival rate of gastric adenocarcinomas patients who died in the period of years after operation Journal of Practical Medicine, 6(366), - 25 Son TH (2000) Anatomopathology and staging of gastric adenocarcinomas Journal of Practical Medicine, 12, 43-47 26 Cheon SH, Rha SY, Jeung HC, et al (2008) Survival benefit of combined curative resection of the stomach (D2 resection) and liver in gastric cancer patients with liver metastases Ann Oncol, 19(6), 1146-53 27 Linhares E, Monteiro M, Kesley R, et al (2003) Major hepatectomy for isolated metastases from gastric adenocarcinoma HPB (Oxford), 5(4), 235-7 JMR 118 E4 (2) - 2019 ... Japanese gastric cancer treatment guidelines 2014 (ver 4) Gastric Cancer, 20(1), 1-19 Despite of the small size of study group and lack of long-time follow-up, surgery with perioperative chemotherapy. .. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and 63 JOURNAL OF MEDICAL RESEARCH Treatment of Cancer. .. acceptable with toxicity of grade or less than 12% [10] Similar results were reported in the FNCLCC / FFCD trial in France with 224 cases of gastric cancer of stage II or higher with a higher rate of