landmark practice changing clinical trials in carcinoma rectum

1. Landmark trials in
carcinoma rectum
Dr. Mohammad Masoom Parwez
M.Ch Resident, Dept of Surgical Oncology
July 4, 2022

3. SirW. Ernest
Miles (1869-1947)
On December 19 of 2008, the Surgical
Community celebrated 100th anniversary
of the publication, in the Lancet, of W.
Ernest Miles’ treatise on the abdomino-
perineal excision of the rectum (APER)

6. Prior to this,TME - mainstay of treatment
TME - Improved local control and survival over blunt dissection for
rectal CA
Pre-op short course RT - improved local control and overall survival
with blunt dissection – Swedish trial
Dutch trial - Landmark study - test value of short RT withTME
Randomised 1861 patients with resectable rectal CA b/w 1996-1999
into:
Pre-op RT 25 Gy +TME versusTME alone
IfTME alone group had positive margins - post-op RT of 50.4 Gy was added

10. 10 yr cumulative incidence of local recurrence rate
of 5% vs 11% (p < 0.0001)
10 yrs overall survival were
equivalent (48% vs 49%)

11. Results:
Of the 1749 patients; 46 recurred in pre-op RT arm and 97 in Sx alone
arm
10 yr cumulative incidence of local recurrence rate of 5% vs 11% (p <
0.0001)
Cumulative incidence of distant metastases was not significant (25%
vs 29%)
10 yrs overall survival were equivalent (48% vs 49%)
10 yr cumulative incidence of local recurrence in negative surgical
margins - 3% vs 9% (p < 0.0001)
10 yr survival probabilities in negative surgical margin patients - 56%
vs 57%

12. Conclusion:
 Study demonstrated benefit of Pre-op RT to be most significant in stage III rectal
tumors
 Effect was stronger in pt with negative surgical margin with RR reduction of 64%
local recurrence
 Also a decrease in overall recurrence rate
 However, no difference in overall survival

14.  This changed the “standard of care” forT3,T4, and/or N0/N+, non
metastatic rectal CA
 Patients were assessed by CT or ERUS - randomised to receive either pre-
op ChemoRT (421) or post-op ChemoRT (402)
 CCRT - continuous inf of 5FU in 1st and 5th week of RT
 RT – 50.4 Gy in 1.8 Gy # and boost of 5.4 Gy to tumor bed in post-op arm
 Adj CT - 4# of 5FU 500mg/m2 iv bolus D1-D5 starting 4 weeks after Sx
and repeated 4 weekly

15.  The overall five-year survival rates were 76 percent and 74 percent,
respectively (P=0.80)
 The 5-year cumulative incidence of local relapse was 6% vs 13%(P=0.006)
 Grade 3 or 4 acute toxic effects occurred in 27% vs 40% (P=0.001)
 Conclusion:
 Pre-op ChemoRT, as compared with post-op ChemoRT, improved local
control, with reduced toxicity but did not improve overall survival

17.  Local recurrence rate at 10 yrs improved in pre-op group (7.1% vs 10.1%)
 OS and DFS were not significantly different
 10 yr OS was 59.6% vs 59.9%
 Rate of distant mets at 10 years - 29.8% vs 29.6%

19. Conclusion:
Pre-op CRT associated with significantly less cumulative incidence of local
recurrence (7.1 vs 10.1%)
Helped estb the current standard of care of giving pre-op CRT inT3,T4; N0/N+
status rectal CA

21.  Addition of post-op chemotherapy to preoperative ChemoRT
 clinical stageT3 orT4 resectable rectal cancer
 Pre-op ChemoRT - 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks
with chemo (5FU + Folinic acid) in 1st and 5th week
 Adj Chemotherapy - fluorouracil (350 mg/m² per day intravenous bolus) and folinic acid
(leucovorin; 20 mg/m² per day intravenous bolus) given in four cycles, every 3 weeks
 primary endpoint - overall survival
 1011 patients were randomly assigned to treatment between April, 1993, and March,
2003

22.  Results:
 10-year OS was 50·7% for the pre-op chemoRT group vs 51·8% for the adjuvant
chemotherapy group
 10-year DFS was 46·4% for the pre-op chemoRT group vs 47% for the adjuvant chemotherapy
group
 At 10 years, cumulative incidence of local relapse was 11·8% for the pre-op chemoRT group vs
14·5% for the adjuvant chemotherapy group
 longterm side-effects did not differ between the groups
 Conclusion:
 Adjuvant fluorouracil-based chemotherapy after preoperative ChemoRT does not affect
disease-free survival or overall survival

