新辅助化疗期间肌肉指数变化值预测胃癌根治术预后的临床价值

Clinical value of muscle index changing value during neoadjuvant chemotherapy in predicting the prognosis of gastric cancer after radical gastrectomy

  • 摘要:
    目的 探讨新辅助化疗期间肌肉指数变化值预测胃癌根治术预后的临床价值。
    方法 采用回顾性队列研究方法。收集2010年1月至2017年12月3家医学中心收治的362例(福建医科大学附属协和医院163例、青海大学附属医院141例、圣玛丽亚医院58例)行新辅助化疗联合胃癌根治术病人的临床病理资料;男270例,女92例;中位年龄为61岁,年龄范围为26~79岁。362例病人中,福建医科大学附属协和医院与青海大学附属医院收治的304例病人设为建模组;圣玛丽亚医院收治的58例病人设为验证组。观察指标:(1)建模组病人行新辅助化疗期间身体成分、肿瘤标志物及应激状态指标变化情况。(2)随访及生存情况。(3)影响建模组病人预后因素分析。(4)预后预测模型的构建与比较。(5)预后预测模型评价。采用门诊、电话、信件方式进行随访,了解病人术后生存情况。随访时间截至2021年4月。正态分布的计量资料以x±s表示。偏态分布的计量资料以M(范围)表示。计数资料以绝对数表示。单因素和多因素分析采用COX比例风险模型。采用Kaplan‑Meier法计算生存时间,采用Log‑rank检验进行生存分析。
    结果 (1)建模组病人行新辅助化疗期间身体成分、肿瘤标志物及应激状态指标变化情况。建模组304例病人行新辅助化疗前皮下脂肪指数、内脏脂肪指数、肌肉指数、癌胚抗原(CEA)、CA19‑9、体质量指数(BMI)、预后营养指数(PNI)、修正全身炎症评分(mSIS)分别为31.2 cm2/m2(0.6~96.0 cm2/m2),25.1 cm2/m2(0.1~86.3 cm2/m2),47.1 cm2/m2(27.6~76.6 cm2/m2),43.2 μg/L(0.2~1 000.0 μg/L),108.7 U/mL(0.6~1 000.0 U/mL),21.9 kg/m2(15.6~29.7 kg/m2),46.8(28.6~69.0),(1.0±0.8)分;行胃癌根治术前上述指标分别为32.5 cm2/m2(5.1~112.0 cm2/m2),25.4 cm2/m2(0.2~89.0 cm2/m2),47.0 cm2/m2(16.8~67.0 cm2/m2),17.0 μg/L(0.2~1 000.0 μg/L),43.9 U/mL(0.6~1 000.0 U/mL),21.6 kg/m2(31.1~29.0 kg/m2),47.7(30.0~84.0),(1.0±0.8)分;行新辅助化疗期间上述指标变化值分别为1.4 cm2/m2(-31.0~35.1 cm2/m2),0.2 cm2/m2(-23.5~32.6 cm2/m2),-0.1 cm2/m2(-18.2~15.9 cm2/m2), -26.2 μg/L(-933.5~89.9 μg/L),-64.9 U/mL(-992.1~178.6 U/mL),-0.3 kg/m2(-9.7~7.1 kg/m2),0.9(-27.1~38.2),(0.0±0.8)分。(2)随访及生存情况。建模组304例病人中,284获得随访,随访时间为3~130个月,中位随访时间为36个月;随访期间,130例病人因肿瘤复发转移死亡,9例病人因非肿瘤原因死亡,病人5年总体生存率为54.6%。验证组58例病人中,52例获得随访,随访时间为2~91个月,中位随访时间为29个月;随访期间,21例病人死亡,病人5年总体生存率为63.8%。(3)影响建模组病人预后因素分析。