RESULTS OF SURGICAL TREATMENT OF LOCALLY ADVANCED PROXIMAL GASTRIC CANCER

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1 Yu.A. Vinnik V.V. Оlеksеnkо S.V. Efetov 3 K.A. Aliyev Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine SI «Crimea State Medical University named after S.I. Georgievsky» 3 CRI «Oncologic Clinical Dispensary named after V.M. Efetov», Simferopol, AR of Crimea Key Words: locally advanced proximal gastric cancer, multivisceral resections, longterm outcome. RESULTS OF SURGICAL TREATMENT OF LOCALLY ADVANCED PROXIMAL GASTRIC CANCER Summary. Objective: to analyze the postoperative and longterm results of surgical treatment in patients with locally advanced proximal gastric cancer. Object and methods: the study included 80 patients with tumor in the proximal part of the stomach type II and III by J.R. Siewert, of whom 73 patients (study group) underwent multivisceral resection, 07 (control group) the standard surgical intervention. The average age of the study group was 60,5 ± 7,9 years (44 76), control 6,9 ± 7,3 years (34 76). Results: performing multivisceral resection, 3 (43,9 ± 5,8%) patients underwent en bloc resection or ectomy of one adjacent to the stomach organ, in 0 (7,4 ± 5,%) patients of two organs, in 6 (8, ± 3,%) three, 3 (7,8 ± 4,5%) four and five organs (,7 ±,9%) in two patients. Conclusions: it is defined that multivisceral resections in case of locally advanced proximal gastric cancer was accompanied with the increase in postoperative morbidity and mortality. Pancreatectomy was significantly associated with a greater number of postoperative complications. The regional lymph node metastasis in locally advanced proximal gastric cancer impairs longterm outcome. In absence of early diagnosis surgical treatment in patients stage pt4 remains the only chance prolonging life, due to that developing efforts aimed to improve the outcomes of these patients remain relevant. INTRODUCTION Gastric cancer (GC) remains one of the leading causes of death in the structure of cancer mortality in many countries of the world, occupying second place after lung cancer [], in Ukraine third place after lung tumors and colorectal cancer (death rate constitutes 0.7%) [5]. Over the last decade, some decrease of GC incidence due to the tumors of distal localization has been noticed. At the same time, frequency of proximal gastric cancer (PGC) strongly tends to grow. PGC constitutes 037% among all GC localizations; according to the data of the most of international cancerregisters, there is no tumor of other localization demonstrating such intensive increase of incidence that determines permanent high GC death rate []. Results of PGC treatment cannot be recognized satisfactory. Rates of operability of this malignant neoplasm vary from 40 to 70%, resectability from 38 to 69% that has an effect on the longterm results of treatment [8]. Causes of fatal course of PGC are complications of diagnostics of preclinical stages Tis and T. Early diagnostics is one of the priority and effective means of mortality decrease. In contrast to Japan, where more than half of newly diagnosed cases are related to the early cancer, most patients in Ukraine on the moment of diagnosis have advanced stage: III 4.9%, IV 30.8% [5]. PGC with involvement of zone of esophagogastric junction in ptis and ptstage does not exceed 89% of all new cases, in 65% of patients IIIIV stages are diagnosed [4]. Surgical treatment of GC still remains in the center of attention. Despite certain progress in anesthetic and reanimation facilities, prognosis in extensive local dissemination of GC with invasion of tumor in adjacent anatomic structures remains complicated surgical problem and in number of cases remains the cause of unreasonable rejection of radical surgeries, especially in unspecialized health care institutions [3]. When analyzing published data of modern literature concerning direct and longterm results of surgical treatment of advanced forms of GC, inconsistence of these data becomes obvious. For instance, frequency of complications after combined radical surgeries varies from 5 to 59.4%, postoperative lethality from 3.3 to 4.% [9, 0, 3]. Such wide range of rates does not allow to make clear conclusion. Series of studies contain no longterm results demonstrating 5year survival of radically treated patients,

