what is the role of chemoradiation in locally advanced pancreatic cancer?

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