A Report from ASCO 2007 Adjuvant Colorectal Cancer

A Report from ASCO 2007

Adjuvant Colorectal Cancer

John L. Marshall, MDChief, Division of Hematology/OncologyAssociate Director of Clinical Research

Director, Developmental Therapeutics and GI OncologyLombardi Comprehensive Cancer Center

Georgetown University Medical CenterWashington, DC

Abstract 4007

Oxaliplatin/5-FU/LV in Adjuvant Colon Cancer: Updated Efficacy Results of the Mosaic Trial, Including Survival, with a Median Follow-up of

6-Years

Aimery de Gramont, Corrado Boni, Matilde Navarro,

Josep Tabernero, Tamas Hickish, Clare Topham, Andrea Bonetti, Philip Clingan, Christelle Lorenzato, Thierry André, and

MOSAIC investigators

MOSAIC: Study Design

• Primary end-point: disease-free survival• Secondary end-points: safety, overall survival

N = 2246

Enrollment: Oct 1998–Jan 2001 (146 centres; 20 countries)

• Completely resected colon cancer

• Stage II, 40%; Stage III, 60%

• Age 18–75 years

• KPS ≥60

• No prior chemotherapy

R

LV5FU2

FOLFOX4(LV5FU2 + oxaliplatin 85 mg/m²)(N = 1,123)

(N = 1,123)

LV5FU2: Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days

FOLFOX4: LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1

MOSAIC: Cut-off Dates for Efficacy Analyses

2003 3-year DFS: primary endpoint

2006 5-year DFS: final update

(No further updates on relapses)

2007 Overall Survival: 6-year, final analysis

André, et al. N Engl J Med 2004;350:2343–2351.

Primary End-Point: Disease-Free Survival

• DFS allows for a quicker determination regarding the efficacy of a new treatment

• Clinical trials can be completed more quickly• Drug development time can be shortened• Better therapy can be made available to patients more

quickly• DFS can be considered as an endpoint of its own merit

in decreasing the high cost, quality-of life impact, and debilitating consequence of recurrent disease

Sargent, et al. J Clin Oncol 2005;23:8664–8670.

3-Year DFS vs. 5-Year OS

Sargent, et al. J Clin Oncol 2005;23:8664–8670.

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.5 0.55 0.6 0.65 0.7 0.75 0.8

r = 0.88

3-Y

ear

DF

S

5-Year OS

3-years

(April 2003)

5-years

(June 2006)

FOLFOX4 LV5FU2 FOLFOX4 LV5FU2

Median follow-up, mos. 37.9 37.8 73.5 73.4

Events (%) 21.1 26.1 27.1 32.1

DFS (%) 78.2 72.9 73.3 67.4

HR

[95% CI]

0.77

[0.65–0.91]

0.80

[0.68–0.93]

P-value 0.002 0.003

Andre, et al. N Engl J Med 2004;350:2343–2351.

MOSAIC: Disease-Free Survival

Events = Relapse + Second Primary Colon Cancer + Death by any cause

MOSIAC: Disease-Free Survival (ITT)

Data cut-off: June 2006

Disease-Free Survival (months)

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54

Events

FOLFOX4 304/1123 (27.1%)

LV5FU2 360/1123 (32.1%)

HR [95% CI]: 0.80 [0.68–0.93]

5.9%

P = 0.003

MOSIAC: Disease-Free SurvivalStage II and Stage III Patients

Data cut-off: June 2006Months

HR [95% CI] P-value

Stage II 0.84 [0.62–1.14] 0.258

Stage III 0.78 [0.65–0.93] 0.005

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 72

3.8%

7.5%

P = 0.258

P = 0.005

MOSIAC: Disease-Free Survival High-Risk Stage II Patients

Disease-Free Survival (months)

FOLFOX4 (N = 286)

LV5FU2 (N = 290)

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 72

3-year 5-year

FOLFOX4 85.4% 82.1%

LV5FU2 80.4% 74.9%

HR [95% CI]: 0.74 [0.52–1.06]

High-Risk Stage II – defined as at least one of the following:

• T4• Tumor perforation• Bowel obstruction• Poorly differentiated tumor• Venous invasion • <10 lymph nodes examined

