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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

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
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

slide3
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
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

radiation therapy
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
T10-T11

L3

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

Koong et al. Stanford; IJROBP 2004

slide7
Adjuvant PTV=1,413 cm3

NeoadjuvantPTV=174 cm3

potential benefits of neoadjuvant therapy
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
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
slide10
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
modern treatment devices
Modern Treatment Devices

TRILOGY

SYNERGY

CYBER-KNIFE

standard rt vs stereotactic rt
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
slide13
IMRT: Duodenal Sparing

SBRT: Duodenal Sparing

technical advances in sbrt
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
sbrt fiducial guided fluoroscopy
SBRT: Fiducial Guided Fluoroscopy

Simulation DRR

Fluoroscopy prior to RT (ABC)

summary of data sbrt
Summary of Data – SBRT

Chang et al. JOP 2008

summary of data sbrt18
Summary of Data – SBRT

Chang et al. JOP 2008

slide19
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
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
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

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
Future Directions
    • 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
dpc4 status and patterns of failure
DPC4 Status and Patterns of Failure

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.

slide27
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
Adjuvant Pancreas Cancer:

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
Mouse SBRTSmall 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
Longitudinal BLI Monitoring of Tumor Growth

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
Target Volume Planning

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
ABT-888 Combination Study

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
A Phase I Study of 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
Conclusions
  • 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
Pancreatic Cancer Team Members
  • 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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