CM923700-1

Time-dependent patterns of Time-dependent patterns of failure and treatment benefit failure and treatment benefit

from adjuvant therapy for from adjuvant therapy for resectable colon cancer: resectable colon cancer: Lessons from the 20,800 Lessons from the 20,800 patient ACCENT datasetpatient ACCENT dataset

Time-dependent patterns of Time-dependent patterns of failure and treatment benefit failure and treatment benefit

from adjuvant therapy for from adjuvant therapy for resectable colon cancer: resectable colon cancer: Lessons from the 20,800 Lessons from the 20,800 patient ACCENT datasetpatient ACCENT dataset

D Sargent D Sargent

for the Adjuvant Colon Cancer Endpoints (ACCENT) Groupfor the Adjuvant Colon Cancer Endpoints (ACCENT) Group

D Sargent D Sargent

for the Adjuvant Colon Cancer Endpoints (ACCENT) Groupfor the Adjuvant Colon Cancer Endpoints (ACCENT) Group

CM923700-2

The Adjuvant Colon Cancer The Adjuvant Colon Cancer Endpoints (ACCENT) databaseEndpoints (ACCENT) database

The Adjuvant Colon Cancer The Adjuvant Colon Cancer Endpoints (ACCENT) databaseEndpoints (ACCENT) database

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

• Individual patient data from large Individual patient data from large adjuvant clinical trialsadjuvant clinical trials

• Jointly owned by all contributorsJointly owned by all contributors

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

• Individual patient data from large Individual patient data from large adjuvant clinical trialsadjuvant clinical trials

• Jointly owned by all contributorsJointly owned by all contributors

CM923700-3

Total: 18 trials; 20,898 pts

3517QUASAR867GIVIO

905GERCOR718NSABP C02

3547INT 0089773NSABP C01

1078SWOG 9415259FFCD

878N914653359NCIC

915N894651239Siena

2176NSABP C05408N874651

2151NSABP C04926INT 0035

1081NSABP C03247N784852

NTrialNTrial

Active ControlNo Treatment Control

Trials IncludedTrials IncludedTrials IncludedTrials Included

CM923700-4

Mining the ACCENT databaseMining the ACCENT databaseMining the ACCENT databaseMining the ACCENT database

• ASCO 2004: DFS surrogate for OSASCO 2004: DFS surrogate for OS

• ASCO 2005: Concordance stronger in ASCO 2005: Concordance stronger in stage III than stage IIstage III than stage II

• ASCO 2007ASCO 2007

•Survival after recurrence – M O’ConnellSurvival after recurrence – M O’Connell

•Prognostic importance of race – G YothersPrognostic importance of race – G Yothers

•Lessons for trialistLessons for trialist

• ASCO 2004: DFS surrogate for OSASCO 2004: DFS surrogate for OS

• ASCO 2005: Concordance stronger in ASCO 2005: Concordance stronger in stage III than stage IIstage III than stage II

• ASCO 2007ASCO 2007

•Survival after recurrence – M O’ConnellSurvival after recurrence – M O’Connell

•Prognostic importance of race – G YothersPrognostic importance of race – G Yothers

•Lessons for trialistLessons for trialist

CM923700-5

Three questions facing adjuvant Three questions facing adjuvant colon cancer trialistscolon cancer trialists

Three questions facing adjuvant Three questions facing adjuvant colon cancer trialistscolon cancer trialists

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

• Long term recurrence ratesLong term recurrence rates

• Adequacy of statistical assumptions, Adequacy of statistical assumptions, using DFS endpointusing DFS endpoint

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

• Long term recurrence ratesLong term recurrence rates

• Adequacy of statistical assumptions, Adequacy of statistical assumptions, using DFS endpointusing DFS endpoint

CM923700-6

Duration of adjuvant therapy Duration of adjuvant therapy benefitbenefit

Duration of adjuvant therapy Duration of adjuvant therapy benefitbenefit

• Benefit of adjuvant therapy on OS is durable; Benefit of adjuvant therapy on OS is durable; long-term OS benefitlong-term OS benefit

• ACCENT: 80% of recurrences within first 3 ACCENT: 80% of recurrences within first 3 yearsyears

• Duration of adjuvant therapy benefit for DFS?Duration of adjuvant therapy benefit for DFS?

• Restrict analysis to studies of 5-FU based rx Restrict analysis to studies of 5-FU based rx vs no adjuvant rx (N=3305)vs no adjuvant rx (N=3305)

• Benefit of adjuvant therapy on OS is durable; Benefit of adjuvant therapy on OS is durable; long-term OS benefitlong-term OS benefit

• ACCENT: 80% of recurrences within first 3 ACCENT: 80% of recurrences within first 3 yearsyears

• Duration of adjuvant therapy benefit for DFS?Duration of adjuvant therapy benefit for DFS?

