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中华结直肠疾病电子杂志

中华结直肠疾病电子杂志 ›› 2021, Vol. 10 ›› Issue (02) : 177 -186. doi: 10.3877/cma.j.issn.2095-3224.2021.02.011

所属专题： 文献；

论著

全程新辅助治疗局部进展期直肠癌疗效和安全性的Meta分析
李干斌1, 韩加刚1,†(), 王振军1   
  1. 1. 100020　北京，首都医科大学附属北京朝阳医院普通外科
  • 收稿日期:2020-08-14 出版日期:2021-04-25
  • 通信作者: 韩加刚
  • 基金资助:
    首都卫生发展科研专项(首发2018-1-2032); 北京朝阳医院1351人才培养计划项目; 北京市属医院科研培育项目(PX2019012)

A meta-analysis of efficacy and safety on total neoadjuvant therapy for locally advanced rectal cancer

Ganbin Li1, Jiagang Han1,†(), Zhenjun Wang1   

  1. 1. Department of General Surgery, Beijing Chaoyang Hosptial, Capital Medical University, Beijing 100020, China
  • Received:2020-08-14 Published:2021-04-25
  • Corresponding author: Jiagang Han
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引用本文：

李干斌, 韩加刚, 王振军. 全程新辅助治疗局部进展期直肠癌疗效和安全性的Meta分析[J]. 中华结直肠疾病电子杂志, 2021, 10(02): 177-186.

Ganbin Li, Jiagang Han, Zhenjun Wang. A meta-analysis of efficacy and safety on total neoadjuvant therapy for locally advanced rectal cancer[J]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2021, 10(02): 177-186.

目的

比较全程新辅助治疗（TNT）和新辅助放化疗（nCRT）治疗中低位局部进展期直肠癌的疗效和安全性。

方法

全面检索中文数据库（中国知网、万方、中国生物医学文献数据库）和英文数据库（PubMed、Embase）公开发表的有关TNT和nCRT治疗局部进展期直肠癌疗效和安全性的临床研究。随机对照研究的质量评价采用Cochrane协作网提供的偏倚评价工具，非随机对照研究质量评价选择Newcastle-Ottawa量表。采用RevMan 5.3软件对TNT和nCRT组的pCR率、肿瘤降期率、R0切除率、保肛率、3/4级急性毒性反应发生率、围手术期并发症率、局部复发和远处转移率以及生存预后等进行Meta分析。

结果

最终纳入研究14项，其中6项为随机对照研究。共纳入病例3 797例，TNT组1 865例，nCRT组1 932例。两组基线资料具有可比性。Meta分析结果表明，TNT组的pCR率（OR=1.57，95%CI：1.30~1.90，P＜0.00001）、T分期降期率（OR=2.16，95%CI：1.63~2.57，P＜0.00001）和R0切除率（OR=1.42，95%CI：1.09~1.85，P=0.009）均显著高于nCRT组。两组3/4级急性毒性反应发生率和围手术期并发症率差异无统计学意义。TNT组的5年OS（HR=0.84，95%CI：0.69~1.02，P=0.08）和DFS（HR=0.94，95%CI：0.03~1.39，P=0.74）与nCRT组相近。

结论

与nCRT相比，尽管TNT未显著改善5年OS和DFS，但明显提高了肿瘤的pCR率、降期率和R0切除率。

关键词: 直肠肿瘤, 全程新辅助治疗, 新辅助放化疗, 局部进展期直肠癌, 疗效, 安全性, Meta分析
Objective

To evaluate the efficacy and safety of total neoadjuvant therapy for locally advanced rectal cancer.

Methods

A systemic search of CNKI, WanFang, CBM, PubMed and Embase was conducted for the studies that compared the efficacy of TNT and nCRT for rectal cancer. The quality evaluation of randomized controlled trials was based on the Cochrane's risk of bias tool, while non-randomized trials were assessed using Newcastle-Ottawa Scale. RevMan 5.3 software was used for meta-analisis, and the rate of pCR, T-downstaging, R0 resection and sphincter preservation rate, grade 3/4 acute toxicity during treatment, perioperative complications and survival benefits were compared between the two groups.

