Randomized studies have shown low compliance to adjuvant chemotherapy in rectal cancer patients receiving preoperative chemotherapy and external beam radiation (CT/EBRT) with total mesorectal excision. We hypothesize that giving neoadjuvant CT before local treatment would improve CT compliance.
Between 2010-2017, 180 patients were randomized (2:1) to either Arm A (AA) with FOLFOX x6 cycles prior to high dose rate brachytherapy (HDRBT) and surgery plus adjuvant FOLFOX x6 cycles, or Arm B (AB), with neoadjuvant HDRBT with surgery and adjuvant FOLFOX x12 cycles. The primary endpoint was CT compliance to ≥85% of full-dose CT for the first six cycles. Secondary endpoints were ypT0N0, five-year disease free survival (DFS), local control and overall survival (OS).
Patients were randomized to either AA (n = 120, median age (MA) 62 years) or AB (n = 60, MA 63 years). 175/180 patients completed HDRBT as planned (97.2%). In AA, two patients expired during CT; three patients post-randomization received short course EBRT because of progression under CT (n=2, AA) or personal preference (n=1, AB). ypT0N0 was 31% in AA and 28% in AB (p=0.7). CT Compliance was 80% in AA and 53% in AB (p=0.0002). Acute G3/G4 toxicity was 35.8% in AA and 27.6% in AB (p=0.23). With a median follow-up of 48.5 months (IQR 33-72), the five-year DFS was 72.3% with AA and 68.3% with AB (p = 0.74), the five-year OS 83.8% for AA and 82.2% for AB (p = 0.53), and the five-year local recurrence was 6.3% for AA and 5.8% for AB (p=0.71).
We confirmed improved compliance to neoadjuvant CT in this study. Although there is no statistical difference in ypT0N0 rate, local recurrence, and DFS between the two arms, a trend towards favourable oncological outcomes is observed.
In patients with locally advanced rectal cancer, the standard of care consists of preoperative pelvic external beam radiotherapy (EBRT) followed by total mesorectal excision (TME); EBRT either consists of long course chemoradiotherapy (LCRT) with 5-FU/ Capecitabine or short course hypofractionated radiotherapy (SCRT)(1-6). Oxaliplatin in combination with fluoropyrimidine-based chemotherapy (CT) has resulted in improved response rates, progression-free survival (PFS), and overall survival (OS) in metastatic colorectal cancer(7-14) and survival benefit in the adjuvant setting(15, 16). For rectal cancer treatment, adjuvant CT is recommended according to randomized trials including colon and rectal cancers, though there was no strong evidence for the rectal cancer subpopulation. One hypothesis could be related to the low compliance to adjuvant CT in rectal patients after CRT and surgery. Intensification of neoadjuvant CRT failed to demonstrate OS benefit from addition of oxaliplatin to fluoropyrimidine-based CRT, and all(17-20) but the CAOI/ARO/AIO-04 trial(21), reported increased rates of grade 3 and 4 toxicity. Therefore, 5-FU-based CT remains standard with neoadjuvant LCRT and OS unchanged. Thus, the rationale for neoadjuvant CT was introduced to reduce distant metastasis through the early initiation of systemic treatment: better compliance to treatment is expected with this approach, as patients are fitter before TME than in the postoperative phase. At our institution, image-guided high dose rate endorectal brachytherapy (HDRBT)(22, 23) was developed as a highly targeted neoadjuvant radiation (RT) modality for low T2 with close mesorectal fascia (MRF) and T3 rectal cancer. In 678 patients treated with a median follow-up time of 63 months(24), the LR rate was 4.5%, and the five-year overall survival was 71%. In contrast EBRT, HDRBT is given without CT over four consecutive days and allows for lower RT dose to pelvic normal tissue, in particular to bone marrow; additionally, HDRBT offers more targeted RT to the tumor bed than EBRT. Our study was designed to optimize the delivery of systemic CT using HDRBT. More specifically, we sought to explore the value of induction CT in the management of patients with rectal cancer at high risk of systemic recurrence in a randomized multicenter phase II study.
Study design and participants.

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