Efficacy findings from a randomized phase III trial of capecitabine plus

oxaliplatin versus bolus 5-FU/LV for stage III colon cancer (NO16968): No impact of

age on disease-free survival (DFS).

Discussant: Aimery de Gramont

Treatment of Colorectal Cancer in Elderly Patients

• Metastatic setting– Folprecht JCO 2008 - N=2,692 (22% 70 yrs)

• 4 trials of irinotecan-based therapy • Improved PFS, trend to improved OS for elderly w/addition of

irinotecan

– Goldberg JCO 2006 - N=3,742 (16% 70 yrs) • 4 trials of oxaliplatin-based therapy• Similar survival benefit and toxicity in age subgroups

Treatment of Colorectal Cancer in Elderly Patients

• Adjuvant setting– Sargent NEJM 2001 – N=3351 (15% 70 yrs)

• 7 trials of 5-FU + levamisole/leucovorin v surgery

• No significant interaction observed between age and efficacy of treatment

D. Haller, J. Cassidy, J. Tabernero, J. MarounF. de Braud, T. Price, E. Van Cutsem, M. Hill

F. Gilberg, H-J. Schmoll

Phase III Trial of Capecitabine + Oxaliplatin vs. Bolus 5-FU/LV in

Stage III Colon Cancer (NO16968)

Impact of Age on Disease-free Survival

Chemo/radiotherapy-naive

stage III colon ≤8 weeks since resection

N=1886

n=944

n=942

RANDO MIZATION

NO16968 Trial Design

• Primary endpoint: DFS• Secondary endpoints: RFS, OS, tolerability

Bolus 5-FU/LV (6 months) Mayo Clinic [n=664]

orRoswell Park [n=278]

XELOX (6 months) capecitabine 1000mg/m2 bid d1–14

oxaliplatin130mg/m2 d1 q3w

8 cycles

DFS At 3, 4 and 5 Years: Benefit with XELOX Maintained and Increased Over Time

1.0

0.0

0.2

0.4

0.6

0.8

0 1 2 3 4 5 6

Years

ITT population

Δ at 4 years: 6.1%Δ at 5 years: 6.3%

Δ at 3 years: 4.5%

70.9% 68.4%

3-yearDFS

66.5% 62.3%

4-yearDFS

5-yearDFS

59.8%66.1%

XELOX

5-FU/LV

Subgroup Analysis of DFS by Age

• Unplanned analysis performed to:– Compare with data presented from ACCENT.– Assess benefits of XELOX vs. 5-FU/LV in

patients aged >65 and >70 years.– Determine if ACCENT and MOSAIC findings

are FOLFOX- or oxaliplatin-specific.

Subgroup Analysis of DFS by Age

3-year DFSHazard ratio

(95% CI)XELOX 5-FU/LV <70 years, n=1477 72% 69% 0.79 (0.66,0.94)

≥70 years, n=409 66% 60% 0.87 (0.63,1.18)

ITT population

Subgroup Analysis of OS by Age5-year OS

Hazard ratio(95% CI)XELOX 5-FU/LV

<70 years, n=1477 80% 76% 0.86 (0.69,1.08)

≥70 years, n=409 69% 67% 0.94 (0.66,1.34)

Comparison with ACCENT Analysis

*Values <1 favor oxaliplatin-based therapy vs. 5-FU/LV.†Data for oxaliplatin-based regimens.4. McCleary et al. ASCO 2009 (poster 4010)

Hazard ratio (95% CIs)*DFS OS

ACCENT analysis4†

<70 years, n=3877 0.77 (0.68,0.86) 0.81 (0.71,0.93)

≥70 years, n=703 1.04 (0.80,1.35) 1.19 (0.90,1.57)

NO16968

<70 years, n=1477 0.79 (0.66,0.94) 0.86 (0.69,1.08)

≥70 years, n=409 0.87 (0.63,1.18) 0.94 (0.66,1.34)

Treatment Exposure by Age: NO16968

Mean value

XELOX 5-FU/LV

<70 years(n=748)

≥70 years(n=190)

<70 years(n=711)

≥70 years(n=215)

Duration of therapy, days

5-FU – – 175 164

Capecitabine 158 130 – – Oxaliplatin 154 124 – –

Dose intensity

5-FU – – 0.82 0.76 Capecitabine 0.78 0.59 – – Oxaliplatin 0.79 0.63 – –

Safety population

Safety by Age

*Includes granulocytopenia.Safety population

Grade 3/4 AEs, %

XELOX 5-FU/LV

<70 years(n=748)

