围手术期益生菌治疗对新辅助化疗联合胃癌根治术后近期临床结局影响的前瞻性研究

Influence of perioperative probiotics supplement on short⁃term clinical outcomes in gastric cancer patients receiving neoadjuvant chemotherapy combined with radical gastrectomy: a prospective study

  • 摘要:
    目的 探讨围手术期益生菌治疗对新辅助化疗联合胃癌根治术后近期临床结局的影响。
    方法 采用前瞻性随机对照研究方法。选取2020年7月至2021年9月青岛大学附属医院收治的80例行新辅助化疗联合胃癌根治术患者的临床病理资料,按照随机数字表法分为两组。患者围手术期行益生菌治疗设为试验组,围手术期行常规治疗设为对照组。观察指标:(1)入组患者分组情况。(2)术中情况。(3)随访和术后情况。(4)炎症相关血液学指标情况。采用电话和门诊方式进行随访。随访内容包括术后并发症和辅助化疗启动情况。随访时间截至2021年10月31日。正态分布的计量资料以x±s表示,组间比较采用独立样本t检验;偏态分布的计量资料以M(范围)表示,组间比较采用Mann‑Whitney U检验。计数资料以绝对数表示,组间比较采用χ²检验或Fisher确切概率法。等级资料采用Mann‑Whitney U检验。重复测量数据采用重复测量方差分析或广义估计方程。
    结果 (1)入组患者分组情况:筛选出符合条件的患者80例,男51例,女29例;年龄为64(42~80)岁。80例患者中,试验组和对照组各40例。(2)术中情况:两组患者均顺利施行胃癌根治术。试验组患者新辅助治疗后TNM分期(0期、Ⅰ期、Ⅱ期、Ⅲ期),手术方式(腹腔镜胃癌根治术、达芬奇机器人手术系统胃癌根治术),手术时间,术中出血量,消化道重建方式(Billroth Ⅱ吻合、Roux⁃en⁃Y吻合)分别为2、7、15、13例,19、21例,205(180~240)min,50(30~60)mL,6、34例;对照组上述指标分别为4、6、12、16例,23、17例,218(190~251)min,50(43~60)mL,11、29例;两组患者上述指标比较,差异均无统计学意义(U=683.00,χ²=0.80,U=668.00、681.00,χ²=1.87,P>0.05)。(3)随访和术后情况:80例患者均获得术后1个月随访。试验组和对照组患者术后感染性并发症分别为6例和15例,两组比较,差异有统计学意义(χ²=5.23,P<0.05)。试验组患者抗菌药物使用、术后肛门首次排气时间、术后首次排便时间、固体食物耐受时间、术后住院时间、术后化疗启动时间分别为3(3~6)剂、53(49~66)h、72(62~82)h、(72±18)h、6.0(5.5~7.0)d、26.0(25.0~28.0)d;对照组上述指标分别为6(3~10)剂、66(60~88)h、94(82~112)h、(107±23)h、7.0(6.4~8.3)d、30.0(28.0~33.0)d;两组患者上述指标比较,差异均有统计学意义(U=471.50、432.00、343.50,t=-7.62,U=411.50、319.50,P<0.05)。(4)炎症相关血液学指标情况:①试验组患者术前及术后第1、3、5天白细胞计数分别为(5.6±1.4)×109/L、(9.9±3.2)×109/L、(7.7±2.6)×109/L、(6.8±1.8)×109/L;对照组分别为(6.1±1.9)×109/L、(12.3±2.9)×109/L、(9.7±3.6)×109/L、(7.8±2.7)×109/L,满足球形检验(χ²=4.17,P>0.05),采用主体内效应检验结果显示:两组患者白细胞计数的时间效应、干预效应、交互效应比较,差异均有统计学意义(F=106.61、10.45、4.56,P<0.05)。②试验组患者术前及术后第1、3、5天中性粒细胞百分比分别为55%±10%、76%±11%、73%±9%、69%±9%;对照组分别为56%±9%、84%±5%、79%±8%、74%±9%,不满足球形检验(χ²=16.63,P<0.05),采用多变量检验结果显示:两组患者中性粒细胞百分比的时间效应、干预效应、交互效应比较,差异均有统计学意义(F=92.42、11.46、5.55,P<0.05)。③试验组患者术前及术后第1、3、5天C‑反应蛋白分别为1.35(1.15~1.97)mg/L、14.94(8.24~21.22)mg/L、33.39(13.02~66.02)mg/L、18.36(8.27~60.43)mg/L;对照组分别为1.62(0.97~2.27)mg/L、24.03(10.42~36.52)mg/L、81.66(31.20~116.76)mg/L、46.84(28.30~80.26)mg/L,不满足正态分布,采用广义估计方程统计学检验结果显示:两组患者C‑反应蛋白的时间效应、干预效应、交互效应比较,差异均有统计学意义(Waldχ²=145.74、9.48、9.90,P<0.05)。④试验组患者术前及术后第1、3、5天降钙素原分别为0.02(0.02~0.04)μg/L、0.08(0.06~0.12)μg/L、0.12(0.07~0.21)μg/L、0.09(0.06~0.15)μg/L;对照组分别为0.02(0.02~0.04)μg/L、0.14(0.07~0.71)μg/L、0.35(0.14~0.71)μg/L、0.24(0.10~0.48)μg/L,不满足正态分布,采用广义估计方程统计学检验结果显示:两组患者降钙素原的时间效应、干预效应、交互效应比较,差异均有统计学意义(Waldχ²=62.88、14.71、18.33,P<0.05)。
    结论 新辅助化疗联合胃癌根治术患者行围手术期益生菌治疗,可降低术后感染性并发症发生率、减少抗菌药物使用、加快胃肠道功能恢复、降低术后炎性指标、缩短术后住院时间,可尽早行术后化疗。

