New pattern of locally advanced rectal cancer treatment: total neoadjuvant therapy_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

RAN Rui ,  LI Yang , LIU Guangyi , LIU Rui , PAN Wenjing

Department of Gastrointestinal and Anorectal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P. R. China;

Corresponding author：

LI Yang, Email: liyang_68813@126.com

Keywords：

locally advanced rectal cancer; total neoadjuvant therapy; watch and wait strategy; review

DOI：

10.7507/1007-9424.202109029

Video：

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Objective To explore the clinical value, latest research progress, and clinical controversy of total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC). Method We searched and reviewed on the latest literatures about studies of the clinical research of TNT in LARC. Results TNT could make the tumor downstage rapidly and improve the patients’ treatment compliance. In terms of organ preservation rate, 3-year disease-free survival and pathological complete remission rate, TNT had advantages and was a especial potential treatment strategy compared with traditional methods. Conclusions TNT decreases local recurrence rate and improves the long-term survival. For LARC patients with strong desire for organ preservation, TNT is a good treatment choice and has the value of clinical promotion.

Citation： RAN Rui, LI Yang, LIU Guangyi, LIU Rui, PAN Wenjing. New pattern of locally advanced rectal cancer treatment: total neoadjuvant therapy. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(5): 688-693. doi: 10.7507/1007-9424.202109029 Copy