• Restrict analysis to studies of 5-FU based rx Restrict analysis to studies of 5-FU based rx vs no adjuvant rx (N=3305)vs no adjuvant rx (N=3305)

CM923700-7

Hazard Rates for OSHazard Rates for OSHazard Rates for OSHazard Rates for OS

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

CM923700-8

Hazard Rates for OS and DFSHazard Rates for OS and DFSHazard Rates for OS and DFSHazard Rates for OS and DFS

Overall Survival 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

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

CM923700-9

0 2 4 6 8

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

Time in Years

Log

haza

rd r

atio

95% pointwise CIs

Hazard Ratios for Rx vs ControlHazard Ratios for Rx vs ControlHazard Ratios for Rx vs ControlHazard Ratios for Rx vs Control

Overall Survival

CM923700-10

0 2 4 6 8

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

Time in Years

Log

haza

rd r

atio

95% pointwise CIs

Hazard Ratios for Rx vs ControlHazard Ratios for Rx vs ControlHazard Ratios for Rx vs ControlHazard Ratios for Rx vs Control

Overall Survival Disease-Free Survival

0 2 4 6 8

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

Time in Years

Log

haza

rd r

atio

95% pointwise CIs

CM923700-11

Findings: Duration of benefitFindings: Duration of benefitFindings: Duration of benefitFindings: Duration of benefit

• OSOS• Significant OS chemotherapy benefit Significant OS chemotherapy benefit

consistent over timeconsistent over time

• DFS DFS • Risk of event spikes in first 2 years in Risk of event spikes in first 2 years in

control group, then similar between rx and control group, then similar between rx and controlcontrol

• Hazard ratio for treatment only significantly Hazard ratio for treatment only significantly differs between rx and control for first 4 differs between rx and control for first 4 yearsyears

• OSOS• Significant OS chemotherapy benefit Significant OS chemotherapy benefit

consistent over timeconsistent over time

• DFS DFS • Risk of event spikes in first 2 years in Risk of event spikes in first 2 years in

control group, then similar between rx and control group, then similar between rx and controlcontrol

• Hazard ratio for treatment only significantly Hazard ratio for treatment only significantly differs between rx and control for first 4 differs between rx and control for first 4 yearsyears

CM923700-12

Conclusions: Duration of benefitConclusions: Duration of benefitConclusions: Duration of benefitConclusions: Duration of benefit

• Long term, constant OS benefit: no Long term, constant OS benefit: no detrimental long-term effect of 5-FU detrimental long-term effect of 5-FU based chemotherapybased chemotherapy• Treated patients have reduced risk Treated patients have reduced risk

of death every single yearof death every single year

• Long term, constant OS benefit: no Long term, constant OS benefit: no detrimental long-term effect of 5-FU detrimental long-term effect of 5-FU based chemotherapybased chemotherapy• Treated patients have reduced risk Treated patients have reduced risk

of death every single yearof death every single year

0 2 4 6 8

-2.0

-1.0

0.0

1.0

Time in Years

Log

haza

rd r

atio

95% pointwise CIs

CM923700-13

Conclusions: Duration of benefitConclusions: Duration of benefitConclusions: Duration of benefitConclusions: Duration of benefit

• Short term DFS benefits translate Short term DFS benefits translate into long-term OS benefitinto long-term OS benefit

• DFS hazards never reverse – 5-FU DFS hazards never reverse – 5-FU based chemotherapy prevents, not based chemotherapy prevents, not just delays, recurrencejust delays, recurrence

• Short term DFS benefits translate Short term DFS benefits translate into long-term OS benefitinto long-term OS benefit

• DFS hazards never reverse – 5-FU DFS hazards never reverse – 5-FU based chemotherapy prevents, not based chemotherapy prevents, not just delays, recurrencejust delays, recurrence

Follow-up Time (Years)

Haz

ard

Rat

e

0 2 4 6 8

0.0

0.00

020.

