Transcript Cancer of the colorectum

Should we use chemotherapy
or chemoradiation for
borderline resectable
pancreatic cancer?
Jordan D. Berlin, M.D.
Ingram Professor of Medicine/ Clinical Research
Co-director, GI Oncology
Director, Phase I Research
Vanderbilt-Ingram Cancer Center
Disclosures
• Advisory Boards here and
there in last year
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Genentech/Roche
Sanofi-Aventis
Abbott
Amgen
Astra Zeneca
Clavis/Clovis
Infiinity
Otsuka
Arno
BMS
Synta
• Research Support
– Amgen,
Genentech/Roche,
Lilly/Imclone,
OSI/Astellas, Bayer,
Pfizer, Novartis
• Honorarium
– Lilly
• Added this week
– Symphogen
– Lilly
Stage at Diagnosis:
We catch disease late
Unstaged
Localized
disease
15%
8%
Locally
advanced
disease
26%
Ries et al (eds). SEER Cancer Statistics Review, 1975-2001.
52%
Metastatic
disease
5-Year Survival by Stage
Still Poor at All Stages
We have not really gone far since
this data so there is room for
improvement
Ries et al (eds). SEER Cancer Statistics Review, 1975-2001.
TNM staging vs Practical Staging
• In pancreatic cancer, we have not traditionally
made our decisions based purely on TNM staging
• Instead, we had 3 stages:
– Localized, resectable
– Localized, unresectable
– Metastatic
• Now. We have a new group in town:
– Borderline resectable
• These are patients whose disease appears able to be removed
surgically
• However, there is a high probability of margin positivity
Defining Borderline Resectable Pancreas
Cancer is Complex
• Surgically resectable is in the eye of the beholder
– The lines of what can be removed have become
increasingly blurred with
• New techniques for vascular reconstruction
• Varying surgical skills
• Variable radiologic studies/techniques
• Pathologic margins are not always
reported/identified in the same way
– Retroperitoneal margin/SMA margin
MD Anderson Definition of Borderline
Resectable
• Includes (not all at once)
– Abutment of the SMA involving < 180° of the
circumference of the artery
– Encasement of a short segment of the hepatic artery,
without evidence of tumor extension to the celiac axis,
that is amenable to resection and reconstruction
– Short-segment occlusion of the SMV, PV, or SMPV
confluence with a suitable option for vascular
reconstruction
• Does not address colon and/or mesocolon
invasion
Varadhachary, et al Annals of Surgical Oncology 13: 1035-1046
AHPBA Consensus Conference Refined
the MDACC Criteria
• Includes:
– No distant metastases.
– Venous involvement of the SMV/portal vein
demonstrating tumor abutment with or without
impingement and narrowing of the lumen, encasement
of the SMV/portal vein but without encasement of the
nearby arteries,
• or short segment venous occlusion resulting from either tumor
thrombus or encasement but with suitable vessel proximal and
distal to the area of vessel involvement, allowing for safe
resection and reconstruction
Callery, et al Ann Surg Oncol (2009) 16:1727–1733
AHPBA Consensus Statement II
• Continued
– Gastroduodenal artery encasement up to the hepatic
artery with either short segment encasement or direct
abutment of the hepatic artery, without extension to the
celiac axis
– Tumor abutment of the SMA not to exceed 180° of the
circumference of the vessel wall.
• Note: Method of assessment: Multidetector CT
scan, 2 phases, with 3-dimensional reconstruction
• NCCN guidelines use this definition
Callery, et al Ann Surg Oncol (2009) 16:1727–1733
Separate European Guidelines Don’t Exist
• No definition of borderline resectable in ESMO
guidelines, but treatment consideration is as
follows:
– “Patients who present borderline resectable disease
may benefit from preoperative therapy (chemoradiation
or induction chemotherapy followed by chemoradiation)
in order to increase the rate of R0 resections.”
