Abstract

Benefits and adverse events in younger (age <50) vs older patients receiving

adjuvant chemotherapy for colon cancer: Findings from the 33,574

patient ACCENT dataset

Benefits and adverse events in younger (age <50) vs older patients receiving

adjuvant chemotherapy for colon cancer: Findings from the 33,574

patient ACCENT dataset

Daniel Sargent, Greg Yothers, Erin Green, Charles Blanke, Michael O’Connell, R Labianca, Archie Bleyer, A DeGramont, and David Thomas as a joint project of the LIVESTRONG Young Adult Alliance and the ACCENT collaborative group

AbstractAbstractBackgroundLimited data exists regarding outcomes and AT benefit/toxicity in Y pts with stage II and III CC. We examined overall survival (OS), disease free survival (DFS), recurrence free interval (RFI) and AEs in the 33,574 pt ACCENT dataset.MethodsIndividual pt data from 24 randomized Phase III clinical trials (CT) was obtained for survival outcomes, and 10 CT for AE outcomes. Two age-based cut-offs were used to define Y pts, age < 40 and < 50. Cox models stratified by study and adjusted for gender and stage. AT benefit analyses were limited to 9 CT testing 5-FU/LV or Lev vs control (7 CT) or oxaliplatin+5-FU/LV vs 5-FU/LV (2 CT).Results1758 (5.2%) pts were age < 40; 5817 (17.3%) were < 50; only 299 (0.9%) were age < 30. No differences in gender or stage were present in Y vs older pts. Y and older pts did not differ in RFI (HR=1.02 for each age cutpoint, p>0.35). Y pts had improved OS and DFS (Table), even when restricting to age < 50 vs 50-60 (HR = 1.08, p=0.0061 for DFS comparing < 50 to 50-59). In trials demonstrating AT benefit, similar benefit was observed in Y and older pts (DFS HR for AT benefit 0.66 for pts < 50, 0.76 for pts >50, interaction p=0.19). No clinically meaningful differences in AEs were observed between ages.ConclusionsAmong pts on CT, Y (age 30-50) stage II and III CC pts had similar RFI and AT benefit as older pts, with no clinically meaningful differences in AEs. Y pts have improved OS and DFS, likely primarily due to to fewer competing causes of death. Adjuvant therapy is beneficial for CC pts aged 30-50 meeting typical CT eligibility criteria.

ACCENTACCENT

• Initially established in 2003, to validate disease-free survival (DFS) as an endpoint in adjuvant colon cancer

• Individual patient data from 24 large adjuvant randomized clinical trails, 33,574 patients

• Jointly owned by all contributors

MethodsMethods

• Analyses of individual patient data

• Endpoints:

• Primary: Disease Free Survival (PFS)

• Secondary: Overall Survival (OS), grade ≥ 3 adverse

events (AE)

• Cox regression models adjusted by age and gender, stratified

by study:

• Effect of age with cut points of < 40 and < 50

• Age-by-treatment interaction to assess relative benefit in 9

trials that demonstrated adjuvant therapy benefit

Surgery alone control vs 5-FU

Monotherapy 5-FU

Combination vs monotherapy

Trial N Trial N Trial NN784852* 247 NSABP C03 1081 MOSAIC* 2246

INT 0035* 926 NSABP C04 2151 NSABP C07* 2434

N874651* 408 NSABP C05 2176 CALGB 89803 1264

Siena* 239 N894651 915 PETACC-3 3188

NCIC* 359 N914653 878

FFCD* 259 SWOG 9415 1078

NSABP C01 773 INT 0089 3547

NSABP C02 718 GERCOR 905

GIVIO* 867 QUASAR 3517

X-ACT 1987

NSABP C06 1557

ACCENT: Trials included

*Trials included in adjuvant therapy benefit analysis

Baseline Characteristics by AgeBaseline Characteristics by Age

Age <40(N=1758)

Age >40 (N=31,816)

P-value

Age <50(N=5817)

Age >50(N=27,757)

P-value

Gender Male, n (%) Female, n (%)

923 (53)833 (48)

17,436 (55)14,378 (45) 0.07

2985 (51)2830 (49)

15,374 (55)12,381 (45) <0.0001

Stage I, n (%) II, n (%) III, n (%)

5 (0.3)567 (32)

1184 (67)

217 (0.7)9606 (30)

21,962 (69)0.03

17 (0.3)1858 (32)3933 (68)

205 (0.7)8315 (30)

19,213 (69)<0.0001

Disease Free SurvivalAll Studies, Age Cutoff - 40Disease Free SurvivalAll Studies, Age Cutoff - 40

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% D

isea

se F

ree

and

Ali

ve

Age < 40

Age > 40Age 5 Year Rates (95% CI)

HR

(95% CI)

P-value

< 40 67.5%

(65.3%-69.8%)

1.2

(1.1-1.3)

<0.001

> 40 63.4%

(62.9%-64.0%)

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% D

isea

se F

ree

and

Ali

ve

Age < 50

Age > 50Age 5 Year Rates (95% CI)

HR

(95% CI)

P-value

< 50 67.3%

(66.1%-68.5%)

1.2

(1.1-1.3)

<0.001

> 50 62.9%

(62.3%-63.5%)

Disease Free SurvivalAll Studies, Age Cutoff - 50Disease Free SurvivalAll Studies, Age Cutoff - 50

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% D

iseas

e Fre

e Age < 40

Age > 40

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% A

live

Age < 40

Age > 40

Time to Recurrence & Overall SurvivalAll Studies, Age Cutoff - 40


Age 5 Year Rates (95% CI)