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	杜灵彬, 李辉章, 王悠清, 等. 2013年中国结直肠癌发病与死亡分析. 中华肿瘤杂志, 2017, 39(9): 701-706.
3.	Benson AB, Venook AP, Al-Hawary MM, et al. Rectal Cancer, Version 2. 2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 2018, 16(7): 874-901.
4.	Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol, 2015, 16(2): 200-207.
5.	Alawawdeh A, Krishnan T, Roy A, et al. Curative therapy for rectal cancer. Expert Rev Anticancer Ther, 2021, 21(2): 193-203.
6.	Ludmir EB, Palta M, Willett CG, et al. Total neoadjuvant therapy for rectal cancer: An emerging option. Cancer, 2017, 123(9): 1497-1506.
7.	Smith CA, Kachnic LA. Evolving treatment paradigm in the treatment of locally advanced rectal cancer. J Natl Compr Canc Netw, 2018, 16(7): 909-915.
8.	陈功, 肖巍魏, 张荣欣, 等. 基于器官功能保全的局部进展期直肠癌诊治新策略. 中国癌症防治杂志, 2019, 11(1): 13-20.
9.	Chua YJ, Barbachano Y, Cunningham D, et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol, 2010, 11(3): 241-248.
10.	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 Clin Oncol, 2012, 30(14): 1620-1627.
11.	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 Clin Oncol, 2010, 28(5): 859-865.
12.	Hospers G, Bahadoer RR, Dijkstra EA, et al. Short-course radiotherapy followed by chemotherapy before TME in locally advanced rectal cancer: The randomized RAPIDO trial. J Clin Oncol, 2020, 38(15_suppl): 4006. doi: 10.1200/ JCO.2020.38.15_suppl.4006.
13.	Conroy T, Lamfichekh N, Etienne PL, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: Final results of PRODIGE 23 phase Ⅲ trial, a UNICANCER GI trial. J Clin Oncol, 2020, 38(15_suppl): 4007. doi: 10.1200/ JCO.2020.38.15_suppl.4007.
14.	Garcia-Aguilar J, Patil S, Kim JK, et al. Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial. J Clin Oncol, 2020, 38(15_suppl): 4008.
15.	龙飞, 胡桂, 马敏, 等. 2021. V1 版 NCCN 临床实践指南: 结肠癌/直肠癌更新解读 (外科部分). 临床外科杂志, 2021, 29(5): 401-404.
16.	Shiao JC, Fakhoury KR, Olsen J. Total neoadjuvant therapy for rectal cancer: Current status and future directions. Current Colorectal Cancer Reports, 2020, 16(6): 125-134.
17.	孙培焱, 吴刚, 孙培春. 直肠癌治疗新模式—全程新辅助治疗. 肿瘤防治研究, 2018, 45(9): 701-706.
18.	Glynne-Jones R, Wyrwicz L, Tiret E, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2017, 28(suppl_4): iv22-iv40.
19.	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. Lancet Oncol, 2015, 16(8): 957-966.
20.	Marco MR, Zhou L, Patil S, et al. Consolidation mFOLFOX6 chemotherapy after chemoradiotherapy improves survival in patients with locally advanced rectal cancer: Final results of a multicenter phase Ⅱ trial. Dis Colon Rectum, 2018, 61(10): 1146-1155.
21.	Cercek A, Roxburgh CSD, Strombom P, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol, 2018, 4(6): e180071. doi: 10.1001/jamaoncol.2018.0071.
22.	Fokas E, Allgäuer M, Polat B, et al. Randomized phase Ⅱ trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12. J Clin Oncol, 2019, 37(34): 3212-3222.
23.	Petrelli F, Trevisan F, Cabiddu M, et al. Total neoadjuvant therapy in rectal cancer: A systematic review and meta-analysis of treatment outcomes. Ann Surg, 2020, 271(3): 440-448.
24.	van der Valk MJM, Marijnen CAM, van Etten B, et al. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer -Results of the international randomized RAPIDO-trial. Radiother Oncol, 2020, 147: 75-83.
25.	Muroyama Y, Nirschl TR, Kochel CM, et al. Stereotactic radiotherapy increases functionally suppressive regulatory T cells in the tumor microenvironment. Cancer Immunol Res, 2017, 5(11): 992-1004.
26.	Feeney G, Sehgal R, Sheehan M, et al. Neoadjuvant radiotherapy for rectal cancer management. World J Gastroenterol, 2019, 25(33): 4850-4869.
27.	钟清华, 吴培煌, 秦启元, 等. 直肠癌术前放疗造成手术切缘放射性损伤的病理学研究. 中华外科杂志, 2017, 55(7): 507-514.
28.	Sun W, Dou R, Chen J, et al. Impact of long-course neoadjuvant radiation on postoperative low anterior resection syndrome and quality of life in rectal cancer: Post hoc analysis of a randomized controlled trial. Ann Surg Oncol, 2019, 26(3): 746-755.
29.	Cienfuegos JA, Rodríguez J, Baixauli J, et al. Neoadjuvant chemotherapy without radiotherapy for patients with locally advanced rectal cancer. Oncologic outcomes. Rev Esp Enferm Dig, 2020, 112(1): 16-22.
30.	Deng Y, Chi P, Lan P, et al. Neoadjuvant modified FOLFOX6 with or without radiation versus fluorouracil plus radiation for locally advanced rectal cancer: Final results of the Chinese FOWARC Trial. J Clin Oncol, 2019, 37(34): 3223-3233.
31.	Schrag D. PROSPECT: Chemotherapy alone or chemo therapy plus radiation therapy in treating patients with locally advanced rectal cancer undergoing surgery. 2012-01-24. https://clinicaltrials.gov/ct2/show/NCT01515787, 2012-01-24/2021-08-17/2021-09-05.