• ESDO met this AM to develop expert opinion
– Next slide
Cascinu, et al Ann Oncol (2010) 21 (suppl 5): v55-v58
ESDO Expert Opinion meeting Identified
Key Weaknesses in the Guidelines
• AHPBA, NCCN and MD Anderson all use very
similar definitions of borderline resectable, but
– We are unclear if we have truly separated unresectable
from borderline resectable
– Terms about the radiographic findings including
impingement, abutment, involvement and encasement
while used commonly may not be as clearly defined as
they could be
• I will add that we have not tested to see if there is
consistency between radiologists in defining these
findings
Differing Criteria for Borderline Resectable
may Produce Different Results
• Recent study of FDR gemcitabine + capecitabine
as neoadjuvant therapy (no XRT)
– Local criteria used: 33 borderline resectable patients
and 10 unresectable patients
– NCCN criteria used: 18 borderline resectable, 25
unresectable
– By local criteria, 15 BR went to surgery, 13 R0
resections and 1 of 2 UR who went to surgery had R0
resection
– By NCCN criteria, 11 BR went to surgery, 9 R0
resections and 5 of 6 UR who went to surgery had R0
resection
Lee J-L, et al Surgery 2012, epub ahead of print, June 6
3 Principle Goals of Neoadjuvant Therapy
• Response
– This may not be RECIST response
– Needs to “sterilize” the margins
– Needs to shrink away from the vessels if possible
• Margin free resection
– All data suggests that margin + resections result in
poorer survival outcomes
• Not interfering with surgical outcome
– Treatment should not cause increased
morbidity/increased post-operative complications
– Treatment should not cause fibrosis/scarring that make
the operation more difficult
Combined Analysis of Published Data
Shows Low Response Rates
CR
PR
SD
PD
All patients (n = 330)
1.8%
18.8%
59.2%
18.9%
Resectable (n = 196)
0.8%
9.5%
73.9%
17%
4%
31.8%
40.9%
21.8%
Borderline/unresectable
(n =134)
54.2% of all patients underwent resection
65.8% of resectable patients unwderwent resection
80.6% of these were R0
31.6% of borderline/unesectable patients underwent resection
62.2% of these were R0
All patients received chemo, 85% had chemoxrt
Mura Assifi, et al Surgery 150:466-73, 2011
Combined Analysis Shows We Can
Achieve RO Resection
• Suggests that neoadjuvant therapy leads to high
R0 resection rate
– These studies had differing definitions of resectable,
borderline and unresectable
– Intriguingly, borderline and unresectable patients who
had resection had the same survival (22.3months) as
resectable patients (23 months)
• Does this suggest our definitions of borderline resectable are
just bad on these studies?
– Did not differentiate chemo from chemoradiation
Does chemoradiation have a higher
response rate than chemo alone?
• Very little evidence of this
• Even in the combined analysis, the definitions of
response varied over the years
• Primary pancreatic cancers
– Appear less responsive than metastases (this is
different from most other tumor types)
– Are difficult to measure even with high quality scans
E4201: Locally Advanced pancreatic
Cancer Trial Schema
Stratify:
• PS (0 vs 1)
• Weight loss
( >10% vs <10%)
R
A
N
D
O
M
I
Z
E
ARM A: INDUCTION
GEMCITABINE 1000mg/M2
Once weekly x 6 weeks
ARM B: INDUCTION
GEMCITABINE 600 mg/M2
Once weekly x 6 weeks
CONCURRENT RT 180 cGy/day
5 days week x 6 weeks
Total dose 50.40 Gy
1 week rest
ARM A: CONSOLIDATION
GEMCITABINE 1000mg/M2
Once weekly x 3
weeks
Followed by 1 week
rest x 5 cycles
1 cycle = 4 weeks
4 weeks rest
ARM B: CONSOLIDATION
GEMCITABINE 1000mg/M2
Once weekly x 3
weeks
Followed by 1 week
rest x 5 cycles
1 cycle = 4 weeks
E4201: Response is the Same for
Chemo and ChemoXRT
GEM alone
N = 35
5%
GEM plus XRT
N = 34
6%
Stable Disease
35%
68%
Progression
Inevaluable*
16%
46%
6%
21%
Partial Resp.
* Clinical “progression’ without confirmation scans
or scans performed outside of scheduled times
E4201: But ChemoXRT has More
Stable Disease
GEM alone
N = 35
5%
GEM plus XRT
N = 34
6%
Stable Disease
35%
68%
Progression
Inevaluable*
16%
46%
6%
21%
Partial Resp.
* Clinical “progression’ without confirmation scans
or scans performed outside of scheduled times
E4201: ChemoXRT May Decrease
Incidence of Local Relapse
Local
GEM alone
41%
GEM plus XRT
23%
Distant
14%
23%
Local and Distant
Not documented*
5%
41%
9%
44%
* Clinical “progression’ without confirmation scans
or scans performed outside of scheduled times
E4201: Conclusions
• Despite no improvement in response or PFS
– This study appeared to show a modest survival benefit
(time was equal to the time patients spent getting
radiated)
– While response was not higher for XRT, local relapse
appeared modestly less likely when XRT was used
– Does not give conclusive evidence of anything as it was
underpowered due to poor accrual
Can Chemotherapy Before ChemoXRT
Provide Better Outcomes
• 70 patients with borderline (n = 24), or
unresectable (n = 46) disease treated with
chemoXRT
– Two strategies
• ChemoXRT with 50.4Gy (53% unresectable pre-treatment)
• Chemo (gem based) followed by ChemoXRT if no PD after
chemo (83% unresectable pre-treatment)
• 20% in both strategies had resection
– The patients who underwent chemo followed by
chemoradiation had an improved OS (18.7 vs 12.4
months, p =0.02) compared to chemoXRT alone
Arvold ND, et al Cancer 2012;118:3026-35
Is FOLFIRINOX the neoadjuvant regimen
of choice?