2 and in other studies it is not higher than 49.3% [, 3, 7, 0,, 3]. Localization of tumor in proximal part determines most pessimistic results of treatment compared with other GC localizations. The lowest rates of survival are marked at locally advanced PGC in pt4 stage. Mean lifespan (MLS) constituted.5 ± 5.3 months, median survival (MS) 9 months, e.g. more than half of patients die during the first year of observation. At invasion of tumor in surrounding organs, the frequency of lymphogenous metastasis increases: from 6.% at pn0 to 33.8% at pn3. At the same time, the involvement of the remote lymphcollectors, to which mediastinal and paraaortic lymph nodes (LN) are referred, reaches 3.5% [8] that raises the issue concerning the optimal volume of lymphodissection or expediency of its enhancement to the D3 volume. Lack of the common surgical tactics, contradictory direct and longterm results of treatment have determined relevance of the present study. The aim of the study was to analyze the direct and longterm results of surgical treatment of patients with locally advanced PGC. OBJECT AND METHODS OF STUDY According to the R.J. Siewert [4], PGC are divided into 3 types: I tumor in distal part of esophagus (Barrett s adenocarcinoma of the distal esophagus); II tumor in gastroesophageal junction; III subcardiac tumor. In this research are represented results of treatment of patients with tumors of II and III type. Stratification of the present data is based on the A.A. Rusanov classification [6], which became most popular in CIS: cardiac cancer tumor of cardiac stomach; b) gastrocardiac cancer tumor of cardiac and downstream regions of stomach; c) cardioesophageal cancer tumor of cardiac region of stomach with dissemination in esophagus; d) gastroesophageal cancer most large involvement of stomach, which includes downstream regions of stomach and esophagus. Analysis of the results of surgical treatment of 80 PGC patients, who underwent treatment on the basis of clinics of cancer of CRI «Oncologic Clinical Dispensary named after V.M. Efetov» over the period from 999 to 008, became the basis of our retrospective study. Taking into account the volume of surgical intervention, patients have been divided into comparable groups: the study group 73 patients, who underwent combined surgery due to the local dissemination of gastric tumor, and control 07 patients, who underwent standard by volumes surgical interventions. Mean age of patients of the study group has constituted 60.5 ± 7.9 years, control 6.9±7.3 years (p = 0.4). Ratio of men to women in the study group has constituted 49 (67.%) to 4 (3.9%), in control 73 (68.%) to 34 (3.8%). Program of study was the same for the all patients of both groups and included application of clinical, instrumental and laboratory methods of examination. For evaluation of dissemination of tumor process, fibroesophagogastroscopy, ultrasound investigation of abdominal cavity, radioscopy, computer tomography of organs of thoracic cage and abdominal cavity has been applied (Table ). Table Features of observation groups Rate Study group (n = 73), n (%) Control group (n = 07), n (%) Total number of patients (n =80), n (%) Tumor is stage pt* (0.9) (0.5) Tumor is stage pt (.) (6.7) Tumor is stage pt3 7 (3.3) 94 (87.9) (6.7) Tumor is stage pt4 56 (76.7) 56 (3.) Regional LN pn0 3 (3.5) 47 (43.9) 70 (38.9) Regional LN pn 30 (4.) 45 (4.) 75 (4.7) Regional LN pn 0 (7.4) 5 (4.0) 35 (9.4) Note: *according to the international TNM classification (006 edition) Adenocarcinoma of different stage of differentiation has been diagnosed in 58 (79.4%) patients of the study and 78 (7.9%) patients of control group: signetring cell cancer in (6.4%) and (9.7%) patients correspondingly; by case of epidermoid cancer, lymphoma, sarcoma in every group (.4 and 0.9% correspondingly) has been detected; in control group in 4 (3.8%) patients the dimorphous cancer has been diagnosed and in (0.9%) patient carcinoid. Radical surgeries in R0 volume have been performed in 66 (90.4 ± 3.4%) patients of the study and 0 (95.3 ±.0%) control group. Surgeries in R, R volume referred to palliative have been performed in 7 (9.6 ± 3.4%) patients of the study group and in 5 (4.7 ±.0%) patients of the control group.

