Flashcards in Colon CA - Adjuvant Deck (49):
How does Leucovorin work?
- By increasing the intercellular pools of 5,10 methylenetetrahydrofolate
- hence increasing the extent and duration of thymidylate synthetase inhibition
- This is one main mechanisms of 5FU
What increases the risk of colon cancer?
1) Polyposis Syndromes
- Familial Polyposis
- Peutz Jeghers
- Juvenile polyposis
2) Non-Polyposis Syndromes
- Inflammatory bowel disease
- prior colon cancer
- prior polyps
- first-deg relative Dx when
How does the mutation in FAP result in colon cancer?
APC is the Gene affected.
- APC is a key regulator of the wnt-signaling pathway
Mutation of APC Gene leads to the formation of a dysfunctional protein.
The dysfunctional protein cannot bind to beta-catenin.
Free beta-catenin can then activate the transcription of various oncogenes
Result is 100s-1000s of colonic polyps, predisposing to malignant tumors at a young age.
~0.5-1% of overall CLR CA
APC or beta-catenin mutations activating the want-signaling pathway have been found in 80-85% of sporadic colorectal CA
How did we come to use Oral Capecitabine as adjuvant treatment for colorectal cancer?
In met setting, Cape was established as an alternative to Bolus 5FU+Leucovorin.
Study by Twelves et al NEJM 2005
N=2000 resected stage III colon cancer
A) Oral Capecitabine
B) Bolus 5FU +Leucovorin (Mayo clinic regimen)
- Cape improved RFS HR 0.86, a/w sig fewer adverse events than 5FU+Leu
In which group of patients are the indications to start adjuvant chemo in strong? (For stage II)
Inadequately sampled LN
Perforation at tumor site
What are considered walk indications to start adjuvant chemo in Stage II?
Poorly diff adenoCA
High pre-op CEA
Peri neural invasion
What is the 5y survival in Stage III Colon CA with + LN?
What are the studies in support of adjuvant chemotherapy for stage II CLR CA?
1) Netherlands Adjuvant Colon Cancer Project
4) NSABP pooled analysis (non-RCT)
5) Japanese meta-analysis (non-RCT)
Tell me about the Netherlands Adjuvant Colon Ca Project?
N=1000, Colon CA 700, Rectal Ca 300
45% stage II, 55% stage III
S/p curative surgery
Then randomized to 2 arms:
1) 1 y 5FU/Levamisole
Improved 5yOS for both stage II and III
- Stage II 80% vs 70%
- Stage III 55% vs 40%
Trial had closed early
What is Levamisole?
An anthelmintic immunomodulator
What is the active metabolite of Fluorouracil?
Tell me about the profile of the patients enrolled in QUASAR
S/p curative resection
70% Colon Ca,
8% Stage III, 90% Stage II, 0.5% Stage I
10% T4 tumors
What were the results of the QUASAR study (arm comparing adjuvant vs no adjuvant)
Relative risk of recurrence HR 0.78 in favor of chemo for Stage II
- 0.7 for rectal cancer
Absolute improvement in survival of 3.6% in Stage II
What was the treatment regimen with Oxaliplatin used in the MOSAIC study
2-Hr Leucovorin (200) D1,2
Bolus 5FU (400) D1,2
22-Hr CI 5FU (600) D1,2
2-Hr Oxaliplatin (85) D1
Q14 days X 12#
Tell me about the profile of the patients in MOSAIC Study
Stage III 60%
- 1-3 LN 45%
- 4 or more LN 15%
Stage II 40%
- High risk Stage 2 25%, 15% not
What are the results of the MOSAIC study? (6y update)
5y DFS 73% vs 67%
- Stage 3 66% vs 59%
- Stage 2 84% vs 80%
6y OS 78.5% vs 76%
- Stage 3 73% vs 69%
- Stage 2 87% vs 87%
Summarize the 4 NSABP studies
NSABP C-01: MOF > Observation
- 3% OS Benefit, p =0.7
- OS 72 vs 75%
NSABP C-02 = PVI 5FU > Obs
- OS 76% vs 88%, 12% OS benefit, p sig.
NSABP C-03 = 5FU/LV > MOF
- 8% OS benefit 84% vs 92% p sig
NSABP C-04 = 5FU/LV > 5FU/LEV
- 4% benefit 81% vs 85% p not sig
What stage is T4N0M0
What stage is T3N0M0?
What is DNA mismatch repair ?
Evolutionarily conserved process that corrects:
1) Mismatches generated during DNA replication/recombination and damage
2) repair of small insertions/deletions in micro satellites
- these are repetitive DNA sequences throughout the genome
What is the impact of defective MMR?
MMR Deficiency leads to inability to repair the small insertions/deletions in micro satellites.
This leads to:
1) accumulation of mutations causing a hyper mutated state
2) frame shift mutations - truncating mutations that can inactivate tumor suppressor genes
Tell me about the QUASAR Multigene Assay (Oncotype Dx)
This is a 12-gene recurrence signature that predicts recurrence risk.