0004

0.00

06

Surgery Alone Arms

5-FU Based Rx Arms

CM923700-14

Long-term recurrence rates Long-term recurrence rates Long-term recurrence rates Long-term recurrence rates

CM923700-15

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

Re

cu

rre

nc

e R

ate

(%

)Recurrence Rate by time from

randomization (all pts)

After 5 years, recurrence After 5 years, recurrence rates < 1.5% / yearrates < 1.5% / year

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

CM923700-16

Conclusions: Long-term Conclusions: Long-term follow-upfollow-up

Conclusions: Long-term Conclusions: Long-term follow-upfollow-up

• For DFS endpoint, long-term follow-For DFS endpoint, long-term follow-up will provide few eventsup will provide few events

• After 5 years, follow-up for After 5 years, follow-up for recurrence may be reduced, and recurrence may be reduced, and increase focus on other factors increase focus on other factors

• For DFS endpoint, long-term follow-For DFS endpoint, long-term follow-up will provide few eventsup will provide few events

• After 5 years, follow-up for After 5 years, follow-up for recurrence may be reduced, and recurrence may be reduced, and increase focus on other factors increase focus on other factors

CM923700-17

Adequacy of Statistical ModelsAdequacy of Statistical ModelsAdequacy of Statistical ModelsAdequacy of Statistical Models

• Current methods assume Current methods assume

• Constant risk of eventConstant risk of event

• Constant treatment effectConstant treatment effect

• Both assumptions violated for DFS endpointBoth assumptions violated for DFS endpoint

• Risk of event spikes dramatically in first 2 Risk of event spikes dramatically in first 2 yearsyears

• Treatment effect diminishes after 2 years, Treatment effect diminishes after 2 years, non-significant after 4 yearsnon-significant after 4 years

• Current methods assume Current methods assume

• Constant risk of eventConstant risk of event

• Constant treatment effectConstant treatment effect

• Both assumptions violated for DFS endpointBoth assumptions violated for DFS endpoint

• Risk of event spikes dramatically in first 2 Risk of event spikes dramatically in first 2 yearsyears

• Treatment effect diminishes after 2 years, Treatment effect diminishes after 2 years, non-significant after 4 yearsnon-significant after 4 years

CM923700-18

Adequacy of Statistical ModelsAdequacy of Statistical ModelsAdequacy of Statistical ModelsAdequacy of Statistical Models

• More complex statistical models available, More complex statistical models available, but are they necessary?but are they necessary?

• Considered trial designed under standard Considered trial designed under standard methods to have 90% power to detect HR methods to have 90% power to detect HR of 0.77 ( of 0.77 ( ↑ ↑ 3 yr DFS from 68% to 74%) at 3 yr DFS from 68% to 74%) at = 0.05= 0.05

• Assumption: event-based analysis, log-Assumption: event-based analysis, log-rank testingrank testing

• More complex statistical models available, More complex statistical models available, but are they necessary?but are they necessary?

• Considered trial designed under standard Considered trial designed under standard methods to have 90% power to detect HR methods to have 90% power to detect HR of 0.77 ( of 0.77 ( ↑ ↑ 3 yr DFS from 68% to 74%) at 3 yr DFS from 68% to 74%) at = 0.05= 0.05

• Assumption: event-based analysis, log-Assumption: event-based analysis, log-rank testingrank testing

CM923700-19

Power: Constant Rx Effect Power: Constant Rx Effect (HR=0.77)(HR=0.77)

Power: Constant Rx Effect Power: Constant Rx Effect (HR=0.77)(HR=0.77)

0.4

0.6

0.8

1

1.2

0 1 2 3 4 5 6

Year

Haz

ard

Rat

io

Scenario 1Power = 88.4%

CM923700-20

Power: Non-Constant Rx EffectPower: Non-Constant Rx EffectPower: Non-Constant Rx EffectPower: Non-Constant Rx Effect

0.4

0.6

0.8

1

1.2

0 1 2 3 4 5 6

Year

Haz

ard

Rat

io

Scenario 1

Scenario 2

Power = 88.4%

Power = 89.6%

CM923700-21

Power: Non-Constant Rx EffectPower: Non-Constant Rx EffectPower: Non-Constant Rx EffectPower: Non-Constant Rx Effect

0.4

0.6

0.8

1

1.2

0 1 2 3 4 5 6

Year

Haz

ard

Rat

io

Scenario 1

Scenario 2

Scenario 3

Power = 88.4%

Power =90.1%

Power = 89.6%

CM923700-22

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

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

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

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

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

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

Conclusions: Adequacy of Conclusions: Adequacy of Statistical modelsStatistical models

Conclusions: Adequacy of Conclusions: Adequacy of Statistical modelsStatistical models

CM923700-23

DiscussionDiscussionDiscussionDiscussion

• Continued data mining of large datasets Continued data mining of large datasets can yield new information can yield new information

• Treatment effectsTreatment effects

• Trial planning and conductTrial planning and conduct

• Findings should be validated on newer Findings should be validated on newer trialstrials

• Treatments with different mechanism Treatments with different mechanism of action may impact DFS differentlyof action may impact DFS differently

• Continued data mining of large datasets Continued data mining of large datasets can yield new information can yield new information

