Colorectal - GL Flashcards
KEYNOTE-394
P: Phase III - Advanced HCC and progression during or after tx with sorafenib or oxaliplatin-based chemotherapy
I: Pembrolizumab (200 mg) once every 3 weeks
C: Placebo
O: mOS 14.6 vs 13.0; mPFS 2.6 v 2.3;
AEs: 14% grade 3+ in Pembro
JCOG 0603
Adjuvant chemo for liver only met CRC post Hepatectomy
P: mCRC with liver mets post-R0 resection. Phase II/III
I: OR + Folfox6 x 12 cycles
C: OR only
O: Primary outcome DFS = 49.8 vs 39. 5-year OS WORSE with 71 vs 83% (n.s.)
5 similar trials, all with better DFS. This is the only with numerically worse OS
KEYNOTE-177
First-line Pembrolizumab vs Chemotherapy for MSI-H/dMMR mCRC
P: treatment naive MSI-H/dMMR stage IV CRC
I/C: Phase 3 placebo-controlled
Arm 1: Pembro 200 mg q3 weeks
Arm 2: chemo (FOLFOX/FOLFIRI) +/- Bev +/- Cetuximab
mPFS: 16.5 mo vs 8.2 mo. PFS benefit 8 months HR 0.6
OS: HR 0.74 n.s. 3-year survival 50-60%
60% crossover to PD-1/PD-L1 second line probably hurt the OS difference.
DESTINY-CRC01: HER2-Expressing Metastatic CRC
Phase 2 multi-cohort, not controlled.
P: HER2 positive mCRC progressed on 2+ line
I: HER2 Dxd 6.4 mg/kg IV q3weeks
HER2 3+ or FISH+:
O: 45% partial response in cohort A (HER2 3+ or 2+ and FISH +).
Other cohorts (2+/1+) no response.
9% had ILD grade 3+
Paradigm Study
Phase III RCT
P: Ras WT CRC, no prev therapy, met or unresectable. 75% of pop left sided.
I: FOLFOX, add panitumumab vs bev
O: mOS: Left sided 38mo pani vs 34mo bev (HR 0.82, sig)
- L+R Combined analysis maintained sig OS benefit
-Pani worse in right sided in sub analysis though
This is the first prospective evidence, to say use anti-EGFR therapy over bev (with chemo) in the 1st line for RAS WT, left-sided mCRC.
PFS was not sig different; suggests PFS is a poor surrogate for OS.
Why can you delay OR after short course RT for rectal Ca?
The Non-inferiority Stockholm III trial
Patients: Rectal Ca that was upfront resectable
○ Arms: Preop short course rads VS preop short course rads with delay VS
preop long course rads (without concurrent chemo) with delay
○ Results: No significant difference regarding time to local or distant
recurrence, recurrence- free survival, or overall survival.
Bottom line: Instead of OR within 10 days of RT, we now say within 8 weeks.
Rapido (Lancet 2021)
NeoAdj Rectal
Include in-depth inclusion criteria
Pop: Rectal Ca, distal extension less than 16 cm from anal verge
Has MRI with a high risk feature: cT4a; cT4b; extramural vascular invasion (EMVI); cN2 (4 or more nodes); involved mesorectal fascia (tumour or lymph node ≤1 mm from the
mesorectal fascia = CRM compromised); or enlarged lateral lymph nodes considered to be metastatic
I/C: image
Primary outcome DRTF = Disease-related treatment failure (does not include all cause mort)
3-year DRTF 24% vs 30%, HR 0.75
Also better distant mets (20% vs 27%) at 3-years
BUT at 5 year update, had worse local regional control. Arguably failed its primary objective.
**GRAPHIC IS WRONG; PRODIGE only got 6 cycles before CRT, not 12.
PRODIGE 23
NeoAdj Rectal
P: Rectal cT3 or cT4
I/C: image
O: 3-year DFS 76 vs 69% (HR 0.7)
More toxic than RAPIDO, but supports the philosophy of neoadj in rectal.
**GRAPHIC IS WRONG; PRODIGE only got 6 cycles before CRT, not 12.
2023 OPREA trial.
Management of early stage rectal Ca. Include tumour size cuttoff. Primary benefit?
Phase 3 RCT
P: cT2, cT3a, cT3b adenoCa of low-mid rectum, <5cm diameter, and cN0 or cN1 smaller than 8mm.
All pts had neoAdj CRT 45Gy external beam in 25frac with cape.
I: Contact x-ray brachytherapy, 90 Gy in 3 fracs.
C: Boost of external beam 9 Gy in 5 frac
O: Primary outcome was organ preservation at 3y: 81% (bracy) vs 59% (HR 0.36).
