Ca Rectum Trials

Question 1

Timeline of trial for ca rectum

Answer 1

1986: Introduction of TME (Total Mesorectal Excision) [1].

1997: Preoperative SCRT improves local control over surgery (Swedish Rectal Cancer Trial) [2].

2001: SCRT improves local control over TME (Dutch Trial) [3].

2004: Preoperative CRT improves local control over postoperative CRT (German Rectal Cancer Study) [4].

2005: Adjuvant chemotherapy does not improve outcomes after CRT (EORTC22921) [5].

2006: Neoadjuvant CRT does not increase survival nor local control over SCRT (Polish Trial) [6].

2006: MRI predicts CRM (Circumferential Resection Margin) (MERCURY) [7].

2009: Preoperative SCRT improves local control and DFS over postoperative treatment (MRC CR07) [8].

2012: Incorporating oxaliplatin pre- and postoperatively improves DFS (CAO/ARO/AIO 04) [9].

2014: Addition of oxaliplatin to CRT does not improve outcomes (NSABP R04) [10].

2018: Introduction of the Watch and Wait strategy [11].

2019: Delayed surgery after SCRT (Stockholm III) [12].

2020: Total Neoadjuvant Therapy becomes standard of care (RAPIDO [13] & PRODIGE 23 [14]).

Question 2

Whom should TNT be offered for?

Answer 2

1. Locally advanced Low rectal cancer ie any T3,4 N+ and/or
2. If mid or upper rectal cancers Patients who are at higher risk for local and/or distant metastases,

High risk patients include:
- T4,
- EMVI,
-Tumor deposits identified on MRI
-Threatened MRF, -Threatened intersphincteric plane

Question 3

For patients with lower risk locally advanced rectal cancer, is CRT or chemotherapy with FOLFOX and selective CRT recommended?

Answer 3

In lower risk locally advanced upper or middle rectal cancer T2N1, T3 N0 to N1RT can be avoided if they achieve >20% reduction in tumour area after NACT
(PROSPECT phase II/III trial)

Question 4

Trials of comparison of NACT versus NA-CRT

Answer 4

1. PROSPECT trial 2023 Basch E (US,Canada,Switzerland) NEJM
2. CONVERT trial 2023 Mei WJ (China) LANCET
3. FOWARC trial 2019 Deng Y (China) JCO

Question 5

Trials of comparison of NACT versus NA-CRT

1. PROSPECT trial 2023 Basch E (US,Canada,Switzerland) NEJM

Answer 5

Inclusion Criteria:
-T2N1, T3N0, or T3N1​
-Tumor located in the mid-to-upper rectum​
-Candidates for sphincter-sparing surgery​

Exclusion Criteria:
-T4 tumors​
-Low rectal tumors not amenable to sphincter preservation​

Study Arms:
1. Neoadjuvant FOLFOX CT with Selective CRT:
-6 cycles of mFOLFOX over 12 weeks​
-Selective use of CRT for patients with inadequate response​
-Followed by total mesorectal excision (TME)​

2. Standard Neoadjuvant Chemoradiation:
   -Pelvic CRT with fluorouracil (5-FU) over 5.5 weeks​
   -Followed by TME)

Primary Objective:
To determine if neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation is non-inferior to standard neoadjuvant chemoradiation in terms of disease-free survival (DFS) at 5 years.​

Results:
Disease-Free Survival (DFS) at 5 Years:
a. FOLFOX Group: 80.8% (95% CI, 77.9%–83.7%)​
b. Chemoradiation Group: 78.6% (95% CI, 75.4%–81.8%)​

Local Recurrence-Free Survival:
a. FOLFOX Group: 98.2%​
b. Chemoradiation Group: 98.4%​

Overall Survival (OS) at 5 Years:
a. FOLFOX Group: 89.5%​
b. Chemoradiation Group: 90.2%​

Use of Chemoradiation in FOLFOX Arm:
Approximately 10% of patients required chemoradiation due to inadequate response to FOLFOX.​

Conclusion:
The PROSPECT trial demonstrated that neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation is non-inferior to standard neoadjuvant chemoradiation in terms of disease-free survival for patients with locally advanced rectal cancer. This approach allows for the omission of pelvic radiation in approximately 90% of patients, potentially reducing treatment-related toxicity without compromising oncologic outcomes.

