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Adjuvant Matters. Richard M Goldberg MD UNC Lineberger Comprehensive Cancer Center Chapel Hill, NC. Disclosures. I have been a paid consultant to sanofi-aventis Genentech Pfizer Memberships NSABP (Wolmark, Allegra abstracts) ACCENT (de Gramont abstract) Coauthor

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adjuvant matters

Adjuvant Matters

Richard M Goldberg MD

UNC Lineberger Comprehensive

Cancer Center

Chapel Hill, NC

disclosures
Disclosures
  • I have been a paid consultant to
    • sanofi-aventis
    • Genentech
    • Pfizer
  • Memberships
    • NSABP (Wolmark, Allegra abstracts)
    • ACCENT (de Gramont abstract)
  • Coauthor
    • Ribic NEJM paper upon which some of the presentation by Sargent is based
slide3

NSABP Protocol C-07:

A Phase III Trial Comparing

FU/LV to FU/LV + Oxaliplatin

in Stage II or III Colon Cancer: Survival Data

Wolmark, Wieand, Kuebler,

Colangelo, O'Connell, Yothers

and the NSABP Investigators

questions
Questions
  • Answered
    • Does oxaliplatin add to PFS and OS?
    • Does 5-FU schedule matter?
    • Is 5 years of follow-up adequate for OS?
  • Unanswered
    • What’s the optimal adjuvant therapy duration?
    • How much total oxaliplatin is optimal?
    • How do we best manage Stage II patients?
slide5

Stage ll + lll

Randomize

FU/LV

FLOX

critical statistics
Critical Statistics
  • 5.5 year median follow-up
  • Outcomes better than projected
    • Expected # deaths 700
    • Actual # deaths 560
    • Consequent reduction in power
  • % Stage II:
    • C-07 28%
    • MOSAIC 40%
slide7

C-07 DFS

p = 0.002

HR: 0.81 [0.70 – 0.93]

3y 5y

FLOX 76.1% 69.4%

FULV 71.5% 64.2%Δ 4.6% 5.2%

19% risk reduction

slide8

C-07 Survival

D(n) 5y 6y

FLOX 259 80.3% 77.7%

FULV 301 78.3% 73.5%Δ 42 2.0% 4.2%

p = 0.06

HR: 0.85 [0.72 – 1.01]

15% risk reduction

slide9

C-07 Survival after Recurrence

Median

FLOX 17.6

FULV 22.2

P = 0.02

HR: 1.24

questions1
Questions
  • Answered
    • Does oxaliplatin add to PFS and OS? Yes
    • Does 5-FU schedule matter? No
    • Is 5 years of follow-up adequate for OS? No
  • Unanswered
    • What’s the optimal adjuvant therapy duration? 3 versus 6 versus other?
    • How much total oxaliplatin is optimal? May differ in different patients
    • How do we best manage Stage II patients? TBDNo treatment, 5-FU alone, or FOLFOX
initial safety report of nsabp c 08

Initial Safety Report of NSABP C-08

Allegra, Yothers, Sharif, O’Connell, Wolmark and the NSABP Investigators

nsabp c 08 schema

Stage II or III Colon Cancer

Stratification

Number of + Lymph Nodes

Randomization

mFOLFOX6 +

Bevacizumab

mFOLFOX6

NSABP C-08 Schema

Disease-free survival: primary endpoint

questions2
Questions
  • Answered
    • Is the frequency of early deaths different?
    • What are the relative toxicities of FOLFOX +/- bevacizumab?
    • Were there any surprises?
  • Unanswered
    • Does bevacizumab add to FOLFOX in the adjuvant setting?
    • Does bevacizumab have any long term toxicity (or benefit)?
early mortality with adjuvant regimens
Early Mortality with Adjuvant Regimens
  • C-08 within 18 months of randomization
    • FOLFOX 1.33%
    • FOLFOX + bev 1.42%
  • MOSAIC data within 7 months of randomization
    • LV5FU2 0.5%
    • FOLFOX 0.5%
  • C89803 data within 6 months of randomization
    • 5-FU/LV 1%
    • IFL 2.8%
questions3
Questions
  • Answered
    • Is the frequency of early deaths different? No
    • What are the relative toxicities of FOLFOX +/- bevacizumab? BP, pain, wounds, proteinuria
    • Were their any surprises? Pain, a bit more oxaliplatin delivered, no major increase in wound complications
  • Unanswered
    • Does bevacizumab add to FOLFOX in the adjuvant setting? No data
      • 28 months median time on study
      • Efficacy analysis: 592 events or 4 years after last entry (DMC evaluation every 6 months, latest October 2010)
    • Does bevacizumab have any long term toxicity (or benefit)? No data
slide19

Association between 3 year DFS and OS is delayed with improved survival after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: Findings from the 20,898 patient ACCENT datasetde Gramont for the ACCENT collaborative group

questions4
Questions
  • Answered
    • Do we need to extend adjuvant trial follow-up beyond 5 years?
    • Is a survival advantage that is apparent after 5 years still meaningful?
    • Should trial design be continuously reevaluated?
  • Unanswered
    • Do we need to change surveillance plans?
mosaic update os with 6 years minimum follow up
MOSAIC Update: OS with 6 Years Minimum Follow-up

1.0

p=0.996

0.9

0.1%

p=0.029

0.8

4.4%

0.7

0.6

Probability

0.5

0.4

HR [95% CI]

