Transcript ASCO_2010_files/Blanke Highlights Non-CRC ASCO 2010

Highlights of the Day:
Non-Colorectal Cancer
Charles D. Blanke, M.D., F.A.C.P., F.R.C.P.C.
University of British Columbia/BC Cancer Agency
DISCLOSURES
Speaker / Consultant :
Novartis
Pfizer
Astra-Zeneca
Oncothyreon
Roche
Non-Colorectal Cancer Highlights
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Epidemiology and background
Key findings in esophagogastric cancers
Key findings in pancreatic cancer
Key findings in hepatobiliary cancers
Future directions
2009 Epidemiology of Non-Colorectal
Cancers:
Site
New Cases
Deaths
Esophagogastric
37,600
25,150
Pancreatic
42,470
35,240
Hepatobiliary
32,380
21,530
• 8% of all United States’ cancers
• 15% of all US cancer deaths
Effect of preoperative concurrent chemoradiotherapy on survival of
patients with resectable esophageal or esophagogastric junction
cancer: Results from a multicenter randomized phase III study.
A. van der Gaast, P. van Hagen, M. Hulshof, M.I. van Berge Henegouwen,
G.A. Nieuwenhuijzen, J.T. Plukker, J.J. Bonenkamp, E.W. Steyerberg,
H.W. Tilanus.
CROSS study group
Courtesy van der Gaast
Abstr 4004
CROSS Study: Background
• Meta-analyses/two modern phase III trials suggest a survival
benefit from pre-operative chemoradiation in esophageal cancer
• The evidence is stronger for adenocarcinoma histology
– Other optimal patient selection factors remain unknown
• It may increase post-operative mortality
6
CROSS Active Treatment Arm
 Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29
 Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy
 Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE)
 Major eligibility: Adeno- or squamous histology; N1 or >T2, PS < 2
 Primary objective: Median overall survival 22 months (versus 16)
CROSS: Major Results
• 93% received all courses chemotherapy
– 95% went to operating room
– ~23% had >grade 3 toxicity from pre-op therapy
• R0 resection rate: 92% versus 67%
p<0.001
– ~26% had pathologic complete remissions
• Post-operative morbidity and mortality almost identical
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CROSS: Overall Survival
CRTx
Surgery
HR 0.67 95% CI (.49 - .91) P=0.012
HR 0.67 95% CI (0.49 - 0.91)
•1-year survival 82 versus 70%
•2-year survival 67 versus 52%
•Median survival 49 versus 26 months
Adapted van der Gaast
CROSS: Investigators’ Conclusions
• Neoadjuvant chemoRT with weekly carbo- and
paclitaxel followed by surgery improves survival over
surgery alone
• Pre-operative chemoRT did not increase morbidity
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Surgery alone vs. chemoradiotherapy followed by
surgery for localized esophageal cancer: analysis of
a randomized controlled phase III trial FFCD 9901
C. Mariette, JF Seitz, E Maillard, F Mornex, PA Thomas, JL Raoul, V
Boige, D Pezet, C Genet, L Bedenne
Fédération Française de Cancérologie Digestive
Dpt of digestive and oncological surgery University Hospital Lille
FRANCE
Abstr 4005
Courtesy Dr. Mariette
FFCD: Methods
• Neoadjuvant CRT group (CRT+S group, n=97)
45Gy/25F/5 weeks
with 2 courses of concomitant CT
5FU 800mg/m2/day D1-D4 + cisplatin 75mg/m2 D1 or D2
vs.
• Surgery alone group (S group, n=98)
• Major eligibility: Adeno- or squamous histology; T1-2N0-1 or
T3N0, PS < 1
• Primary objective: Increase overall survival from 35% to 50%
FFCD: Major Results
• ~23% had >grade 3 toxicity from pre-op therapy
• 86% went to surgery
• R0 resection rate: 88% versus 84% (S alone)
• Post-operative mortality: 7.1% v. 1.1%, p= 0.054
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FFCD: Overall Survival
Survie globale
1.0
0.8
0.6
0.4
0.2
0.0
0
12
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Patients à risque
RT/CT + chirurgie 98
Chirurgie
97
70
81
50
55
36 48 60 72 84
Temps (mois)
37 32 26 20 10
40 32 21 15
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CRT + S group
S group
P
Median survival (months)
31.8 [25.2-72.5]
44.5 [29.8-59.1]
0.68
3-year survival
48.6%
55.2%
96
4
3
FFCD Trial: Investigators’ Conclusions
• Neoadjuvant chemoRT added to surgery does not
improve survival
– …….nor any oncologic outcome
• Due to higher post-operative mortality with preoperative therapy
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Chemoradiotherapy in Esophageal
Cancer: Questions Raised
• Why were the results so different?