3 Out of 73 patients of the study group, who underwent multivisceral resections, true invasion of tumor in adjacent with stomach organs (according to the data of postoperative morphological study) has been diagnosed in 56 patients that constituted 76.7%. In 7 (3.3%) patients, visually detected invasion of tumor in surrounding organs has no morphological confirmation and has been evaluated as inflammatory perigastric infiltration When performing combined surgical interventions, in 3 (43.9 ± 5.8%) patients en bloc resection or resection of one adjacent with stomach organ has been carried out, in 0 (7.4 ± 5.%) patients two, in 6 (8. ± 3.%) three, in 3 (7.8 ± 4.5%) four and in (.7 ±.9%) patients five organs. Volume of multivisceral resections included distal resection of pancreas (), splenopancreatogastrectomy (5), resection of crura and capula of diaphragm (), splenectomy (6), resection of left adrenal gland (6), resection of left lobe of liver (0), resection of mesentery transverse colon (6), planar resection of pancreas (7), resection colon (), nephrectomy (). Following the standards of performance of gastrectomy (proximal resection), independently from macroscopic features of lymph nodes (LN), sizes and form of growth of tumor, the resection of perigastric LN, cellular tissue with LN lengthwise the hepatoduodenal junction, common hepatic artery, left gastric artery, splenic artery has been performed that corresponded the lymphodissection in D volume performed in 75 (97. ±.%) patients. Macroscopic signs of metastasis in LN, which are located lengthwise the abdominal part of aorta, stipulated for the resection of the last ones, starting from retropancreatic part of aorta to zone of esophagealdiaphragm junction that corresponded lymphodissection in D3 volume performed in 5 (.8 ±.%) patients. At carrying out of gastrectomy with resection of esophagus by transtracheal access, additionally the cellular tissue of mediastinum with lower paraesophageal LN has been removed; such intervention has been performed in 30 (6.7 ±.8%) patients. Gastrectomy with resection of lower third of esophagus by abdominalthoracic access supposing performance of doublezone lymphodissection (by ISDE classification, 994) abdominal lymphodissection in volume D and removal of fatty tissue of mediastinum with mediastinal LN to the aortal segment of esophagus or level of bifurcation of thorax has been performed in 65 (36. ± 3.6%) patients. Features of performed surgeries at PGC dependently on localization of tumor in the study (I) and control (II) groups are represented in Table. Table Surgical intervention at PGC Type of surgery Gastrectomy (n = 88) Gastrectomy + resection of esophagus (n = 79) Proximal resection of stomach (n = 3) Localization of tumor I group II group I group II group I group II group Cardiac cancer n 4 5 % 4.5 ±. 5.7 ±.5.5 ± ± 0.0 Gastrocardiac cancer n % 4.0 ± ± ± ± ± ± 7.4 Cardioesophageal cancer n % 8.9 ± ± ± 3.8 Gastroesophageal cancer n 7 5 %.5 ± ± ± 0.0 Total n % 46.6 ± ± ± ± ± ± 7.4 Statistical analysis has been carried out using program of statistical calculations Excel 007, Statistica for Windows v.6.0. Study of direct results of treatment has been conducted using Ucriterion of MannWhitney, Yates corrected Chisquare, exact Fisher test (twotailed). For evaluation of connection between qualitative signs, the coefficient of association φ has been used. Statistical method of study of longterm results of treatment was analysis of survival by KaplanMeier. When comparing survival in several samplings, multisample Gehan test has been applied, at pairwise comparison of samplings twosample test of GehanWilkinson. As critical level of significance of null statistical hypothesis (if no significant intergroup differences were found) was taken Statistically significant was considered criterion of reliability p < 0.05 for all indexes. RESULTS AND DISCUSSION When analyzing indexes reflecting the process of surgical intervention (Table 3), it has been determined that multivisceral resections at performance of gastrectomy, gastrectomy with resection of the lower third of esophagus and proximal resection of stomach are accompanied with reliably higher volume of hemorrhage (р = ; р = 0.000; р = 0.0) compared with standard surgeries. Also the lifespan of patients increases, however, statistically significant difference by this index has been marked only at gastrectomy (р = 0.03).

