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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. Proximity of Pancreas to small bowel:

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Pancreatic Cancer: Contemporary Radiation Therapy and Translational Paradigms

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  1. 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

  2. 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

  3. 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

  4. 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

  5. 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)

  6. T10-T11 L3 Pancreas: Standard Adjuvant RT Field vs. Preoperative/Neoadjuvant Radiation Field Koong et al. Stanford; IJROBP 2004

  7. Adjuvant PTV=1,413 cm3 NeoadjuvantPTV=174 cm3

  8. 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

  9. 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

  10. 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

  11. Modern Treatment Devices TRILOGY SYNERGY CYBER-KNIFE

  12. 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

  13. IMRT: Duodenal Sparing SBRT: Duodenal Sparing

  14. 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

  15. Treatment Planning: PET/CT Fusion

  16. SBRT: Fiducial Guided Fluoroscopy Simulation DRR Fluoroscopy prior to RT (ABC)

  17. Summary of Data – SBRT Chang et al. JOP 2008

  18. Summary of Data – SBRT Chang et al. JOP 2008

  19. 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.

  20. 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

  21. 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

  22. 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

  23. 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

  24. ImprovedSystemicTherapy

  25. 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.

  26. DPC4 Status and Patterns of Failure

  27. 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

  28. HDR-IORT Treatment Area

  29. HDR-IORT: Pancreas

  30. 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

  31. Mouse SBRT Small Animal Radiation Research Platform: Bioluminescent Imaging (BLI) and Targeted Radiation in Small Animals SARRP Research Platform. http://www.xstrahl.com/sarrp.htm.

  32. 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).

  33. 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

  34. 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).

  35. 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

  36. 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

  37. 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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