Surgery and OncologySurgery and OncologyХирургия и онкология2949-5857Publishing House ABV Press2110.17650/2220-3478-2014-0-2-5-12REVIEWОБЗОРЫ ЛИТЕРАТУРЫADJUVANT CHEMOTHERAPY AFTER RECTAL CANCER CHEMORADIOTHERAPYАДЪЮВАНТНАЯ ХИМИОТЕРАПИЯ ПОСЛЕ ХИМИОЛУЧЕВОГО ЛЕЧЕНИЯ РАКА ПРЯМОЙ КИШКИFedyaninM. Yu.ФедянинМ. Ю.
Russian Federation

Отделение клинической фармакологии и химиотерапии

fedianinmu@mail.ruTryakinA. A.ТрякинА. А.
Russian Federation

Отделение клинической фармакологии и химиотерапии

fedianinmu@mail.ruTjulandinS. A.ТюляндинС. А.
Russian Federation

Отделение клинической фармакологии и химиотерапии

fedianinmu@mail.ruDepartment of Clinical Pharmacology and Chemotherapy, N. N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, MoscowФГБУ «Российский онкологический научный центр им. Н. Н. Блохина» РАМН, Москва25052014325122502201525022015Copyright ©; 2014, ABV-pressCopyright ©; 2014, АБВ-пресс2014ABV-pressАБВ-прессhttps://onco-surgery.info/jour/about/editorialPolicieshttps://onco-surgery.info/jour/article/view/21

Combination of surgical treatment and neoadjuvant chemoradiotherapy is the main treatment tactics for cT3 or cN+ rectal cancer patients. Integration of chemoradiotherapy in clinical practice reduced recurrence rate but had impact on overall survival only in patients with R0 resection. Disease progression in most rectal cancer patients occurs mainly by distant metastases development, which dictates the necessity of systemic treatment improvement. Yet till today there was no clinical evidence to support adjuvant chemotherapy after preoperative chemoradiation in rectal cancer patients. This review article focuses on prospective and retrospective data on adjuvant chemotherapy efficacy in rectal cancer patients, who received previous chemoradiation.

Сочетание хирургического и предоперационного химиолучевого лечения является основой лечебной тактики у больных раком прямой кишки начиная со стадии cT3 или cN+. Внедрение в клинику данного подхода значимо снизило частоту рецидивов болезни и привело к улучшению общей выживаемости только при условии выполнения радикального хирургического лечения. Прогрессирование заболевания у большинства больных раком прямой кишки реализуется через отдаленное метастазирование, что диктует необходимость совершенствования системной терапии. Однако к настоящему времени не было доказательной базы эффективности назначения адъювантной химиотерапии (АХТ) после предоперационного химиолучевого лечения больных раком прямой кишки. Настоящий обзор литературы посвящен анализу результатов проспективных и ретроспективных исследований, пытавшихся ответить на вопрос об эффективности АХТ у больных раком прямой кишки после проведенного предоперационного лечения.

