What is the Role of Chemoradiation in Locally Advanced Panc PowerPoint Presentation, PPT - DocSlides

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 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

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 SMV

SMA involved

Chennisi 528261

AHPBA/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

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 metsStratify Prior exploratory surgeryPrimary Endpoint: Overall Survival

R

ANDOMIZE

FFCD-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

Loehrer, 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

ECOG 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

GERCOR 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)

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 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

Treatment 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

Phase 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

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 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.

JHU Rapid Autopsy Series

Iacobuzio

-Donahue et al, JCO, 2009

Local only-22% SMAD4 loss p=0.032Extensive metastatic-78% SMAD4 loss

limited

metastatic

Correlative 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

Pattern 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

University 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

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

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

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 PositionHfx XRT PancCa

67.5

Gy

- 15

fx

-

45Gy

Eligibility:

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

Eligibility: 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

Eligibility: 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

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 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