3 risk groups
- low risk = 12%
- intermediate risk = 18%
- high risk = 22%
Retained significance in multivariate analysis independent of MSI status, T stage, tumor grade and LVI
When is the colorectal Oncotype Dx expected to have the greatest clinical utility?
T3, MMR-proficient patients
This group constitutes the majority about 70% of stage II colon Cancer
Tell me about the NSABCP C-07 trial
Yothers et al. JCO 2011
Stage II/III Colon CA
1) FULV (using Roswell Park regimen)
FULV + IV Ox (85) D1, 15, 29 of each cycle
DFS: HR 0.8, in favor of FLOX
Ox improved OS in this
What had established FU/Levamisole as standard of care?
INT 0035 Moertel et al NEJM 1990
Resected colon cancer. Duke's B/C
3) Levamisole (applicable for stage C only)
F/u 3 years
1) In Stage C: Reduced risk of recurrence by 40%, Overall death rate reduced by 33%
2) Levamisole alone no effect
3) No conclusions for Stage B
What was the evidence behind omitting Levamisole after INT 0035?
INT 0089 by Haller et al JCO 2005
Aim: to assess the relative contributions of Leucovorin and Levamisole in high-risk Stage II and Stage III resected colon CA patients
1) Control arm: Lev + 5FU X 1 year
2) Mayo Regimen, LDLV+5FU
3) Roswel park Regimen, HDLV+5FU
1) 6-8month of LDLV and HDLV W/o Le = 12 months of treatment
2) LDLV = HDLV
Tell me about the X-ACT study
Twelves et al. NEJM 2005
Resected stage III
2) Bolus 5FU/Leu (Mayo clinic)
- Equivalent 3 y DFS
- Improved RFS HR 0.86
- Fewer G3/4 adverse events
Tell me about the XELOXA study
First published in JCO 2007 by Schmoll as a safety analysis then by Haller in CO 2011 with the final results.
Resected stage III colon CA.
B) IV Bolus 5FU/LV
- Mayo regimen or Roswell Park regimen.
- 5y recurrence rate: 31% (XELOX) vs 37.5%(difference 6.5%)
- 3y DFS 71% vs 66.5% (4.5%)
- HR for OS 0.87 in favor of XELOX
- XELOX compared with RP:
>> more G3/4 hematologic AE
>> less G3/4 GI AE
>> G3/4 HFS higher with XELOX
- XELOX compared with Mayo:
>> fewer G3/4 hematologic AE
>> more G3/4 GI adverse events
What is the Mayo regimen?
Rapid infusion of Leucovorin (20)
IV Bolus 5FU (425) D1-5
What is the Roswell Park regimen?
2hr IV Leucovorin (500)
IV Bolus 5FU (500)D1, weeks 1-6, Q8 weeks
Tell me about the PETACC-3 study
Van Cutsem JCO 2009
Aim: To evaluate if addition of Irinotecan to LV5FU2 will improve DFS in Stage 3 colon CA
Stage II/III resected colon CA
F/u 5 y
-5y DFS 57% vs 54% (LV5FU2) p not sig
- increased G3/4 GI events and neutropenia
How about combining Bolus 5FU with Irinotecan. Any good?
- weekly Bolus 5FU/LV
- weekly Bolus CPT-11/FU/LV
No differences in DFS/OS
Toxicity higher in Irinotecan arm.
Tell me about the AVANT trial
De Gramont et al. Lancet Oncol 2012
Bev showed efficacy in met CLR CA.
Hence to assess if Bev+Ox-combination chemo will be of use.
N = 3000
Resected stage III/high-risk stage II CLR CA
B) FOLFOX4 + Bev
C) XELOX + Bev
Did not prolong DFS
Potential detrimental effect with Bev+ Ox-based adjuvant therapy.
What is HNPCC clinically a/w?
Early onset Age of Colon CA
Proximal tumor location
Higher grade at time of Dx
Prognosis is better, independent of stage when compared with pts with MSS tumors
Apparent lower responsiveness to 5FU-based chemotherapy
What is the Amsterdam criteria?
All criteria must be met:
1) FAP must be excluded
2) 3 or more family members with CLR cancer, at least 2 of whom must be 1st degree relatives
3) 2 successive generations are affected
4) Development of CLR Ca
What is the Bethesda criteria ?
Any criterion is sufficient.
1) Cancer in a family that fulfills the Bethesda criteria
- FAP excluded
- 2 successive generations affected
- 3 or more family members with CLR cancer, at least 2 of whom are 1st degree relatives
- Dev of cancer
Tell me about he QUASAR Study
(I) Determine the size and duration of any survival benefit from adjuvant chemotherapy for those with low risk of recurrence.