     

    Abstract:
    Objective To investigate the influence of perioperative probiotics supplement on short⁃term clinical outcomes in gastric cancer patients receiving neoadjuvant chemotherapy combined with radical gastrectomy.
    Methods The prospective randomized controlled study was conducted. The clinicopathological data of 80 patients who underwent neoadjuvant chemotherapy combined with radical gastrectomy in the Affiliated Hospital of Qingdao University from July 2020 to September 2021 were selected. Based on random number table, patients were allocated into two groups. Patients undergoing perioperative probiotics supplement were allocated into the experiment group, and patients undergoing perioperative conventional treatment were allocated into the control group, respectively. Observation indicators: (1) grouping situations of the enrolled patients; (2) intraoperative situations; (3) follow‑up and postoperative situations; (4) inflammation related hematological indexes. Follow‑up was conducted using telephone interview and outpatient examina-tion to detect postoperative complications and startup of adjuvant chemotherapy up to October 31,2021. Measurement data with normal distribution were represented as Mean±SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M(range), and comparison between groups was conducted using the Mann‑Whitney U test. Count data were described as absolute numbers, and comparison between groups was performed using the chi‑square test or Fisher exact probability. Comparison of ordinal data was analyzed using the Mann‑Whitney U test. Repeated measurement data were analyzed by the repeated ANOVA or generalized estimating equation.
    Results (1) Grouping situations of the enrolled patients. A total of 80 patients were selected for eligibility. There were 51 males and 29 females, aged 64(42-80)years. Of the 80 patients, there were 40 patients in the experiment group and 40 patients in the control group, respectively. (2) Intraoperative situations. All patients in the experiment group and the control group underwent radical gastrectomy successfully. Cases with yield pathologic TNM (ypTNM) stage 0, stage Ⅰ, stage Ⅱ, stage Ⅲ after neoadjuvant chemotherapy, cases undergoing laparoscopic radical gastrectomy or Da Vinci robotic radical gastrectomy, the operation time, the volume of intraoperative blood loss, cases undergoing digestive tract recons-truction as Billroth Ⅱ anastomosis or Roux‑en‑Y anastomosis were 2, 7, 15, 13, 19, 21,205(180-240)minutes, 50(30-60)mL, 6, 34 in the experiment group, versus 4, 6, 12, 16, 23, 17, 218(190-251)minutes, 50(43-60)mL, 11, 29 in the control group, showing no significant difference in the above indicators between the two groups (U=683.00, χ²=0.80, U=668.00, 681.00, χ²=1.87, P>0.05). (3) Follow‑up and postoperative situations. All the 80 patients were followed up for 1 month after surgery. Cases with postoperative infectious complications were 6 in the experiment group, versus 15 in the control group, showing a significant difference between the two groups (χ²=5.23, P<0.05). The application of antimicrobial agent, time to postoperative first flatus, time to postoperative first defecation, time to tolerance of solid food, duration of postoperative hospital stay, time