32.	Wilson K, Flood M, Narasimhan V, et al. Complete pathological response in rectal cancer utilising novel treatment strategies for neo-adjuvant therapy: A systematic review. Eur J Surg Oncol, 2021, 47(8): 1862-1874.
33.	Liao YT, Lin YL, Huang J, et al. Downstaged ypT0-2N0 rectal cancer after neoadjuvant chemoradiation therapy may not need adjuvant chemotherapy: a retrospective cohort study. Int J Colorectal Dis, 2021, 36(3): 509-516.
34.	Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med, 2004, 351(17): 1731-1740.
35.	Turner MC, Keenan JE, Rushing CN, et al. Adjuvant chemotherapy improves survival following resection of locally advanced rectal cancer with pathologic complete response. J Gastrointest Surg, 2019, 23(8): 1614-1622.
36.	Hu X, Li YQ, Ma XJ, et al. Adjuvant chemotherapy for rectal cancer with complete pathological response (pCR) may not be necessary: a pooled analysis of 5 491 patients. Cancer Cell Int, 2019, 19: 127. doi: 10.1186/s12935-019-0851-9.
37.	Polanco PM, Mokdad AA, Zhu H, et al. Association of adjuvant chemotherapy with overall survival in patients with rectal cancer and pathologic complete response following neoadjuvant chemotherapy and resection. JAMA Oncol, 2018, 4(7): 938-943.
38.	van der Valk MJM, Hilling DE, Bastiaannet E, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet, 2018, 391(10139): 2537-2545.
39.	Pedraza R, Herzig D, Lu KC. Systematic review and analysis of harm of patients with rectal cancer undergoing watch and wait following total neoadjuvant therapy. Dis Colon Rectum, 2020, 63(6): e144.
40.	Smith JJ, Strombom P, Chow OS, et al. Assessment of a Watch-and-Wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy. JAMA Oncol, 2019, 5(4): e185896.
41.	Habr-Gama A, São Julião GP, Gama-Rodrigues J, et al. Baseline T classification predicts early tumor regrowth after nonoperative management in distal rectal cancer after extended neoadjuvant chemoradiation and initial complete clinical response. Dis Colon Rectum, 2017, 60(6): 586-594.
42.	Hiotis SP, Weber SM, Cohen AM, et al. Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients. J Am Coll Surg, 2002, 194(2): 131-136.
43.	王小豪, 周程静, 张术, 等. 直肠癌新辅助治疗后临床完全缓解患者应用等待观察策略与根治性手术治疗的远期疗效对比分析. 中华胃肠外科杂志, 2020, 23(3): 266-273.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. 杜灵彬, 李辉章, 王悠清, 等. 2013年中国结直肠癌发病与死亡分析. 中华肿瘤杂志, 2017, 39(9): 701-706.
3. Benson AB, Venook AP, Al-Hawary MM, et al. Rectal Cancer, Version 2. 2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 2018, 16(7): 874-901.
4. Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol, 2015, 16(2): 200-207.
5. Alawawdeh A, Krishnan T, Roy A, et al. Curative therapy for rectal cancer. Expert Rev Anticancer Ther, 2021, 21(2): 193-203.
6. Ludmir EB, Palta M, Willett CG, et al. Total neoadjuvant therapy for rectal cancer: An emerging option. Cancer, 2017, 123(9): 1497-1506.
7. Smith CA, Kachnic LA. Evolving treatment paradigm in the treatment of locally advanced rectal cancer. J Natl Compr Canc Netw, 2018, 16(7): 909-915.
8. 陈功, 肖巍魏, 张荣欣, 等. 基于器官功能保全的局部进展期直肠癌诊治新策略. 中国癌症防治杂志, 2019, 11(1): 13-20.
9. Chua YJ, Barbachano Y, Cunningham D, et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol, 2010, 11(3): 241-248.
10. 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 Clin Oncol, 2012, 30(14): 1620-1627.
11. 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 Clin Oncol, 2010, 28(5): 859-865.
12. Hospers G, Bahadoer RR, Dijkstra EA, et al. Short-course radiotherapy followed by chemotherapy before TME in locally advanced rectal cancer: The randomized RAPIDO trial. J Clin Oncol, 2020, 38(15_suppl): 4006. doi: 10.1200/ JCO.2020.38.15_suppl.4006.
13. Conroy T, Lamfichekh N, Etienne PL, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: Final results of PRODIGE 23 phase Ⅲ trial, a UNICANCER GI trial. J Clin Oncol, 2020, 38(15_suppl): 4007. doi: 10.1200/ JCO.2020.38.15_suppl.4007.
14. Garcia-Aguilar J, Patil S, Kim JK, et al. Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial. J Clin Oncol, 2020, 38(15_suppl): 4008.
15. 龙飞, 胡桂, 马敏, 等. 2021. V1 版 NCCN 临床实践指南: 结肠癌/直肠癌更新解读 (外科部分). 临床外科杂志, 2021, 29(5): 401-404.
16. Shiao JC, Fakhoury KR, Olsen J. Total neoadjuvant therapy for rectal cancer: Current status and future directions. Current Colorectal Cancer Reports, 2020, 16(6): 125-134.
17. 孙培焱, 吴刚, 孙培春. 直肠癌治疗新模式—全程新辅助治疗. 肿瘤防治研究, 2018, 45(9): 701-706.
18. Glynne-Jones R, Wyrwicz L, Tiret E, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 2017, 28(suppl_4): iv22-iv40.
19. 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. Lancet Oncol, 2015, 16(8): 957-966.