Results

A total of 14 studies was included with the amount of 3 797 patients, 1 865 and 1 932 in TNT group and nCRT group respectively. Meta analysis revealed that, a significant difference existed in the rate of pCR (OR=1.57,95%CI:1.30~1.90, P＜0.00001), T-downstaging (OR=2.16,95%CI:1.63~2.57, P＜0.00001) and R0 resection (OR=1.42,95%CI:1.09~1.85, P=0.009). There was no significant difference in the rate of perioperative complication and acute toxicity between the two groups. The 5-OS and 5-DFS were comparable between TNT group and nCRT group, indicating that TNT showed no survival benefits on rectal cancer patients.

Conclusion

Compared to nCRT, though no significant improvement in OS and DFS, the rate of pCR, tumor downstaging and R0 resection rate was improved in TNT group.

Key words: Rectal neoplasms, Total neoadjuvant therapy, Neoadjuvant chemoradiotherapy, Locally advanced rectal cancer, Efficacy, Safety, Meta-analysis
图1 纳入研究流程图
表1 纳入研究一般特征
作者 发表年份 国家 研究类型 总样本量 样本量 纳入研究质量评价
TNT nCRT
Garcia [9] 2015 美国 前瞻性研究 259 199 60 6
翟志伟[11] 2020 中国 回顾性研究 134 79 55 6
Cercek[12] 2018 美国 回顾性研究 628 308 320 8
Markovina[13] 2017 美国 前瞻性研究 138 69 69 6
Zhu[14] 2019 美国 回顾性研究 1079 372 707 8
Fernandez[15] 2015 美国 随机对照研究 103 54 49 －
Maréchal[18] 2012 比利时 随机对照研究 57 28 29 －
Calvo[19] 2014 西班牙 回顾性研究 335 207 128 7
Bhatti[20] 2015 巴基斯坦 回顾性研究 154 93 61 7
Bujko[21] 2016 波兰 随机对照研究 515 261 254 －
Kim[22] 2018 韩国 随机对照研究 110 54 56 －
Liang[23] 2019 中国 前瞻性研究 156 76 80 5
Moore[24] 2017 澳大利亚 随机对照研究 49 25 24 －
李雷蕾[25] 2017 中国 随机对照研究 80 40 40 －
表2 TNT组和nCRT组放化疗方案及具体剂量
作者 TNT nCRT
IT/CT 化疗方案 剂量 放疗方案 同步化疗方案
Garcia [9] CT mFOFLOX 5-FU 400 mg/m2；LV 200 mg/m2；OX 85 mg/m2 45.0 Gy/25 f 5-FU 225 mg/m2
翟志伟[11] CT CAPEOX CAP 1 000 mg/m2; OX 130 mg/m 2 50.4 Gy/28 f CAP 850 mg/m2
Cercek[12] IT mFOFLOX 5-FU 400 mg/m2；LV 200 mg/m2；OX 85 mg/m2 45.0 Gy/25 f 5-FU 225 mg/m2/CAP 850 mg/m2
Markovina[13] IT mFOFLOX 5-FU/LV/OX 45.0 Gy/25 f 5-FU/CAP
Zhu[14] IT FOFLOX/CAPEOX －

45.0 Gy/25 f

50.4 Gy/25~28 f

 －
Fernandez[15] IT CAPEOX CAP/ OX 45.0 Gy/25 f CAP
Maréchal[18] IT mFOFLOX 5-FU 400 mg/m2；LV 400 mg/m2；OX 100 mg/m2 45.0 Gy/25 f 5-FU 225 mg/m2
Calvo[19] IT mFOFLOX 5-FU 400 mg/m2；LV 200 mg/m2；OX 85 mg/m2 45.0 Gy/25 f 5-FU 425 mg/m2
Bhatti[20] IT CAPEOX CAP 1 000 mg/m2; OX 130 mg/m2 50.4 Gy/25~28 f CAP 825 mg/m2
Bujko[21] CT mFOFLOX 5-FU/LV/OX 50.4 Gy/25~28 f 5-FU 325 mg/m2/LV 20 mg/m2
Kim[22] CT CAPEOX CAP 1 700 mg/m2; OX 100 mg/m2 50.4 Gy/25~28 f CAP
Liang[23] CT