Stage II 1.00 [0.71–1.42]

Stage III 0.80 [0.66–0.98]

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

0.3

0.2

0.1

0

0

6

12

18

24

30

36

42

48

54

60

66

72

78

84

90

96

Overall survival (months)

ASCO 2007

slide22

ACCENT: 3yr DFS vs 5yr OS

R2 = 0.80

May 2004: ODAC recommends3-yr DFS as new regulatory endpointfor FULL approval in adjuvant colon cancer

why was 6 years required for mosaic to become positive for os
Why Was 6 Years Required for MOSAIC to Become Positive for OS?
  • Previous analyses with 5FU/LV showed excellent association between 3 yr DFS & 5 yr OS
    • ACCENT: Median time from recurrence to death: 12 months
    • MOSAIC: Median ~ 24 months
      • Improved imaging to detect recurrence earlier
      • Enhanced treatment post-recurrence
      • Secondary resections in selected patients
impact of longer survival following recurrence on clinical trials
Impact of longer survival following recurrence on clinical trials
  • Longer follow-up for OS required to observe benefit
    • improved post-recurrence treatments
  • DFS even a more important endpoint
  • Treatments that delay rather than prevent recurrence may send misleading DFS signals
questions5
Questions
  • Answered
    • Do we need to extend adjuvant trial follow-up beyond 5 years? Yes
    • Is a survival advantage only apparent after 5 years still meaningful? Absolutely
    • Should trial design be continuously reevaluated? Absolutely, by clinician & statistician teams
  • Unanswered
    • Do we need to change surveillance plans? Probably
slide27
Deficient Mismatch Repair as a Predictive Marker for Lack of Benefit from 5-FU based Chemotherapy in Adjuvant Colon Cancer

Sargent, Marsoni, Thibodeau, Labianca, Hamilton, Torri, Monges, Ribic, Grothey, Gallinger

questions6
Questions
  • Answered
    • Should MMR testing be considered prior to 5-FU based Rx for stage II pts?
  • Unanswered
    • Should MMR testing be considered prior to 5-FU based Rx for stage III pts?
    • Should other agents be used in MSI-H pts?
    • Why are MSI-H different then MSS tumors?
biology
Biology
  • 15% of CRC pts have MSI-H tumors
    • Most hypermethylation, not mutation
  • MSI-H cells have a growth advantage in the presence of 5-FU Carrethers, Gastro, 1999
    • MMR cells unable to bind 5-FU modified DNA
  • MSI-H cell lines
    • are more sensitive to irinotecan Bras-Goncalves, BJC, 2000
    • are not resistant to oxaliplatin Sergent, Canc Chemo Pharmacol 2002
dfs by mmr status pooled data
DFS By MMR Status, Pooled Data

Treated (N=512)

Untreated (N=515)

5 yr DFS

HR: 0.79 (0.49-1.25)

p=0.30

dMMR 70%

pMMR 67%

5 yr DFS

dMMR 80%

pMMR 56%

HR: 0.51 (0.29-0.89)

p=0.009

overall survival by treatment stage ii dmmr patients
Overall Survival By Treatment, Stage II dMMR Patients

N = 55

N = 47

P-value = 0.014 for treatment

by MMR status interaction

5 yr OS

HR: 3.15 (1.07-9.29)

p=0.03

Untreated 93%

Treated 75%

conclusions
Conclusions
  • dMMR validated as a prognostic marker in untreated patients
  • No suggestion of benefit from 5-FU based treatment in dMMR patients
  • Significant OS decrement to 5-FU based treatment in stage II patients
take home message
Take Home Message

When considering a Stage II patient for 5-FU-based therapy,

mismatch repair status,

by MSI or IHC,

should be used to determine

whom not to treat

calgb 89803 5 fu lv irinotecan
CALGB 89803: 5-FU/ LV +/- Irinotecan
  • 854/1264 tumors evaluated for MSI
    • Patients with samples no different from overall population
    • 153 (18%) MSI-H by DNA microsatellite analysis
    • PFS (p=0.04) advantage and OS trend (p=0.17) for IFL over FL treated MSI-H patients
    • No PFS or OS advantage for MSS patientsBertagnolli, submitted
slide36

Disease free survival

Overall survival

MSI-H

tumors

p= 0.0391

p = 0.1736

Non-

MSI-H

tumors

p = 0.6681

p = 0.5111

questions7
Questions
  • Answered
    • Should MMR testing be considered prior to 5-FU based Rx for stage II pts? Yes
  • Unanswered
    • Should MMR testing be considered prior to 5-FU based Rx for stage III pts? Unclear
    • Should other agents be used in MSI-H pts? Needs verification
      • Irinotecan and oxaliplatin cell line data
      • CALGB clinical data
    • Why are MSI-H different then MSS tumors? TBD
conclusions adjuvant matters
ConclusionsAdjuvant Matters
  • 5-FU/Oxaliplatin standard for adjuvant Rx of Stage III colon cancer
    • Should be considered in high-risk stage II
    • No advantage over 5-FU/LV in pooled stage II
  • Bevacizumab is not standard adjuvant Rx
  • Adjuvant trials need to be bigger and longer
  • MSI status appears relevent to likelihood of benefit from 5-FU and possibly other agents
  • At last we have useful markers of heterogeneity
    • K-ras and MSI appear to be prognostic and predictive