rectal cancerchemoradiotherapyadjuvant chemotherapyрак прямой кишкихимиолучевая терапияадъювантная химиотерапия1. Van Gijn W., Marijnen C. A., Nagtegaal I. D. et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol 2011 Jun;12(6):575–82.Van Gijn W., Marijnen C. A., Nagtegaal I. D. et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol 2011 Jun;12(6):575–82.2. Fokas E., Liersch T., Fietkau R. et al. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO / ARO / AIO-94 trial. J Clin Oncol 2014 May 20;32(15):1554–62.Fokas E., Liersch T., Fietkau R. et al. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO / ARO / AIO-94 trial. J Clin Oncol 2014 May 20;32(15):1554–62.3. Park I. J., Eng C., You Y. N. et al. Exploratory analysis of adjuvant chemotherapy effects after preoperative chemoradiotherapy and radical resection for rectal cancer. J Clin Oncol 2012;30(suppl 4; abstr 557).Park I. J., Eng C., You Y. N. et al. Exploratory analysis of adjuvant chemotherapy effects after preoperative chemoradiotherapy and radical resection for rectal cancer. J Clin Oncol 2012;30(suppl 4; abstr 557).4. Wolmark N., Fisher B., Rockette H. et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst 1988;80:30–6.Wolmark N., Fisher B., Rockette H. et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst 1988;80:30–6.5. Wolmark N., Rockette H., Fisher B. et al. The benefit of leucovorin modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993;11:1879–87.Wolmark N., Rockette H., Fisher B. et al. The benefit of leucovorin modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993;11:1879–87.6. Andre T., Boni C., Mounedji-Boudiaf L. et al. Multicenter international study of oxaliplatin / 5-fluorouracil / leucovorin in the adjuvant treatment of colon cancer (MOSAIC) investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343–51.Andre T., Boni C., Mounedji-Boudiaf L. et al. Multicenter international study of oxaliplatin / 5-fluorouracil / leucovorin in the adjuvant treatment of colon cancer (MOSAIC) investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343–51.7. Andre T., Boni C., Navarro M. et al. Improved overall survival with oxaliplatin, fluorouracil and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109–16.Andre T., Boni C., Navarro M. et al. Improved overall survival with oxaliplatin, fluorouracil and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109–16.8. Petersen S. H., Harling H., Kirkeby L. T. et al. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 2012;3:CD004078.Petersen S. H., Harling H., Kirkeby L. T. et al. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 2012;3:CD004078.9. Bosset J. F., Collette L., Calais G. et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114–23.Bosset J. F., Collette L., Calais G. et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114–23.10. Bosset J. F., Calais G., Mineur L. et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results – EORTC 22921. J Clin Oncol 2005;23:5620–7.Bosset J. F., Calais G., Mineur L. et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results – EORTC 22921. J Clin Oncol 2005;23:5620–7.11. Collette L., Bosset J. F., den Dulk M. et al. Patients with curative resection of cT3–4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracilbased chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 2007;25:4379–86.Collette L., Bosset J. F., den Dulk M. et al. Patients with curative resection of cT3–4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracilbased chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 2007;25:4379–86.12. Collette L., Calais G., Mineur L. et al. Patients with R0 resection of T3–4 rectal cancer after preoperative radioor radiochemotherapy: does anybody benefit of post-operative LV / 5-FU chemotherapy? Further results of EORTC trial 22921. Eur J Cancer 2005;3:170(suppl; abstr 607).Collette L., Calais G., Mineur L. et al. Patients with R0 resection of T3–4 rectal cancer after preoperative radioor radiochemotherapy: does anybody benefit of post-operative LV / 5-FU chemotherapy? Further results of EORTC trial 22921. Eur J Cancer 2005;3:170(suppl; abstr 607).13. Bosset J. F., 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. Lancet Oncol 2014;15:184–90.Bosset J. F., 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. Lancet Oncol 2014;15:184–90.14. Cionini L., Sainato A., De Paoli A. et al. Final results of randomized trial on adjuvant chemotherapy after preoperative chemoradiation in rectal cancer. Radiother Oncol 2010;96(suppl 1):S113.Cionini L., Sainato A., De Paoli A. et al. Final results of randomized trial on adjuvant chemotherapy after preoperative chemoradiation in rectal cancer. Radiother Oncol 2010;96(suppl 1):S113.15. Breugom A. J., van den Broek C. B.M., van Gijn W. et al. The value of adjuvant chemotherapy in rectal cancer patients after preoperative radiotherapy or chemotherapy followed by TME-surgery: the PROCTOR / SCRIPT study. Eur J Cancer 2013;49(suppl 3):S1.Breugom A. J., van den Broek C. B.M., van Gijn W. et al. The value of adjuvant chemotherapy in rectal cancer patients after preoperative radiotherapy