20. Marco MR, Zhou L, Patil S, et al. Consolidation mFOLFOX6 chemotherapy after chemoradiotherapy improves survival in patients with locally advanced rectal cancer: Final results of a multicenter phase Ⅱ trial. Dis Colon Rectum, 2018, 61(10): 1146-1155.
21. Cercek A, Roxburgh CSD, Strombom P, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol, 2018, 4(6): e180071. doi: 10.1001/jamaoncol.2018.0071.
22. Fokas E, Allgäuer M, Polat B, et al. Randomized phase Ⅱ trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12. J Clin Oncol, 2019, 37(34): 3212-3222.
23. Petrelli F, Trevisan F, Cabiddu M, et al. Total neoadjuvant therapy in rectal cancer: A systematic review and meta-analysis of treatment outcomes. Ann Surg, 2020, 271(3): 440-448.
24. van der Valk MJM, Marijnen CAM, van Etten B, et al. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer -Results of the international randomized RAPIDO-trial. Radiother Oncol, 2020, 147: 75-83.
25. Muroyama Y, Nirschl TR, Kochel CM, et al. Stereotactic radiotherapy increases functionally suppressive regulatory T cells in the tumor microenvironment. Cancer Immunol Res, 2017, 5(11): 992-1004.
26. Feeney G, Sehgal R, Sheehan M, et al. Neoadjuvant radiotherapy for rectal cancer management. World J Gastroenterol, 2019, 25(33): 4850-4869.
27. 钟清华, 吴培煌, 秦启元, 等. 直肠癌术前放疗造成手术切缘放射性损伤的病理学研究. 中华外科杂志, 2017, 55(7): 507-514.
28. Sun W, Dou R, Chen J, et al. Impact of long-course neoadjuvant radiation on postoperative low anterior resection syndrome and quality of life in rectal cancer: Post hoc analysis of a randomized controlled trial. Ann Surg Oncol, 2019, 26(3): 746-755.
29. Cienfuegos JA, Rodríguez J, Baixauli J, et al. Neoadjuvant chemotherapy without radiotherapy for patients with locally advanced rectal cancer. Oncologic outcomes. Rev Esp Enferm Dig, 2020, 112(1): 16-22.
30. Deng Y, Chi P, Lan P, et al. Neoadjuvant modified FOLFOX6 with or without radiation versus fluorouracil plus radiation for locally advanced rectal cancer: Final results of the Chinese FOWARC Trial. J Clin Oncol, 2019, 37(34): 3223-3233.
31. Schrag D. PROSPECT: Chemotherapy alone or chemo therapy plus radiation therapy in treating patients with locally advanced rectal cancer undergoing surgery. 2012-01-24. https://clinicaltrials.gov/ct2/show/NCT01515787, 2012-01-24/2021-08-17/2021-09-05.
32. Wilson K, Flood M, Narasimhan V, et al. Complete pathological response in rectal cancer utilising novel treatment strategies for neo-adjuvant therapy: A systematic review. Eur J Surg Oncol, 2021, 47(8): 1862-1874.
33. Liao YT, Lin YL, Huang J, et al. Downstaged ypT0-2N0 rectal cancer after neoadjuvant chemoradiation therapy may not need adjuvant chemotherapy: a retrospective cohort study. Int J Colorectal Dis, 2021, 36(3): 509-516.
34. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med, 2004, 351(17): 1731-1740.
35. Turner MC, Keenan JE, Rushing CN, et al. Adjuvant chemotherapy improves survival following resection of locally advanced rectal cancer with pathologic complete response. J Gastrointest Surg, 2019, 23(8): 1614-1622.
36. Hu X, Li YQ, Ma XJ, et al. Adjuvant chemotherapy for rectal cancer with complete pathological response (pCR) may not be necessary: a pooled analysis of 5 491 patients. Cancer Cell Int, 2019, 19: 127. doi: 10.1186/s12935-019-0851-9.
37. Polanco PM, Mokdad AA, Zhu H, et al. Association of adjuvant chemotherapy with overall survival in patients with rectal cancer and pathologic complete response following neoadjuvant chemotherapy and resection. JAMA Oncol, 2018, 4(7): 938-943.
38. van der Valk MJM, Hilling DE, Bastiaannet E, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet, 2018, 391(10139): 2537-2545.
39. Pedraza R, Herzig D, Lu KC. Systematic review and analysis of harm of patients with rectal cancer undergoing watch and wait following total neoadjuvant therapy. Dis Colon Rectum, 2020, 63(6): e144.
40. Smith JJ, Strombom P, Chow OS, et al. Assessment of a Watch-and-Wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy. JAMA Oncol, 2019, 5(4): e185896.
41. Habr-Gama A, São Julião GP, Gama-Rodrigues J, et al. Baseline T classification predicts early tumor regrowth after nonoperative management in distal rectal cancer after extended neoadjuvant chemoradiation and initial complete clinical response. Dis Colon Rectum, 2017, 60(6): 586-594.
42. Hiotis SP, Weber SM, Cohen AM, et al. Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients. J Am Coll Surg, 2002, 194(2): 131-136.
43. 王小豪, 周程静, 张术, 等. 直肠癌新辅助治疗后临床完全缓解患者应用等待观察策略与根治性手术治疗的远期疗效对比分析. 中华胃肠外科杂志, 2020, 23(3): 266-273.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

New pattern of locally advanced rectal cancer treatment: total neoadjuvant therapy

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