Transcript 2007_files/BlankeCRC Highlights ASCO2007

Highlights of the Day:
Colorectal Cancer
Charles D. Blanke, M.D.
OHSU Cancer Institute
Colorectal Cancer Highlights
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Background and epidemiology
Key findings in adjuvant treatment of colorectal cancer
Key findings in metastatic colorectal cancer
Future directions
Conclusions
2007 Epidemiology of Colorectal Cancer:
United States
• 3rd leading cause cancer death men and women
• 2nd leading cause cancer death Americans
• Age-adjusted incidence rates decreasing for 20+
years due to screening
• 153,760 cases and 52,180 deaths are expected
2007 Epidemiology of Colorectal Cancer:
United States
• 3rd leading cause cancer death men and women
• 2nd leading cause cancer death Americans
• Age-adjusted incidence rates decreasing for 20+
years due to screening
• 153,760 cases and 52,180 deaths are expected
Approved Agents in Metastatic Colorectal Cancer
• Breakthroughs have occurred because of new drugs
• 5FU: Only approved primary drug 1957 through 1996
• Recently approved chemotherapeutic agents:
– Irinotecan and oxaliplatin
– Capecitabine
• Recently approved biologic agents:
– Bevacizumab
– Cetuximab, panitumumab
Adjuvant Therapy of Colon Cancer
• 5-FU/lev superior to
surgery alone
• 6- and 12-month treatment
cycles equivalent
•Irinotecan does not
improve efficacy
• 5-FU/LV superior to
surgery alone
•FOLFOX improves
PFS
1990
1994
1998
2002
2003
2004-5
•Capecitabine more
effective/less toxic than 5FU6
ACCENT Database: Background
• ACCENT = Adjuvant Colon Cancer Endpoints Group,
established 2003 to validate DFS as an adjuvant colon
cancer trial endpoint
– Disclosure: I represent 1/40th of this group
• Included individual data from 18 trials and > 20,800 stage II
and III patients
• Goals were to “explore” and “inform” re:
– Adjuvant therapy benefit
– Survival and recurrence
– Examination of statistical models with disease-free survival
endpoint
• A good ASCO for ACCENT: 2 orals and a poster discussion
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ACCENT 1: Time-Dependent Patterns of
Failure and Treatment Benefit
-Dr. D. Sargent
HR for Overall Survival
Disease-Free Survival
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ACCENT 1: Take-Home Points
• Risk of event (recurrence) spikes first 2 years
• Hazard ratio for treatment only differs between
treatment and control for the first four years
• After 8 years, recurrence rates overall were < 0.5%/yr
• There was a long-term, constant OS 5FU benefit
– Treated pts had benefit every single-year
– 5FU-based therapy cures, versus just delaying
recurrence
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ACCENT 2: Prognostic Factors and Survival
Following Recurrence
-Dr. M O’Connell
• Time from randomization on surgical adjuvant protocol
to tumor recurrence
• Initial stage of colon cancer (II, III)
• 5FU-based adjuvant therapy versus surgery alone
• Era patient entered onto surgical adjuvant protocol
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Time from Recurrence to Death
by Year of Recurrence
100
Year 0- 1 (N=1846)
Year 1-2 (N=1854)
Year 2-3 (N=924)
Year 3-4 (N=516)
Year 4+ (N=582)
% Alive
80
60
Total
40
(N=5722)
Log Rank P-Value = <0.0001
20
0
0
1
2
3
4
Time (Years)
5
6
7
8
Time from Recurrence to Death by Stage
100
% Alive
Stage II (N=1153)
80
Stage III (N=4550)
60
Total
(N=5703)
Log Rank P-Value = <0.0001
40
20
0
0
1
2
3
4
5
Time (Years)
6
7
8
ACCENT 2: Author Conclusions
• Time from surgery and stage of the primary are
important prognostic variables
• Failing after adjuvant therapy leads to a worse outcome
than failing after surgery alone
• Survival following recurrence improved over the 15-year
period studied
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Questions Raised by ACCENT
• How do findings change with incorporation of newer
drugs/trials?