7.2%

Exploratory analysisData cut-off: June 2006

MOSIAC: Long-Term Safety

FOLFOX

5.3%

LV5FU2

5.7%

0

10

20

30

40

50

60

During Tx 6 months 1-year 2-year 3-year 4-year

Grade 1

Grade 2

Grade 3

Data cut-off: January 2007

Second CancerPeripheral Sensory Neuropathy

Evaluable Patients

(N = 811)

Grade 0 84.3%

Grade 1 12.0%

Grade 2 2.8%

Grade 3 0.7%

De Gramont A, et al. ASCO 2007. Abstract #4007.

MOSIAC: Overall Survival(ITT)


Overall Survival (months)

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

Events

FOLFOX4 243/1123 (21.6%)

LV5FU2 279/1123 (24.8%)

HR [95% CI]: 0.85 [0.72–1.01]

2.6%

P = 0.057


MOSIAC: Overall SurvivalStage II and Stage III


FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Overall Survival (months)

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

HR [95% CI]

Stage II 1.00 [0.71–1.42]

Stage III 0.80 [0.66–0.98]

0.1%

4.4%

P = 0.996

P = 0.029


MOSIAC: Conclusions

For FOLFOX4 vs. LV5FU2:• The DFS benefit at 3-years was maintained at 5-years• Trend showing improved DFS in “high-risk” stage II

patients• Significant OS benefit in stage III patients • No increase in the rate of secondary cancers• Continued recovery from sensory neuropathy


Abstract 4022

Tissue Biomarkers (BIOM) in Colon Cancer (COC): The Translational Study on the Randomized Phase III Trial

Comparing Infused Irinotecan/5-fluorouracil (5-FU)/Folinic Acid (FA) to 5-FU/FA in Stage II-III COC

Patients (Pts) (PETACC 3 - EORTC 40993 -SAKK 60-00)

A.D. Roth1, S. Tejpar2, P. Yan3, R. Fiocca4, D. Dietrich5, G. Bodoky6, R. Labianca7, D. Cunningham8, E. Van Cutsem2, F. Bosman3

1Oncosurgery, Geneva University Hospital, Geneva, Switzerland, 2Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium, 3Dpt of Pathology, Lausanne University, Lausanne, Switzerland, 4Dpt of Surgical and Morphological Sciences, University of Genova,

Genova, Italy, 5Swiss Group of Clinical Cancer Research, Bern, Switzerland, 6Oncology, St Lazlo Hospital, Budapest, Hungary, 7Unit of Medical Oncology, Ospedali Riuniti, Bergamo, Italy,

8Medical Oncology, The Royal Marsden Hospital, Sutton, United Kingdom.

Methods (1)

• FFPE tissue blocks prospectively collected and cut in 5-20µ sections

• Immunohistochemistry (IHC)– P53: mouse mAb clone D07, ABC Basic DAB Detection

(Ventana medical system)– SMAD4: mouse mAb clone B8 (IgG1, Santa Cruz

Biotechnology). Novocastra polymer detection kit– Thymidylate Synthetase (TS): Monoclonal antibody TS

106/4H4B1 (IgG1, Zymed). DAKO EnVision detection system– Telomerase (HTERT): Monoclonal antibody NCL-hTERT (IgG2,

Novocastra). DAKO EnVision detection system

Roth AD, et al. ASCO 2007. Abstract #4022.

Methods (2)

• DNA was extracted with phenol/chloroform from normal (Nor) and tumoral (Tu) tissues after microdissection of FFPE sections

• Molecular analysis:– Microsatellite Instability (MSI): assessed on 10 markers

• (BAT-25, BAT-26, D5S346, D2S123, D17S250, BAT-40, TGF-ß RII, D18S58, D18S69, D17S787)

– 18q and 8p LOH: multiple SNPs typing by pyrosequencing on Nor/Tu DNA

– KRAS exon 2 and BRAF exon 15: Allele specific real time PCR on Tu DNA

– UGT1A1 7/7 genotype: PCR and fragment sizing on Nor DNA


Analysis Success Rate

• 1,530 patient slides analyzed by IHC • DNA successfully extracted from 1,201 patient slides (91.2%)