单因素分析结果显示:术后病理学类型、术后病理学分期是影响建模组304例胃癌病人行胃癌根治术后5年总体生存率风险比=1.685,2.619,95%可信区间(CI)为1.139~2.493,1.941~3.533,P<0.05和5年疾病无进展生存率的相关因素(风险比=1.468,2.577,95%CI为1.000~2.154,1.919~3.461,P<0.05)。多因素分析结果显示:术后病理学类型、术后病理学分期是建模组304例病人行胃癌根治术后5年总体生存率的独立影响因素(风险比=1.508,2.287,95%CI为1.013~2.245,1.691~3.093,P<0.05);术后病理学分期是建模组304例病人行胃癌根治术后5年疾病无进展生存率的独立影响因素(风险比=2.317,95%CI为1.719~3.123,P<0.05)。(4)预后预测模型的构建与比较。304例建模组胃癌病人皮下脂肪指数变化值、内脏脂肪指数变化值、CEA变化值、CA19‑9变化值、BMI变化值、PNI变化值、mSIS变化值预后预测模型受试者工作特征曲线下面积(AUC)分别为0.549(95%CI为0.504~0.593)、0.501(95%CI为0.456~0.546)、0.566(95%CI为0.521~0.610)、0.519(95%CI为0.474~0.563)、0.588(95%CI为0.545~0.632)、0.553(95%CI为0.509~0.597)、0.539(95%CI为0.495~0.584),与肌肉指数变化值预后预测模型AUC0.661(95%CI为0.623~0.705)比较,差异均有统计学意义(Z=3.960,5.326,3.353,4.786,2.455,3.448,3.987,P<0.05)。肌肉指数变化值预后预测模型最佳截点值为0.7 cm2/m2,Kaplan‑Meier生存曲线结果显示:建模组肌肉指数变化值<0.7 cm2/m2胃癌病人与肌肉指数变化值≥0.7 cm2/m2胃癌病人总体生存率和疾病无进展生存率比较,差异均有统计学意义(χ²=27.510,21.830,P<0.05)。选取肌肉指数变化值、术后病理学类型、术后病理学分期为预后指标,在建模组病人中构建肌肉指数变化值+术后病理学类型+术后病理学分期列线图预后预测模型,其在建模组和验证组的AUC分别为0.762(95%CI为0.708~0.815)和0.788(95%CI为0.661~0.885),术后病理学分期预后预测模型在建模组和验证组的AUC分别为0.706(95%CI为0.648~0.765)和0.727(95%CI为0.594~0.835),列线图预后预测模型与术后病理学分期预后预测模型建模组和验证组AUC比较,差异均有统计学意义(Z=3.522,1.830,P<0.05)。(5)预后预测模型评价。肌肉指数变化值+术后病理学类型+术后病理学分期列线图预后预测模型结果显示:列线图风险评分0~6分为低风险,评分>6分且≤10分为中低风险,评分>10分且≤13分为中高风险,评分>13分为高危风险。Kaplan‑Meier生存曲线结果显示:建模组及验证组低风险、中低风险、中高风险、高风险病人总体生存率比较,差异均有统计学意义(χ²=75.276,14.989,P<0.05)。决策曲线分析结果显示:在建模组和验证组中,肌肉指数变化值+术后病理学类型+术后病理学分期列线图预后预测模型预测性能优于术后病理学分期预后预测模型。
    结论 新辅助化疗期间病人肌肉指数变化值可作为胃癌根治术后病人预后预测指标,肌肉指数变化值+术后病理学类型+术后病理学分期列线图风险评分可评估病人行胃癌根治术后生存预后。

     

    Abstract:
    Objective To investigate the clinical value of muscle index changing value during neoadjuvant chemotherapy in predicting the prognosis of gastric cancer after radical gastrec-tomy.
