results of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. Comparative efficiency of hypofractionation and classical fractionation schedules

Objective: comparison of the effectiveness of the results of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer using classical and hypofractionated schedule of radiation therapy.

Materials and methods. This study is based on a retrospective analysis of a database of patients with locally advanced rectal cancer (T3C–D, positive circumferential resection margin or T4) who underwent a prolonged course of neoadjuvant chemoradiotherapy followed by surgery. The patients were divided into two groups: the first (main) group, 71 patients who received a course of chemoradiotherapy in hypofractionation schedule as part of neoadjuvant treatment (4 Gy × 40 Gy, 3 fractions per week) in combination with chemotherapy with capecitabine 1650 mg / m2 in two doses on weekdays. The second group (control group) included 79 patients who treated with long-course chemoradiotherapy in the classic fractionation mode (2 Gy × 50–58 Gy, 5 fractions per week) in combination with chemotherapy with capecitabine 1650 mg / m2 in two doses on weekdays. In the preoperative period, along with chemoradiotherapy, 4–8 courses of the systemic chemotherapy in the CapOx mode was used. The primary endpoint of this study was pathological complete response. Secondary endpoints included the seve rity of early radiation and hematological toxicity, the incidence of local recurrence, distant metastases, overall and disease-free survival.

Results. The study included 150 patients. The overall frequency of acute radiation toxicity of grade III–IV was 5.6 % in the main group and 8.9 % in the control group (p = 0.658), from them hematological toxicity – 2.82 % and 7.6 %, respectively (p = 0.350), skin and pelvic organ toxicity – 2.82 % and 1.3 %, respectively (p = 0.926). Complete pathological response of III degree in the groups achieved 22.5 % and 19 %, respectively (p = 0.593), grade IV – 18.3 % and 15.2 %, respectively (p = 0.829). In the main and control groups, 4.2 % and 3.8 % of local recurrence were registered, respectively (p = 0.954; hazard ratio (HR) 1.05; 95 % confidence interval (CI) 0.21–5.22). The median time of disease-free survival was 39.4 months. The three-year disease-free survival in the main group was 73.2 % and in the control group 64.6 %, respectively (p = 0.353; HR 0.79; 95 % CI 0.42–1.35). The three-year overall survival in the main and control groups were 84.5 % and 82.3 %, respectively (p = 0.743; HR 0.87; 95 % CI 0.39–1.92).

Conclusions. The hypofractionation schedule can be considered as an alternative and not inferior to the standard dose fractionation regimen in a prolonged course of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. 

1. Benson A.B., Venook A.P., Cederquist L. et al. Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2017;15(3):370–98. DOI: 10.6004/jnccn.2017.0036.

2. 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):iv22–40. DOI: 10.1093/annonc/mdx224.

3. Zhou Z.R., Liu S.X., Zhang T.S. et al. Short-course preoperative radiotherapy with immediate surgery versus long-course chemoradiation with delayed surgery in the treatment of rectal cancer: a systematic review and meta-analysis. Surg Oncol 2014;23(4):211–21. DOI: 10.1016/j.suronc.2014.10.003.

4. Liu S.X., Zhou Z.R., Chen L.X. et al. Short-course versus long-course preoperative radiotherapy plus delayed surgery in the treatment of rectal cancer: a meta-analysis. Asian Pac J Cancer Prev 2015;16(14):5755–62. DOI: 10.7314/apjcp.2015.16.14.5755.

5. Kairevičė L., Latkauskas T., Tamelis A. et al. Preoperative long-course chemoradiotherapy plus adjuvant chemotherapy versus short-course radiotherapy without adjuvant chemotherapy both with delayed surgery for stage II–III resectable rectal cancer: 5-year survival data of a randomized controlled trial. Medicina (Kaunas) 2017;53(3):150–8. DOI: 10.1016/j.medici.2017.05.006.

6. Ngan S.Y., Burmeister B., Fisher R.J. et al. Randomized 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(31):3827–33. DOI: 10.1200/JCO.2012.42.9597.

7. Барсуков Ю.А., Кузьмичев Д.В., Ткачев С.И. и др. Комплексное лечение больных раком прямой кишки с использованием неоадъювантной термохимиолучевой терапии. Онкологическая колопроктология 2014;(3):23–8. [Barsukov Yu.A., Kuzmichev D.V., Tkachev S.I. et al. Comprehensive treatment of patients with rectal cancer using neoadjuvant thermochemoradiotherapy. Onkologicheskaya Koloproktologiya = Colorectal Oncology 2014;(3):23–8. (In Russ.)]. DOI: 10.17650/2220-3478-2014-0-3-23-28.

8. Cox J., Stetz J., Pajak T. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;1(5):1341–6. DOI: 10.1016/0360-3016(95)00060-C.

9. Suarez J., Vera R., Balen E. et al. Pathologic response assessed by Mandard grade is a better prognostic factor than down staging for disease-free survival after preoperative radiochemotherapy for advanced rectal cancer. Colorectal Dis 2008;10(6):563–8.

10. Dhadda A.S., Dickinson P., Zaitoun A.M. et al. Prognostic importance of Mandard tumour regression grade following preoperative chemo/radiotherapy for locally advanced rectal cancer. Eur J Cancer 2011;47(8):1138–45.

11. Vecchio F.M., Valentini V., Minsky B.D. et al. The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer. Int J Radiat Oncol Biol Phys 2005;62(3):752–60.

12. Dworak O., Keilholz L., Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997;12(1):19–23.

13. Lee S.U., Kim D.Y., Kim S.Y. et al. Comparison of two preoperative chemoradiotherapy regimens for locally advanced rectal cancer: capecitabine alone versus capecitabine plus irinotecan. Radiat Oncol 2013;8:258. DOI: 10.1186/1748-717X-8-258.