ACRNaCT trial protocol: efficacy of adjuvant chemotherapy in patients with clinical T3b/T4, N+ rectal Cancer undergoing Neoadjuvant Chemoradiotherapy: a pathology-oriented, prospective, multicenter, randomized, open-label, parallel group clinical trial

Qingguo Li, Dakui Luo, Ji Zhu, Lifeng Yang, Qi Liu, Yanlei Ma, Lei Liang, Sanjun Cai, Zhen Zhang, Xinxiang Li, ACRNaCT study group, Qingguo Li, Dakui Luo, Ji Zhu, Lifeng Yang, Qi Liu, Yanlei Ma, Lei Liang, Sanjun Cai, Zhen Zhang, Xinxiang Li, ACRNaCT study group

Abstract

Background: The CAO/ARO/AIO-94 demonstrated that neoadjuvant chemoradiotherapy (CRT) could decrease the rate of local recurrence rather than distal metastases in advanced rectal cancer. Adjuvant chemotherapy (ACT) can eliminate micrometastasis, and render a better prognosis to rectal cancer. However, adoption of ACT mainly depends on the evidence from colon cancer. Neoadjuvant CRT can lead to tumor shrinkage in a number of patients with advanced rectal cancer. The administration of adjuvant therapy depending on pretreatment clinical stage or postoperative yield pathological (yp) stage remains controversial. At present, the clinical guidelines recommend ACT for patients with stage II/III (ypT3-4 N0 or ypTanyN1-2) rectal cancer following neoadjuvant CRT and surgery. However, the yp stage may influence the guidance of ACT.

Methods: According to the postoperative pathological stage, the present study was divided into two parts with different study design procedures. Patients will undergo different therapeutic strategies after collecting data related to postoperative pathological stage. For patients with pathologic complete response or yp stage I, the study was designed as a non-inferiority trial to compare the patients' long-term outcomes in observational group and those in treatment group with 5-fluorouracil. For patients at yp stage II or III, the study was designed as a superiority trial to compare the oncological effect of oxaliplatin combined with 5-fluorouracil, in addition to 5-fluorouracil alone in ACT. The primary endpoint is 3-year disease-free survival (DFS). Secondary endpoints are 3-year, 5-year overall survival, 5-year DFS, and the rate of local recurrence and adverse events resulted from chemotherapy and the patients' quality of life postoperatively.

Discussion: The ACRNaCT trial aims to investigate whether observation is not inferior than 5-fluorouracil for pathologic complete response or yp stage I, and indicate whether combined chemotherapy contains superior outcomes than 5-fluorouracil alone for yp stage II or III in patients receiving neoadjuvant CRT and surgery for locally advanced rectal cancer (LARC). This trial is expected to provide individualized adjuvant treatment strategies for LARC patients following neoadjuvant CRT and surgery.

Trial registration: The trial has been registered in ClinicalTrials.gov on January 30, 2018 (Registration No. NCT03415763), and also, that was registered in Chinese Clinical Trial Registry on November 12, 2018 (Registration No. ChiCTR1800019445).

Keywords: Adjuvant chemotherapy; Locally advanced rectal cancer; Neoadjuvant chemoradiotherapy; Yield pathological stage.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Overview of ACRNaCT trail