or chemotherapy followed by TME-surgery: the PROCTOR / SCRIPT study. Eur J Cancer 2013;49(suppl 3):S1.16. Hofheinz R. D., Wenz F., Post S. et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012;13:579–88.Hofheinz R. D., Wenz F., Post S. et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012;13:579–88.17. Ngan S. Y., Burmeister B., Fisher R. J. et al. Randomised trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group Trial 01.04. J Clin Oncol 2012;30:3827–33.Ngan S. Y., Burmeister B., Fisher R. J. et al. Randomised trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group Trial 01.04. J Clin Oncol 2012;30:3827–33.18. Rцdel C., Liersch T., Becker H. et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initia results of the German CAO / ARO / AIO-04 randomised phase 3 trial. Lancet Oncol 2012:13:679–87.Rцdel C., Liersch T., Becker H. et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initia results of the German CAO / ARO / AIO-04 randomised phase 3 trial. Lancet Oncol 2012:13:679–87.19. Bujko K., Glynne-Jones R., Bujko M. Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials. Ann Oncol 2010;21:1743–50.Bujko K., Glynne-Jones R., Bujko M. Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials. Ann Oncol 2010;21:1743–50.20. Glynne-Jones R., Counsell N., Quirke P. et al. Chronicle: Results of a randomized phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (Xelox) versus control. Ann Oncol 2014 Apr 8.Glynne-Jones R., Counsell N., Quirke P. et al. Chronicle: Results of a randomized phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (Xelox) versus control. Ann Oncol 2014 Apr 8.21. Hong Y. S., Nam B. H., Jung K. H. et al. Adjuvant chemotherapy with oxaliplatin / 5-fluorouracil / leucovorin (FOLFOX) versus 5-fluorouracil / leucovorin (FL) in patients with locally advanced rectal cancer after preoperative chemoradiotherapy followed by surgery: a randomized phase II study (The ADORE). J Clin Oncol 2013;31(suppl; abstr 3570).Hong Y. S., Nam B. H., Jung K. H. et al. Adjuvant chemotherapy with oxaliplatin / 5-fluorouracil / leucovorin (FOLFOX) versus 5-fluorouracil / leucovorin (FL) in patients with locally advanced rectal cancer after preoperative chemoradiotherapy followed by surgery: a randomized phase II study (The ADORE). J Clin Oncol 2013;31(suppl; abstr 3570).22. Reinel H., SchдЯburger K., Meyer D. et al. 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) as postoperative adjuvant chemotherapy (CT) for node-positive rectal cancer after radiochemotherapy (R-CT) and surgery. J Clin Oncol 2010;28(suppl; abstr e14125).Reinel H., SchдЯburger K., Meyer D. et al. 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) as postoperative adjuvant chemotherapy (CT) for node-positive rectal cancer after radiochemotherapy (R-CT) and surgery. J Clin Oncol 2010;28(suppl; abstr e14125).23. Gresham G., Speers C., Woods R. et al. Association of time to adjuvant chemotherapy (TTAC) and overall survival among patients with rectal cancer treated with preoperative radiation. J Clin Oncol 2012;30(suppl 34; abstr 461).Gresham G., Speers C., Woods R. et al. Association of time to adjuvant chemotherapy (TTAC) and overall survival among patients with rectal cancer treated with preoperative radiation. J Clin Oncol 2012;30(suppl 34; abstr 461).24. Khrizman P., Niland J. C., ter Veer A. et al. Postoperative adjuvant chemotherapy use in patients with stage II / III rectal cancer treated with neoadjuvant therapy: a National Comprehensive Cancer Network analysis. J Clin Oncol 2013;31:30–8.Khrizman P., Niland J. C., ter Veer A. et al. Postoperative adjuvant chemotherapy use in patients with stage II / III rectal cancer treated with neoadjuvant therapy: a National Comprehensive Cancer Network analysis. J Clin Oncol 2013;31:30–8.25. Fietkau R., Barten M., Klautke G. et al. Adjuvant chemotherapy may not be necessary for patients with ypN0-category after neoadjuvant chemoradiotherapy of rectal cancer. Dis Colon Rectum 2006;49:1284–92.Fietkau R., Barten M., Klautke G. et al. Adjuvant chemotherapy may not be necessary for patients with ypN0-category after neoadjuvant chemoradiotherapy of rectal cancer. Dis Colon Rectum 2006;49:1284–92.26. Kiran R. P., Kirat H. T., Burgess A. N. et al. Is adjuvant chemotherapy really needed after curative surgery for rectal cancer patients who are node-negative after neoadjuvant chemoradiotherapy? Ann Surg Oncol 2012;19:1206–12.Kiran R. P., Kirat H. T., Burgess A. N. et al. Is adjuvant chemotherapy really needed after curative surgery for rectal cancer patients who are node-negative after neoadjuvant chemoradiotherapy? Ann Surg Oncol 2012;19:1206–12.27. Huh J. W., Kim H. R. Postoperative chemotherapy after neoadjuvant chemoradiation and surgery for rectal cancer: is it essential for patients with ypT0-2N0? J Surg Oncol 2009;100:387–91.Huh J. W., Kim H. R. Postoperative chemotherapy after neoadjuvant chemoradiation and surgery for rectal cancer: is it essential for patients with ypT0-2N0? J Surg Oncol 2009;100:387–91.28. Govindarajan A., Reidy D., Weiser M. R. et al. Recurrence rates and prognostic factors