转化手术治疗Ⅳ期胃癌的临床疗效

Clinical efficacy of surgical treatment for stage Ⅳ gastric cancer after conversion therapy

目的：探讨转化治疗后手术治疗Ⅳ期胃癌的临床疗效。方法：采用回顾性队列研究方法。收集2012年1月至2016年6月大连医科大学附属第一医院收治的50例Ⅳ期胃癌的患者的临床病理资料。50例患者均为单一远处转移，均进行化疗，其中21例患者化疗后具备手术指征，行胃切除术（R0切除或R1切除），设为转化手术治疗组；29例化疗后评估无手术指征，仅给予化疗，设为单纯化疗组。患者行S1＋奥沙利铂方案或S1＋多西他赛方案化疗。化疗后患者行开腹远端或全胃切除术。观察指标：（1）化疗疗效评估（完全缓解、部分缓解、疾病稳定、疾病进展病例数），不良反应分级。（2）转化手术治疗组患者的术中及术后情况：手术方式，术中情况（手术时间、术中出血量、淋巴结清扫数目、手术切缘）和术后情况（术后并发症、术后住院时间）。（3）两组患者的随访和生存情况比较。（4）影响Ⅳ期胃癌患者预后的因素分析。采用门诊、信件和电话等方式进行随访。了解患者术后生存情况。记录的生存时间是自手术当日至末次随访时间或死亡时间。随访时间截至2016年9月。正态分布的计量资料以±s表示。计数资料比较和单因素分析采用x2检验。等级资料采用非参数检验。采用KaplanMeier法计算生存率，生存分析比较采用Logrank检验。采用COX比例风险模型进行多因素分析。结果：（1）化疗疗效评估：50例患者中， 24例采用S1＋奥沙利铂方案，26例采用S1＋多西他赛方案。转化手术治疗组21例患者化疗后，腹膜转移均阴性、淋巴结转移N2期以内（第16组淋巴结消失或缩小）、肿瘤浸润深度〈T4b期、肝转移明显缩小或消失。术前中位化疗周期为4.2个周期（2.0～9.0个周期）。21例患者对化疗反应为：15例部分缓解，6例疾病稳定。单纯化疗组29例患者化疗后不符合手术指征，未行手术治疗。一线化疗的中位化疗周期为 5.5个周期（2.0～10.0个周期）。29例患者对化疗反应为：13例部分缓解，11例疾病稳定，5例疾病进展。50例患者化疗不良反应：26例WBC减少，其中6例为Ⅲ～Ⅳ级；29例中性粒细胞减少，其中12例为Ⅲ～ Ⅳ级；18例贫血，其中6例为Ⅲ～Ⅳ级；12例PLT减少，其中2例为Ⅲ～Ⅳ级；27例厌食症，其中5例为Ⅲ～Ⅳ级；7例口腔炎；9例腹泻；3例Cr升高；4例手足综合征；3例神经感觉异常。无化疗相关死亡发生。（2）转化手术治疗组患者的术中及术后情况：转化手术治疗组21例患者中，8例行根治性全胃切除＋D3淋巴结廓清术，6例行根治性远端胃切除＋D3淋巴结清扫术，7例行根治性远端胃切除＋D2淋巴结清扫术（包括 4例联合肝脏转移瘤切除、1例肝转移瘤RFA）。21例患者的手术时间为（216±31）min，术中出血量为 （128±52）mL，淋巴结清扫数目为（31±8）枚，17例R0切除，4例R1切除（3例胃切缘阳性、1例肝脏切缘阳性）。术后胃肠功能恢复时间为（3.0±0.7）d。无死亡患者。21例患者中7例出现术后并发症，其中胰瘘 2例、腹腔出血1例、肠梗阻1例、肺炎1例、腹腔感染1例、切口感染1例，均经保守治疗后痊愈出院。 21例患者术后住院时间为（13.0±3.0）d。（3）两组患者的随访和生存情况比较：50例患者均获得随访，随访时间为6～46个月，中位随访时间为24个月。转化手术治疗组和单纯化疗组患者3年累积生存率分别为33.3%和6.9%，两组比较，差异有统计学意义（x^2=7.678，P〈0.05）。进一步分析结果显示：转化手术治疗组21例患者中17例R0切除患者生存时间为（25.3±2.8）个月，4例R1切除患者生存时间为（8.3± 0.9）个月，两者比较，差异有统计学意义（x^2=16.242，P〈0.05）。（4）影响Ⅳ期胃癌患者预后的因素分析：单因素分析结果显示：肿瘤T分期、N分期、化疗疗效评估、化疗后手术及肿瘤根治程度是影响Ⅳ期胃癌患者预后的相关因素（x^2=5.288，12.645，25.581，8.372，12.001，P〈0.05）。多因素分析结果显示：转化治疗后肿瘤根治程度为R1切除是Ⅳ期胃癌患者预后不良的独立危险因素（HR=14.021，95%可信区间：1.928～10.938，P〈0.05）。结论：Ⅳ期胃癌患者进行转化治疗后行根治性手术可提高患者生存率，转化治疗后肿瘤根治程度为R1切除是Ⅳ期胃癌患者预后不良的独立危险因素。