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492.
    1. Gunderson LL, Jessup JM, Sargent DJ, Greene FL, Stewart A. Revised tumor and node categorization for rectal cancer based on surveillance, epidemiology, and end results and rectal pooled analysis outcomes. J Clin Oncol. 2010;28(2):256–263. doi: 10.1200/JCO.2009.23.9194.
    1. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–1740. doi: 10.1056/NEJMoa040694.
    1. Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, 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 Clin Oncol. 2012;30(16):1926–1933. doi: 10.1200/JCO.2011.40.1836.
    1. Petersen SH, Harling H, Kirkeby LT, Wille-Jorgensen P, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev. 2012;3:CD004078.
    1. Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, Bardet E, Beny A, Ollier JC, Bolla M, 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):184–190. doi: 10.1016/S1470-2045(13)70599-0.
    1. Sainato A, Cernusco Luna Nunzia V, Valentini V, De Paoli A, Maurizi ER, Lupattelli M, Aristei C, Vidali C, Conti M, Galardi A, et al. No benefit of adjuvant fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): long term results of a randomized trial (I-CNR-RT) Radiother Oncol. 2014;113(2):223–229. doi: 10.1016/j.radonc.2014.10.006.
    1. Breugom AJ, van Gijn W, Muller EW, Berglund A, van den Broek CB, Fokstuen T, Gelderblom H, Kapiteijn E, Leer JW, Marijnen CA, 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. Ann Oncol. 2015;26(4):696–701. doi: 10.1093/annonc/mdu560.
    1. Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, Ledermann J, Sebag-Montefiore D. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol. 2014;25(7):1356–1362. doi: 10.1093/annonc/mdu147.
    1. Breugom AJ, Swets M, Bosset JF, Collette L, Sainato A, Cionini L, Glynne-Jones R, Counsell N, Bastiaannet E, van den Broek CB, 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. doi: 10.1016/S1470-2045(14)71199-4.
    1. Hong YS, Nam BH, Kim KP, Kim JE, Park SJ, Park YS, Park JO, Kim SY, Kim TY, Kim JH, et al. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2014;15(11):1245–1253. doi: 10.1016/S1470-2045(14)70377-8.
    1. Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015;16(8):979–989. doi: 10.1016/S1470-2045(15)00159-X.
    1. Fokas E, Liersch T, Fietkau R, Hohenberger W, Beissbarth T, Hess C, Becker H, Ghadimi M, Mrak K, Merkel S, 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;32(15):1554–1562. doi: 10.1200/JCO.2013.54.3769.
    1. Vecchio FM, Valentini V, Minsky BD, Padula GD, Venkatraman ES, Balducci M, Micciche F, Ricci R, Morganti AG, Gambacorta MA, 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):752–760. doi: 10.1016/j.ijrobp.2004.11.017.
    1. Dhadda AS, Dickinson P, Zaitoun AM, Gandhi N, Bessell EM. Prognostic importance of Mandard tumour regression grade following pre-operative chemo/radiotherapy for locally advanced rectal cancer. Eur J Cancer. 2011;47(8):1138–1145. doi: 10.1016/j.ejca.2010.12.006.
    1. Garcia-Albeniz X, Gallego R, Hofheinz RD, Fernandez-Esparrach G, Ayuso-Colella JR, Bombi JA, Conill C, Cuatrecasas M, Delgado S, Gines A, et al. Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation. World J Gastroenterol. 2014;20(42):15820–15829. doi: 10.3748/wjg.v20.i42.15820.
    1. Hu X, Li YQ, Li QG, Ma YL, Peng JJ, Cai SJ. Adjuvant chemotherapy seemed not to have survival benefit in rectal Cancer patients with ypTis-2N0 after preoperative radiotherapy and surgery from a population-based propensity score analysis. Oncologist. 2019;24(6):803–811. doi: 10.1634/theoncologist.2017-0600.
    1. Maas M, Nelemans PJ, Valentini V, Crane CH, Capirci C, Rodel C, Nash GM, Kuo LJ, Glynne-Jones R, Garcia-Aguilar J, et al. Adjuvant chemotherapy in rectal cancer: defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients. Int J Cancer. 2015;137(1):212–220. doi: 10.1002/ijc.29355.
    1. Dossa F, Acuna SA, Rickles AS, Berho M, Wexner SD, Quereshy FA, Baxter NN, Chadi SA. Association between adjuvant chemotherapy and overall survival in patients with rectal Cancer and pathological complete response after Neoadjuvant chemotherapy and resection. JAMA Oncol. 2018;4(7):930–937. doi: 10.1001/jamaoncol.2017.5597.
    1. Ma B, Ren Y, Chen Y, Lian B, Jiang P, Li Y, Shang Y, Meng Q. Is adjuvant chemotherapy necessary for locally advanced rectal cancer patients with pathological complete response after neoadjuvant chemoradiotherapy and radical surgery? A systematic review and meta-analysis. Int J Color Dis. 2019;34(1):113–121. doi: 10.1007/s00384-018-3181-9.

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