HR

(95% CI)

P-value

< 40 68.4%

(66.3%-70.7%)

1.0

(0.9-1.1)

0.62

> 40 66.8%

(66.2%-67.3%)


HR

(95% CI)

P-value

< 40 75.1%

(73.0%-77.1%)

1.3

(1.2-1.4)

<0.001

> 40 71.2%

(70.7%-71.7%)

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% A

live

Age < 50

Age > 50

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% Di

seas

e Fre

e Age < 50

Age > 50


HR

(95% CI)

P-value

< 50 68.4%

(67.2%-69.7%)

1.02

(0.97-1.10)

0.35

> 50 66.5%

(66.0%-67.1%)


HR

(95% CI)

P-value

< 50 75.8%

(74.7%-76.9%)

1.33

(1.26-1.40)

<0.001

> 50 70.5%

(70.0%-71.0%)



0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% D

iseas

e Fre

e and

Aliv

e ControlExperimental

DFS: Experimental vs Control 9 Studies w/ Treatment Benefit


Tx 5 Year Rates (95% CI)

HR

(95% CI)

P-value

Con 66.8%

(60.8%-73.5%)

0.76

(0.51-1.00)

0.05

Exp 74.3%

(68.8%-80.2%)

Age < 40 Age > 40

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% D

iseas

e Fre

e and

Aliv

e

ControlExperimental


HR

(95% CI)

P-value

Con 62.5%

(61.0%-64.2%)

0.75

(0.69-0.80)

<0.001

Exp 70.0%

(68.5%-71.5%)

Interaction p-value = 0.78

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% D

iseas

e Fre

e and

Aliv

e

ControlExperimental

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% D

iseas

e Fre

e and

Aliv

e

ControlExperimental


HR

(95% CI)

P-value

Con 66.0%

(62.6%-69.7%)

0.66

(0.54-0.80)

<0.001

Exp 74.4%

(71.2%-77.8%)

Age < 50 Age > 50


HR

(95% CI)

P-value

Con 62.1%

(60.4%-63.8%)

0.76

(0.70-0.82)

<0.001

Exp 69.4%

(67.8%-71.0%)




0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% A

live

ControlExperimental

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% A

live

ControlExperimental


HR

(95% CI)

P-value

Con 78.2%

(72.8%-83.9%)

0.94

(0.64-1.38)

0.74

Exp 78.8%

(73.6%-84.4%)

Age < 40 Age > 40


HR

(95% CI)

P-value

Con 72.4%

(71.0%-73.9%)

0.79

(0.73-0.86)

<0.001

Exp 76.6%

(75.3%-78.0%)

OS: Experimental vs Control 9 Studies w/ Treatment Benefit



0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% A

live

ControlExperimental

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% A

live

ControlExperimental


HR

(95% CI)

P-value

Con 77.8%

(74.8%-81.0%)

0.79

(0.63-0.98)

0.03

Exp 79.8%

(76.8%-82.9%)

Age < 50 Age > 50


HR

(95% CI)

P-value

Con 71.6%

(70.0%-73.2%)

0.79

(0.73-0.87)

<0.001

Exp 76.1%

(74.7%-77.6%)




Adverse Events by AgeAdverse Events by Age

AE endpoint(Grade > 3)

Age<40

Age>40

OR(95% CI)

P-value

Age <50

Age >50

OR(95% CI)

P-value

Diarrhea 15% 16% 1.08(0.78-

1.52)

0.68 15% 16% 1.15(0.94-1.41)

0.19

Leukopenia 3% 8% 2.82(1.12-

4.66)

0.02 4% 8% 1.89(1.30-2.74)

0.007

Stomatitis 6% 9% 1.71(0.97-

3.01)

0.06 6% 10% 1.60(1.17-2.17)

0.003

Nausea/Vomiting

10% 7% 0.64(0.42-

0.98)

0.04 8% 7% 0.80(0.60-1.05)

0.11

DiscussionDiscussion

• Even restricting comparison to patients < 50 vs 50-60, p = 0.0061 (HR=1.08) for improved DFS for < 50

• Detailed data on dosing not available

ConclusionsConclusions

• Among patients on clinical trials, younger (age 30-50) stage II and III colon cancer pts had similar adjuvant therapy benefit as older patients

• No clinically meaningful differences in AEs were present between age groups

• Younger pts have improved OS and DFS, likely primarily due to fewer competing causes of death

• Adjuvant therapy is beneficial for colon cancer patients aged 30-50 meeting typical clinical trials eligibility criteria

ACCENT collaboratorsACCENT collaboratorsS Wieand, G Yothers, M O’Connell, N Wolmark – NSABPJ Benedetti, C Blanke – SWOGR Labianca – Ospedali Riuniti (Italy)D Haller, P Catalano, A Benson – ECOGC O’Callaghan – NCICJF Seitz – University of the Mediterranean (France)G Francini – University of Siena (Italy)A de Gramont, T Andre – GERCORR Goldberg, L Saltz, J Meyerhardt, N Jackson – CALGBM Buyse – IDDI (Belgium)R Gray, D Kerr – QUASARA Grothey, S Alberts, B Bot, E Green, Q Shi –Mayo ClinicC Twelves -University of Bradford (UK)J Cassidy – University of Glasgow (UK)F Sirzen – Roche ; L Cisar - PfizerE Van Cutsem –University Hospital Gasthuisberg (Belgium); A Sobrero - Ospedale San Martino (Italy)

Abstract

Documents

effect of age

age cutpoint

older pts dfs hr

cc pts

y vs older

agebased cutoffs

conclusionsamong pts

experimental vs control