• Which variables are the most important for
stratification in future trials?
• Should 2-year DFS be the endpoint for Cooperative
Group Adjuvant Colon phase III studies?
• Should we stop or at least minimize monitoring for
recurrence after 5 (8) years?
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MOSAIC Adjuvant Trial: Background
• 2248 patient phase III trial FOLFOX4 versus LVFU2 in
curatively-resected stage II/III colon cancer patients
• Safety data reported 2002
• Efficacy data first reported 2003
• With 4-year follow-up, FOLFOX improved DFS by
6.6% over LVFU2, with an insignificant 3.2%
augmentation of overall survival1
1PASCO
2005, abstr 3501
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MOSAIC 2007
• SStudy now presented with > 5 years follow-up
• 6 6% DFS benefit maintained HR = 0.8, p = 0.003
Prob OS 6 years
5FU
FOLFOX
p
Overall
76%
78.6%
0.057
Stage II
86.8%
86.9%
0.996
Stage III
68.6%
73%
0.029
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Questions Raised by MOSAIC
• There aren’t a lot: FOLFOX clearly represents the SOC for
resected node-positive colon cancer patients
• How should we treat resected stage II patients adjuvantly?
– There were no DFS or OS benefits for node-negative patients
– Is this statistics or are they biologically different?
– How do we weigh the risk:benefit ratio in this population?
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Pooled Analysis Assessing PS in 1st-Line
CRC -Goldberg
• Phase III studies classically enroll < 10% PS 2 pts
• Poor PS = bad prognosis, but lacking sufficient data,
oncologists may under- or over-treat
• Retrospective analysis of 6286 frontline pts from 9 trials
– Primary endpoint was PFS
– Secondary endpoints were AEs, 60-day mortality, OS, and
ORR
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PS Study: Conclusions
• Severe N/V worse PS 2 pts; diarrhea, neutropenia not
• 60-day mortality greater PS 2 pts (12% vs. 3%)
• PFS, OS, ORR all significantly worse PS 2 pts
– PFS 4.9 vs 7.6 mo
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PFS – Treatment by PS
p-value < 0.0001
100
Control ~ PS 0-1 (median = 6.7 mos)
HR: 0.82 (0.77-0.86)
90
Treatment ~ PS 0-1 (median = 8.4 mos)
% Progression Free
80
Control ~ PS 2 (median = 4.0 mos)
70
Treatment ~ PS 2 (median = 6.0 mos)
60
50
p-value = 0.02
40
HR: 0.79 (0.66-0.96)
30
20
10
Interaction p-value = 0.68
0
0
2
4
6
8
Months
CM923700-20
10
12
14
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OS – Treatment by PS
p-value < 0.0001
HR: 0.87 (0.82-0.93)
100
Control ~ PS 0-1 (median = 16.4 mos)
90
Treatment ~ PS 0-1 (median = 17.9 mos)
80
Control ~ PS 2 (median = 8.2 mos)
70
p-value = 0.21
% Alive
Treatment ~ PS 2 (median = 8.8 mos)
HR: 0.88 (0.73-1.07)
60
50
40
30
20
10
0
0
5
10
15
Months
Interaction p-value = 0.41
CM923700-21
20
25
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PS Study: Additional Considerations
• Authors concluded “superior” treatment benefits all patients
• Study could not definitively address the reason behind poor PS
– It is likely eligibility requirements elminated many patients with
non-cancer related poor PS
– Goldberg’s patients likely had poor PS related to cancer
– It is reasonable to treat cancer-related poor PS patients with
aggressive chemotherapy, including combinations and new
agents
• PS 2 patients do terribly, even with therapy (OS < 9 mo; 12%
dead within 2 mo)
– ?Interesting population for all biologics
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OPTIMOX2 Background
• Chemo-holidays a hot topic in CRC for last 4 years