≥70 years(n=190)

<70 years(n=711)

≥70 years(n=215)

All grade 3/4 57 70 51 60

Diarrhea 18 26 19 25

Nausea/vomiting 8 11 6 5Stomatitis <1 1 9 8

Neutropenia* 9 10 16 17

Febrile neutropenia <1 <1 4 4Hand-foot syndrome 6 4 <1 <1Neurosensory 11 11 <1 0

NO16968 (XELOXA): Conclusions • In the total patient population, XELOX significantly

improves DFS compared with bolus 5-FU/LV in adjuvant therapy for stage III colon cancer.

• DFS and OS improvements with XELOX are maintained in patients >65 and >70 years, in spite of shorter treatment duration and lower dose intensity in the elderly.

• These findings differ from those of the MOSAIC study and the ACCENT analysis.

• Reasons for this apparent difference between other 5-FU/LV-oxaliplatin regimens (FOLFOX, FLOX) and XELOX are unknown.

• Current analysis supports consideration of XELOX for patients with stage III colon cancer, regardless of age.

• These other statements are vague: what analyses????

Impact of NO16968 Findings on Practice

DFS

0 6 12 18 24 30 36 42 48 54 60 66 720.0

0.2

0.4

0.6

0.8

1.0 FOLFOX4 >70LV5FU2 > 70

months

pro

bab

ilit

y

HR 0.914 [0.622-1.343]

MOSAIC data in patients > 70 years

DFS

DFS

0 6 12 18 24 30 36 42 48 54 60 66 720.0

0.2

0.4

0.6

0.8

1.0 FOLFOX4 >70LV5FU2 > 70FOLFOX4 <70LV5FU2 < 70

months

pro

bab

ilit

y

MOSAIC data in patients > 70 years

DFS

OS

0 6 12 18 24 30 36 42 48 54 60 66 720.0

0.2

0.4

0.6

0.8

1.0

FOLFOX4>70LV5FU2>70

months

pro

bab

ilit

y

HR 1.096 [0.73-1.65]

MOSAIC data in patients > 70 years

OS

OS

0 6 12 18 24 30 36 42 48 54 60 66 720.0

0.2

0.4

0.6

0.8

1.0

FOLFOX4>70LV5FU2>70FOLFOX4<70LV5FU2<70

months

pro

bab

ilit

y

MOSAIC data in patients > 70 years

OS

Impact of older age on the efficacyof newer adjuvant therapies in

>12,500 patients with stage II / III colon cancer:

Findings from the ACCENT Database

N. Jackson McCleary, J.A. Meyerhardt, E. Green, G. Yothers, A. de Gramont, E. Van Cutsem, M.

O’Connell, C.J. Twelves, L.B. Saltz, D.J. Sargent for the ACCENT collaborative group

ACCENT update: 6 trials added

Trial AccrualPeriod

# pts % pts≥70 yrs

Experimentaltreatment arm†

% stage III‡

MOSAIC 1998-01 2246 14 FOLFOX4 60

NSABP C-07 2000-02 2434 16 FLOX 71

CALGB 89803 1999-01 1263 24 IFL 98

PETACC-3 2000-02 3186 13 FOLFIRI 71

NSABP C-06 1997-99 1557 23 Uracil/tegafur 53

X-ACT 1998-01 1983 20 Capecitabine 100

† Compared to control arm of intravenous 5-flourouracil (IV 5-FU) and

leucovorin (LV)

‡ Remaining patients were stage II or unknown

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2

Hazard Ratio

Age < 70

Age >= 70

Oxaliplatin

Oral

Irinotecan

Overall

Forest Plots of Hazard RatiosDisease-Free Survival

Forest Plots of Hazard RatiosOverall Survival

Forest Plots of Hazard RatiosOverall Survival

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2

Hazard Ratio

Age < 70

Age >= 70

Oxaliplatin

Oral

Irinotecan

Overall

Limitations• Lack of …

– Toxicity data– Dose-intensity – Comorbidity data

…may confound interaction between age & newer adjuvant chemotherapy regimens

Dewys WD, et al. Am J Med 1980; Eagles JM, et al. BMJ 1990; Landi F ZG, et al. J Am Geriatr Soc 1999; Lee Y et al. J Epidemiol Community Health 2000; Satariano WA, et al. Ann Intern Med 1994; Wedding U, et al. J Cancer Res Clin Oncol 2007.