Question 6

Trials of comparison of NACT versus NA-CRT
2. CONVERT trial 2023 Mei WJ (China) LANCET

Answer 6

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT)

Inclusion Criteria:
- Clinical stage cT3–4a, N0–2, M0
- Uninvolved mesorectal fascia (MRF-negative)

Exclusion Criteria:
- MRF-positive tumors
- Prior pelvic radiation therapy
- Metastatic disease

Study Arms:

1. Neoadjuvant Chemotherapy (nCT) Arm:
- Four cycles of CAPOX regimen:
- Oxaliplatin 130 mg/m² IV on day 1
- Capecitabine 1000 mg/m² orally BD on days 1–14
- Cycles repeated every 3 weeks
- Followed by TME
- Adjuvant CT administered postoperatively

2. Neoadjuvant Chemoradiotherapy (nCRT) Arm:
- Radiotherapy: 50 Gy in 25 fractions over 5 weeks
- Concurrent oral capecitabine 825 mg/m² twice daily on radiotherapy days
-Followed by TME
- Adjuvant CT administered postoperatively

Primary Objective:
- To determine if neoadjuvant chemotherapy with CAPOX (nCT) is non-inferior to standard neoadjuvant chemoradiotherapy (nCRT) in terms of 3-year local-regional failure-free survival.

Results:

Pathologic Complete Response (pCR):
- nCT Group: 11.0% (95% CI, 7.8%–15.3%)
- nCRT Group: 13.8% (95% CI, 10.1%–18.5%)
- P-value: 0.33

Tumor Regression Grade (TRG 0–1):
- nCT Group: 23.2%
- nCRT Group: 36.8%
- P-value: <0.001

Perioperative Distant Metastases:
- nCT Group: 0.7%
- nCRT Group: 3.1%
- P-value: 0.03

Sphincter Preservation Rate:
- nCT Group: 94.9%
- nCRT Group: 94.3%
- P-value: 0.76

Conclusion:
The CONVERT trial demonstrated that neoadjuvant chemotherapy with CAPOX (nCT) achieved similar pathologic complete response and tumor downstaging rates compared to standard neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer with uninvolved mesorectal fascia. Additionally, the nCT approach was associated with a lower incidence of peri

Question 7

Trials of comparison of NACT versus NA-CRT
3. FOWARC trial 2019 Deng Y (China) JCO

Answer 7

• Patients: Adults aged 18 to 75 years with stage II/III rectal cancer.

Treatment Arms

1. Fluorouracil plus Radiotherapy Arm:
   
   • Neoadjuvant Treatment:
     
     • Five cycles of infusional fluorouracil regimen (leucovorin 400 mg/m², fluorouracil 400 mg/m², and fluorouracil 2.4 g/m² delivered over 48 hours)
     • Radiotherapy: 46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4.
   • Adjuvant Treatment:
     
     • Seven cycles of the same infusional fluorouracil regimen.
2. mFOLFOX6 plus Radiotherapy Arm:
   
   • Neoadjuvant Treatment:
     
     • The same infusional fluorouracil regimen as above plus intravenous oxaliplatin at 85 mg/m² on day 1 of each cycle.
   • Adjuvant Treatment:
     
     • Seven cycles of mFOLFOX6.
3. mFOLFOX6 Alone Arm:
   
   • Neoadjuvant Treatment:
     
     • Four to six cycles of mFOLFOX6 (no radiotherapy).
   • Adjuvant Treatment:
     
     • Six to eight cycles of mFOLFOX6.

• Primary Endpoint: 3-year Disease-Free Survival (DFS).

Follow-Up and Numerical Outcomes

• Median Follow-Up Period: 45.2 months.
• DFS Events Reported:
  
  • Fluorouracil plus radiotherapy arm: 46 events.
  • mFOLFOX6 plus radiotherapy arm: 39 events.
  • mFOLFOX6 alone arm: 46 events.
• 3-Year Disease-Free Survival (DFS) Probabilities:
  
  • Fluorouracil plus radiotherapy: 72.9%.
  • mFOLFOX6 plus radiotherapy: 77.2%.
  • mFOLFOX6 alone: 73.5%.
  • P-value: .709 (indicating no significant difference).
• 3-Year Local Recurrence Probabilities (after R0/1 resection):
  
  • Fluorouracil plus radiotherapy: 8.0%.
  • mFOLFOX6 plus radiotherapy: 7.0%.
  • mFOLFOX6 alone: 8.3%.
  • P-value: .873 (no significant difference).
• 3-Year Overall Survival Rates:
  
  • Fluorouracil plus radiotherapy: 91.3%.
  • mFOLFOX6 plus radiotherapy: 89.1%.
  • mFOLFOX6 alone: 90.7%.
  • P-value: .971 (no significant difference).

