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Pancreatic Cancer: Contemporary Radiation Therapy and Translational Paradigms. Joseph Herman, MD, MSc Director Pancreatic Multi-disciplinary Clinic Johns Hopkins Department of Radiation Oncology and Molecular Radiation Sciences. Proximity of Pancreas to small bowel:

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Pancreatic cancer contemporary radiation therapy and translational paradigms l.jpg

Pancreatic Cancer: Contemporary Radiation Therapy and Translational Paradigms

Joseph Herman, MD, MSc

Director Pancreatic Multi-disciplinary Clinic

Johns Hopkins Department of Radiation Oncology and Molecular Radiation Sciences


Unique challenges of radiation to pancreatic cancer l.jpg

Proximity of Pancreas to small bowel:

Even moderate doses of RT to small bowel is associated with a high risk of late stenosis, ulceration, bleeding, and perforation

Risk of late bowel complications heightened with higher doses of RT

Retroperitoneal Margin

Unique Challenges of Radiation to Pancreatic Cancer

Compliments N. Merchant


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Pancreatic Cancer: Treatment

Biopsy Proven or Suspected Pancreatic Cancer

Staging Work-up: Genetics, Family Hx, Functional Status

Imaging: 3-D CT scan, MRI, Functional Imaging

Labs: CBC, Liver function, Ca 19-9

Borderline Resectable

Unresectable

Resectable

Neoadj CRT

Surgery

Chemotherapy

CRT

Chemo

SRT

or

3X10

ADJ Tx

Surgery

(IORT?)

Metastatic or Unresectable


Summary treatment options l.jpg
Summary Treatment Options

  • Unresectable (locally advanced)

    • Chemotherapy alone

    • Chemotherapy and Radiation Therapy

    • Stereotactic Body Radiation Therapy (SBRT)

  • Resectable/borderline (neaodj/preoperative):

    • Chemotherapy

    • Chemotherapy and Radiation

  • Adjuvant (Resected):

    • Chemotherapy alone for 6 months

    • Chemotherapy plus Radiation (before or after Chemotherapy)

    • IORT followed by chemotherapy

    • Observation (favorable pathology))

Encourage clinical trial enrollment

Decision based on imaging, performance status, patient preference


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Radiation Therapy

  • External Beam Radiation Therapy (EBRT) is currently used.

    • Neoadjuvant, Adjuvant, Borderline, LAPC

    • Delivered over 5-6 weeks with chemotherapy

  • Palliative (2 fields)

  • Conformal Radiation (3-4 Fields)

  • Intensity Modulated Radiation Therapy (IMRT) (3-10 fields)

    • Volumetric modulated arc therapy (VMAT)

    • Tomotherapy

  • Stereotactic Body Radiation Therapy (SBRT) (multiple fields)

  • Intraoperative radiation therapy (IORT)


Pancreas standard adjuvant rt field vs preoperative neoadjuvant radiation field l.jpg

T10-T11

L3

Pancreas: Standard Adjuvant RT Field vs. Preoperative/Neoadjuvant Radiation Field

Koong et al. Stanford; IJROBP 2004


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Adjuvant PTV=1,413 cm3

NeoadjuvantPTV=174 cm3


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Potential Benefits of Neoadjuvant Therapy

  • Resectable and borderline patients

  • Decreased toxicity

  • Enhanced efficacy

  • Improved compliance of therapy (20-30 % don’t receive adjuvant therapy)

  • Increased likelihood of an R0 resection

  • May prevent micrometastases

  • Drawbacks

    • reluctance to postpone resection

    • Patient may become unresectable or develop mets

    • no phase III trials to support its use


Evidence for neoadjuvant crt l.jpg
Evidence for Neoadjuvant CRT

  • Studies demonstrate potential benefit for neoadjuvant therapy with median OS comparable to adjuvant CRT

    • Mt. Sinai (Snady et al. 2000)

      • N=15 9 23. 6 mo.(neo) vs. 14.0mo(surg+/-adj) mOS, p=0.006

    • MDACC (Breslin et al. 2001)

