What are the key findings and treatment implications from landmark trials in rectal cancer?

Landmark Trials in Rectal Cancer

Total Neoadjuvant Therapy (TNT) Trials

The RAPIDO, PRODIGE-23, POLISH II, and STELLAR trials have fundamentally transformed rectal cancer treatment by demonstrating that total neoadjuvant therapy improves survival and disease control compared to standard chemoradiotherapy alone. 1

RAPIDO Trial

• Demonstrated that TNT with short-course radiotherapy plus consolidation chemotherapy significantly reduced disease-related treatment failure at 3 years (RR 0.79,95% CI 0.63-1.00, p=0.048) compared to standard long-course chemoradiotherapy 1
• Improved overall survival (HR 0.78,95% CI 0.62-0.97) when TNT was compared to standard chemoradiotherapy across multiple trials 1
• However, 5-year follow-up revealed a critical limitation: locoregional recurrence was higher with short-course RT-based TNT (10%) versus standard long-course chemoradiotherapy (6%), emphasizing that long-course chemoradiotherapy provides superior local control 2
• Grade 3-4 treatment-related adverse events were significantly higher in the TNT group, though long-term quality of life and bowel function showed no significant differences in patients without disease-related treatment failure 1

PRODIGE-23 Trial

• Evaluated induction FOLFIRINOX followed by capecitabine-based chemoradiotherapy versus standard treatment 1
• Achieved significantly improved pathologic complete response rates (OR 1.74,95% CI 1.45-2.10) and 3-year disease-free survival compared to standard chemoradiotherapy 1, 3
• The trial used induction chemotherapy before chemoradiotherapy, contrasting with consolidation approaches 1

POLISH II Trial

• Compared short-course radiotherapy plus consolidation FOLFOX chemotherapy versus standard long-course chemoradiotherapy 1
• Demonstrated lower acute toxicity in the TNT group versus standard chemoradiotherapy, likely explained by shorter duration of neoadjuvant chemotherapy 1

STELLAR Trial

• Confirmed that consolidation CAPOX after chemoradiotherapy achieved 3-year disease-free survival of 64.5% with manageable toxicity 3
• Supported the use of oxaliplatin-based consolidation regimens in the TNT approach 3

Key TNT Synthesis

• Meta-analysis of these four phase III trials showed TNT significantly improved pathologic complete response and overall survival but not disease-free survival (HR 0.86,95% CI 0.71-1.04) 1
• Consolidation chemotherapy after chemoradiotherapy is now preferred over induction chemotherapy before chemoradiotherapy, as demonstrated by superior outcomes in OPRA and CAO/ARO/AIO-12 trials 1, 2

Organ Preservation Trials

OPRA Trial (Organ Preservation in Rectal Adenocarcinoma)

• This landmark phase II randomized trial demonstrated that organ preservation is achievable in approximately half of patients treated with TNT 1
• Compared induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy followed by consolidation chemotherapy 1
• 3-year TME-free survival was 41% in the induction group versus 53% in the consolidation group, favoring the consolidation approach 1
• Disease-free survival was 76% for both groups at 3 years, matching historical 75% rates with standard treatment 1
• 5-year follow-up confirmed durable organ preservation in half of patients, with 5-year DFS of 71% (induction) and 69% (consolidation) 1
• Critical surveillance finding: 94% of tumor regrowth occurred within the first 2 years and 99% within 3 years, establishing the critical surveillance window 1
• TME-free survival at 5 years was 39% for induction and 54% for consolidation chemotherapy 1

International Watch & Wait Database (IWWD)

• Pooled data from 880 patients with clinical complete response managed by watch-and-wait showed 2-year local recurrence incidence of 25.2%, with 88% occurring in the first 2 years 1
• 5-year overall survival was 85% and disease-specific survival was 94%, demonstrating oncologic safety of the approach 1, 4
• Updated 2021 analysis of 793 patients showed probability of remaining free of local recurrence for an additional 2 years was 88.1% after 1 year of disease-free survival, 97.3% after 3 years, and 98.6% after 5 years 1, 4
• Distant metastasis-free survival at these same intervals was 93.8%, 97.8%, and 96.6% respectively 1

Dostarlimab Trial (dMMR/MSI-H Rectal Cancer)

• Small prospective phase II trial of dostarlimab (anti-PD-1) in 12 patients with dMMR stage II-III rectal adenocarcinoma achieved 100% clinical complete response 1
• No patients received chemoradiotherapy or surgery, and no progression or recurrence occurred with follow-up ranging 6-25 months 1
• 2024 ASCO update with 48 enrolled patients confirmed all 42 patients who completed treatment maintained clinical complete response with no additional therapy needed 1

Historical Foundation Trials

German CAO/ARO/AIO-94 Trial

• Established preoperative chemoradiotherapy as superior to postoperative treatment 3
• Demonstrated lower 10-year local recurrence with preoperative therapy (7.1% vs 10.1%, p=0.048) 3
• Reduced treatment toxicity significantly (27% vs 40%, p=0.001) with preoperative approach 3
• This trial fundamentally shifted the treatment paradigm from postoperative to preoperative therapy 3

PROSPECT Trial

• Phase II/III trial comparing FOLFOX chemotherapy alone versus chemoradiotherapy in 1,194 patients with cT2N1, cT3N0-N1 disease 1
• 85% had mid-to-high tumor location, establishing that select patients may avoid radiation 1
• Demonstrated that neoadjuvant chemotherapy without radiation is a viable option for carefully selected patients 1

Staging and Surgical Quality Trials

High-Resolution MRI Validation Studies

• Prospective data demonstrated that high-resolution MRI preoperatively assessing extramural spread and relationship to the TME plane allows appropriate patient selection for neoadjuvant therapy 1
• Extramural vascular invasion (EMVI) and tumor deposits identified on MRI were the only factors retaining significant association with distant recurrence on multivariate analysis 1
• EMVI or extranodal tumor deposits are associated with four-fold increased risk of distant recurrence 1

Total Mesorectal Excision (TME) Evidence

• TME with intact mesorectal fascia became the surgical standard based on evidence showing damaged fascia adversely affects outcomes and increases local recurrence 1
• Quality of TME specimen is prognostically relevant, and surgeons can be trained to achieve this technique with resultant reduction in local recurrence rates 1

Common Pitfalls in Applying Trial Evidence

• Do not apply short-course RT-based TNT when local control is paramount, as RAPIDO's 5-year data showed increased locoregional recurrence; long-course chemoradiotherapy is preferred for high-risk features 2
• Do not offer watch-and-wait outside experienced multidisciplinary centers, as rigorous surveillance protocols are essential for detecting the 25% of patients who develop local regrowth 4
• Do not delay surveillance beyond 4-month intervals in the first 2 years after clinical complete response, as 94-99% of regrowth occurs during this window 1, 4
• Do not use induction chemotherapy before chemoradiotherapy when organ preservation is the goal, as consolidation chemotherapy after chemoradiotherapy achieves superior TME-free survival (53% vs 41%) 1, 2