Presentations text content in What is the Role of Chemoradiation in Locally Advanced Panc
Slide1
What is the Role of Chemoradiation in Locally Advanced Pancreatic Cancer?
Christopher H. Crane, M.D.ProfessorProgram Director and Section Chief, Gastrointestinal Section Department of Radiation Oncology
Slide2No Disclosures
Slide3Why 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
Slide4Rationale for Local treatment Pancreatic Cancer
Resected patients15-25% 5 yr OS Locally advanced patients30% Local only disease JHU Autopsy Series30-40% Local progression - MDACC phase II trialSelection based on SMAD4(DPC4)?
Iacobuzio
-Donahue et al,
JCO
, 2009
Crane et al,
JCO,
2011
Slide5Patients commonly die of
Stent complications / biliary sepsis
Gastric outlet obstruction
Acute SMV / PV occlusion
Slide6JHU Rapid Autopsy Series
Iacobuzio-Donahue et al, JCO, 2009
Local
only-30% LAPD
limited
metastatic
Slide7Time to Radiographic Local Tumor Progression n=67
Median LP–
18.41yr – 22.0%2yr – 59.0%
1st Site LF/ (mo): 32.731.2, 25.0,23.320.1 18.3,16.7, 16.5,16.1
Crane, JCO 2011
Slide8Localized Pancreatic Cancer: Role of XRT vs Arterial Involvement
T4 “borderline”
T4
Surgery helpful? Yes
Maybe No XRT helpful? Maybe HELPS the MOST Yes
T 1-3
Slide9SMV
Locally Advanced
Occluded SMV
SMA involved
Chennisi 528261
Slide10AHPBA/SSO/SSAT/NCCNResectableBorderlineLocally AdvancedSMV/PVNo contactAbut, encase or occludeNot reconstructableSMA/HepaticNo contactAbutEncaseCHANo contactAbut or short-segment encaseLong-segment encaseCeliac TrunkNo contactNo contactAny contact
Borderline Resectable PDACR1 resection likely
NCCN Pancreatic Reference
,
Abrams Ann
Surg
Oncol
2009
Slide11Chauffert, et al. Ann Oncol, 2008
Locally Advanced PCN= 119 (of 176)
5-FU + Cisplatin + Radiation (60 Gy)↓Gemcitabine
FFCD-SFRO Phase III
Gemcitabine
Eligibility ECOG PS 0 or 1; No metsStratify Prior exploratory surgeryPrimary Endpoint: Overall Survival
R
ANDOMIZE
Slide12FFCD-SFRO Phase III 5FU-Cis-RT + Gem vs Gemcitabine
Initial CMT(N= 59)Gemcitabine(N= 60)P-ValueMed Suvival8.6 mths13 mthsp= 0.031-yr survival32%53%Gd 3-4 Tox36%31%22%18%InductionMaintenance
Chauffert, et al. Ann Oncol, 2008
Slide13Loehrer, et al. ASCO, 2008 (LBA #4504)
Locally Advanced PCN= 316
Gem + Radiation↓Gemcitabine
ECOG 4201
Gemcitabine
Eligibility ECOG PS 0 or 1; No metsPrimary Endpoint: Overall Survival (88% power, 50% improvement from 8 → 12 months)
R
ANDOMIZE
Slide14ECOG 4201 (N= 71)
GemGem+RTP-valueMedian PFS6.7 mths6 mths0.5Median OS9.2 mths11 mths0.034Two-year OS4%12%G3/4 Fatigue6%32%0.006G3/4 GI14%38%0.03
Loehrer, et al.
JCO
2011
Slide15GERCOR LAP07 Phase III (NCT00634725)
Primary Endpoints: Overall Survival +/- Erlotinib +/- Capecitabine-Radiation
LAPC
N=
900
Gemcitabine + Erlotinib x 4
Gemcitabine x 4 cycles
RANDOMIZE
2
nd
Randomization+/-ChemoRT
P. Hammel (PI, GERCOR)
Slide16Overall Survival by Random 1 status
Slide17Overall survival by Random 2 status
Slide18Questions 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?