Objective：To investigate the clinical efficacy of surgical treatment for stage Ⅳ gastric cancer after conversion therapy. Methods：The retrospective cohort study was conducted. The clinicopathological data of 50 stage Ⅳ gastric cancer patients who were admitted to the First Affiliated Hospital of Dalian Medical University between January 2012 and June 2016 were collected. All the 50 patients who were diagnosed with single distal metastasis underwent chemotherapy. After chemotherapy, 21 patients with operation indication receiving gastrectomy （R0 or R1 resection） were allocated into the conversion surgery group and 29 without operation indication continuing to chemotherapy were allocated into the chemotherapy group. Patients received S1＋oxaliplatin or S1 ＋ docetaxel regimen. Patients underwent open distal or total gastrectomy. Observation indicators： （1） response assessment of chemotherapy （complete remission, partial remission, stable disease and progressive disease）, grading of of adverse reactions; （2） intra and postoperative situations of conversion surgery group： operation procedures, intraoperative situations （operation time, volume of blood loss, number of lymph node dissected and surgical margin） and postoperative situations （complications and duration of hospital stay）; （3） comparison of followup and survival between the 2 groups; （4） prognostic factors analysis affecting stage Ⅳ gastric cancer patients. Followup using outpatient examination, correspondence and telephone interview was performed to detect postoperative survival of patients up to September 2016. Survival time was from operation to the last followup or death. Measurement data with normal distribution were represented as ±s. Comparison of count data and univariate analysis were done using the chisquare test. Ordinal data were analyzed by the nonparametric test. The survival rate was calculated by the KaplanMeier method, and the Logrank test was used for survival analysis. Multivariate analysis was done using the COX regression model. Results：（1） Response assessment of chemotherapy： of 50 patients, 24 received S1 ＋ oxaliplatin regimen and 26 received S1 ＋ docetaxel regimen. Twentyone patients in the conversion surgery group underwent chemotherapy, with negative peritoneal metastasis, N2 and below of lymph node metastasis （No.16 lymph node disappeared or reduced）, invasive depth 〈T4b and narrowing or disappeared hepatic metastasis. A median preoperative chemotherapy cycle was 4.2 cycles （range, 2.0-9.0 cycles）. Chemotherapy reaction of 21 patients： 15 had partial remission and 6 had stable disease. Twentynine patients without operation indication in the chemotherapy group didn′t receive surgery. The median cycle of firstline chemotherapy was 5.5 cycles （range, 2.0-10.0 cycles）. Chemotherapy reaction of 29 patients： 13 had partial remission, 11 had stable disease and 5 patient had progressive disease. Chemotherapy adverse reactions of 50 patients： 26 had reduced white blood cells （WBCs）, including 6 with grade Ⅲ-Ⅳ of adverse reactions; 29 had reduced neutrophils, including 12 with grade Ⅲ-Ⅳ of adverse reactions; 18 had anemia, including 6 with grade Ⅲ-Ⅳ of adverse reactions; 12 had reduced platelets, including 2 with grade Ⅲ-Ⅳ of adverse reactions; 27 had apositia, including 5 with grade Ⅲ-Ⅳ of adverse reactions; 7 had stomatitis; 9 had diarrhea; 3 had elevated serum creatinin; 4 had handfoot syndrome; 3 had abnormal sensory nerve. There was no chemotherapyrelated death. （2） Intra and postoperative situations of conversion surgery group： of 21 patients in the conversion surgery group, 8 underwent radical total gastrectomy ＋ D3 lymph node dissection, 6 underwent radical distal gastrectomy ＋ D3 lymph node dissection and 7 underwent radical distal gastrectomy ＋ D2 lymph node dissection （including 4 combined with resection of hepatic metastatic tumors and 1 combined with radiofrequency ablation of hepatic metastatic tumor）. Operation time, volume of blood loss, number of lymph node dissected and recovery time of gastrointestinal function of 21 patients were （216±31）minutes, （128±52）mL, 31±8 and （3.0±0.7）days, respectively. There were 17 patients receiving R0 resection and 4 receiving R1 resection （3 with positive gastric margin and 1 with positive hepatic margin）. There was no death. Seven of 21 patients with complications were cured by conservative treatment, including 2 with pancreatic fistula, 1 with intraabdominal hemorrhage, 1 with intestinal obstruction, 1 with pneumonia, 1 with intraabdominal infection and 1 with wound infection. Duration of hospital stay of 21 patients was （13.0±3.0）days. （3） Comparison of followup and survival between the 2 groups： 50 patients were followed up for 6-46 months, with a median time of 24 months. The 3year cumulative survival rates in the conversion surgery and chemotherapy groups were respectively 33.3% and 6.9%, with a statistically significant difference between the 2 groups （x^2=7.678, P〈0.05）. Results of further analysis showed that R0 resection of 17 patients and R1 resection of 4 patients in the conversion surgery group were respecgtively （25.3±2.8）months and （8.3±0.9）months, with a statistically significant difference between the 2 groups （x^2=16.242, P〈0.05）. （4） Prognostic factors analysis affecting stage Ⅳ gastric cancer patients： results of univariate analysis showed that T stage, N stage, response assessment of chemotherapy, surgery after chemotherapy and degree of tumor radical resection were related factors affecting prognosis of stage Ⅳ gastric cancer patients （x^2=5.288, 12.645, 25.581, 8.372, 12.001, P〈0.05）. Results of multivariate analysis showed that R1 resection after conversion therapy was an independent risk factor affecting prognosis of stage Ⅳ gastric cancer patients （HR=14.021, 95% confidence interval： 1.928-10.938, P〈0.05）. Conclusion：Radical resection after conversion therapy can increase survival rate of stage Ⅳ gastric cancer patients, and R1 resection after conversion therapy is an independent risk factor affecting poor prognosis of stage Ⅳ gastric cancer patients.