What is the Role of
Chemoradiation in Locally
Advanced Pancreatic
Cancer?
Christopher H. Crane, M.D.
Professor
Program Director and Section Chief, Gastrointestinal Section
Department of Radiation Oncology
No Disclosures
Why is pancreatic cancer a bad
disease?
• Anatomy: proximity to critical vessels
• Biology: early metastatic spread
– localized disease at dx: 30% will not metastasize
• Physiology: exocrine insufficiency,
cachexia
– Poor tolerance to treatment
• Treatment resistance
Rationale for Local treatment
Pancreatic Cancer
• Resected patients
– 15-25% 5 yr OS
• Locally advanced patients
– 30% Local only disease JHU Autopsy Series
– 30-40% Local progression - MDACC phase II trial
– Selection based on SMAD4(DPC4)?
Iacobuzio-Donahue et al, JCO, 2009
Crane et al, JCO, 2011
Patients commonly die of
• Stent complications / biliary sepsis
• Gastric outlet obstruction
• Acute SMV / PV occlusion
JHU Rapid Autopsy Series
Local only30% LAPD
limited
metastatic
Iacobuzio-Donahue et al, JCO, 2009
Time to Radiographic Local Tumor Progression
n=67
1st Site LF/
(mo):
32.7
31.2,
25.0,
23.3
Median LP– 18.4
20.1
1yr – 22.0%
18.3,
2yr – 59.0%
16.7,
16.5,
16.1
Crane, JCO 2011
Localized Pancreatic Cancer: Role of XRT
vs Arterial Involvement
T 1-3
Surgery helpful?
XRT helpful?
Yes
Maybe
T4
“borderline”
Maybe
HELPS the MOST
T4
No
Yes
SMV
Locally Advanced
Occluded SMV
SMA involved
Chennisi 528261
Borderline Resectable PDAC
R1 resection likely
AHPBA/SSO/SSAT/NCCN
Resectable
Borderline
Locally
Advanced
SMV/PV
No contact
Abut, encase or
occlude
Not
reconstructable
SMA/Hepatic
No contact
Abut
Encase
CHA
No contact
Abut or shortsegment
encase
Long-segment
encase
Celiac Trunk
No contact
No contact
Any contact
NCCN Pancreatic Reference,
Abrams Ann Surg Oncol 2009
FFCD-SFRO Phase III
Locally
Advanced PC
N= 119 (of 176)
Eligibility
R
A
N
D
O
M
I
Z
E
Gemcitabine
5-FU + Cisplatin +
Radiation (60 Gy)
↓
Gemcitabine
₋ ECOG PS 0 or 1; No mets
₋Stratify Prior exploratory surgery
Primary Endpoint: Overall Survival
Chauffert, et al. Ann Oncol, 2008
FFCD-SFRO Phase III
5FU-Cis-RT + Gem vs Gemcitabine
Initial CMT Gemcitabine
P-Value
(N= 59)
(N= 60)
Med Suvival
8.6 mths
13 mths
1-yr survival
32%
53%
Gd 3-4 Tox
36%
31%
22%
18%
Chauffert, et al. Ann Oncol, 2008
p= 0.03
Induction
Maintenance
ECOG 4201
Locally
Advanced PC
N= 316
R
A
N
D
O
M
I
Z
E
Gemcitabine
Gem + Radiation
↓
Gemcitabine
Eligibility
₋ ECOG PS 0 or 1; No mets
Primary Endpoint: Overall Survival
(88% power, 50% improvement from 8 → 12 months)
Loehrer, et al. ASCO, 2008 (LBA #4504)
ECOG 4201 (N= 71)
Gem
Gem+RT P-value
Median PFS
6.7 mths
6 mths
0.5
Median OS
9.2 mths
11 mths 0.034
Two-year OS
4%
12%
G3/4 Fatigue
6%
32%
0.006
G3/4 GI
14%
38%
0.03
Loehrer, et al. JCO 2011
GERCOR LAP07 Phase III
(NCT00634725)
LAPC
N= 900
R
A
N
D
O
M
I
Z
E
Gemcitabine
x 4 cycles
Gemcitabine
+ Erlotinib x 4
2nd
Randomization
+/ChemoRT
Primary Endpoints: Overall Survival
+/- Erlotinib
+/- Capecitabine-Radiation
P. Hammel (PI, GERCOR)
Overall Survival by Random 1 status
Overall survival by Random 2 status
Questions about LAP-07
• Quality assurance of CXRT
• # of patients treated off study with
CXRT was at least 20%
• How many were non-complaint with
CXRT?