– ?Different chemotherapy or RT
• Was it the varying histology?
• What do we do now with early stage esophageal
cancer patients?
16
Systemic Therapy in Advanced Gastric
Cancer: Background
• >4 randomized trials show an OS advantage for
chemotherapy
• Chemotherapy improves QOL in incurable patients
• Median survival with modern drugs ~ 8-10 months
– ~10% or more of patients are long-term survivors
• Combination chemo- is better than single-agent
– ?how many
• Trastuzumab only “standard” biologic
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AVAGAST: a randomized, doubleblind placebo-controlled, phase III
study of first-line capecitabine and
cisplatin + bevacizumab or placebo
in patients with advanced gastric
cancer (AGC)
Y-K Kang, A Ohtsu, E Van Cutsem, SY Rha, A Sawaki
SR Park, H-Y Lim, J Wu, B Langer, MA Shah
on behalf of AVAGAST investigators
Courtesy Kang
Abstr LBA4007
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AVAGAST: Study Design
Cape or 5FU/Cisplatin (XP)
Locally advanced
or metastatic
gastric cancer
+ Placebo q3w
R
Cape or 5FU/Cisplatin (XP)
+ Bevacizumab q3w
Methods:
Eligibility: Adenocn stomach or GEJ;
PS < 2
Primary objective: OS (10 to 12.8 mo)
Adapted Kang
AVAGAST: Major Results
• Interim analysis skipped
• 95% PS <1; vast majority gastric origin
• Adverse events exactly as expected
• ORR with bevacizumab 46% v. 37%, p = 0.03
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AVAGAST: Overall Survival by Region
Region
Chemorx
HR
95% CI
(mo)
Chemo +
Bev (mo)
Asia
12.1
13.9
0.97
.75-1.25
Europe
8.6
11.1
0.85
.63-1.14
America
6.8
11.5
0.63
.43-.94
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AVAGAST:
Investigators’ Conclusions
• Primary endpoint (overall survival) not met
• Secondary endpoints indicate clinical activity
bev + chemo in gastric cancer
• Heterogeneous efficacy results across geographic
regions
• Biomarker analysis ongoing
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AVAGAST: Questions Raised
• Should “the world” use bev in gastric cancer now?
• Should Americans use bev now?
– Why did they do so poorly with chemotherapy alone?
• Will correlative work help us?
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Advanced Pancreatic Cancer:
Background
• Lots of positive phase II trials; ~zippo in phase III
• No new chemotherapy for last 5 years
• Total failure of bevacizumab and cetuximab
• We clearly need to understand more about the biology
of the disease
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RANDOMIZED PHASE III TRIAL COMPARING FOLFIRINOX (5FU/leucovorin,
irinotecan and oxaliplatin)
VS GEMCITABINE AS FIRST-LINE TREATMENT
FOR METASTATIC PANCREATIC ADENOCARCINOMA
Prodige 4 - ACCORD 11/0402 trial: final results
T. Conroy, F. Desseigne, M. Ychou, M. Ducreux, O. Bouché,
R. Guimbaud, Y. Bécouarn, C. Montoto-Grillot, S. Gourgou-Bourgade,
A. Adenis, FNCLCC-FFCD Prodige group
Centre Alexis Vautrin, Nancy; Centre Léon Bérard, Lyon; Centre Val d'Aurelle, Montpellier;
Institut Gustave Roussy, Villejuif; Centre Hospitalier R. Debré, Reims;
Institut Claudius Regaud, Toulouse; Institut Bergonié, Bordeaux;
Fédération Nationale des Centres de Lutte Contre le Cancer - BECT, Paris;
Centre Oscar Lambret, Lille; FRANCE
Abstr 4010
Experimental Arm: FOLFIRINOX
Oxaliplatin 85 mg/m2 over 2 hours,
Leucovorin 400 mg/m2 over 2 hours,
Irinotecan 180 mg/m2 in 90 mn infusion,
5-FU
400 mg/m2 bolus,
5-FU
2400 mg/m2 on 46-h infusion.