CAPEOX

FOFLOX

CAP 1 000 mg/m2; OX 130 mg/m2

5-FU 400 mg/m2; LV 400 mg/m2;OX 85 mg/m2

 50.4 Gy/25~28 f CAP 825 mg/m2
Moore[24] CT 5-FU/LV 5-FU 450 mg/m2; LV 50 mg/m2 45.0 Gy/25 f 5-FU 225 mg/m2
李雷蕾[25] CT FOFLOX 5-FU 400 mg/m2; LV 200 mg/m2;OX 85 mg/m2 50.4 Gy/25~28 f 5-FU 225 mg/m2
图2 纳入随机对照研究的质量评价表
图3 TNT和nCRT组急性3/4级毒性反应的比较分析
图4 TNT和nCRT组围手术期并发症的比较分析
图5 TNT和nCRT组pCR率的比较分析
图6 TNT和nCRT组肿瘤T分期降期率的比较分析
图7 TNT和nCRT组R0切除率的比较分析
图8 TNT和nCRT组保肛率的比较分析
图9 TNT和nCRT组局部复发情况的比较分析
图10 TNT和nCRT组远处转移情况的比较分析
图11 TNT和nCRT组5年OS比较分析
图12 TNT和nCRT组5年DFS比较分析
图13 纳入研究的发表偏移情况（pCR）
1
Benson AB, Venook AP, Al-Hawary MM, et al. Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology[J]. J Natl Compr Canc Netw, 2018, 16(7): 874-901.
2
Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years[J]. J Clin Oncol, 2012, 30(16): 1926-1933.

URL    
3
Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study[J]. Lancet Oncol, 2014, 15(2): 184‐190.

URL    
4
Van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial[J]. Lancet Oncol ,2011, 12(6): 575-582.

URL    
5
Breugom AJ, van Gijn W, Muller EW, et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial[J]. Ann Oncol, 2015, 26(4): 696-701.
6
Petrelli F, Trevisan F, Cabiddu M, et al. Total neoadjuvant therapy in rectal cancer: A systematic review and meta-analysis of treatment outcomes[J]. Ann Surg, 2020, 271(3): 440-448.
7
Weiser MR. AJCC 8th Edition: Colorectal Cancer[J]. Ann Surg Oncol, 2018, 25(6): 1454-1455.
8
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses[J]. Eur J Epidemiol, 2010, 25(9): 603-605.

URL    
9
Garcia-Aguilar J, Chow OS, Smith DD, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial[J]. Lancet Oncol, 2015, 16(8): 957-966.
10
Cercek A, Goodman KA, Hajj C, et al. Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer[J]. J Natl Compr Canc Netw, 2014, 12(4): 513-519.
11
翟志伟, 张坤宁, 王琛,等. 中低位局部进展期直肠癌新辅助治疗与全程新辅助治疗的近期疗效和安全性比较[J]. 中华胃肠外科杂志, 2020, 23(3): 274-280.
12
Cercek A, Roxburgh CSD, Strombom P, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer[J]. JAMA Oncol, 2018, 4(6): e180071.
13
Markovina Stephanie, Youssef Fady, Roy Amit, et al. Improved metastasis-and disease-free survival with preoperative sequential short-course radiation therapy and FOLFOX chemotherapy for rectal cancer compared with neoadjuvant long-course chemoradiotherapy: results of a matched pair analysis[J]. Int. J. Radiat Oncol. Biol. Phys, 2017, 99: 417-426.
14
Zhu S, Brodin NP, English K, et al. Comparing outcomes following total neoadjuvant therapy and following neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer[J]. Eclinical Medicine, 2019, 16: 23-29.
15
Fernandez-Martos C, Garcia-Albeniz X, Pericay C, et al. Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial[J]. Ann Oncol, 2015, 26(8): 1722-1728.
16
Fernández-Martos C, Pericay C, Aparicio J, et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study[J]. J Clin Oncol,2010,28(5): 859-865.
17
Marco MR, Zhou L, Patil S, et al. Consolidation mFOLFOX6 chemotherapy after chemoradiotherapy improves survival in patients with locally advanced rectal cancer: Final sesults of a multicenter phase II trial[J]. Dis Colon Rectum, 2018, 61(10): 1146-1155.
18
Maréchal R, Vos B, Polus M, et al. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study[J]. Ann Oncol, 2012, 23(6): 1525-1530.
19
Calvo FA, Sole CV, Serrano J, et al. Preoperative chemoradiation with or without induction oxaliplatin plus 5-fluorouracil in locally advanced rectal cancer. Long-term outcome analysis[J]. Strahlenther Onkol, 2014, 190(2): 149-157.