4 Volume of surgery Intrasurgical indexes of studied groups Gastrectomy Gastrectomy with resection of esophagus Proximal resection of stomach I group II group I group II group I group II group Table 3 Loss of blood, ml 384. ± ± ± ± ± ± 43.7 р Length of surgery, min 00.0 ± ± ± ± ± ± 4.8 р Basing on the analysis of data reflecting direct results of different surgical interventions at PGC (Table 4), the conclusion can be made that frequency of postoperative complications and lethality at performance of multivisceral resection is slightly higher than at standard surgeries, however, no statistically significant differences were determined (p = 0.8 and p = 0.5 correspondingly). Postoperative complications and lethality among patients of studied groups Study group (n = 73) Control group (n = 07) Table 4 Type of complications Number of complications Died Number of complications Died n % (М ± m) n % (М ± m); n % (М ± m) n % (М ± m) Surgical ± 4.5; p = ± 3.; p = ± ±.6 Pancreonecrosis Abscess of abdominal cavity Inconsistence of EIA* Pancreatitis Ileus Wound abscess Mesenteric ischemia Lymphorrhagia Eventration ± ±.7.7 ±.9.3 ±.3.3 ±.3.3 ±.3.3 ±.3.3 ±.3.7 ±.9.3 ±.3.3 ±.3.3 ± ± ±.8.9 ±.3.9 ±.3 Therapeutic ±.9; p = ±.3; p = ± ±.6 Pulmonary embolism Pneumonia Plevritis Cardiac infarction.7 ±.9.3 ±.3.3 ±.3.3 ±.3.7 ±.9.3 ±.3.9 ±.3.9 ±.3.9 ±.3 Total ± ± ± ±. Note: *EIA esophagealintestinal anastamosis. Despite reliable fact of increase of hemorrhage at additional resection or ectomy of organ, it has been determined during stratification of data by number of resected organs and postoperative complications that increase of level of postoperative complications and lethality at increase of quantity of removed and resected organs is not statistically significant. For instance, postoperative complications and lethality at additional resection of one adjacent with stomach organ constituted.5 (р =.0) and 9.4% (р = 0.56) correspondingly, two organs 35 (р = 0.069) and 0% (р =.0), three 33.3 (р = 0.4) and 6.7% (р = 0.5) four 30.8 (р = 0.3) and 5.4% (р = 0.9), five 50.0 (р = 0.9) и 50.0% (р = 0.9). Most of postoperative complications in the study group were associated with resection of pancreas (planar, distal, splenopancreatogastrectomy). Resection of pancreas performed in 44 patients has been accompanied with development of complications in postoperative period in 5 (34.%) patients; at other multivisceral resections in 3 (0.3%) out of 9 cases. Coefficient of association φ has constituted 0.69 (Phisquare = ). Obtained value φ indicates quite weak association (at 0.0 < φ < 0.9) between resection of pancreas and development of postoperative complications, though indexes of this category of patients of the study group statistically significantly (p = 0.07) differ from the same at other surgeries.