(II) Determine if Leucovorin/Levamisole needed
90% stage II, 70% Colon Ca
2 parts of the study:
Part I: Adjuvant chemo or no adjuvant chemo
(A) FU/Folinic Acid with high-dose or low-dose Folinic acid
- Six 5-day courses Q28days OR
- 30 once-weekly courses of IV 5FU
Part II: whether HDLV or LDLV and whether Lev improved survival
- Placebo Levamisole
F/u 5.5 years:
- Chemo vs Observation, RR of death HR 0.8
- RR of recurrence 0.8
- Absolute improvement in survival of 3.6% in Stage II
Survival worse with Lev than placebo 69% vs 71.5% at 3 years. Also Lev a/w more recurrence.
Limitations of QUASAR:
- understated population
- median LN harvested only 6
- ~25% had >12 LN harvested
- population of Stage II likely contaminated by Stage III
What are the evidences that go against using Irinotecan in the adjuvant setting?
1) CALGB 89803
- n=1200, all Stage III
- weekly Bolus FU/LV vs weekly Bolus CPT-11/FU/LV
- ~DFS, ~OS, increase both lethal and non lethal toxicity with addition of Irinotecan
- n=2000, based on Stage III patients. (Original study had stage II/III, 3300 patients)
- LV5FU2/Irinotecan vs LV5FU2
- ~OS 70%, increased G3/4 toxicities
3) FNCLCC Accord 02/FFCD 9802
- n=400, postop N1/2
- LV5FU2 vs LV5FU2/Iri
- more T4 tumors and 15or more positive LN noted in experimental arm.
- 3y DFS 60% vs 50% (Iri)
- 5y OS 67% vs 61%
- no improvement even when targeted group is high-risk for relapse
Story of Capecitabine in adjuvant setting
1) NEJM 2005 Twelves et al
Capecitabine = 5FU/LV
2) Schmoll JCO 2007; Haller JCO 2011
XELOX = 5FU/LV
- 5FU/LV by Mayo clinic or Roswell Park regimen
Story of Oxaliplatin
1) Ox shows improvement in met CLR CA
2) Andre NEJM 2004
N=2300, Stage II/III colon CA
FLOX > FL
3y DFS 80% (FLOX) vs 70%
3) NSABP C-07, Kuebler et al JCO 2007
Stage II/III, n=2400
FLOX > FULV
4y DFS 67% (FULV) vs 73% for FLOX
OS ~ in updated analysis JCO 2011, but subset analysis showed OS effect of Ox in those LV5FU2
10y OS 67% vs 72% (p sig)
10y OS Stage II 80% vs 78%
10y OS 60% vs 67% (p sig)
Which is better?
De Gramont regimen or Mayo regimen.
De Gramont > Mayo
De Gramont = all given D1 and 2
Leucovorin (200) over 2 hours
Bolus 5FU (400)
CI 5FU (600) over 22 hours
Mayo: D1-5, Q28days
GRECOR study, Andre 2003/2007
Resected Stage II and III, n=1000
6y DFS and OS equivalent
No benefit of 36 weeks over 24 weeks
De Gramont less toxic. Less diarrhea/neutropenia/mucositis
How about CI 5FU and Mayo regimen.
Which is better?
Chua Royal Marsden, Saini BJC
Resected Colon CA, n=800
12w CI5FU (300mg/m2/day) = 6m of Mayo 5FU/LV (SAFFA Trial)
Less mucositis, less GI Toxicity. But more PPE
CI 5FU with trend to Bette 5y DFS (73% vs 67%) as well as 5y OS 76% s 72%
What are the trials for Bevacizumab (Adjuvant setting)
1) NSABP C-08
Stage II/III n-2750
- mFOLFOX6 + Bev
Stage II/III n=3450
- XELOX + Bev
- FOLFOX4 + Bev
What are the trials for Cetuximab in the Adjuvant setting?
Stage III n=2400
- FOLFOX4 vs FOLFOX4+Cetuximab
2) Intergroup 0147
Stage III n=3600
- mFOLFOX6 vs mFOLFOX6+Cetuximab
Why should we not use Cetuximab in mutant k-RAS?
N-0147 study, Nair et al.
Stage 3 colon CA, n=3700
Wt-KRAS randomized to: mFOLFOX6 vs mFOLFOX6+Cetuximab
Those who are mut K-RAS, treatment given as per physician.
(1) KRAS WT (trend)
3y DFS 76% vs 72% (Cetuximab)
3y OS 88% vs 84% (Cetuximab)
(2) KRAS mutant (trend)
3y DFS 67% vs 64% (Cetuximab)
3y OS 88% vs 80% (Cetuximab)
Tell me about the AVANT trial
De Gramont et al Lancet 2012
Resected Stage III or high-risk Stage II
1) FOLFOX4 Q2w X 12#
2) Bev 5mg/kg + FOLFOX4 --> Bevcizumab monotherapy 7.5mg/kg q3w for 8#
3) Bev 7.5mg/kid +XELOX
What is an advanced Adenoma?
1) Villous polyp
2) Polyp > 1cm
3) High-grade dysplasia
When do we consider Adjuvant RT?
- Estimated risk of recurrence to be 30% or more
- Ascending/Descending colon with T4b disease
- Positive Resection margins