• 2 randomized trials were presented ASCO 2003
– Phase II salvage study CPT-11 showed no benefit to
indefinite therapy vs a fixed number of cycles
– OPTIMOX showed stopping oxaliplatin after a fixed
number of cycles did not hurt PFS
• OPTIMOX2 looked at a complete cessation of
chemotherapy after 6 cycles of FOLFOX vs
maintenance LVFU2
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OPTIMOX2 Results
Maintenance
No Maintenance
p
ORR
60%
59%
NS
2nd ORR
21%
25%
NS
Oxali reintro
52%
60%
NS
PFS
36 weeks
29 weeks
0.08
OS
26 months
19 months
0.0549
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OPTIMOX2 Results
Maintenance
No Maintenance
p
ORR
60%
59%
NS
2nd ORR
21%
25%
NS
Oxali reintro
52%
60%
NS
PFS
36 weeks
29 weeks
0.08
OS
26 months
19 months
0.0549
Author conclusions: Maintenance chemotherapy may prolong PFS and OS
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OPTIMOX2 Interpretation
• This was a smaller than intended and non-definitive
trial
– Patient numbers downgraded from 600 to 200
– Maintenance chemotherapy looked better, but not
statistically so
• A more attractive strategy would be biologic
maintenance
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Circulating tumor cells and survival in metastatic
colorectal cancer
-Dr. N. Meropol
• Assessment of cirulating tumor cells in metastatic
CRC patients, correlating with imaging and outcome
• Independent predictor of PFS and OS
• ???Can we use this information to make early
changes to non-effective therapy, hoping to improve
outcome???
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Randomized study of sequential versus
combination chemotherapy
-Dr. CJ Punt
• Capecitabine followed by irinotecan followed by CapOx
versus
CapIri followed by CapOx
• 36% on sequential arm, versus 53% on combo got all 3
agents
• Combo therapy had more toxicity, a 2 month improvement
in PFS, and no change in OS
• This trial could not say who should get what
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REMINDER: Other Exciting Colorectal
Cancer Session are Ahead!
• Today: General Poster Session S Hall A2
• Today: Education Session on the Continuum of Care in
CRC N Hall B1
• Today: Plenary Session Results of Neoadjuvant
Chemotherapy for Metastasectomy in Liver Metastases N
Hall B1
• Tomorrow: Clinical Science Symposium on EGFR as a
Therapeutic Target E Arie Crown
A Phase II Trial of Celecoxib + IFL
Chemotherapy in Patients with Advanced
Colorectal Cancer
R
E
G
Celecoxib
I
Celecoxib x 2
weeks
S
T
E
R
Treat until:
+
Progression
IFL
Toxicity
Celecoxib 400 mg BID
Irinotecan 125 mg/m2 weekly x 4 every 43d
5-FU
500 mg/m2 weekly x 4 every 43d
LV
20 mg/m2 weekly x 4 every 43d
PASCO 2002
What do We Know Now
Compared to Before?
•Are we moving forward?
Schilsky ASCO 2002
NO!!!
Highlights of the Day: Colorectal
Cancer Conclusions 2007
• Prior ASCOs have mostly focused on generic use of
new drugs
• This ASCO did confirm previous findings on a “new”
drug-oxaliplatin clearly benefits patients when used
after potentially curative resection of colon cancer
• Additionally, this seemed to be the ASCO of colorectal
cancer “strategy development”
Highlights of the Day: Additional
Colorectal Cancer Conclusions 2007
•Large patient databases can help set endpoint
guidelines and stratification variables for future largescale trials
•PS 2 patients, if sick from cancer, may benefit from
aggressive chemotherapy
•Maintenance therapy does not clearly benefit those on
chemo-holidays, but I will still use it
What do We Know Now
Compared to Before?
•Are we moving forward?
Blanke ASCO 2007
YES!!!!