Number of Samples with Results

Marker SamplesSuccess Rate

(%)Telomerase 826 54%

TS 1,269 83%

SMAD4 1,443 94%

P53 1,447 95%

MSI 1,327 94%

KRAS 1,379 98%

BRAF 1,386 99%

LOH in 18q

- at least one snip OK1,220 87%

UGT1A1 1,335 95%

Biomarker Alteration Observed (Mutation, Expression, or Deletion)

Alterations Rate Observed

Alteration Rate Reported (literature)

P53 overexpression* 37% 25-76%

SMAD4 loss** 15% 13-63%

TS*** 48% No consistent data available

HTERT 48% No data available

MSI 15% 10-17%

18q 65% 70%

KRAS 37% 32-40%

BRAF 8% 10%

UGT1A1 (7/7 genotype) 12% 10-15%

* Intense expression, More than 45% cells positive ** Any loss*** Positive = more than 25% cell positive Roth AD, et al. ASCO 2007. Abstract #4022.

SMAD4: Preliminary Results (Stage III)

At Risk: 145 95 57 2817 663 449 38

0 500 1000 1500

0.4

0.5

0.6

0.7

0.8

0.9

1.0

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Day

Pro

port

ion

Dis

ease

-Fre

e

No ExpressionExpression Present


Cutpoint% Patients

≤ Cutpoint

Estimated 3-Year DFSLog-Rank

P-value≤ Cutpoint > Cutpoint

0 15% 53% 68% < 0.001

MSI: Preliminary Results (Stage III)

At Risk:

753 595 396 33104 89 61 3

0 500 1000 1500

0.5

0.6

0.7

0.8

0.9

1.0/

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Day

Pro

port

ion

Dis

ease

-Fre

e

Stable/LowHigh

% Patients

High

Estimated 3-Year DFSLog-Rank

P-valueStable/Low High

12% 65% 74% < 0.04Roth AD, et al. ASCO 2007. Abstract #4022.

Abstract 4008

Time-dependent Patterns of Failure and Treatment Benefit from Adjuvant Therapy for Resectable Colon Cancer: Lessons from the

20,800 Patient ACCENT Dataset

D Sargent, for the Adjuvant Colon Cancer Endpoints (ACCENT) Group

Total: 18 trials; 20,898 pts

3,517 QUASAR867 GIVIO

905 GERCOR718 NSABP C02

3,547 INT 0089773 NSABP C01

1,078 SWOG 9415259 FFCD

878 N914653359 NCIC

915 N894651239 Siena

2,176 NSABP C05408 N874651

2,151 NSABP C04926 INT 0035

1,081 NSABP C03247 N784852

N TrialN Trial

Active ControlNo Treatment Control

ACCENT Dataset Trials Included

Sargent D, et al. ASCO 2007. Abstract #4008.

Three Questions Facing Adjuvant Colon Cancer Trialists

• Nature and duration of treatment benefit on overall survival (OS), disease-free survival (DFS)

• Long-term recurrence rates

• Adequacy of statistical assumptions, using DFS endpoint


Hazard Rates for OS and DFS

Disease-Free Survival

Follow-up Time (Years)

Haz

ard

Rat

e

0 2 4 6 8

0.0

0.00

020.

0004

0.00

06 Surgery Alone Arms5-FU Based Rx Arms

Overall Survival

Follow-up Time (Years)

Haz

ard

Rat

e

0 2 4 6 8

0.0

0.00

020.