      • N=132; 21mo.(neo) mOS

    • Fox Chase (Sasson et al. 2003)

      • N=116; 23mo(neo) vs. 16mo(adj) mOS, p=0.03

    • Duke (White et al. 2005)

      • N=193; 23 mo.(neo+/-surg) mOS

  • Method for ideal patient selection for neoadjuvant therapy has not been determined


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Locally Advanced Pancreatic Cancer

  • Persistent Problems with CRT:

    • High local failure rate

    • Marginal improvements in OS

  • Treatment advances for LAPC

    • Adding full dose Gemcitabine with RT (Michigan)

    • Incorporating hypofractionated radiation regimens (SBRT)

    • Employing IOERT for dose escalation

    • Increased conformality of IMRT to help with dose escalation to the gross tumor and minimize dose to bowel

    • Combining RT with sensitizers (targeted agents/chemo)

    • Selecting patients for CRT with upfront chemotherapy for 2-4 cycles


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Modern Treatment Devices

TRILOGY

SYNERGY

CYBER-KNIFE


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Standard Radiation Therapy

Delivered over 5-6 weeks, Mon-Friday

Low doses of RT/day (1.8 – 2 Gy)

Large margins

Less beams of radiation

Usually combined with chemotherapy

Normal tissue can repair

Shorter treatment times per day (10-15 minutes)

Acute > Chronic toxicity

Less Convenient (worse quality of life)

Good long term data

Stereotactic Radiation Therapy

Delivered over one week

High doses of RT/day (5-30 Gy)

Small margins

More difficult for normal tissues to repair the damage

Treatment times sometimes >1 hour

Chronic > Acute Toxicity

Better quality of life

Less data

No concurrent therapy?

Standard RT vs. Stereotactic RT


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IMRT: Duodenal Sparing

SBRT: Duodenal Sparing


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Technical Advances in SBRT

  • Advances in Immobilization/Set-Up Error

    • Custom body frames with CT/MRI compatible radio-opaque markers (Lax et al 1994)

    • Treatment planning with PET/CT fusion

    • Cone beam CT (Letourneau et al 2005)

  • Advances in Tumor Motion Compensation (Lax et al 1994, Onimaru et al 2003, Underberg et al 2005, Wilson et al 2005)

    • 4-D CT scans (simulation)

    • Airway-Breathing-Control (ABC)

    • Respiratory gating (skin or tissue fiducials)

    • Abdominal compression devices



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SBRT: Fiducial Guided Fluoroscopy

Simulation DRR

Fluoroscopy prior to RT (ABC)


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Summary of Data – SBRT

Chang et al. JOP 2008


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Summary of Data – SBRT

Chang et al. JOP 2008


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Phase II Multi-Institutional Study of Stereotactic

Body Radiation Therapy for Unresectable Panceatic Cancer

Locally Advanced Pancreatic

Cancer

(Gemcitabine, up to 1 Cycle allowed)*

SBRT

6.6 Gy x 5

Mon-Fri

Gemcitabine Chemotherapy

(3 wks on, 1 wk off)

Until toxicity or progression

>2 week

break

2 week

break

Primary endpoint: Late GI Toxicity > 4 months

Secondary: Tumor Progression Free Survival

N=60

Trial open at Stanford and Johns Hopkins. Memorial Sloan Kettering Pending.


Pancreas adjuvant therapy l.jpg
Pancreas: Adjuvant Therapy

  • Adjuvant radiation controversial

  • GITSG and EORTC: Benefit of Adjuvant 5-FU CRT

  • ESPAC: Adjuvant RT detrimental

  • Retrospective studies at high volume institutions: 5-FU CRT>observation

  • CONKO trial: Gem>observation (ca 19-9 <90)

  • ESPAC-3: 5-FU>Gem

  • RTOG 9704: Gem=5-FU before/after 5-FU based CRT

  • EORTC study (2010): Gem/RT>Gem (local control)

