Neoadjuvant mFOLFOXIRI Plus Bevacizumab in Patients With High-Risk Locally Advanced Rectal Cancer

Neoadjuvant mFOLFOXIRI Plus Bevacizumab Versus Induction FOLFOX Followed by Concomitant Chemoradiotherapy in Patients With High-Risk Locally Advanced Rectal Cancer: Multicenter Randomized Phase III Trial

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.

This trial is a two-arm, multicenter, open labelled, prospective, randomized phase III studies. Eligible patients with high-risk locally advanced rectal cancer patients (cT3 with any MRF involved, any cT4a/b or lateral node positive) will be randomly assigned, in a 1:1 ratio, to receive either neoadjuvant mFOLFOXIRI plus bevacizumab with selective radiotherapy or induction FOLFOX followed by concomitant chemoradiotherapy.

Inclusion Criteria:

1. Willing and able to provide written informed consent.
2. Male or female subjects > 18 years < 70 of age.
3. Histological or cytological documentation of adenocarcinoma of the rectal (<12 cm from the anal verge).
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Evaluated by pelvic contrast-enhanced MRI as having high-risk locally advanced disease: cT3 with mesorectal fascia involvement, or cT4a/b, or positive lateral lymph nodes (TNM staging reference provided).
6. No prior systemic anti-cancer therapy for colorectal cancer, including cytotoxic drugs, immune checkpoint inhibitors, molecular targeted therapy, or endocrine therapy.
7. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment
8. Willing and able to comply with the study protocol and visit schedule.

Exclusion Criteria:

1. Evidence of distant metastasis (M1) confirmed by systemic CT, MRI, or PET-CT (at minimum including chest, abdomen, and pelvis).
2. Previous or concurrent cancer that is distinct in primary site or histology from colon cancer within 5 years prior to randomization.
3. Complete intestinal obstruction, active bleeding, or perforation requiring emergency surgery.
4. Tumor invasion into the small intestine, or presence of intestinal fistula (including but not limited to rectovesical or rectovaginal fistula), or abscess.
5. Previous or concurrent other active malignancies, except for malignancies treated with curative intent and disease-free for >5 years, or adequately treated carcinoma in situ.
6. Prior pelvic radiotherapy, or any anti-cancer therapy (chemotherapy, targeted therapy, hormonal therapy, immunotherapy, biologic therapy, etc.) within 12 months prior to enrollment.
7. History of thromboembolic events within 12 months prior to enrollment, such as cerebrovascular accident (including transient ischemic attack), pulmonary embolism, or deep vein thrombosis.
8. Any of the following within 12 months prior to enrollment: myocardial infarction, severe/unstable angina, NYHA Class II or greater cardiac dysfunction, clinically significant supraventricular or ventricular arrhythmia, or symptomatic congestive heart failure.
9. Diagnosis of dMMR or MSI-High tumor by immunohistochemistry or PCR testing.
10. Current or within 2 weeks prior to enrollment: therapeutic antiplatelet therapy or high-dose anticoagulant therapy.
11. Major surgery (e.g., laparotomy, thoracotomy, visceral resection via laparoscopy) or severe trauma within 2 months prior to enrollment (except for colostomy performed prior to enrollment; surgical incision must be fully healed before enrollment).
12. Known history of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
13. Presence of interstitial lung disease, non-infectious pneumonitis, or uncontrolled systemic diseases (e.g., diabetes, hypertension, pulmonary fibrosis, acute pneumonia, aneurysm, coagulation disorders, etc.).
14. Untreated active hepatitis (Hepatitis B, defined as HBV-DNA ≥500 IU/mL; Hepatitis C, defined as HCV-RNA above the lower limit of detection of the assay) or co-infection with HBV and HCV.
15. Subjects with known allergy to the study drugs or to any of its excipients.
16. Breast- feeding or pregnant women.
17. Any other severe physical or mental illness or abnormal laboratory finding that may increase the risk associated with study participation, interfere with study results, or make the patient unsuitable for the study in the investigator's judgment.