Metastatic
pancreatic
cancer
R
A
N
D
O
M
I
Z
E
Folfirinox
for both
arms:
CT scans:
obtained
every 2 months
Gemcitabine
6 months of
chemotherapy
recommended
Stratification :
•
•
•
center
performance status: 0 versus 1
location of the tumor: head versus other location of the primary
FOLFIRINOX Response Rate is High
Folfirinox
Gemcitabine
N=171
N=171
Complete response
0.6%
0%
Partial response
31%
9.4%
CR/PR 95% CI
[24.7-39.1]
[5.9-15.4]
Stable disease
38.6%
41.5%
Disease control
CR+PR+SD
70.2%
50.9%
Progression
15.2%
34.5%
Not assessed
14.6%
14.6%
Median duration
of response
5.9 mo.
4 mo.
p
0.0001
0.0003
ns
Overall Survival
Median follow up: 26.6 months [95% CI: 20.5 – 44.9]
Folfirinox
N=171
Gemcitabine
N=171
p
HR
11.1 mo.
6.8 mo.
<0.0001
0.57
[ 9 - 13.1]
[ 5.5 - 7.6]
1-yr. survival
48.4%
20.6%
18-mo. survival
18.6%
6%
Median survival
[CI 95%]
FOFLIRINOX Conclusions
• It is a more effective regimen in every parameter
(RR, PFS, OS) and significantly so
• It is logical (synergy between oxali and each of
the other two drugs)
• It is more toxic than gemcitabine
• Key point: all patients were metastatic and it
is not clear the response rate would be as
high with local disease only
FOLFIRINOX Neoadjuvant Analysis: There
is Concern it is not Enough
• Retrospective analysis of 18 patients
treated with neoadjuvant FOLFIRINOX
– Borderline and unresectable patients
• 14 borderline resectable by AHPBA guidelines
• 4 resectable after treatment by imaging, 2 of whom
had R0, 1 had R1 and 1 was unresectable
• 3 of 3 unresectable patients deemed resectable after
treatment had R0 resection
It is Not Clear RECIST is the Parameter we
Should Use to Say a Regimen Helps
• MDACC Retrospective Analysis
– 122 of 129 patients with borderline resectable disease
– RECIST 1.1 was used:
•
•
•
•
PR: 15 patients (12%): All resected
SD 84 patients (69%): 70 (84%) resected
PD: 23 patients (19%): 0 resected
Changed to resectable: 1 (0.8%) resected
– 85 patients underwent resection
• 95% had R0 resection
• Median OS was 33 months (12 months for unresected)
• RECIST response did not predict survival
Katz MHG, et al Cancer, epub 2012
“Pathologic Response” is a Criteria?
• Retrospective review was designed to compare 32
patients with borderline resectable disease treated with
chemoXRT then surgery to 104 patients with resectable
disease taken to surgery
– 18/32 patients had “pathologic response”
• Degree of pathological responses was graded based on the proportion
of fibrosis and necrosis replacing primary tumor involvement and was
estimated as percentages of the total tumor volume.
– Pathologic Response correlated with T stage
– Not sure if this is a legitimate criteria as it is subjective and the
disease has fibrosis and necrosis without treatment
Kang CM, et al J Gastrointest Surg (2012) 16:509–517
Alliance A021101 Protocol
Pre-Registration allows for
•
Biliary decompression
•
Central review of staging scans (restaging also
reviewed centrally)
Alliance A021101 Protocol
• Endpoints
– Primary:
• Estimate the 1-year overall survival (OS) rate
– Secondary:
• To estimate the rate of treatment-related toxicity during
preoperative therapy.
• To estimate the R0 resection rate following preoperative
therapy.
• To estimate the rate of radiographic and histopathologic
response to preoperative therapy.
• To estimate the time to locoregional and distant recurrence
following completion of treatment.
Other benefits of Alliance A021101
Protocol
• There is currently no reported, completed
multicenter clinical trial focusing on borderline
resectable disease, so this may:
– Establish a baseline for future study
– Establish parameters for assessing margins
– Establish standards for borderline resectable disease
• By radiographic criteria
– Establish surgical standardization
Borderline Resectable Conclusions
• We need to establish more standards for this
category
–
–
–
–
Pathology
Surgery
Radiology
Treatment choice
• These definitions need to truly separate borderline
unresectable from truly unresectable patients
• Standard of care is not clearly defined
• It is clear we need more and better studies.