Neoadjuvant mFOLFOXIRI Plus Bevacizumab in Patients With High-Risk Locally Advanced Rectal Cancer
Status:
Recruiting
Trial end date:
2025-02-01
Target enrollment:
Participant gender:
Summary
Multimodality treatment that comprises preoperative fluoropyrimidine with concurrent
radiotherapy followed by total mesorectal excision (TME) surgery and adjuvant
fluoropyrimidine-based chemotherapy is recommended as a standard treatment of patients with
stage II/III rectal cancer. However, the main target of radiotherapy is local control but no
improvement in disease-free survival (DFS) or overall survival (OS) has been shown with this
treatment strategy, which leaves approximately 30% of patients in whom distant metastases
will develop. Moreover, the short- and long-term adverse effects of radiotherapy such as
chronic pain, faecal incontinence and urogenital/anal dysfunction are associated with poor
quality of life.
Neadajuvant chemotherpay (NACT) alone has been proposed instead of preoperative
chemoradiotherapy (CRT) with the aim of elimination of potential micrometastasis as early as
possible while avoiding the adverse effects of radiotherapy, without jeopardizing local
control.
Evidence from the UK CR07 trial suggests that, without RT, a local recurrence rate of 5%
(27/543) can be achieved if a complete mesorectal excision is carried out with a negative
CRM. A small single-center phase II pilot trial treated patients with stage II or III rectal
cancer with induction FOLFOX/bevacizumab chemotherapy followed by CRT only in those with
stable or progressive disease and resection in all patients. All 32 of the participants had
an R0 resection, and the 4-year DFS was 84%. Another phase II trial, which included 60
patients with stage II/III rectal cancer, assessed the R0 resection rate after FOLFOX plus
either bevacizumab or cetuximab. An R0 resection was achieved in 98.3% of the participants,
and the pathologic complete response rate was 16.7%. The phase III FOWARC trial, compared
neoadjuvant therapy with and without radiation and found that perioperative mFOLFOX6 alone
led to a similar downstaging rate as fluorouracil-radiotherapy, and no significant difference
in outcomes was found between mFOLFOX6 without radiotherapy and 5-FU- radiotherapy.
On the basis of the results of these trials, The investigators hypothesized that radiotherapy
could be selectively omitted for patients who respond to NACT alone. The results of TRIBE
showed that FOLFOXIRI plus bevacizumab yield a high objective response rate (ORR) (65%),
early tumor shrinkage (ETS) (62.7%) and depth of response (DoR) (43.4%) in patients with
metastatic colorectal cancer.
The investigators were motivated to investigate this triplet-drugs chemotherpay plus
bevacizumab both by the possibility of avoiding the toxicities of radiation without
compromising local control, and the possibility that earlier introduction of intensive
systemic therapy might achieve rapid tumor shrinkage, and improve distant control.
The investigators conducted this phase III trial to compare neoadjuvant mFOLFOXIRI plus
bevacizumab with selective radiotherapy with induction FOLFOX followed by concomitant
chemoradiotherapy in patients with high-risk locally advanced rectal cancer.