Slide19Treatment Results – LADPhase II and III data Multi-inst
Dose XRT MS
Chemotherapy alone
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
Chemoradiation
RTOG 9812, 2004
50.4
Paclitaxel
11.3
FFCD-SSRO, 2006
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
Slide20Treatment Results single institution
Single Institutional Studies - Chemoradiation
Dose XRT
Phase
Drugs
MS from DX
MS from D1 CXRT
MDACC,
Crane JCO2006
50.4/28fx
I
Cape + Bev
14.4
11.9
MSKCC,
Duffy Ann Onc2008
50.4/28fx
I
Erlotinib
+ Gem
(laparoscopy)
18.7
MDACC,
Crane JCO 2011
50.4/28fx
II
Gem/Ox/
Erb
then Cape XRT
Erb
19.2
17.0
U Michigan
Ben Josef, 2012
55/25fx
1
Gem
14.8
MDACC,
Skinner
, pGIsymp2012
50.4/28
I
Cape + Bev +
Erlotinib
23.6
21.0
Slide21Phase II trial Cetuximab based chemoradiation2004-0983
2 mo. Gemcitabine / Oxaliplatin / CetuximabXRT/ Capecitabine / Cetuximab
Doses:Gem: 1000mg/m2 over 100 min Q2wkOxaliplatin: 100mg/m2 over 2 Hrs Q2wkCetuximab (400 mg/m2, then 500mg/m2) Q2wkRadiotherapy: 50.4 Gy**3DCRT to Gross tumor only
Crane, JCO 2011
Slide22Unresected
, n=60Median - 19.2 months1yr – 67.2%2yr – 27.0% 5yr – 10.2%
Resected, n=7
Overall Survival: Resected vs Unresected Tumors
Crane, JCO 2011
Slide23SMAD4/DPC4
Tumor suppressor geneSMAD4/DPC4 Gene Status Encodes for protein in TGFβ pathwayInactivation/mutation associated with poor prognosis and higher risk of metastasesLoss of SMAD4/DPC4 expression increases with more advanced metastatic tumor burden
Iacobuzio-Donahue, C. J Clin Oncol, 2009. Blackford, A. Clin Can Res, 2009.
Slide24JHU Rapid Autopsy Series
Iacobuzio
-Donahue et al, JCO, 2009
Local only-22% SMAD4 loss p=0.032Extensive metastatic-78% SMAD4 loss
limited
metastatic
Slide25Correlative studies
IHC of available diagnostic cytology specimens(60 pts, 49 available slides, 41 enough material)Destained slides, harvested DNA for Sequenom41 samples, majority would not workPossibly due to the de-staining process
Crane, JCO 2011
Slide26Pattern of Progression, n=41Locally InvasiveDistantDominantDOD/Unknown PatternNo progress-ionDPC-4 intact11433(56, 20, 10 mo)DPC-4loss41051(17.7 mo)Chi Square, p =0.016
Crane, JCO 2011
Slide27University of Michigan: IMRT dose Escalation trial
Total doseDose perfractionBED*Dose equivalent (1.8 Gy/fraction)Level 145.01.853.145.0Level 2**50.02.060.050.4Level 352.52.163.554.0Level 455.02.267.157.0Level 557.52.370.760.0Level 660.02.474.463.0
* BED=Biological Effective Dose; a/b=10** The initial dose level was Level 3
Ben-Josef E,.
IJROBP2012
Slide28IMRT FOR PANCREAS CANCERDOSE DISTRIBUTION
BenJosef
, IJROBP 2012
Slide29Median 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
Slide30LAPC(1 Cycle Gem allowed)*
2 week
break
>2 week
break
SBRT
6.6 Gy x 5Mon-Fri
Gemcitabine Chemotherapy(3 wks on, 1 wk off)Until toxicity or progression
Trial open at Stanford, Johns Hopkins., Memorial Sloan Kettering.
Phase II Multi-Institutional Study of
Stereotactic Body Radiation
Therapy for
Unresectable
Panceatic
Cancer
Slide31Median 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
Slide32Hazard ratio for CA19-9 >= 90 U/
mL at diagnosis: 6.18 (p=0.021)
Herman, pASTR0, 2011
Slide33IGRT - Monitoring Stomach PositionHfx XRT PancCa
67.5
Gy
- 15
fx
-
45Gy
Slide34Eligibility:
Locally Advanced UnresectableNo prior Chemotherapy or RT, PS 0-1
RTOG 1201: SMAD4/DPC4 Directed Treatment Original Proposal: Integral Biomarker
Gem
x
3 mo
50.4
Gy
SMAD4/DPC4
Status
FOLFIRINOX x 3 mo
3D CRT
“INTACT”
“LOSS”
Gem
x
3 mo
IMRT
63Gy
50.4
Gy
Slide35Eligibility: Locally Advanced UnresectableNo prior Chemotherapy or RT, PS 0-1
RTOG 1201: SMAD4 Directed Treatment Locally Advanced Pancreatic Cancer
Gem
x
3 mo
50.4
Gy
FOLFIRINOX x 3 mo
3D CRT
LAPC
Stratify:
SMAD4 Status
Ca 19-9 < 90
Gem
x
3 mo
IMRT
63Gy
50.4
Gy
Slide36Eligibility: Locally Advanced UnresectableNo prior Chemotherapy or RT, PS 0-1
RTOG 1201: Proposed modification
3D CRT
LAPC
Stratify:
SMAD4 Status
Ca 19-9 < 90
Gem/Nab-paclitaxel x 3 mo
IMRT
63Gy
50.4
Gy
*
Maintanance
chemo until progression in all arms
Slide37Smad4 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
Slide38Personalization 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)
Slide39Success 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?
Slide40Conclusions, Role of XRT Locally advanced PC
Effective local therapy is necessary for long term survival in LAPC12 mo MS is not good enough!CTX and CXRT are complementary modalitiesStandard sequencing is chemo(2-4 mo) then CXRTSelect patients who may benefit from CXRT
What is the Role of Chemoradiation in Locally Advanced Panc
Download Presentation - The PPT/PDF document "What is the Role of Chemoradiation in Lo..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.