1 cycle = 14 days
Bolus 5-FU 400 mg/m2
2h
Oxaliplatin
85 mg/m2
2h
Leucovorin
400 mg/m2
Irinotecan
180 mg/m2
1 h 30
Courtesy Dr. Conroy
Continuous 5-FU
2.400 mg/m2
46 h
q2wks
Prodige 4 - ACCORD 11/0402:
Study Details
• Eligibility:
– Measurable disease
– < 75 years old
– PS 0 or 1
• Primary objective: Overall survival (7 10 months)
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Efficacy Results
Overall Survival
HR=0.57 : 95%CI [0.45-0.73]
1.00
0.75
Median 11.1 versus 6.8 months
Stratified Log-rank test, p<0.0001
0.50
0.25
0.00
0
3
6
9
12
15
18
21
24
27
30
33
36
2
3
2
2
2
2
Months
Number at risk
Gemcitabine 171 134 89 48
Folfirinox 171 146 116 81
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62
14
34
7
20
6
13
3
9
Gemcitabine
•PFS 6.4 versus 3.3 months
•ORR 31 versus 9.4%
3
5
Folfirinox
Adapted Conroy
Safety
Folfirinox
AE, % per patient
Gemcitabine
p
All
Grade 3/4 (2)
All
Grade 3/4 (2)
Febrile Neutropenia
7.2
5.4
2.4
0.6
0.009
Peripheral neuropathy
70.5
9
0.6
0
0.0001
Vomiting
61.4
14.5
43.2
4.7
0.002
Fatigue
87.3
23.2
78.7
14.2
0.036
Diarrhea
73.3
12.7
30.8
1.2
0.0001
Alopecia (grade 2)
32.5
(11.4)
3.0
(0.6)
0.0001
Adapted Conroy
*1 toxic death each arm
PRODIGE 4-ACCORD:
Authors’ Conclusions
• Using FOLFIRINOX requires vigilant patient
“selection, education, monitoring, and active
management”
• The regimen will be tested in the adjuvant setting
• FOLFIRINOX is the new worldwide standard of care
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Questions Raised by PRODIGE 4ACCORD
• Can the trial be methodologically criticized?
• Why have other combination trials been negative?
• Is FOLFIRINOX the new “worldwide standard”?
– How about in specific subsets of pancreatic ca pts?
• Does the trial require confirmation?
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HCC: Background
• Most patients are not candidates for cure
• Transcatheter arterial chemoembolization (TACE) is an
effective option that improves survival
– 70-80% or TACE-treated pts progress and die from HCC
• Sorafenib improves survival in advanced HCC
• The combination is attractive
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Courtesy Dr. Chung
Phase II Trial of Study in Asia of the Combination of TACE (Transcatheter
arterial chemoembolization) with Sorafenib in Patients with Hepatocellular
Carcinoma Trial (START): 2nd Interim Safety and Efficacy Analysis
Y.H. Chung, B. Kim, C.Y. Chen, T.Y. Lee, J. Wang, J. Yoon, K. Seetalarom, S.H. Bae, C.P. Li, Y. Chao
Abstr 4026
Adapted Chung
Study design
HCC patients
- BCLC B
- ECOG PS 0, 1
- Child-Pugh score < 7
- Size of largest tumor <=
10cm
- TACE naïve
Primary objective:
TACE*
Doxorubicin:
30-60mg
+
Sorafenib**
400mg bid
Safety (NCI CTCAE
version 3.0)
Secondary objective:
Efficacy
Repeated every 6 to 8 weeks
*Patients treated until “no vital tumor”
**Patients then maintained on sorafenib
START Results
• 63 (50) very healthy patients were reported on
• 62% had grade 3/4 AEs
• Efficacy: 30% CR and 60% PR/SD
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42 year old female, multiple lesions, 2 cycles of TACE and Sorafenib
After 2 cycles of TACE + Sorafenib there was complete necrosis of tumour.
START Author Conclusions
• TACE + sorafenib is safe and tolerable
– And, the regimen appears to have good response rates
• A robust trial is necessary to really evaluate efficacy
Questions Raised by START
• Did it change standard of care?
• Who can we give this regimen to?
Other Potentially Important UGI Work
• Abstr 4019: Bev can be safely added to ECX in
pre-op gastric cancer cases
• Abstr LBA4012: Post-op resected panc canc pts
given 5FU/cis/RT/INF live a long time
• Abstr 4008: FOLFOX4 does not/does improve OS
over adria alone (HCC)
ASCO 2010 UGI Highlights
• Pre-operative chemoRT works in esoph cancer
• Bevacizumab not to be given to all advanced
gastric cancer patients
– But, some may benefit a lot
• FOLFIRINOX: A new possibility in advanced
pancreatic cancer