The Lancet Oncology APRIL 13, 2021

Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23)

Thierry Conroy, Jean-François Bosset, Pierre-Luc Etienne, et al.

Bottom Line

The PRODIGE 23 trial demonstrated that total neoadjuvant therapy (TNT) with FOLFIRINOX followed by chemoradiotherapy, surgery, and adjuvant chemotherapy significantly improves disease-free survival and overall survival in patients with locally advanced rectal cancer compared to the standard-of-care approach.

Key Findings

1. The experimental TNT arm achieved significantly improved disease-free survival (DFS) compared to the standard-of-care, with 7-year DFS rates of 67.6% versus 62.5% (restricted mean survival time [RMST] difference of 5.73 months, P = 0.048).

2. Overall survival (OS) was significantly improved in the TNT arm, reaching 81.9% at 7 years compared to 76.1% in the control arm (RMST difference of 4.37 months, P = 0.033).

3. Metastasis-free survival (MFS) was significantly higher in the neoadjuvant chemotherapy group, with a 7-year rate of 79.2% versus 72.3% (RMST difference of 6.1 months, P = 0.021).

4. The pathologic complete response (pCR) rate was notably higher in the neoadjuvant chemotherapy arm (27.8%) compared to the standard-of-care (12.1%).

Study Design

Design

RCT

Open-Label

Sample

461

Patients

Duration

82.2 mo

Median

Setting

Multicenter, France

Population Patients with cT3 or cT4, M0 rectal adenocarcinoma located within 15 cm from the anal verge, age 18-75 years, and WHO performance status ≤ 1.

Intervention Neoadjuvant mFOLFIRINOX (6 cycles) followed by chemoradiotherapy (50 Gy + capecitabine), total mesorectal excision, and 3 months of adjuvant chemotherapy.

Comparator Preoperative chemoradiotherapy (50 Gy + capecitabine) followed by total mesorectal excision and 6 months of adjuvant chemotherapy.

Outcome Disease-free survival at 3 years.

Study Limitations

• The trial was open-label, which introduces potential bias in patient management and subjective assessments.

• The study population was predominantly composed of fit patients with good performance status (WHO PS ≤ 1), potentially limiting the generalizability of results to older or frailer individuals.

• Proportional hazard assumptions were not met in long-term follow-up analyses, necessitating the use of alternative statistical methods like RMST.

• The trial used a specific triplet chemotherapy regimen (FOLFIRINOX) which may be associated with distinct toxicity profiles compared to doublet regimens.

Clinical Significance

The PRODIGE 23 trial establishes total neoadjuvant therapy (TNT) as a standard-of-care option for locally advanced rectal cancer, demonstrating that early systemic control of micrometastases via intensive neoadjuvant chemotherapy improves long-term survival outcomes while maintaining high rates of locoregional control.

Historical Context

Before the adoption of TNT, the standard-of-care for locally advanced rectal cancer relied on preoperative chemoradiotherapy followed by surgery and postoperative adjuvant chemotherapy. High rates of distant recurrence prompted investigation into shifting the timing and intensity of chemotherapy, with PRODIGE 23 providing definitive phase III evidence for the superiority of neoadjuvant triplet chemotherapy.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the biological rationale for moving systemic chemotherapy from the adjuvant (postoperative) setting to the neoadjuvant (preoperative) setting in the treatment of locally advanced rectal cancer?

Key Response

Total neoadjuvant therapy (TNT) allows for earlier treatment of occult micrometastases when the patient is most fit and the tumor vasculature is intact. This approach also increases the likelihood of tumor downstaging and pathologic complete response (pCR), which can facilitate R0 resection or even organ preservation strategies.

Resident

In the PRODIGE 23 trial, how did the experimental arm modify the traditional 'sandwich' approach of chemotherapy-radiotherapy-surgery, and what was the impact on the primary endpoint?

Key Response

PRODIGE 23 introduced six cycles of FOLFIRINOX before long-course chemoradiotherapy (induction chemotherapy), followed by surgery and then six months of adjuvant chemotherapy (de-escalated from the standard duration). This 'TNT' approach significantly improved 3-year disease-free survival (DFS) from 69% in the control group to 76% in the experimental group.

Fellow

Comparing the results of PRODIGE 23 with the RAPIDO trial, how should the choice between induction FOLFIRINOX (PRODIGE 23) and consolidation CAPOX/FOLFOX after short-course radiotherapy (RAPIDO) be navigated in clinical practice?

