Three-year outcomes of sandwich therapy in patients with locally advanced cancer of the middle and lower rectum

Background. The most important criteria for the effectiveness of the treatment of locally advanced rectal cancer are indicators of overall survival (OS) and disease-free survival (DSF). Conducting systemic chemotherapy in addition to chemoradiotherapy at the preoperative stage can increase these indicators.
Objective: to study analyze the indicators of 3-year OS and DFS, as well as the frequency of local relapses and distant metastases.
Materials and methods. From 2013 to 2020, 72 patients with T≥3(CRM+)N0–2M0 lower and middle ampullar rectal cancer were included in the study using sandwich therapy. At the first stage, 2 courses of induction polychemotherapy were carried out according to the CapOx scheme (capecitabine 2000 mg/m2  orally for 14 days and oxaliplatin 130 mg/m2 intravenously once every 3 weeks). Further, chemoradiation therapy was carried out with a total focal dose of 50–56 Gy while taking capecitabine 1650 mg/m²  per day orally on the days of irradiation. After the end of chemotherapy, the patients underwent 2 courses of consolidating polychemotherapy according to the CapOx scheme (capecitabine 2000 mg/m²  orally for 14 days and oxaliplatin 130 mg/m²  intravenously once every 3 weeks). The control group consisted of 72 patients who underwent neoadjuvant treatment in accordance with current clinical guidelines (chemotherapy course with a total focal dose of 50–56 Gy while taking capecitabine 1650 mg/m²  per day orally on the days of irradiation).
Results. In 19 (26.4 %) patients from the study group and in 6 (8.3 %) patients from the control group, the achievement of pCR was recorded (p = 0.006). The overall complication rate was 48 (66.7 %) in the study group and 37 (51.4 %) in the control group (p = 0.072), the frequency of grade III–IV toxicity was 8 (11.1 %) and 7 (9.7 %), respectively (p = 0.072). Sphincter-sparing surgical interventions were performed in 52 (72.2 %) and 40 (55.6 %) patients in the sandwich-therapy group and the control group of chemoradiation therapy, respectively (p = 0.037). Resection in the R0 volume was achieved in 71 (98.6 %) and 72 (100 %) patients, respectively (p = 0.316).
Conclusion. The use of sandwich therapy is a promising trend in the treatment of patients with locally advanced rectal cancer. There were no significant differences in the frequency of 3-year OS (96.1 % versus 91.5 %, p = 0.247), DFS (89.8 % versus 84.0 %, p = 0.117) and local relapses (0 % versus 4.2 %, p = 0.997). In our study, statistically significant differences were obtained in the incidence of distant metastases (6.9 % versus 18.1 %, p = 0.05), which may indicate a positive trend towards an increase in OS and DFS rates.

1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Cancer. Available at: https://www.nccn.org/guidelines/guidelinesdetail?category=1&id=1461.

2. Peeters K.C., Marijnen C.A., Nagtegaal I.D. et al. The TME trial after a median followup of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 2007;246(5):693–701.

3. Chen C., Sun P., Rong J. et al. Short course radiation in the treatment of localized rectal cancer: A systematic review and meta-analysis. Sci Rep 2015;5:10953.

4. Sineshaw H.M., Jemal A., Thomas C.R., Mitin T. Changes in treatment patterns for patients with locally advanced rectal cancer in the United States over the past decade: An analysis from the National Cancer Data Base. Cancer 2016;122(13):1996–2003.

5. Yanwu S., Zhekun H., Yiyi Zh. et al. Is early initiation of adjuvant chemotherapy beneficial for locally advanced rectal cancer following neoadjuvant chemoradiotherapy and radical surgery? World J Surg 2020;44(9):3149–57. DOI: 10.1007/s00268-020-05573-4.

6. Rödel C., Liersch T., Becker H. et al. Preoperative chemo-radiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol 2012;13(7):679–87.

7. 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(2):184–90. DOI: 10.1016/S1470-2045(13)70599-0.

8. Shu-Biao Y., Yi-Kan Ch., Lin Zh. et al. Association of mismatch repair status with survival and response to neoadjuvant chemo(radio)therapy in rectal cancer. NPJ Precis Oncol 2020;4:26. DOI: 10.1038/s41698-020-00132-5.

9. Akildzhonov F.R., Buziashvili Yu.I., Stilidi I.S. et al. Cardiac biomarkers in patients after chemotherapy. Meditsinskiy alfavit = Medical Alphabet 2021;19(471):49–53. (In Russ.).

10. Gérard J.P., Azria D., Gourgou-Bourgade S. et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol2010;28(10):1638–44.

11. Aschele C., Cionini L., Lonardi S. et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results ofthe STAR-01 randomized phase III trial. J Clin Oncol 2011;29(20):2773–80.

12. Artamonova E.V. Current treatment strategy for metastatic colorectal cancer as a key to increase survival of patients with metastatic colorectal cancer negative for RAS mutations. Meditsinskiy alfavit = Medical Alphabet 2021;19(471):54–63. (In Russ.). DOI: 10.33667/2078-5631-2021-19-54-63.

13. Glynne-Jones R., Mawdsley S., Harrison M. Cetuximab and chemoradiation for rectal cancer – is the water getting muddy? Acta Oncol 2010;49(3):278–86. DOI: 10.3109/02841860903536010.

14. Hu Y.H., Wei J.W., Chang H. et al. The high pCR rate of sandwich neoadjuvant treatment in locally advanced rectal cancer may translate into a better long-term survival benefit: 5-year outcome of a Phase II clinical trial. Cancer Manag Res 2018;10: 4363–9. DOI: 10.2147/CMAR.S168573.

15. Golo D., But-Hadzic J., Anderluh F. et al. Induction chemotherapy, chemoradiotherapy and consolidation chemotherapy in preoperative treatment of rectal cancer – long-term results of Phase II OIGIT-01 Trial. Radiol Oncol 2018;52(3):267–74. DOI: 10.2478/raon-2018-0028.

16. Xiao J., Chen Z., Li W. et al. Sandwichlike neoadjuvant therapy with bevacizumab for locally advanced rectal cancer: a phase II trial. Cancer Chemother Pharmacol 2015;76(1):21–7.

17. Kit O.I., Gevorkyan Yu.A., Soldatkina N.V. et al. Current prognostic factors in colorectal cancer. Koloproktologiya = Coloproctology 2021;2(76):42–9. (In Russ.).

18. Williams G.T., Quirke P., Shepherd N.A. Dataset for Colorectal Cancer. 2nd edn, 2007. Available at: http://www.rcpath.org/resources/worddocs/G049ColorectalDatasetAppendixC-Sep07.doc.

19. Chand M., Bhangu A., Wotherspoon A. et al. EMVI-positive stage II rectal cancer has similar clinical outcomes as stage III disease following pre-operative chemoradiotherapy. Ann Oncol 2014;25(4):858–63. DOI: 10.1093/annonc/mdu029.