to postopera-tive startup of adjuvant chemotherapy were 3(3-6)doses, 53(49-66)hours, 72(62-82)hours, (72±18)hours, 6.0(5.5-7.0)days, 26.0(25.0-28.0)days in the experiment group, versus 6(3-10)doses, 66(60-88)hours, 94(82-112)hours, (107±23)hours, 7.0(6.4-8.3)days, 30.0(28.0-33.0)days in the control group, showing significant differences in the above indicators between the two groups (U=471.50, 432.00, 343.50, t=-7.62, U=411.50, 319.50, P<0.05). (4) Inflam-mation related hematological indexes. ① The white blood cell counts before surgery and at postoperative day 1, 3, 5 were (5.6±1.4)×109/L, (9.9±3.2)×109/L, (7.7±2.6)×109/L, (6.8±1.8)×109/L in the experiment group, versus (6.1±1.9)×109/L, (12.3±2.9)×109/L, (9.7±3.6)×109/L, (7.8±2.7)×109/L in the control group, meeting the mauchly′s test of sphericity (χ²=4.17, P>0.05). Results of intrasubject effect test showed that there were significant differences in the time effect, intervention effect and interaction effect of white blood cell counts between the two groups (F=106.61, 10.45, 4.56, P<0.05). ② The neutrophilic granulocyte percentages before surgery and at postoperative day 1, 3, 5 were 55%±10%, 76%±11%, 73%±9%, 69%±9% in the experiment group, versus 56%±9%, 84%±5%, 79%±8%, 74%±9% in the control group, not meeting the mauchly′s test of sphericity (χ²=16.63, P<0.05). Results of multi-variate test showed that there were significant differences in the time effect, intervention effect and interaction effect of neutrophilic granulocyte percentages between the two groups (F=92.42, 11.46, 5.55, P<0.05). ③ The levels of C‑reactive protein before surgery and at postoperative day 1, 3, 5 were 1.35(1.15-1.97)mg/L, 14.94(8.24-21.22)mg/L, 33.39(13.02-66.02)mg/L, 18.36(8.27-60.43)mg/L in the experiment group, versus 1.62(0.97-2.27)mg/L, 24.03(10.42-36.52)mg/L, 81.66(31.20-116.76)mg/L, 46.84(28.30-80.26)mg/L in the control group, not meeting the normal distribution. Results of generalized estimation equation test showed that there were significant differences in the time effect, intervention effect and interaction effect of levels of C‑reactive protein between the two groups (Waldχ²=145.74, 9.48, 9.90, P<0.05). ④ The levels of procalcitonin before surgery and at postoperative day 1, 3, 5 were 0.02(0.02-0.04)μg/L, 0.08(0.06-0.12)μg/L, 0.12(0.07-0.21)μg/L, 0.09(0.06-0.15)μg/L in the experiment group, versus 0.02(0.02-0.04)μg/L, 0.14(0.07-0.71)μg/L, 0.35(0.14-0.71)μg/L, 0.24(0.10-0.48)μg/L in the control group, not meeting the normal distribution. Results of generalized estimation equation test showed that there were signifi-cant differences in the time effect, intervention effect and interaction effect of levels of procalcitonin between the two groups (Waldχ²=62.88, 14.71, 18.33, P<0.05).
    Conclusion Perioperative supple-ment of probiotics can reduce the incidence of postoperative infectious com-plications and the application of antimicrobial agent, promote recovery of gastrointestinal function, reduce the level of inflammation related indexes, shorten the duration of postoperative hospital stay and the time to postoperative startup of chemotherapy in patients undergoing neoadjuvant chemotherapy combined with radical gastrectomy.

     

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