Treatment Results – LAD
Phase II and III data Multi-inst
Dose XRT
Chemotherapy alone
MS
LAP07, 2013
-
Gem
13.6
LAP07, 2013
-
Gem / Erlotinib
11.9
FFCD-SSRO, 2006
-
Gem
13.0
CALGB 308303, 2007
-
Gem +/- Bev
9.9
ECOG 6201, 2006
-
Gem +/- Oxali
9.1
GERCOR 2005
-
Gem +/- Oxali
10.3
ECOG 4201, 2008
-
Gem
9.2
50.4
Paclitaxel
11.3
60
5-FU / CDDP
8.6
RTOG PA-0020, 2006
50.4
Paclitaxel/ Gem
11.7
ECOG 4201, 2008
50.4
Gemcitabine
11.0
RTOG PA-0411, 2008
50.4
Cape + Bev
11.9
Chemoradiation
RTOG 9812, 2004
FFCD-SSRO, 2006
Treatment Results
single institution
Single Institutional Studies - Chemoradiation
MDACC,
Dose
XRT
Phase
Drugs
MS
from
DX
MS
from
D1
CXRT
50.4/28fx
I
Cape + Bev
14.4
11.9
50.4/28fx
I
Erlotinib + Gem
(laparoscopy)
18.7
50.4/28fx
II
Gem/Ox/Erb then
Cape XRT Erb
19.2
55/25fx
1
Gem
14.8
50.4/28
I
Cape + Bev +
Erlotinib
23.6
Crane JCO2006
MSKCC,
Duffy Ann Onc2008
MDACC,
Crane JCO 2011
U Michigan
17.0
Ben Josef, 2012
MDACC,
Skinner,
pGIsymp2012
21.0
Phase II trial Cetuximab based chemoradiation
2004-0983
2 mo. Gemcitabine / Oxaliplatin / Cetuximab
XRT/ Capecitabine / Cetuximab
Doses:
Gem: 1000mg/m2 over 100 min Q2wk
Oxaliplatin: 100mg/m2 over 2 Hrs Q2wk
Cetuximab (400 mg/m2, then 500mg/m2) Q2wk
Radiotherapy: 50.4 Gy*
*3DCRT to Gross tumor only
Crane, JCO 2011
Overall Survival: Resected vs
Unresected Tumors
Resected, n=7
Unresected, n=60
Median - 19.2 months
1yr – 67.2%
2yr – 27.0%
5yr – 10.2%
Crane, JCO 2011
SMAD4/DPC4
• Tumor suppressor gene
• SMAD4/DPC4 Gene Status
– Encodes for protein in TGFβ pathway
– Inactivation/mutation associated with poor
prognosis and higher risk of metastases
• Loss of SMAD4/DPC4 expression
increases with more advanced
metastatic tumor burden
Iacobuzio-Donahue, C. J Clin Oncol, 2009. Blackford, A. Clin Can Res, 2009.