Conclusion

The trial demonstrated that while the mFOLFOX6 plus radiotherapy arm resulted in a higher pathologic complete response rate compared to fluorouracil plus radiotherapy, neither mFOLFOX6 (with or without radiotherapy) significantly improved the 3-year DFS over the standard treatment with fluorouracil plus radiotherapy. Additionally, the outcomes between the mFOLFOX6 alone arm and the fluorouracil plus radiotherapy arm were comparable, suggesting that further investigation is needed to define the optimal role of radiotherapy in these treatment regimens.

Question 8

How do you divide the trials in TNT

Answer 8

RT followed by Consolidation CT followed by surgery
● SCRT → 18 weeks of CAPOX or FOLFOX4 (Rapido)
● SCRT → 4 cycles of CAPOX → Surgery → 2 cycles of
CAPOX (Stellar)
● SCRT → 3 cycles of FOLFOX4 (Polish 2)

Induction CT followed by RT followed by surgery
● 6 cycles of FOLFIRINOX → 5FU-CRT → Surgery (Prodige 23)

Induction CT vs Consolidation CT
● CAO/ARO/AIO 12
● OPRA

Organ Preservation - Local excision or Wait-and-Watch after TNT or CRT
● GRECCAR2
● OPRA
● OPERA

Question 9

RAPIDO (Bahadoer); 2020/2023
Lancet Oncol/Annsurg

Answer 9

Inclusion criteria:
-cT4a or cT4b,
-cN2,
-EMVI
- Involved mesorectal fascia,
- Enlarged lateral lymph nodes
- Tumour location less than 16 cm from the anal verge

Intervention: SCRT 5 × 5 Gy followed by consolidation
6 cycles of CAPOX or 9 cycles of FOLFOX4 followed by TME

control: LCRT 50.4/28 or 50/25 with concomitant capecitabine 825 mg/m2 BID followed by
TME and, if stipulated by hospital policy, adjuvant
chemotherapy with 8 cycles of CAPOX or 12 cycles of
FOLFOX4.

Results:
pCR (Pathologic Complete Response):

Experimental (E): 28%

Standard (S): 14%

Local Recurrence:

E: 12%

S: 8%

Includes 5-year early locoregional failure (eLRF) and locoregional recurrence (LRR)

DFS (Disease-Free Survival):

E: 27.8% (95% CI: 23.7–31.8)

S: 34.0% (95% CI: 29.6–38.4)

Endpoint: 5-year disease-related treatment failure

OS (Overall Survival):

E: 81.7% (95% CI: 78.2–85.22)

S: 80.2% (95% CI: 76.5–83.9)

5-year overall survival

Question 10

🧪 STELLAR Trial (Jin, 2023, JCO)

Answer 10

🧪 STELLAR Trial (Jin, 2023, JCO)

• Phase: 3
• Inclusion Criteria:
  
  • cT3 or T4
  • cN+
  • Tumor located in distal or middle third of rectum
• Intervention Arm:
  
  • SCRT 5 × 5 Gy followed by 4 cycles of CAPOX, then TME
  • Adjuvant: 2 cycles CAPOX post-op
• Control Arm:
  
  • LCCRT (50/25 with concurrent capecitabine 825 mg/m² BID), then TME
  • Adjuvant: 6 cycles CAPOX post-op
• Timing of Surgery: 6–8 weeks post-treatment in both arms
• pCR:
  
  • E: 21.8%
  • S: 12.3%
• Local Recurrence (3-year LRR):
  
  • E: 8%
  • S: 11%
• DFS (3-year):
  
  • E: 64.5%
  • S: 62.3%
• OS (3-year):
  
  • E: 86.5% (95% CI: 82.1–90.8)
  • S: 75.1% (95% CI: 69.4–80.8)

Question 11

🧪 POLISH 2 Trial (Bujko, 2016/2019, Ann Onc)

Answer 11

🧪 POLISH 2 Trial (Bujko, 2016/2019, Ann Onc)

• Phase: 3
• Inclusion Criteria:
  
  • Palpably fixed cT3
  • cT4 tumors
• Intervention Arm:
  
  • SCRT 5 × 5 Gy + 3 cycles FOLFOX4, followed by TME
• Control Arm:
  
  • LCCRT: 50.4/28 Gy with bolus 5-FU and leucovorin (D1–5, weeks 1 & 5), followed by TME
  • Oxaliplatin used at discretion of centers
• Timing of Surgery:
  
  • 12 weeks after RT start and 6 weeks after end of neoadjuvant treatment
• pCR:
  
  • E: 16%
  • S: 11.5%
  • p = 0.19 (not significant)
• Local Recurrence:
  
  • E: Not specifically stated numerically here
  • S: Not stated
• DFS (8-year):
  
  • E: 43%
  • S: 41%
  • p = 0.65
• OS (8-year):
  
  • E: 49%
  • S: 49%