- Small population, - Only two trials in each subgroup- Different FP regimens

Impact of ACCENT Analysis on Practice

• ACCENT conclusions have resulted in changes to:– German treatment guidelines– PETACC-8 trial design – UK and US clinical practice (some

investigators)

N>70 % DFS HR OS HR reference

ACCENT

Oral FP

755 21.3 1.13 1.17 ASCO 2009

X-ACTa 397 20.0 0.93b 0.93b Twelves NEJM 2005, ASCO GI 2008

C-06 358 22.3 NA >1.13 NA >1.17 Lembersky JCO 2006

ACCENT

Oxaliplatin

703 15.0 1.04 1.19 ASCO 2009

MOSAIC 315c 14.0 0.91 1.10 unpublished

C-07 388 16.9 NA >1.04 NA >1.19 Kuebler JCO 2007

NO16968a 409 21.7 0.87 0.94 ASCO GI 2010

b estimated from forest plot c stage III 190 patientsa stage III

Population and Hazard-Ratios

*http://seer.cancer.gov/statfacts/html/colorect.html

In trials ~ 20% of the patients are > 70 years of age

In the US, from 2002-2006, the median age at diagnosis for cancer of the colon and rectum was 71 years of age (M69, F73)*

Population

There is a benefit in DFS in all trials except NSABP C06 and C07Role of the FP regimen?

The benefit might be lower in the ederly population than in the younger populationHR~0.9 vs ~0.8- dose-intensity- toxicity

Disease-free Survival

There is no benefit in OS (HR>1) in all trials except a small benefit in the two capecitabine-based trials (HR 0.93 and 0.94)

Results are better in stage III than in stage II.C-06, C-07 and MOSAIC include both stage II and stage III patientsX-ACT and NO16968a include stage III only

Overall Survival

FOLFOX LV5FU2 P

N 155 160

Comorbidities* 85 93

cardiovascular 74 75

malignancy 1 1

endocrine 12 13

multiple 19 18

SAE 30 15 0,018

MOSAIC data in patients > 70 yearsOS

Comorbidities and Serious Adverse Events

*Adult Comorbidity Evaluation-27 Washington University School of Medicine

FOLFOX LV5FU2 P

N 155 160

living with relapse 7 13

Relapse 51 53

Chemotherapy 23 34 0.070

Irinotecan/oxali/(both) 16: 10/6 30: 14/17/(1) 0.011

Surgery Metastases 9 22 0.010

Death colon cancer 29 34

Death other 22 11 0,043

Second K 9 1 0,020

Cardiovascular 7 4

OS

MOSAIC data in patients > 70 years

Management of Relapse and Causes of Death

OS post DFS > 70 years

0 6 12 18 24 30 36 42 48 54 60 66 720.0

0.2

0.4

0.6

0.8

1.0

FOLFOXLV5FU2

P 0.0286 HR 1.579 CI (1.054-2.599)Median survival FOLFOX 4.44 monthsMedian survival LV5FU 15.98 months

months

pro

bab

ilit

y

Death other than colon cancer

Management of relapse

MOSAIC data in patients > 70 yearsSurvival after DFS

Both trials have comparable:Population: stage III, ~20% >70 yearsControl arm: 5FU bolus

Capecitabine alone or with Oxaliplatin in patients > 70 years?

N>70 % DFS HR OS HR reference

X-ACTa 397 20.0 0.93* 0.93* Twelves NEJM 2005, ASCO GI 2008

NO16968a 409 21.7 0.87 0.94 ASCO GI 2010

* estimated from forest plot

The benefit of oxaliplatin in DFS might be reduced in the ederly population- Decreased dose intensity NO16968- increased toxicity NO16968, MOSAIC

The lack of survival benefit in OS - is not due to imbalance in comorbidities (MOSAIC)- might be due to deaths of concomitant disease (cancer) and less intensive management of relapse (MOSAIC)

Worst outcome of second cancer and less intensive management of relapse might be patient- related or physician-related

CONCLUSIONS

Capecitabine alone, in stage III patients, might be a reasonable option

XELOX or FOLFOX can still be considered for the DFS advantage. OS might be improved with a more intensive management of relapse or second-cancer. The results of the AVANT trial will provide a comparison between the two regimens

A reduced duration of chemotherapy should be tested and could help ederly patients to accept to resume therapy: IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Colon Cancer Prospective Pooled Analysis

Which adjuvant treatment in ederly pts?