0004

0.00

06 Surgery Alone Arms5-FU Based Rx Arms


0

1

2

3

4

5

6

7

8

9

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Year

Rec

urre

nce

Rat

e (%

) • After 5 years, recurrence rates < 1.5% / year

• After 8 years, recurrence rates < 0.5% / year

Recurrence Rate by Time from Randomization (All Patients)


Adequacy of Statistical ModelsConclusions

• Similar exercises demonstrated < 2% power loss due to non-constant risk of event

• Real world impact of DFS endpoint on trial design, for range of treatment effects observed in ACCENT, is minimal

• Continued use of standard approaches for sample size determination remains appropriate


Abstract 4009

Survival Following Recurrence in Patients with Adjuvant Colon Cancer: Findings from the ACCENT Dataset

MJ O’Connell, for the ACCENT Collaborative Group

Total: 17 trials; 17,381 pts

3,517 QUASAR867 GIVIO

905 GERCOR718 NSABP C02

3,547 INT 0089773 NSABP C01

1,078 SWOG 9415259 FFCD

878 N914653359 NCIC

915 N894651239 Siena

2,176 NSABP C05408 N874651

2,151 NSABP C04926 INT 0035

1,081 NSABP C03 247 N784852

N TrialN Trial

Active ControlNo Treatment Control

ACCENT Dataset Trials Included

O’Connell M, et al. ASCO 2007. Abstract #4009.

Prognostic Factors Examined

• Time from randomization on surgical adjuvant protocol to tumor recurrence (<1, 1-2, 2-3, 3-4, >4 years)

• Initial stage of colon cancer (II, III)

• 5-FU-based adjuvant therapy vs. surgery alone

• Era patient entered onto surgical adjuvant protocol (1978-1985, 1986-1992, 1993-1999)



Time from Recurrence to Deathby Year of Recurrence

100

Time (Years)

Year 0- 1 (N = 1,846)

Year 1-2 (N = 1,854)

Year 2-3 (N = 924)

Year 3-4 (N = 516)

Year 4+ (N = 582)

Total (N = 5,722)

0

20

40

60

80

0 1 2 3 4 5 6 7 8

% A

live

P < 0.0001


Time from Recurrence to Death byYear of Recurrence for Stage II Patients

P = 0.1368

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8Time (Year)

% A

live

Year 0-1 (N = 311)

Year 1-2 (N = 351)

Year 2-3 (N = 198)

Year 3-4 (N = 118)

Year 4+ (N = 175)

Total (N = 1,153)


Time from Recurrence to Death byYear of Recurrence for Stage III Patients

P < 0.0001

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Time (Year)

% A

live

Year 0-1 (N = 1,533)

Year 1-2 (N = 1,499)

Year 2-3 (N = 724)

Year 3-4 (N = 394)

Year 4+ (N = 400)

Total (N = 4,550)

P < 0.0001

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Time (Years)

% A

live

Stage II (N = 1,153)

Stage III (N = 4,550)

Total (N = 5,703)


Time from Recurrence to Death by Stage

Time (Years)

P < 0.0001

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

% A

live

1978-1985 (N = 628)

1986-1992 (N = 3,904)

1993-1999 (N = 1,190)

Total (N = 5,722)


Time from Recurrence to Death by Era


0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Time (Years)

% A

live

Surgery Alone (N = 916)

Adjuvant Treatment (N = 754)

Total (N = 1,670)

P < 0.0005

Time from Recurrence to Death byAdjuvant Treatment vs. Surgery Alone

Conclusions

• Time from initial surgery and stage of the primary colon cancer were important prognostic variables in patients with recurrent colon cancer

• Patients who have recurrent tumor following 5-FU-based adjuvant therapy had worse prognosis than those without adjuvant chemotherapy

• Survival following recurrence improved from 1978-1999


Abstract 4019

The Impact of Dietary Patterns on Cancer Recurrence and Survival in

Patients with Stage III Colon Cancer: Findings from CALGB 89803

Jeffrey A. Meyerhardt1, Donna Niedzwiecki2, Donna Hollis2, Leonard B. Saltz3, Walter Willett4, Robert J. Mayer1,

Charles S. Fuchs1

1Dana-Farber Cancer Institute, Boston, MA; 2CALGB Statistical Center, Durham,

NC; 3Memorial Sloan-Kettering Cancer Center, New York, NY; 4 Harvard School of Public Health, Boston, MA

Pearson Correlation Coefficients for the Relationship Between Food Intake and Factors Representing Dietary Patterns

*values < 0.15 are not shown (---). † Vegetables other than yellow, cruciferous, or leafy-green vegetables. ‡ Potato, corn chips, crackers, or popcorn.

