What is the Role of Chemoradiation in Locally Advanced Pancreatic Cancer?
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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
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
Iacobuzio-Donahue et al, JCO, 2009
Local only-30% LAPD
limited metastatic
Time 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
Localized 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
SMV Locally Advanced Occluded SMVSMA involved
Chennisi 528261
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 contactAbut or short-
segment encase
Long-segment encase
Celiac Trunk No contact No contact Any contact
Borderline Resectable PDACR1 resection likely
NCCN Pancreatic Reference, Abrams Ann Surg Oncol 2009
Chauffert, 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 mets₋ Stratify Prior exploratory surgery
Primary Endpoint: Overall Survival
RANDOMIZE
Chauffert, et al. Ann Oncol, 2008
FFCD-SFRO Phase III 5FU-Cis-RT + Gem vs Gemcitabine
Initial CMT(N= 59)
Gemcitabine(N= 60) P-Value
Med Suvival 8.6 mths 13 mths p= 0.03
1-yr survival 32% 53%
Gd 3-4 Tox36%31%
22%18%
InductionMaintenance
Loehrer, et al. ASCO, 2008 (LBA #4504)
Locally Advanced PC
N= 316 Gem + Radiation↓
Gemcitabine
ECOG 4201
Gemcitabine
Eligibility₋ ECOG PS 0 or 1; No mets
Primary Endpoint: Overall Survival (88% power, 50% improvement from 8 → 12 months)
RANDOMIZE
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
P. Hammel (PI, GERCOR)
GERCOR LAP07 Phase III (NCT00634725)
Primary Endpoints: Overall Survival+/- Erlotinib+/- Capecitabine-Radiation
LAPCN= 900
Gemcitabine + Erlotinib x 4
Gemcitabine x 4 cycles
RANDOMIZE
2nd Randomization
+/-ChemoRT
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 – LADPhase II and III data Multi-inst
Dose XRT MSChemotherapy alone
LAP07, 2013 - Gem 13.6LAP07, 2013 - Gem / Erlotinib 11.9FFCD-SSRO, 2006 - Gem 13.0CALGB 308303, 2007 - Gem +/- Bev 9.9ECOG 6201, 2006 - Gem +/- Oxali 9.1GERCOR 2005 - Gem +/- Oxali 10.3ECOG 4201, 2008 - Gem 9.2
ChemoradiationRTOG 9812, 2004 50.4 Paclitaxel 11.3FFCD-SSRO, 2006 60 5-FU / CDDP 8.6RTOG PA-0020, 2006 50.4 Paclitaxel/ Gem 11.7ECOG 4201, 2008 50.4 Gemcitabine 11.0RTOG PA-0411, 2008 50.4 Cape + Bev 11.9
Treatment Results single institution
Single Institutional Studies - ChemoradiationDose 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 MichiganBen Josef, 2012
55/25fx 1 Gem 14.8
MDACC, Skinner, pGIsymp2012
50.4/28 I Cape + Bev + Erlotinib
23.6 21.0
Phase II trial Cetuximab based chemoradiation2004-0983
2 mo. Gemcitabine / Oxaliplatin / Cetuximab
XRT/ Capecitabine / CetuximabDoses:
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 onlyCrane, JCO 2011
Unresected, 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
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
Iacobuzio-Donahue et al, JCO, 2009
Local only-22% SMAD4 loss
p=0.032Extensive metastatic-78% SMAD4 losslimited
metastatic
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
Locally Invasive
DistantDominant
DOD/Unknown
Pattern
No progress-
ionDPC-4 intact
11 4 3 3(56, 20, 10 mo)
DPC-4loss
4 10 5 1(17.7 mo)
Chi Square, p =0.016
Crane, JCO 2011
University of Michigan: IMRT dose Escalation trialTotal dose Dose per
fractionBED* Dose equivalent
(1.8 Gy/fraction)
Level 1 45.0 1.8 53.1 45.0Level 2** 50.0 2.0 60.0 50.4Level 3 52.5 2.1 63.5 54.0Level 4 55.0 2.2 67.1 57.0Level 5 57.5 2.3 70.7 60.0Level 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 CANCERDOSE 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
LAPC(1 Cycle Gem allowed)* 2 week
break
>2 week break
SBRT6.6 Gy x 5
Mon-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
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
Eligibility: Locally Advanced Unresectable
No prior Chemotherapy or RT, PS 0-1
RTOG 1201: SMAD4/DPC4 Directed Treatment Original Proposal: Integral Biomarker
Gem x 3 mo50.4 Gy
SMAD4/DPC4 Status
FOLFIRINOX x 3 mo
3D CRT
“INTACT”
“LOSS”
Gem x 3 moIMRT 63Gy
50.4 Gy
Eligibility: Locally Advanced Unresectable
No prior Chemotherapy or RT, PS 0-1
RTOG 1201: SMAD4 Directed Treatment Locally Advanced Pancreatic Cancer
Gem x 3 mo50.4 Gy
FOLFIRINOX x 3 mo
3D CRT
LAPC
Stratify:SMAD4 StatusCa 19-9 < 90
Gem x 3 moIMRT 63Gy
50.4 Gy
Eligibility: Locally Advanced Unresectable
No prior Chemotherapy or RT, PS 0-1
RTOG 1201: Proposed modification
3D CRT
LAPC
Stratify:SMAD4 StatusCa 19-9 < 90
Gem/Nab-paclitaxel
x 3 mo
IMRT 63Gy
50.4 Gy
*Maintanance chemo until progression in all arms
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
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