Transcript Post ASCO GI Non-Colorectal Cancer

Pre-Operative Therapy for Borderline
Resectable Pancreatic Cancer:
The Potential Role of Chemotherapy
Robert A. Wolff, M.D.
Associate Professor of Medicine
Department of GI Medical Oncology
U.T.M.D. Anderson Cancer Center
Meet The Professor Session
2009 Gastrointestinal Cancers Symposium
San Francisco
January 16th, 2009
[email protected]
Pre-Operative Therapy for Borderline
Resectable Pancreatic Cancer
Lessons from Resectable Pancreatic Cancer
Point #1. Pre-Operative Chemoradiation
decreases local failure.
Study
N %R1 %T3 %N1 %LF
ESPAC-1
289 18
NS
54
63
CONKO-001 194 16
82
70
38
ID98-020
64
6
67
38
11
ID01-341
52
4
83
60
25
Neoptolemos JP et al. NEJM, 2004
Oettle H, et al. JAMA, 2007
Evans DB, et al. JCO, 2008
Varadhachary GR, et al. JCO, 2008
Pre-Operative Therapy for Borderline
Resectable Pancreatic Cancer
Lessons from Resectable Pancreatic Cancer
Point #2. Pre-Operative Chemotherapy
Data is more limited.
Author
Heinrich
# Pts Treatment Resection
Rate
%R1
Median
%LF
Overall
Survival
26.5 M
28
Gem/Cis
86%
NS
26
Gem/Cis
70%
25%
?
?M
28.4
Palmer
24
Gem
38%
25%
Heinrich S, et al. Ann Surg Onc, 2008. Palmer DH, et al. Ann Surg Onc, 2007.
Pre-Operative Therapy for Borderline
Resectable Pancreatic Cancer
Lessons from Resectable Pancreatic Cancer
Point #3. Chemotherapy does not add
benefit over Pre-Operative ChemoXRT
Pre-Operative
Regimen
Elapsed
Time to
Restaging
Resection
Rate
%R1
Median
Survival
(Resected
Patients)
Gem + XRT
12 Weeks
74%
11%
34 months
Gem/Cis
Gem + XRT
17 weeks
66%
4%
31 months
Evans DB, et al. JCO, 2008.
Varadhachary GR, et al. JCO, 2008.
Pre-Operative Therapy for Borderline
Resectable Pancreatic Cancer
Lessons Learned in Resectable Pancreatic Cancer
Point #3. Well, maybe more
chemotherapy does help.
PreOperative
Regimen
Number of
Resected
Patients
pT3
pN1
Median
Survival
Gem + XRT
64
67%
38%
34 months
Gem/Cis
Gem + XRT
52
83%
60%
31 months
Pre-Operative Therapy for Borderline
Resectable Pancreatic Cancer
Lessons from Resectable Pancreatic Cancer
Point #4. Full Dose Chemotherapy is NOT a factor.
Study
Gemcitabine Dose
(mg/m2)
Total Intended
Gemcitabine
Dose (mg/m2)
Median
Survival
CONKO 001
1,000 mg/m2
3 wk on,1 off
X 6 cycles
18,000 mg/m2
23 months
Gem/XRT
400 mg/m2
Weekly X 7
2,800 mg/m2
34 months
Gem/Cis
Gem/XRT
750 mg/m2
q 2 wks X 4 doses
400 mg/m2 X 4
4,600 mg/m2
31 months
Pre-Operative Therapy for Borderline
Resectable Pancreatic Cancer
Lessons from Resectable Pancreatic Cancer
Point #5. The criteria used to decide on surgery
MATTERS!
Author
Year
Regimen
#
Patients
Resection
Rate
Median
Survival
Resected
Evans
2008
Gem/XRT
84
74%
34 M
Varadhachary Gem/Cis
2008
Gem/XRT
Katz
2008
Variable
96
66%
31 M
84
(Type A)
38%
40 M
Can’t
Progress!
Must
Respond!
Evans DB, et al. JCO, 2008.
Katz MH, et al. J Am Coll Surg, 2008.
Varadhachary GR, et al. JCO, 2008.
Borderline Resectable Pancreatic Cancer
Current Challenges
●
It remains unclear if borderline resectable
pancreatic cancer is biologically distinct from
resectable pancreatic cancer, or if the role of
neoadjuvant therapy is simply to help achieve a
negative margin.
● What is best approach?
Chemoradiation?
● Systemic chemotherapy and chemoradiation?
●
●
How long to treat to determine favorable biology?
Investigational Strategies for
Locally advanced pancreatic cancer
ChemoXRT +
Molecular
Agent
Localized
Induction
Chemotherapy
with molecular
agent
Targeted Rx as
Maintenance
Restage
Metastatic
2nd Line Rx or
Best
Supportive
Care
Current MDACC Strategy for
Borderline Resectable Pancreatic cancer
ChemoXRT +
Molecular
Agent
Localized
Induction
Chemotherapy
with molecular
agent
Restage
Restage
Vote surgery
up or down!
Metastatic
2nd Line Rx or
Best
Supportive
Care
Current MDACC Protocol:
Gemcitabine-Oxaliplatin-Cetuximab followed by
Chemoradiation
for Locally Advanced Pancreatic Cancer
Induction chemotherapy gemcitabine 1000 mg/m2 with
oxaliplatin 100 mg/m2 day 1, 15, 29, 43. Cetuximab 400
mg/m2 load day 1, with 250 mg/m2 weekly thereafter.
Gem/Ox
C
C
Gem/Ox
C
C
Gem/Ox
C
C
Gem/Ox
C
C
Week 1
2
3
4
5
6
7
8
Capecitabine + Cetuximab +Radiation Therapy
Week 10
11
12
13
14
Upfront
Surgery
Gem-based
Restage
adjuvant
chemotherapy
Restage
?XRT
Truly
Resectable
Protocol-based
PreOperative
Rx
Borderline
Resectable
ALL Patients
SHOULD
UNDERGO
Neoadjuvant
Therapy: On or
Off Protocol
Restage
Restage
Surgery
Borderline Resectable Pancreatic Cancer
Current Clinical Research Challenges
●
No broad consensus as to what constitutes borderline
resectable disease.
● Primary tumor anatomy?
● Elevated CA19-9?
● Equivocal evidence for metastatic disease?
●
No consensus about response criteria to proceed with surgery.
●
All Therapies are Empiric!!!!!!!!
● Cytotoxic chemotherapy
● Molecular therapy
● Radiation therapy
WANTED:
Personalized
cancer therapy!
Borderline Resectable Pancreatic Cancer
Personalized Cancer Therapies
Borderline
Resectable
Pre-Rx
Biopsy
Treatment A
Treatment B
Treatment C
Summary
● Borderline resectable pancreatic cancer is a distinct
clinical entity that must be recognized as putting the
patient at risk for a positive surgical margin with upfront
surgery.
● Preoperative therapy for resectable pancreatic cancer
that includes radiation appears to lower rates of positive
surgical margins and decrease the risk of local failure.
● This approach is particularly relevant for patients with
borderline resectable disease.
● Limited single-institutional experience is encouraging.
● Definitions for borderline resectable disease and
response criteria require further refinement if clinical
research is to be fruitful.
● Therapies that are personalized will likely lead to more
success for patients with all stages of pancreatic cancer.