Food grouping Prudent WesternVegetables † 0.72 ---Leafy vegetables 0.71 ---Yellow vegetables 0.67 ---Cruciferous vegetables 0.65 ---Legumes 0.56 ---Fruit 0.55 --Light salad dressing 0.48 ---Tomatoes 0.46 0.36 Garlic 0.39 ---Fish 0.46 ---Poultry 0.37 ---Fruit Juice 0.35 ---Whole grains 0.32 --Low fat mayonnaise 0.31 --Wine 0.19 ---Tea 0.16 ---Diet beverages --- --High-fat dairy --- 0.67 Low-fat dairy --- 0.64

Food grouping Prudent WesternRefined grains --- 0.60Condiments --- 0.51Red meat --- 0.53Sweets and desserts --- 0.53Margarine --- 0.50Processed meat --- 0.45Potatoes 0.17 0.45Regular mayonnaise --- 0.35Butter --- 0.33French fries -0.16 0.37Eggs --- 0.30Snacks ‡ --- 0.36Nuts --- 0.30Coffee --- 0.29Sugar beverages - 0.15 0.29Beer --- 0.22Cream soup or chowder 0.16 0.25Pizza --- 0.26Regular salad dressing 0.19 0.19Liquor --- ---

Meyerhardt J, et al. ASCO 2007. Abstract #4019.

Impact of Western Pattern Diet on Colon Cancer Recurrence and Mortality


Quintile of Western Pattern Diet

1 2 3 4 5 P-value

Cancer recurrence or death-any cause (DFS)

# of events / # at risk 71/201 57/202 73/202 68/202 83/202

Multivariate adjusted hazard ratio Ref 1.2 2.03 2.16 3.91 <0.0001

(0.76-1.89) (1.30-3.16) (1.32-3.52) (2.21-6.89)

Cancer recurrence (Recurrence-Free Survival)

# of events / # at risk 68/201 51/202 68/202 61/202 76/202


(0.66-1.73) (1.16-2.90) (1.06-2.95) (1.73-5.69)

Overall Mortality

# of events / # at risk 57/201 35/202 51/202 53/202 55/202


(0.54-1.71) (1.22-3.57) (1.56-5.05) (1.90-7.41)

Adjusted for gender, age, depth of invasion through bowel wall (T1-2 vs. T3-4), number of positive lymph noses (1-3 vs. 4 or more), presence of clinical perforation at time of surgery, presence of bowel obstruction at time of surgery, baseline performance status (0 vs. 1-2), treatment arm, weight change between 1st and 2nd questionnaire, time-varying body mass index, time-varying physical activity level, and time-varying total calories.

Impact of Prudent Pattern Diet on Colon Cancer Recurrence and Mortality


Quintile of Prudent Pattern Diet

1 2 3 4 5 P-value

Cancer recurrence or death-any cause (DFS)

# of events / # at risk 79/201 79/202 71/202 53/202 70/202

Multivariate adjusted hazard ratio Ref 1.13 0.96 0.7 1.26 0.79

(0.71-1.67) (0.63-1.46) (0.44-1.11) (0.80-1.97)

Cancer recurrence (Recurrence-Free Survival)

# of events / # at risk 73/201 68/202 67/202 52/202 64/202


(0.70-1.60) (0.62-1.49) (0.47-1.22) (0.75-1.94)

Overall Mortality

# of events / # at risk 63/201 58/202 44/202 34/202 52/202


(0.73-1.78) (0.44-1.29) (0.33-1.65) (0.81-2.45)

Adjusted for gender, age, depth of invasion through bowel wall (T1-2 vs. T3-4), number of positive lymph noses (1-3 vs. 4 or more), presence of clinical perforation at time of surgery, presence of bowel obstruction at time of surgery, baseline performance status (0 vs. 1-2), treatment arm, weight change between 1st and 2nd questionnaire, time-varying body mass index, time-varying physical activity level, and time-varying total calories.

Adjuvant Colorectal Cancer

Closing Comments

John L. Marshall, MD

A Report from ASCO 2007 Adjuvant Colorectal Cancer

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Transcript of A Report from ASCO 2007 Adjuvant Colorectal Cancer