• Treatment effectsTreatment effects

• Trial planning and conductTrial planning and conduct

• Findings should be validated on newer Findings should be validated on newer trialstrials

• Treatments with different mechanism Treatments with different mechanism of action may impact DFS differentlyof action may impact DFS differently

CM923700-24

Conclusions: StatisticalConclusions: StatisticalConclusions: StatisticalConclusions: Statistical

• Long term follow-up for recurrence will yield Long term follow-up for recurrence will yield few additional eventsfew additional events

• DFS theoretically violates traditional DFS theoretically violates traditional approach to trial design approach to trial design

• Real world impact minor: standard Real world impact minor: standard approaches to trial design remain approaches to trial design remain appropriate for DFS endpointappropriate for DFS endpoint

• Long term follow-up for recurrence will yield Long term follow-up for recurrence will yield few additional eventsfew additional events

• DFS theoretically violates traditional DFS theoretically violates traditional approach to trial design approach to trial design

• Real world impact minor: standard Real world impact minor: standard approaches to trial design remain approaches to trial design remain appropriate for DFS endpointappropriate for DFS endpoint

CM923700-25

Conclusions: ClinicalConclusions: ClinicalConclusions: ClinicalConclusions: Clinical

• Adjuvant rx provides large short term Adjuvant rx provides large short term DFS benefits, long term OS benefitDFS benefits, long term OS benefit

• Recurrence rates after 5 years modest, Recurrence rates after 5 years modest, after 8 years minimalafter 8 years minimal

•Adjuvant therapy produces curesAdjuvant therapy produces cures

•Follow-up for recurrence after 5 years Follow-up for recurrence after 5 years can be minimizedcan be minimized

• Adjuvant rx provides large short term Adjuvant rx provides large short term DFS benefits, long term OS benefitDFS benefits, long term OS benefit

• Recurrence rates after 5 years modest, Recurrence rates after 5 years modest, after 8 years minimalafter 8 years minimal

•Adjuvant therapy produces curesAdjuvant therapy produces cures

•Follow-up for recurrence after 5 years Follow-up for recurrence after 5 years can be minimizedcan be minimized

CM923700-26

• G Yothers, M O’Connell, N Wolmark, S Wieand– NSABPG Yothers, M O’Connell, N Wolmark, S Wieand– NSABP

• J Benedetti, C Blanke – SWOGJ Benedetti, C Blanke – SWOG

• R Labianca – Ospedali Riuniti (Italy)R Labianca – Ospedali Riuniti (Italy)

• D Haller, P Catalano, A Benson – ECOGD Haller, P Catalano, A Benson – ECOG

• C O’Callaghan – NCICC O’Callaghan – NCIC

• JF Seitz – University of the Mediterranean (France)JF Seitz – University of the Mediterranean (France)

• G Francini – University of Siena (Italy)G Francini – University of Siena (Italy)

• A de Gramont, T Andre – GERCORA de Gramont, T Andre – GERCOR

• R Goldberg – CALGBR Goldberg – CALGB

• M Buyse – IDDI (Belgium)M Buyse – IDDI (Belgium)

• R Gray, D Kerr – OxfordR Gray, D Kerr – Oxford

• D Sargent, A Grothey, E Green, S Alberts - NCCTGD Sargent, A Grothey, E Green, S Alberts - NCCTG

• G Yothers, M O’Connell, N Wolmark, S Wieand– NSABPG Yothers, M O’Connell, N Wolmark, S Wieand– NSABP

• J Benedetti, C Blanke – SWOGJ Benedetti, C Blanke – SWOG

• R Labianca – Ospedali Riuniti (Italy)R Labianca – Ospedali Riuniti (Italy)

• D Haller, P Catalano, A Benson – ECOGD Haller, P Catalano, A Benson – ECOG

• C O’Callaghan – NCICC O’Callaghan – NCIC

• JF Seitz – University of the Mediterranean (France)JF Seitz – University of the Mediterranean (France)

• G Francini – University of Siena (Italy)G Francini – University of Siena (Italy)

• A de Gramont, T Andre – GERCORA de Gramont, T Andre – GERCOR

• R Goldberg – CALGBR Goldberg – CALGB

• M Buyse – IDDI (Belgium)M Buyse – IDDI (Belgium)

• R Gray, D Kerr – OxfordR Gray, D Kerr – Oxford

• D Sargent, A Grothey, E Green, S Alberts - NCCTGD Sargent, A Grothey, E Green, S Alberts - NCCTG

ACCENT Collaborative GroupACCENT Collaborative GroupACCENT Collaborative GroupACCENT Collaborative Group