  • Most develop metastatic disease, LR adds morbidity and can be fatal


Specific aims of adjuvant therapy for resectable pancreatic cancer l.jpg
Specific Aims of Adjuvant Therapy for Resectable Pancreatic Cancer

  • Decrease local failure rate

    • Requires adequate surgical resection (R0) ideally and R1 minimally

    • External beam radiation therapy

    • Intraoperative radiation therapy (IORT)

  • Prevent/delay distant failure

    • Systemic chemotherapy

    • Molecular therapy

    • Immunotherapy

  • Improve survival


Phase i adjuvant pancreatic cancer study erlotinib and capecitabine with concurrent rt l.jpg

Phase I Adjuvant Pancreatic Cancer Study: Erlotinib and Capecitabine with Concurrent RT

Capecitabine: 800 mg/m2 BID daily

Erlotinib: 150 mg Q D

Radiation: 50.4 Gy (IMRT)

Surgery

R0/R1

Gem 1000 mg/m2

Erlotinib 150 mg

  • Previous studies including targeted agents with radiation in the

  • adjuvant setting closed secondary to toxicity

  • Initially started with Cap 800 BID 7 days, Erlotinib 150 mg Q D

  • Study closed after first 6 patients: diarrhea, weight loss

  • Switched to Cap M-F and Erlotinib 100 mg daily no D L T’s (N=7)

  • Regimen appears safe, efficacy data pending

Ma, Herman et al. Trans Onc In press


Future directions l.jpg
Future Directions Capecitabine with Concurrent RT

  • Improved Systemic Therapy

  • Patient Selection (DPC4/BRCA2)

    • DPC4: local vs. systemic therapy

    • BRCA2 testing to guide therapy (PARP)

  • SBRT: neaodjuvant and adjuvant setting

  • Immunotherapy

  • Intraoperative high dose rate radiation therapy (HDR-IORT)

  • Integration of targeted therapies with RT in a preclinical platform


  • Improved systemic therapy l.jpg
    Improved Capecitabine with Concurrent RTSystemicTherapy


    Dpc4 status and patterns of failure l.jpg
    DPC4 Status and Patterns of Failure Capecitabine with Concurrent RT

    Autopsy Study

    DPC4 immunolabeling: DPC4 loss highly correlated with presence of widespread metastasis, but not with locally destructive tumors (p=0.007).

    DPC4 status at diagnosis – potential for stratifying patients into treatment regimens emphasizing local versus systemic therapy.


    Dpc4 status and patterns of failure26 l.jpg
    DPC4 Status and Patterns of Failure Capecitabine with Concurrent RT


    Slide27 l.jpg

    A Phase II study Using DPC4 Status to Guide the Selection of Upfront

    Chemoradiation (IMRT) in Patients with Unresectable Pancreatic Cancer

    GEM 1000 mg/m2

    Eligibility: Locally Advanced Unresectable

    No prior Chemotherapy or RT

    GEM 1000mg/m2 + 55Gy (2.2)

    Xeloda/50.4 Gy (1.8)

    FOLFIRINOX

    EUS Biopsy

    X 3

    Gem/55 Gy (2.2)

    DPC4

    staining

    DPC4 Status

    Enroll

    Cap/55 Gy (2.2)

    X 3

    (Intact)

    Gem x 1 mos

    Cap/50.4 Gy (1.8)

    N=TBD

    (Loss)

    FOLFIRINOX

    1st Endpoint: Median OS

    2nd Endpoints: Safety; DFS/OS (subcohort); Local Progression Free Surv; DM rates;

    Retrospective biomarkers: TBD

    Early Stopping Rules: Based on toxicity, OS, PFS

    Proposed RTOG Trial: Ben-Josef




    Slide30 l.jpg

    Adjuvant Pancreas Cancer: Upfront

    HDR-IORT Trial

    HDR-IORT 20 Gy to 5mm

    Recommend 50.4-54 Gy adjuvant CRT

    Gross disease

    remaining

    At time of resection, evaluate margin status using frozen sections and surgeon’s judgment

