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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
 Unique Challenges of Radiation to
        Pancreatic Cancer
                   Retroperitoneal Margin      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
Compliments N. Merchant
   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




       Resectable                  Borderline Resectable                Unresectable




Neoadj CRT           Surgery          Chemotherapy            CRT             Chemo    SRT
                     ADJ Tx                                                             or
                                                                                       3X10
                                Metastatic or Unresectable        Surgery
                                                                  (IORT?)
        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
   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


                        Koong et al. Stanford; IJROBP 2004
Adjuvant PTV=1,413 cm3




Neoadjuvant PTV=174 cm3
    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
   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
    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




                           TRILOGY
                           SYNERGY
  CYBER-KNIFE
   Standard RT vs. Stereotactic RT
 Standard Radiation Therapy           Stereotactic Radiation
 Delivered over 5-6 weeks,                    Therapy
  Mon-Friday                       Delivered over one week
 Low doses of RT/day (1.8 –       High doses of RT/day (5-30
  2 Gy)                             Gy)
 Large margins                    Small margins
 Less beams of radiation          More difficult for normal
 Usually combined with             tissues to repair the
  chemotherapy                      damage
 Normal tissue can repair         Treatment times sometimes
 Shorter treatment times per
                                    >1 hour
  day (10-15 minutes)              Chronic > Acute Toxicity
 Acute > Chronic toxicity         Better quality of life
 Less Convenient (worse           Less data
  quality of life)                 No concurrent therapy?
 Good long term data
IMRT: Duodenal Sparing




SBRT: Duodenal Sparing
         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
Treatment Planning: PET/CT
         Fusion
   SBRT: Fiducial Guided
       Fluoroscopy
Simulation DRR   Fluoroscopy prior to RT (ABC)
Summary of Data – SBRT




                Chang et al. JOP 2008
Summary of Data – SBRT




                   Chang et al. JOP 2008
    Phase II Multi-Institutional Study of Stereotactic
Body Radiation Therapy for Unresectable Panceatic Cancer

Locally
Advanced
Pancreatic                 SBRT                     Gemcitabine Chemotherapy
                           6.6 Gy x 5 >2 week           (3 wks on, 1 wk off)
Cancer        2 week
                           Mon-Fri     break        Until toxicity or progression
(Gemcitabine, break
up to 1 Cycle
allowed)*

                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
   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
 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


     Surgery           Capecitabine: 800 mg/m2 BID daily
                            Erlotinib: 150 mg Q D                  Gem 1000 mg/m2
     R0/R1                                                         Erlotinib 150 mg
                          Radiation: 50.4 Gy (IMRT)


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
   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
         1.00                                 HR=0.57 : 95%CI [0.45-0.73]


         0.75


         0.50                             Stratified Log-rank test, p<0.0001


         0.25


         0.00
                0   3   6   9 12 15 18 21 24 27 30 33 36
                                       Months
Number at risk
 Gemcitabine 171 134 89 48 28 14 7 6 3        3   2   2    2
    Folfirinox 171 146 116 81 62 34 20 13 9   5   3   2    2

                              Gemcitabine                 Folfirinox
     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.
DPC4 Status and Patterns of Failure
         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             GEM 1000mg/m2 + 55Gy (2.2)
              No prior Chemotherapy or RT                 Xeloda/50.4 Gy (1.8)

                                                            FOLFIRINOX
    EUS Biopsy
                                                         Gem/55 Gy (2.2)               X3
Enroll
              DPC4      DPC4 Status
             staining                                    Cap/55 Gy (2.2)               X3
                        (Intact)       Gem x 1 mos


N=TBD                                                    Cap/50.4 Gy (1.8)
                        (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
HDR-IORT Treatment Area
HDR-IORT: Pancreas
  Adjuvant
  Pancreas Cancer:                         1. HDR-IORT 20 Gy to 5mm
                                           2. Recommend 50.4-54 Gy
  HDR-IORT Trial                              adjuvant CRT

  At time of
  resection,
                                           1. HDR-IORT 20 Gy to
  evaluate margin
                                              5mm
  status using       Microscopic disease   2. Recommend 45 Gy
  frozen sections        remaining            adjuvant CRT
  and surgeon’s
  judgment

                                           1. HDR-IORT 20 Gy to 5mm
Study population:                          2. Recommend adjuvant
20 patients with                              chemotherapy without
resectable                                    external beam radiation
pancreatic head
adenocarcinoma
Small Animal Radiation Research Platform: Bioluminescent Imaging
(BLI) and Targeted Radiation in Small Animals




                                                            Mouse SBRT




                                                         SARRP Research Platform.
                                                         http://www.xstrahl.com/sarrp.htm.
               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




                                        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




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).
 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
   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

   Surgery                     Gastroenterology                      Medical Oncology
        Rich Schulick               Marcia Canto                          Ross Donehower
        Chris Wolfgang              Michael Goggins                       Lei Zheng
        Barish Edil                 Samuel Giday                          Dan Laheru
        Marty Makary           Vaccine Team                               Luis Diaz
        Fred Eckhauser              Elizabeth Jaffee, Dan Laheru,         Dung Le
        Mike Choti                   Barb Biedrzycki, Beth Onners,         Nilo Azad
        Timothy Pawlik               Irena Tartakovksy, Amy           Radiation Oncology
                                      Hamilton, Sara Solt, Guanglan
   Pathology                         Mo, Eric Lutz, GEL                    Joe Herman
        Ralph Hruban                                                       Deborah Frassica
                                Radiology
        Syed Ali                                                           Fariba Asrari
                                     Elliott Fishman
        Scott Kern                                                    Nursing
                                     Karen Horten
        Christine Iacobuzio                                                Barb Biedrzycki
         Donahue                Genetics
                                                                            Amy Hacker
        Anirban Maitra              Jennifer Axilbund
                                                                            Cathy Stanfield
   Administration                   Alison Klein
        John Hundt                  Emily Palmisano                  Social Work
        Terry Langbaum                                                     Nancy Robinson
                                                                       Nutrition
                                                                            Maryeve Brown

				
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