Key Response

While both trials support TNT, they differ in radiation and chemotherapy sequencing. PRODIGE 23 used long-course chemoradiotherapy (CRT) which may be superior for tumors requiring maximal shrinkage for sphincter preservation or where there is a threatened circumferential resection margin (CRM), whereas the RAPIDO approach (Short-course RT followed by consolidation) might be preferred for rapid systemic control and lower logistical burden of radiation.

Attending

Given the significant improvement in metastasis-free survival and overall survival reported in the long-term follow-up of PRODIGE 23, should FOLFIRINOX-based TNT be considered the de facto standard for all fit patients with T3/T4 rectal cancer, or should it be reserved for 'high-risk' features?

Key Response

PRODIGE 23 demonstrated a clear survival benefit, suggesting that for fit patients, triplet chemotherapy (FOLFIRINOX) is superior to standard fluorouracil-based CRT. However, clinicians must balance the 7% absolute DFS benefit against the higher toxicity of FOLFIRINOX, potentially reserving this intensified regimen for patients with high-risk features like extramural venous invasion (EMVI), N2 disease, or threatened mesorectal fascia.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The PRODIGE 23 trial utilized disease-free survival (DFS) as the primary endpoint. Evaluate the statistical and clinical validity of DFS as a surrogate for overall survival (OS) in the context of Total Neoadjuvant Therapy and the increasing adoption of 'Watch and Wait' strategies.

Key Response

While DFS is a standard surrogate, the rise of 'Watch and Wait' complicates its interpretation because local regrowth in non-operative patients may not carry the same prognostic weight as distant recurrence. Furthermore, as systemic treatments improve, the disconnect between DFS and OS may widen, necessitating long-term follow-up (as seen in the later PRODIGE 23 data) to confirm that early gains in DFS actually translate to a significant reduction in cancer-specific mortality.

Journal Editor

Critique the choice of the control arm in PRODIGE 23 and discuss whether the adjuvant chemotherapy component in the experimental arm (only 3 months) might confound the interpretation of the neoadjuvant FOLFIRINOX benefit.

Key Response

The control arm followed the standard of care at the time (preoperative CRT followed by surgery and adjuvant chemotherapy), but the experimental arm received most of its chemotherapy upfront. A tough reviewer would question if the improvement was due to the 'triplet' (FOLFIRINOX) itself or simply the improved compliance and early delivery of systemic therapy, noting that many patients in the control arm often fail to complete adjuvant chemotherapy due to surgical complications.

Guideline Committee

How do the results of PRODIGE 23 impact the current NCCN and ESMO recommendations regarding the sequencing of systemic therapy and radiation in rectal cancer?

Key Response

Current guidelines (NCCN v2.2023) have moved toward recommending TNT as a preferred approach for T3/T4 or N+ disease. PRODIGE 23 provides 'Level 1' evidence that an induction FOLFIRINOX-based TNT approach is a valid alternative to the RAPIDO-style consolidation approach. The findings suggest that guidelines should emphasize triplet chemotherapy as a Category 1 option for patients with high-risk locally advanced rectal cancer (LARC) to maximize both local and systemic control.

Clinical Landscape

Noteworthy Related Trials

2004

CAO/ARO/AIO-94 Trial

n = 823 · NEJM

Tested

Preoperative chemoradiotherapy (5-FU based)

Population

Patients with clinical stage T3 or T4 or node-positive rectal cancer

Comparator

Postoperative chemoradiotherapy

Endpoint

Disease-free survival

Key result: Preoperative chemoradiotherapy was associated with improved local control and reduced toxicity compared to postoperative treatment.

2011

PRODIGE 4/ACCORD 11 Trial

n = 342 · NEJM

Tested

FOLFIRINOX regimen

Population

Patients with metastatic pancreatic cancer

Comparator

Gemcitabine

Endpoint

Overall survival

Key result: FOLFIRINOX demonstrated significantly longer overall survival than gemcitabine, establishing it as a potent systemic chemotherapy regimen.

2020

RAPIDO Trial

n = 920 · Lancet Oncol

Tested

Short-course radiotherapy followed by consolidation chemotherapy (CAPOX or FOLFOX)

Population

Patients with high-risk locally advanced rectal cancer

Comparator

Standard chemoradiotherapy followed by TME and optional adjuvant chemotherapy

Endpoint

Disease-related treatment failure at 3 years

Key result: The experimental treatment significantly reduced the risk of distant metastases compared to the standard of care.

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