    HDR-IORT 20 Gy to 5mm

    Recommend 45 Gy adjuvant CRT

    Microscopic disease

    remaining

    No apparent residual

    disease

    HDR-IORT 20 Gy to 5mm

    Recommend adjuvant chemotherapy without external beam radiation

    Study population:20 patients with resectable pancreatic head adenocarcinoma


    Slide31 l.jpg

    Mouse SBRT Upfront

    Small Animal Radiation Research Platform: Bioluminescent Imaging (BLI) and Targeted Radiation in Small Animals

    SARRP Research Platform.

    http://www.xstrahl.com/sarrp.htm.


    Longitudinal bli monitoring of tumor growth l.jpg
    Longitudinal BLI Monitoring of Tumor Growth Upfront

    Mean tumor volume of untreated mice was > 3x that of irradiated mice (Panels C and D respectively; P < .05, n = 4/group).

    5 Gy x1 treatment results in tumor growth inhibition of 20 days (n = 4/group; Figure 5A).


    Target volume planning l.jpg
    Target Volume Planning Upfront

    E

    F

    A-CT Image, B→ Bioluminescent Image, C-Checkerboard Overlay for Localization of target isocenter.

    D-Double Exposure Radiograph of 15 mm collimator to cover target identified in C

    E-Whole Mount H & E

    F- H2Ax immunofluorescent staining of this coronal section

    Tuli et al. 2010 submitted


    Abt 888 combination study l.jpg
    ABT-888 Combination Study Upfront

    Co-treatment of irradiated panc cells with ABT-888 and gemcitabine led to increased cell death compared with treatment with either drug alone (P<.001).


    Slide35 l.jpg

    A Phase I Study of Upfront veliparib (ABT-888) in combination with Gemcitabine and Intensity Modulated Radiation Therapy in Patients with Locally Advanced, Unresectable Pancreatic Cancer

    RT 36 Gy (2.4 Gy fxs) with full dose gemcitabine and ABT-888

    Patients tested for BRCA mutations prior to treatment

    Tuli et al. 2010


    Conclusions l.jpg
    Conclusions Upfront

    • Local recurrence/progression can lead to morbidity and mortality

    • Radiation therapy results in improved local control

    • New radiation techniques allow for focused radiation to the tumor or tumor bed:

      • Allows for dose escalation

      • Combination with full dose chemotherapy and/or targeted agents

      • Less toxicity/shorter course of RT

    • Future trials should focus on patient selection and quality of life as well as survival


    Pancreatic cancer team members l.jpg
    Pancreatic Cancer Team Members Upfront

    • Surgery

      • Rich Schulick

      • Chris Wolfgang

      • Barish Edil

      • Marty Makary

      • Fred Eckhauser

      • Mike Choti

      • Timothy Pawlik

    • Pathology

      • Ralph Hruban

      • Syed Ali

      • Scott Kern

      • Christine Iacobuzio Donahue

      • Anirban Maitra

    • Administration

      • John Hundt

      • Terry Langbaum

    • Gastroenterology

      • Marcia Canto

      • Michael Goggins

      • Samuel Giday

    • Vaccine Team

      • Elizabeth Jaffee, Dan Laheru, Barb Biedrzycki, Beth Onners, Irena Tartakovksy, Amy Hamilton, Sara Solt, Guanglan Mo, Eric Lutz, GEL

    • Radiology

      • Elliott Fishman

      • Karen Horten

    • Genetics

      • Jennifer Axilbund

      • Alison Klein

      • Emily Palmisano

    • Medical Oncology

      • Ross Donehower

      • Lei Zheng

      • Dan Laheru

      • Luis Diaz

      • Dung Le

      • Nilo Azad

    • Radiation Oncology

      • Joe Herman

      • Deborah Frassica

      • Fariba Asrari

    • Nursing

      • Barb Biedrzycki

      • Amy Hacker

      • Cathy Stanfield

    • Social Work

      • Nancy Robinson

    • Nutrition

      • Maryeve Brown


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