in ypN0 rectal cancer after neoadjuvant chemoradiation and total mesorectal excision. Ann Surg Oncol 2011;18:3666–72.Govindarajan A., Reidy D., Weiser M. R. et al. Recurrence rates and prognostic factors in ypN0 rectal cancer after neoadjuvant chemoradiation and total mesorectal excision. Ann Surg Oncol 2011;18:3666–72.29. Wu S. Y.C., Wei L., Glass K. et al. Survival differences in patients (pts) with resected rectal cancer who received neoadjuvant therapy with or without postoperative chemotherapy (CT). J Clin Oncol 2012;30(suppl 34; abstr 518).Wu S. Y.C., Wei L., Glass K. et al. Survival differences in patients (pts) with resected rectal cancer who received neoadjuvant therapy with or without postoperative chemotherapy (CT). J Clin Oncol 2012;30(suppl 34; abstr 518).30. You K. Y., Huang R., Ding P. R. et al. Selective use of adjuvant chemotherapy for rectal cancer patients with ypN0. Int J Colorectal Dis 2014 Apr;29(4):529–38.You K. Y., Huang R., Ding P. R. et al. Selective use of adjuvant chemotherapy for rectal cancer patients with ypN0. Int J Colorectal Dis 2014 Apr;29(4):529–38.31. Janjan N. A., Crane C., Feig B. W. et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol 2001;24(2):107–12.Janjan N. A., Crane C., Feig B. W. et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol 2001;24(2):107–12.32. Kiran R. P., Nisar P. J., Pelley R. J. et al. Role of routine adjuvant chemotherapy after neoadjuvant chemoradiotherapy and resection in low-risk patients with rectal cancer. J Clin Oncol 2011;29(suppl; abstr e14032).Kiran R. P., Nisar P. J., Pelley R. J. et al. Role of routine adjuvant chemotherapy after neoadjuvant chemoradiotherapy and resection in low-risk patients with rectal cancer. J Clin Oncol 2011;29(suppl; abstr e14032).33. Park I. J., You Y. N., Agarwal A. et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 2012 May 20;30(15):1770–6.Park I. J., You Y. N., Agarwal A. et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 2012 May 20;30(15):1770–6.34. Zahrani A. A., Brierley J. D., Kennedy E. D. et al. Outcomes of oxaliplatin-based adjuvant chemotherapy in pathologically lymph node positive (ypN+) rectal cancer. J Clin Oncol 2013;31(suppl; abstr e14664).Zahrani A. A., Brierley J. D., Kennedy E. D. et al. Outcomes of oxaliplatin-based adjuvant chemotherapy in pathologically lymph node positive (ypN+) rectal cancer. J Clin Oncol 2013;31(suppl; abstr e14664).35. Hong Y.S., Nam B.H., Kim K.P. et al. Adjuvant chemotherapy with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin (FL) for rectal cancer patients whose postoperative yp stage 2 or 3 after preoperative chemoradiotherapy: Updated results of 3-year disease-free survival from a randomized phase II study (The ADORE). J Clin Oncol 2014;32:5s (suppl; abstr 3502).Hong Y.S., Nam B.H., Kim K.P. et al. Adjuvant chemotherapy with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin (FL) for rectal cancer patients whose postoperative yp stage 2 or 3 after preoperative chemoradiotherapy: Updated results of 3-year disease-free survival from a randomized phase II study (The ADORE). J Clin Oncol 2014;32:5s (suppl; abstr 3502).36. Pereira V. S.A., Reig O. et al. Do we need adjuvant therapy in rectal cancer with complete pathologic response (ypT0N0) after induction chemoradiation and laparoscopic mesorectal excision? J Clin Oncol 2012;(suppl; abstr 3536).Pereira V. S.A., Reig O. et al. Do we need adjuvant therapy in rectal cancer with complete pathologic response (ypT0N0) after induction chemoradiation and laparoscopic mesorectal excision? J Clin Oncol 2012;(suppl; abstr 3536).37. Capirci C., Valentini V., Cionini L. et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 2008;72(1):99–107.Capirci C., Valentini V., Cionini L. et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 2008;72(1):99–107.38. Beets G. L., Maas M., Nelemans P. J. et al. Evaluation of response after chemoradiation for rectal cancer as a predictive factor for the benefit of adjuvant chemotherapy: A pooled analysis of 2,724 individual patients. J Clin Oncol 2011;29(suppl 4; abstr 361).Beets G. L., Maas M., Nelemans P. J. et al. Evaluation of response after chemoradiation for rectal cancer as a predictive factor for the benefit of adjuvant chemotherapy: A pooled analysis of 2,724 individual patients. J Clin Oncol 2011;29(suppl 4; abstr 361).39. Chan A. K., Wong A. O., Langevin J. et al. Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study. Int J Radiat Oncol Biol Phys 2000;48(3):843–56.Chan A. K., Wong A. O., Langevin J. et al. Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study. Int J Radiat Oncol Biol Phys 2000;48(3):843–56.40. Vickers M.M., Mercer J., Kumar A., et al. Association of adjuvant chemotherapy with clinical outcomes in patients treated with neoadjuvant chemoradiation for locally advanced rectal cancer. J Clin Oncol 2014;32:5s(suppl; abstr 3628).Vickers M.M., Mercer J., Kumar A., et al. Association of adjuvant chemotherapy with clinical outcomes in patients treated with neoadjuvant chemoradiation for locally advanced rectal cancer. J Clin Oncol 2014;32:5s(suppl; abstr 3628).