<3cm tumour: 97% vs 63% (HR 0.07)
>3cm: 68 vs 55% (HR 0.54)
AEs: proctitis early, 13% in brachy. Late telangiectasia bleeding in 63% of brachy, subsides at 3y.
Esp in small rectal, brachytherapy after CRT avoids OR and preserves organs.
MSI-H Rectal Locally advanced
Phase II RCT
P: MMR def stage II-III rectal Ca, without obstruction.
I: Dostarlimab 500 mg IV q 3 weeks for 6 months (nine cycles).
If “clinical complete response” = negative DRE/endoscopy with biopsy and
rectal MRI T2 negative for residual disease, patients went on to
non-operative F/U.
If not complete response, long course CRT and TME.
O: All 12 patients (100%) that completed 6 months of therapy had a clinical
complete response. No ORs. No grade 3 AEs. No downside, really.
Not yet funded in Canada.
2015 Meta-analysis on adjuvant chemotherapy after preoperative
(chemo)radiotherapy and surgery for patients with rectal cancer.
Results?
Breugom et al. Lancet Oncology 2015
No OS benefit. No DFS benefit.
● Individual patient data (n=1196)
● All patients received neoadjuvant therapy (50% chemoradiation, 50% radiation
alone)
● 60% stage 3, 40% stage 2 (only used pathologic staging and had to have
residual stage II/III disease)
● Mixed use of TME surgery
Subgroup with benefit? high tumors 10-15 cm from anal verge showed improved
DFS (closer to colon cancer)
(Did not include ADORE, which uses oxali and was positive)
IDEA collaboration re: stage 2
FAILED to show non-inferiority of 3 vs 6 months of adj therapy for stage 2 colon Ca based on 5-year DFS 80.7 vs 84%, HR 1.18.
ASCO guideline definition of factors that make someone “high risk” stage II, and therefor should consider adjuvant chemo
Stage IIB, Stage IIC – ie. T4 lesions either penetrating visceral peritoneum
or invasive of surrounding organ, respectively
■ fewer than 12 lymph nodes in the surgical specimen,
■ perineural invasion
■ lymphatic invasion
■ poorly or undifferentiated tumor grade,
■ intestinal obstruction
■ tumor perforation
■ grade BD3 tumor budding (>=10 buds)
DYNAMIC study
June 2022 NEJM
ctDNA in colon Ca
P: resected stage II colon or rectal cancer (couldn’t have hadneoadjuvant chemo rads) with negative margins.
40% were clinical high risk stage II
I: If positive ctDNA at 4 or 7 weeks, got chemo with single-agent 5-FU or FOLFOX/CAPOX. If negative ctDNA, got observation.
C: standard management
O: Using ct-dna to guide management was non-inferior to conventional decision making.
Ct-DNA arm received less chemotherapy, but more oxaliplatin.
recurrence-free survival at 2 years.
Non-inferiority trial with margin of 8.5% points.
MOSAIC trail - 2004
adj colon
P: Stage 2 (40%) and 3 (60%) Colon, >15cm from anal verge (ie not rectal),
I: FOLFOX4 (boluses for 2 days instead of infusion with mfolfox6 we use now)
C: 5-FU with leucovorin
O: 3-year disease free survival - 78.2 vs 72.9% (absolute DFS of ~ 6%).
HR 0.77 (23% reduction in risk) for FOLFOX vs 5-FU
5-year OS 79% vs 81% (+2.1%)
10-year OS 67% vs 72% (+4.6%)
Neuropathy >= grade 3 in 12%
1.3% will have some grade 3 neuropathy at 12 months.
Summarize the data regarding systemic therapy alongside operative resection of oliometastatic disease in colon cancer.
5 recent RCTs, all used DFS, relapse-free survival, or PFS as the primary end point. ALL reported statistically significant or borderline significant results, with 3- to 5-year relative and absolute risk reductions of 19%-44% and 6%-11%, respectively.
Re OS, smaller (and not statistically significant) differences were observed: 4- to 5-year relative and absolute risk reductions ranged between 12%-27% and 0%-10%, respectively.
JCOG0603 (has its own card) was the only trial with a numerical trend toward decreased OS from the use of postoperative chemotherapy.
ESMO:
“Postoperative ChT can be delivered, but the randomized evidence to support this is scarce and therefore it cannot be considered as standard of care.” .. but can consider if haven’t received chemotherapy in the last 12 months for stage II/III disease
NCCN: suggest a six-month perioperative chemotherapy in patients undergoing resection of either isolated liver or lung metastases from colorectal cancer
