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Flashcards in Colon CA - Adjuvant Deck (49):
1

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

2

What increases the risk of colon cancer?

1) Polyposis Syndromes
- Familial Polyposis
- Peutz Jeghers
- Juvenile polyposis
2) Non-Polyposis Syndromes
- HNPCC
3) Other
- Inflammatory bowel disease
- prior colon cancer
- prior polyps
- first-deg relative Dx when

3

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

4

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
2 groups:
A) Oral Capecitabine
B) Bolus 5FU +Leucovorin (Mayo clinic regimen)
24 weeks

Results:
- Cape improved RFS HR 0.86, a/w sig fewer adverse events than 5FU+Leu

5

In which group of patients are the indications to start adjuvant chemo in strong? (For stage II)

(T.I.P.O)

T4 lesions
Inadequately sampled LN
Perforation at tumor site
Obstruction

6

What are considered walk indications to start adjuvant chemo in Stage II?

Poorly diff adenoCA
Lymphovascular invasion
High pre-op CEA
Peri neural invasion

7

What is the 5y survival in Stage III Colon CA with + LN?

30-50%

8

What are the studies in support of adjuvant chemotherapy for stage II CLR CA?

1) Netherlands Adjuvant Colon Cancer Project
2) QUASAR1
3) MOSAIC
4) NSABP pooled analysis (non-RCT)
5) Japanese meta-analysis (non-RCT)

9

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
2) Observation

RESULTS:
Improved 5yOS for both stage II and III
- Stage II 80% vs 70%
- Stage III 55% vs 40%

Trial had closed early

10

What is Levamisole?

An anthelmintic immunomodulator

11

What is the active metabolite of Fluorouracil?

Fluorodeoxyuracil monophosphate

12

Tell me about the profile of the patients enrolled in QUASAR

N=3300
Treatment naive
S/p curative resection
Stage I/II/III

70% Colon Ca,
8% Stage III, 90% Stage II, 0.5% Stage I
10% T4 tumors

13

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

14

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#

15

Tell me about the profile of the patients in MOSAIC Study

N=2300

Stage III 60%
- 1-3 LN 45%
- 4 or more LN 15%
Stage II 40%
- High risk Stage 2 25%, 15% not
T4 20%

16

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%

17

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

18

What stage is T4N0M0

Stage 2B

19

What stage is T3N0M0?

Stage 2A

20

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

21

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

22

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

23

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

24

Tell me about the NSABCP C-07 trial

Yothers et al. JCO 2011

N =2400
Stage II/III Colon CA

2 arms:
1) FULV (using Roswell Park regimen)
2) FLOX
FULV + IV Ox (85) D1, 15, 29 of each cycle

RESULTS:
DFS: HR 0.8, in favor of FLOX
Ox improved OS in this

25

What had established FU/Levamisole as standard of care?

INT 0035 Moertel et al NEJM 1990

N=1300
Resected colon cancer. Duke's B/C
3 arms:
1) observation
2) Levamisole+5FU
3) Levamisole (applicable for stage C only)

F/u 3 years

Results:
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

26

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

N=3500
4 arms:
1) Control arm: Lev + 5FU X 1 year
2) Mayo Regimen, LDLV+5FU
3) Roswel park Regimen, HDLV+5FU
4) LDLV+5FU+Lev

Results:
1) 6-8month of LDLV and HDLV W/o Le = 12 months of treatment
2) LDLV = HDLV

27

Tell me about the X-ACT study

Twelves et al. NEJM 2005

N=2000
Resected stage III
2 arms:
1) Capecitabine
2) Bolus 5FU/Leu (Mayo clinic)
6 months

RESULTS:
- Equivalent 3 y DFS
- Improved RFS HR 0.86
- Fewer G3/4 adverse events

28

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.

N=1900
Resected stage III colon CA.

2 arms:
A) XELOX
B) IV Bolus 5FU/LV
- Mayo regimen or Roswell Park regimen.

RESULTS:
- 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

29

What is the Mayo regimen?

Rapid infusion of Leucovorin (20)
IV Bolus 5FU (425) D1-5
Q28days

30

What is the Roswell Park regimen?

2hr IV Leucovorin (500)
IV Bolus 5FU (500)D1, weeks 1-6, Q8 weeks

31

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

N=2000
Stage II/III resected colon CA
2 arms:
1) LV5FU2
2) LV5FU2+Irinotecan

Results:
F/u 5 y
-5y DFS 57% vs 54% (LV5FU2) p not sig
- increased G3/4 GI events and neutropenia

32

How about combining Bolus 5FU with Irinotecan. Any good?

No.
CALGB 89803

N=1200
2arms:
- weekly Bolus 5FU/LV
- weekly Bolus CPT-11/FU/LV

RESULTS:
No differences in DFS/OS
Toxicity higher in Irinotecan arm.

33

Tell me about the AVANT trial

De Gramont et al. Lancet Oncol 2012

Aim:
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
3 arms:
A) FOLFOX4
B) FOLFOX4 + Bev
C) XELOX + Bev

Results:
5y f/u:
Did not prolong DFS
Potential detrimental effect with Bev+ Ox-based adjuvant therapy.

34

What is HNPCC clinically a/w?

Early onset Age of Colon CA
Proximal tumor location
Mucinous histology
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

35

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

36

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

37

Tell me about he QUASAR Study

Aim:
(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

N=3200 patients
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
(B) Observation
Part II: whether HDLV or LDLV and whether Lev improved survival
- Levamisole
- Placebo Levamisole

Results:
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
HDLV=LDLV
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

38

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

2) PETACC-3
- 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

39

Story of Capecitabine in adjuvant setting

1) NEJM 2005 Twelves et al
N=2000
Capecitabine = 5FU/LV

2) Schmoll JCO 2007; Haller JCO 2011
N=2000
XELOX = 5FU/LV
- 5FU/LV by Mayo clinic or Roswell Park regimen

40

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)

41

Which is better?
De Gramont regimen or Mayo regimen.
Why?

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
Bolus 5FU(400)
Leucovorin (200)

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

42

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%

43

What are the trials for Bevacizumab (Adjuvant setting)

1) NSABP C-08
Stage II/III n-2750
- mFOLFOX6
- mFOLFOX6 + Bev

2) AVANT
Stage II/III n=3450
- FOLFOX4
- XELOX + Bev
- FOLFOX4 + Bev

3) QUASAR2

44

What are the trials for Cetuximab in the Adjuvant setting?

1) PETACC-8
Stage III n=2400
- FOLFOX4 vs FOLFOX4+Cetuximab

2) Intergroup 0147
Stage III n=3600
- mFOLFOX6 vs mFOLFOX6+Cetuximab

45

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.

RESULTS:
(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)

46

Tell me about the AVANT trial

De Gramont et al Lancet 2012

Resected Stage III or high-risk Stage II

3 arms:
1) FOLFOX4 Q2w X 12#
2) Bev 5mg/kg + FOLFOX4 --> Bevcizumab monotherapy 7.5mg/kg q3w for 8#
3) Bev 7.5mg/kid +XELOX

47

What is an advanced Adenoma?

1) Villous polyp
2) Polyp > 1cm
3) High-grade dysplasia

48

When do we consider Adjuvant RT?

- Estimated risk of recurrence to be 30% or more
- Ascending/Descending colon with T4b disease
- Positive Resection margins

49

What are the problems with Bolus 5FU/LV

Higher rates of:
- Myelosuppression
- Nausea/vomiting
- Diarrhoea