JHU Rapid Autopsy Series
Local only22% SMAD4 loss
p=0.032
Extensive
metastaticlimited
78% SMAD4 loss
metastatic
Iacobuzio-Donahue et al, JCO, 2009
Correlative studies
• IHC of available diagnostic cytology
specimens
– (60 pts, 49 available slides, 41 enough
material)
• Destained slides, harvested DNA for
Sequenom
– 41 samples, majority would not work
– Possibly due to the de-staining process
Crane, JCO 2011
Pattern of Progression, n=41
DPC-4
intact
DPC-4
loss
Locally
Distant
DOD/
No
Invasive Dominant Unknown progression
Pattern
11
4
3
3
(56, 20,
10 mo)
4
10
5
1
(17.7 mo)
Chi Square, p =0.016
Crane, JCO 2011
University of Michigan: IMRT
dose Escalation trial
Total dose
Dose per
fraction
BED*
Dose equivalent
(1.8 Gy/fraction)
Level 1
45.0
1.8
53.1
45.0
Level 2**
50.0
2.0
60.0
50.4
Level 3
52.5
2.1
63.5
54.0
Level 4
55.0
2.2
67.1
57.0
Level 5
57.5
2.3
70.7
60.0
Level 6
60.0
2.4
74.4
63.0
* BED=Biological Effective Dose; a/b=10
** The initial dose level was Level 3
Ben-Josef E,. IJROBP2012
IMRT FOR PANCREAS CANCER
DOSE DISTRIBUTION
BenJosef, IJROBP 2012
Median OS 14.8 months; 2-year OS 30%
2-year freedom from local progression is 59%
12 patients underwent resection (10 R0, 2 R1)
2- pCR
BenJosef, IJROBP 2012
Phase II Multi-Institutional Study of
Stereotactic Body Radiation
Therapy for Unresectable Panceatic Cancer
LAPC
Gemcitabine Chemotherapy
SBRT
(1 Cycle Gem
allowed)*
>2 week
2 week
6.6 Gy x 5
break
Mon-Fri break
(3 wks on, 1 wk off)
Until toxicity or progression
Trial open at Stanford, Johns Hopkins., Memorial Sloan Kettering.
Median survival: 15.9 months (95% CI, 9.14 – upper limit not yet reached)
Median follow-up: 12.0 months (range, 2.1-22.6)
Herman, pASTR0, 2011
Hazard ratio for CA19-9 >= 90 U/mL at diagnosis: 6.18 (p=0.021)
Herman, pASTR0, 2011
IGRT - Monitoring Stomach
Position
Hfx XRT PancCa
67.5 Gy
- 15 fx -
45Gy
RTOG 1201: SMAD4/DPC4 Directed Treatment
Original Proposal: Integral Biomarker
SMAD4/DPC4 Status
“INTACT”
IMRT 63Gy
Gem x 3 mo
50.4 Gy
Gem x 3 mo
“LOSS”
3D CRT
50.4 Gy
FOLFIRINOX x 3 mo
Eligibility: Locally Advanced Unresectable
No prior Chemotherapy or RT, PS 0-1
RTOG 1201: SMAD4 Directed Treatment
Locally Advanced Pancreatic Cancer
IMRT 63Gy
LAPC
Gem x 3 mo
50.4 Gy
Stratify:
Gem x 3 mo
SMAD4 Status
Ca 19-9 < 90
3D CRT
50.4 Gy
FOLFIRINOX x 3 mo
Eligibility: Locally Advanced Unresectable
No prior Chemotherapy or RT, PS 0-1
RTOG 1201: Proposed modification
LAPC
Gem/Nabpaclitaxel
IMRT 63Gy
x 3 mo
Stratify:
SMAD4 Status
50.4 Gy
Ca 19-9 < 90
3D CRT
*Maintanance chemo until progression in all arms
Eligibility: Locally Advanced Unresectable
No prior Chemotherapy or RT, PS 0-1
Smad4 identification: RTOG 1201
• IHC of cytology/core bx specimens
– Cell blocks or Endoscopic core biopsies req’d
– ETOH fixed Smears requested
• Correlative study on smears
– Next generation sequencing
Personalization of Care in PC
• hENT1 identified from RTOG 9704
– CO101 designed for hENT1 low to overcome the
transport limitation
– Phase III trial announced as negative
• Stromal SPARK correlated with responses to
GEM/Nab-paclitaxel
– Phase III trial announced as positive
– No details of plans to evaluate SPARK
• Smad4 (DPC4)
Success of local treatment
intensification hinges on selection
• 2000-2010 - Clinical selection (CTX first)
– Select out early DM phenotype
– Location (away from duodenum), tumor size,
low Ca 19-9, response to CTX
• 2010 and beyond - genotypic selection
– Identify ‘locally destructive’ phenotype
– SMAD4 intact?
Conclusions, Role of XRT
Locally advanced PC
• Effective local therapy is necessary for long
term survival in LAPC
– 12 mo MS is not good enough!
• CTX and CXRT are complementary
modalities
• Standard sequencing is chemo
(2-4 mo) then CXRT
• Select patients who may benefit from CXRT