5 When analyzing the longterm results of surgical treatment of PGC patients, data of 6 patients have been obtained: 63 from the study and 98 from the control group. In the study group in longterm terms, 46 patients have died, under dynamic observation are 7 patients, lifespan has constituted from to 40 months, MS and MLS 5.0 and 33.6 ± 4.6 months correspondingly. In control group in longterm terms, 7 patients have died, under dynamic observation are 7 patients; lifespan has constituted from to 4 months, MS and MLS 7.5 and 4.5 ± 39. months correspondingly. We have analyzed the survival of patients in studied groups by time intervals ( year, 3 years and 5 years) (Fig. ). Oneyear survival rate in the study group has constituted 59.3 ± 6.3%, in control group 70.4 ± 4.6%; 3year 33.0 ± 6. and 43.5 ± 5.0%; 5year 8.8 ± 6.0 and 35.8 ± 5.0% correspondingly. No statistically significant differences between groups by rates of and 5 year survival were determined (p = 0.3 and p = 0.0 correspondingly); by rate of 3year survival, insignificant tendency (p = 0.078) to the increase of survival after standard surgeries. Next stage of the research was analysis of survival of patients of study group dependently on involvement of LN pn0 (9 patients), pn (3), pn3 (3) (Fig. ). Most optimistic results of treatment have been obtained at lack of lymphogenous metastasis (pn0): MS 3.0 months, MLS 54.9 ± 5.4 months, year survival 69.4 ± 0.8%; 3year 50.0 ±.8%; 5year 44.4 ±.7%. Lymphogenous metastasis worsens prognostic chances. For instance, for patients with involvement of regional LN of category pn, MS has constituted months, MLS 0.8 ± 9.8 months, year survival 47. ±.% (p = 0.7), 3 year 9.0 ± 7.7% (p = 0.038), 5year 5.8 ± 8.4% (p = 0.04). For patients of category рn 3: MS months, MLS 33. ± 38.3 months, year survival 57.9 ± 3.7% (p = 0.39), 3year 30.8 ±.8% (p = 0.3), 5year 5.4 ± 0.0% (p = 0.3). Slightly better rates of survival of category N3 (absence of statistically significant differences from data of subgroup N0) we associate with small sampling of this category. Fig.. Function of survival for patients of the study and control groups

6 Fig.. Function of survival for patients of the study group of category pn0, pn, pn3. The question concerning the expediency of performance of palliative enlarged surgeries in patients of category N3 and M is still open. Though such cases are quite rare (7 observations), the problem needs solution. We follow such positions that if resectability of the main tumor lesion is possible without technical complications, also surgical intervention regarding metastatic involvement shall be performed. Correctness of such tactics is confirmed, firstly, by lack of lethal complications in such category of patients, secondly, by longterm results of treatment: MS 5.0 months, MLS 45.4 ± 58.4 months. These results undoubtedly are better compared with efficacy of symptomatic surgical interventions. CONCLUSIONS. Combined surgeries at locally advanced PGC are accompanied with higher number of postoperative complications and lethal outcomes.. Resection of pancreas is statistically significantly associated with high number of postoperative complications. 3. Regional lymphogenous metastasis at locally advanced PGC worsens longterm results of surgical treatment of patients. 4. Taking into account lack of early diagnostics, surgical treatment of patients in the pt4 stage remains the only chance for prolongation of life. Therefore, studies on improvement of the results of treatment of this category of patients are relevant. REFERENCES. Абдихакимов АН. Результаты хирургического лечения местнораспространенного рака желудка T4NM0. Анналы хирургии 003; : Давыдов МИ, ТерОванесов МД. Рак проксимального отдела желудка: современная классификация, тактика хирургического лечения, факторы прогноза. Рус мед журн 008; 3 (6): Давыдов МИ, ТерОванесов МД, Абдихакимов АН и др. Рак желудка: что определяет стандарты хирургического лечения. Практ онкол 00; 7: Киркилевский СИ, Кондрацкий ЮН, Притуляк СН. Восстановление пассажа пищи у больных с распространенным кардиоэзофагеальным раком. Клин онкол 0; 7 (3): Рак в Україні, Захворюваність, смертність, показники діяльності онкологічної служби. Бюл Нац канцерреєстру України 0; (): 38, Русанов АА. Рак пищевода и кардиального отдела желудка. Хирургия 978; 6: Скоропад ВЮ. Рациональная тактика лечения местнораспространенного рака желудка: место лучевой терапии. Практ онкол 009; (0): 8 35.

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