URL    
20
Bhatti AB, Waheed A, Hafeez A, et al. Can induction chemotherapy before concurrent chemoradiation impact circumferential resection margin positivity and survival in low rectal cancers?[J]. Asian Pac J Cancer Prev, 2015, 16(7): 2993-2998.
21
Bujko K, Wyrwicz L, Rutkowski A, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study[J]. Ann Oncol, 2016, 27(5): 834-842.
22
Kim SY, Joo J, Kim TW, et al. A randomized phase 2 trial of consolidation chemotherapy after preoperative chemoradiation therapy versus chemoradiation therapy alone for locally advanced rectal cancer: KCSG CO 14-03[J]. Int J Radiat Oncol Biol Phys, 2018, 101(4): 889-899.
23
Liang HQ, Dong ZY, Liu ZJ, et al. Efficacy and safety of consolidation chemotherapy during the resting period in patients with local advanced rectal cancer[J]. Oncol Lett, 2019, 17(2): 1655-1663.
24
Moore J, Price T, Carruthers S, et al. Prospective randomized trial of neoadjuvant chemotherapy during the 'wait period' following preoperative chemoradiotherapy for rectal cancer: results of the WAIT trial[J]. Colorectal Dis, 2017, 19(11): 973-979.
25
李雷蕾, 王文玲, 董洪敏, 等. 局部进展期直肠癌术前同步放化疗后联合新辅助化疗的前瞻性Ⅱ期随机对照研究[J]. 中华放射医学与防护杂志, 2017, 37(2): 107-113.
26
Dewdney A, Cunningham D, Tabernero J, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C)[J]. J Clin Oncol, 2012, 30(14): 1620-1627.

URL    
27
Francois Y, Nemoz CJ, Baulieux J, et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial[J]. J Clin Oncol, 1999, 17(8): 2396.
28
Glynne-Jones R, Wyrwicz L, Tiret E, et al. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2017, 28(suppl_4): iv22–iv40.
29
Hong TS, Wo JY, Borger DR, et al. Phase II study of proton-based stereotactic body radiation therapy for liver metastases: Importance of tumor genotype[J]. J Natl Cancer Inst, 2017, 109(9): djx031.
30
Ludmir EB, Palta M, Willett CG, et al. Total neoadjuvant therapy for rectal cancer: An emerging option[J]. Cancer, 2017, 123(9): 1497-1506.
31
Hong TS, Ryan DP. Total neoadjuvant therapy for locally advanced rectal cancer-The new standard of care?[J]. JAMA Oncol, 2018, 4(6): e180070.
32
Petrelli F, Trevisan F, Cabiddu M, et al. Total neoadjuvant therapy in rectal cancer: A systematic review and meta-analysis of treatment outcomes[J]. Ann Surg, 2020, 271(3): 440-448.
33
王林, 赵一鸣, 孙婷婷, 等. 低风险直肠癌患者全程新辅助治疗后主动性等待观察及器官保留策略:一项前瞻性、单中心、单臂研究(PKUCH-R01)的初步报告[J]. 中华胃肠外科杂志, 2020, 23(03): 258-265.
34
Rullier E, Rouanet P, Tuech JJ, et al. Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label,multicentre, phase 3 trial[J]. Lancet, 2017, 390(10093): 469-479.
35
Stijns RCH, de Graaf EJR, Punt CJA, et al. Long-term oncological and functional outcomes of chemoradiotherapy followed by organ-sparing transanal endoscopic microsurgery for distal rectal cancer:the CARTS study[J]. JAMA Surg, 2019, 154(1): 47-54.
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