Post on 03-Jan-2016
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?