24. • 312 patients
• Either pre-op RT (25Gy in 5# of 5Gy) + Sx within 7 days v/s pre-op chemoRT (50.4Gy
in 28# of 1.8Gy + 5FU/Leucovorin bolus) and Sx after 4-6 weeks
• Median followup of 48 months
• Results:
• Early RT toxicity in CRT group (18% vs 3.2%) p<0.001
• Severe late toxicity 10.1 vs 7.1%
• Compliance 69.2% vs 97%
• Anal sphincter preservation 58.9% vs 61.2%
• Positive CRM rate 4.4% vs 12.9%
• Comparable DFS and OS

26.  80 centres in 4 nations, 1350 patients
 short-course preop RT (25 Gy in five fractions; n=674) to initial surgery with selective
post-operative chemoRT (45 Gy in 25 fractions with concurrent 5-fluorouracil) restricted
to patients with CRM +ve (n=676)
 primary outcome measure was local recurrence
 Findings:
 99 patients developed local recurrence (27 preoperative radiotherapy vs 72 selective
postoperative chemoradiotherapy)
 reduction of 61% in the relative risk of local recurrence for patients receiving preoperative
radiotherapy
 relative improvement in disease-free survival of 24% for patients receiving preoperative
radiotherapy
 Overall survival did not differ between the groups

27. short-course preoperative
radiotherapy is an effective
treatment for patients with operable
rectal cancer

29.  Compared safety and efficacy of post-op FOLFOX with 5FU/Leucovorin in stage II
and III rectal CA after pre-op CRT
 Place: South korea; 6 different centres
 Either 8# of FOLFOX or 4# of 5FU/Leucovorin
 Eligible pt underwentTME with R0 resection and pathological stage II/III disease
 Study randomised 321 patients b/w 2008-2012
 Primary End-point: 3 year DFS
 96% patient completed the planned adjuvant chemotherapy
 Median follow-up was 38.2 months

30. Results:
• 3 yr DFS was improved from 62.9% to 71.6% in FOLFOX arm
• Pathological stage III disease - significantly better DFS with FOLFOX than Stage II
patients
• 3 yr OS - 85.7% vs 95% in FOLFOX group

33. Conclusion:
1st trial to show benefit of FOLFOX in adj setting
Improvement in DFS in stage II and III patients
More adverse events in FOLFOX arm (No significant difference in Grade 3 and 4 adv
events)
Phase 2 trial - limited statistical power
However, patients with worse disease after pre-op CRT might benefit from
FOLFOX

35. • Assess tumor response after RT, optimal dosing and ideal time to surgery after pre-
op RT
• Non-inferiority trial, 840 patients
• SCRT (5# x 5 Gy) with immediate Sx (within 1 week)
• SCRT with delay (Sx after 4-8 weeks)
• LCRT with delay (25# x 2 Gy with Sx after 4-8 weeks)
• Outcomes:
• TRG, pCR, OS,TTR (time to recurrence)
• Result:
• SCRT with delay: lower tumor stage, greaterTRG, high pCR (10.4%), better OS andTTR
• Conclusion: SCRT with delay is a viable alternative to LCRT

38. RAPIDOTRIAL
• R0 resection was similar
• Experimental arm had 28% pCR vs 14% standard arm
• Grade ≥3 adverse events 41% v 25%
• No difference in proportion of patients undergoing Sx and rate of pot-op complications
• OS – 89% vs 88%
• Rate of distant mets – 20% vs 26.8%
• Disease related treatment failure events 23.7% vs 30.4%
• Conclusion: SCRT f/b 18 weeks of CT before Sx decreases probability of disease related
treatment failure mainly by reducing the probability of distant metastasis

40. PRODIGE 23TRIAL
• 461 patients, June 2012 – 2017
• Median followup: 46.7 months
• 3 yr DFS: 76% experimental arm vs 69% in standard arm
• Serious adverse events: 27% vs 22%
• Comparable treatment related deaths in both arms (1%)
• Conclusion: NACT f/b long course chemoRT significantly improves outcomes (DFS) and
decreased neurotoxicity with better compliance than adjuvant chemotherapy

42. “Thank you for your valuable time”
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