    Methods The retrospective cohort study was conducted. The clinicopathological data of 362 gastric cancer patients undergoing neoadjuvant chemotherapy combined with radical gastrectomy in 3 medical centers, including 163 cases in Fujian Medical University Union Hospital, 141 cases in the Affiliated Hospital of Qinghai University and 58 cases in St. Mary′s Hospital, from January 2010 to December 2017 were collected. There were 270 males and 92 females, aged from 26 to 79 years, with a median age of 61 years. Of 362 patients, 304 cases in Fujian Medical University Union Hospital and the Affiliated Hospital of Qinghai University were allocated into modeling group and 58 cases in St. Mary′s Hospital were allocated into validation group. Observation indicators: (1) changes of indicators including body composition parameters, tumor markers and stress status indicators in patients in modeling group during neoadjuvant chemotherapy; (2) follow‑up and survival of patients; (3) analysis of risk factor affecting prognosis of patients in modeling group; (4) construc-tion and comparison of prognostic prediction models; (5) evaluation of prognostic prediction models. Follow‑up was conducted using outpatient examination, telephone interview and mail communication to detect postoperative survival of patients up to April 2021. Measurement data with normal distribution were represented as Mean±SD. Measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers. Univariate and multivariate analysis were performed using the COX proportional hazard model. The Kaplan‑Meier method was used to calculate survival rates and draw survival curves. The Log‑rank test was used for survival analysis.
    Results (1) Changes of indicators including body composition parameters, tumor markers and stress status indicators in patients in modeling group during neoadjuvant chemotherapy: the subcutaneous adipose index, visceral adipose index, muscle index, carcinoem-bryonic antigen, CA19‑9, body mass index, prognostic nutritional index and modified systemic inflammation score of 304 gastric cancer patients in the modeling group before neoadjuvant chemotherapy were 31.2 cm2/m2(range, 0.6‒96.0 cm2/m2), 25.1 cm2/m2(range, 0.1‒86.3 cm2/m2), 47.1 cm2/m2(range, 27.6‒76.6 cm2/m2), 43.2 μg/L(range, 0.2‒1 000.0 μg/L), 108.7(range, 0.6‒ 1 000.0)U/mL, 21.9 kg/m2(range, 15.6‒29.7 kg/m2), 46.8(range, 28.6‒69.0), 1.0±0.8, respectively. The above indicators of 304 gastric cancer patients in the modeling group before radical gastrec-tomy were 32.5 cm2/m2(range, 5.1‒112.0 cm2/m2), 25.4 cm2/m2(range, 0.2‒89.0 cm2/m2), 47.0 cm2/m2(range, 16.8‒67.0 cm2/m2), 17.0 μg/L(range, 0.2‒1 000.0 μg/L), 43.9 U/mL(range, 0.6‒1 000.0 U/mL), 21.6 kg/m2(range, 31.1‒29.0 kg/m2), 47.7(range, 30.0‒84.0), 1.0±0.8, respectively. The changing value of above indicators of 304 gastric cancer patients in the modeling group during neoadjuvant chemotherapy were 1.4 cm2/m2(range, ‒31.0‒35.1 cm2/m2), 0.2 cm2/m2(range, ‒23.5‒32.6 cm2/m2), ‒0.1 cm2/m2(range, ‒18.2‒15.9 cm2/m2), ‒26.2 μg/L(range, ‒933.5‒89.9 μg/L), ‒64.9 U/mL(range, ‒992.1‒178.6 U/mL), ‒0.3 kg/m2(range, ‒9.7‒7.1 kg/m2), 0.9(range, ‒27.1‒38.2), 0.0±0.8, respec-tively. (2) Follow‑up and survival of patients: 284 of 304 patients in the modeling group were followed up for 3 to 130 months, with a median follow‑up time of 36 months. During follow‑up, 130 cases died of tumor recurrence and metastasis and 9 cases died of non‑tumor causes. The 5‑year overall survival rate was 54.6%. Fifty‑two of 58 patients in the validation group were followed up for 2 to 91 months, with a median follow‑up time of 29 months. During follow‑up, 21 cases died with the 5‑year overall survival rate of 63.8%. (3) Analysis of risk factor affecting prognosis of patients in modeling group: results of univariate analysis showed that the postoperative pathological type and postoperative pathological staging were related factors affecting 5‑year overall survival rate hazard ratio=1.685, 2.619, 95% confidence interval(CI): 1.139‒2.493, 1.941‒3.533, P<0.05 and 5-year progression free rate survival of 304 gastric cancer patients in the modeling group after radical gastrectomy (hazard ratio=1.468, 2.577, 95%CI: 1.000‒2.154, 1.919‒3.461, P<0.05). Results of multivariate analysis showed that the postoperative pathological type and postoperative pathological staging were independent influencing factors for 5‑year overall survival rate of 304 gastric cancer patients in the modeling group after radical gastrectomy (hazard ratio=1.508, 2.287, 95%CI: 1.013‒2.245, 1.691‒3.093, P<0.05) and the postoperative patholo-gical staging was an independent influencing factor for 5‑year progression free survival rate of 304 gastric cancer patients in the modeling group after radical gastrectomy (hazard ratio= 2.317,95%CI: 1.719‒3.123, P<0.05). (4) Construction and comparison of prognostic prediction models: the area under curve (AUC) of prognostic prediction model of subcutaneous adipose index changing value, visceral adipose index changing value, carcinoembryonic antigen changing value, CA19‑9 changing value, body mass index changing value, prognostic nutritional index changing value, modified systemic inflammation score changing value for 304 gastric cancer patients in the modeling group were 0.549(95%CI: 0.504‒0.593), 0.501(95%CI: 0.456‒0.546), 0.566(95%CI: 0.521‒0.610), 0.519(95%CI: 0.474‒0.563), 0.588(95%CI: 0.545‒0.632), 0.553(95%CI: 0.509‒0.597), 0.539(95%CI: 0.495‒0.584). The AUC of prognostic prediction model of muscle index changing value was 0.661(95%CI: 0.623‒0.705) with significant differences to the AUC of prognostic predic-tion model of subcutaneous adipose index changing value, visceral adipose index changing value, carcinoembryonic antigen changing value, CA19‑9 changing value, body mass index changing value, prognostic nutritional index changing value, modified systemic inflammation score changing value, respectively (Z=3.960, 5.326, 3.353, 4.786, 2.455, 3.448, 3.987, P<0.05). The optimum cut‑off value was 0.7 cm2/m2 for prognostic prediction model of muscle index changing. Kaplan‑Meier survival curve showed there were significant differences of overall survival and progression free survival for gastric cancer patients with subcutaneous adipose index changing value <0.7 cm2/m2 and ≥0.7 cm2/m2 in the modeling group (χ²=27.510, 21.830, P<0.05). The nomogram prognostic prediction model was cons-tructed based on 3 prognostic indicators including muscle index change value combined with postoperative pathological type and postoperative pathological staging and the AUC of nomogram prognostic prediction model were 0.762(95%CI: 0.708‒0.815) and 0.788(95%CI: 0.661‒0.885) for the modeling group and the validation group, respectively. The AUC of postoperative pathological staging prognostic prediction model were 0.706(95%CI: 0.648‒0.765) and 0.727(95%CI: 0.594‒0.835)for the modeling group and the validation group, respectively. There were significant differences of the AUC between the nomogram prognostic prediction model of muscle index change value combined with postoperative pathological type and postoperative pathological staging and the postoperative pathological staging prognostic prediction model in the modeling group and the validation group, respectively (Z=3.522, 1.830, P<0.05). (5) Evaluation of prognostic prediction models: the nomogram prognostic prediction model of muscle index change value combined with postoperative pathological type and postoperative pathological staging showed that patients with score of 0‑6 were classified in the low risk group, patients with score of >6 and ≤10 were classified in the moderate‑low risk group, patients with score of >10 and ≤13 were classified in the moderate-high risk group and patients with score of >13 were classified in the high risk group. Kaplan‑Meier survival curve showed there were significant differences of the overall survival between the low risk group, moderate‑low risk group, moderate‑high risk group and high risk group patients in the modeling group and the validation group, respectively (χ²=75.276, 14.989, P<0.05). Results of decision making curve showed the nomogram prognostic prediction model of muscle index change value combined with postoperative pathological type and postoperative pathological staging had better clinical utility than the postoperative pathological staging prognostic prediction model in the modeling group and the validation group.
    Conclusions The muscle index changing value of gastric cancer patient during neoadjuvant chemotherapy can be used as a prognostic indicator for gastric cancer patient prognosis after radical gastrectomy. The risk score of the nomogram prognostic prediction model of muscle index change value combined with postoperative pathological type and postoperative pathological staging can be used to evaluate the survival and prognosis of gastric cancer patients after radical gastrectomy.

     

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