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William F. Regine, K.A. Winter, R. Abrams, H. Safran, J.P. Hoffman, A. Konski, A.B. Benson,

RTOG 9704: A Phase III Study of Adjuvant Pre and Post Chemoradiation 5-FU vs. Gemcitabine for Resected Pancreatic Adenocarcinoma. William F. Regine, K.A. Winter, R. Abrams, H. Safran, J.P. Hoffman, A. Konski, A.B. Benson, J.S. Macdonald, C.G. Willett, Tyvin A. Rich.

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William F. Regine, K.A. Winter, R. Abrams, H. Safran, J.P. Hoffman, A. Konski, A.B. Benson,

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  1. RTOG 9704: A Phase III Study of Adjuvant Pre and Post Chemoradiation 5-FU vs. Gemcitabine for Resected Pancreatic Adenocarcinoma William F. Regine, K.A. Winter, R. Abrams, H. Safran, J.P. Hoffman, A. Konski, A.B. Benson, J.S. Macdonald, C.G. Willett, Tyvin A. Rich A U.S. GI INTERGROUP TRIAL

  2. Gemcitabine Single-Agent First-Line: Results of a Randomized Trial* *In Patients with locally advanced/metastatic Pancreatic Ca

  3. RTOG 9704 / US Intergroup Phase III Adjuvant Study To evaluate the impact of the addition of Gemcitabine to 5–FU Chemoradiation (CRT) in the postop adjuvant treatment of patients with pancreatic adenocarcinoma (adenoCa) Main Objective

  4. RTOG 9704 / US INTERGROUP Phase III Study (Schema) Nodal Status Neg. vs. Pos. Tumor Diameter < 3cm vs. >3 cm Surgical Margins Neg. vs. Pos. Vs. Unknown ARM 1: Pre-CRT 5 – FU + CHEMORADIATION (CRT) + Post – CRT 5 – FU ARM 2: Pre-CRT GEMCITABINE + CHEMORADIATION (CRT) + Post – CRT GEMCITABINE STRATIFY RANDOMIZE Resected AdenoCa of the Pancreas

  5. RTOG 9704 / US Intergroup Phase III Adjuvant Study Treatment PRE - CRT CHEMOTHERAPY (Starting 3 - 8 wks Post-op): Arm 1: 5–FU, 250mg/m2/d, Continuous Infusion (CI) x 3 weeks Arm 2: Gemcitabine, 1000mg/m2, weekly x 3 CRT (Initiated 1 - 2 wks after pre – CRT Chemo): Arm 1 & 2: 50.4 Gy/1.8Gy/Fx + 5–FU, 250mg/m2/d, CI x 5 1/2 wks POST – CRT CHEMOTHERAPY (Initiated 3 – 5 wks after CRT): Arm 1: 3 mos of CI 5–FU [(4 wks on + 2 wks off) x 2] Arm 2: 3 mos of Gemcitabine [(3 wks on + 1 wk off) x 3]

  6. Localized AdenoCa of the pancreas S/P gross total/potentially curative resection AJCC 5th Ed. Stages T1-4, N0-1 Protocol Rx to begin w/i 3-8 wks of surgery KPS > 60; Age > 18 Adequate nutrition ( > 1500 calories/day) RTOG 9704 / US Intergroup Phase III Adjuvant Study Entry Criteria

  7. RTOG 9704 / US Intergroup Phase III Adjuvant Study CA19-9 drawn for central submission M1 or NX Disease ineligible Prior RT/ChemoRx ineligible Tumor Types excluded: Non-AdenoCa, AdenoSquamCa, CystAdenoCa, Duodenal, Distal Bile Duct, Ampullary Cas Entry Criteria

  8. Entry Criteria RTOG 9704 / US Intergroup Phase III Adjuvant Study • Prospective Quality Assurance of • Radiation Therapy Fields Required* *First Phase III Adjuvant Pancreas Trial to Do So

  9. Study Endpoints RTOG 9704 US / Intergroup Phase III Adjuvant Study • Primary • Overall Survival • Pts with ‘Pancreatic Head’ tumors • All Patients • Secondary • Disease Free Survival • Toxicity • Prospectively correlate CA19-9 to outcome

  10. Statistical Considerations RTOG 9704 US / Intergroup Phase III Adjuvant Study • Original expected accrual: 330 pts/5.5yrs ( 5/month ) • Study activated July 1998 • By 2001 avg. accrual > 13 pts/mos • > 330 pts by May 2001 • 15-20% Body/Tail lesions ( Different Biology? )

  11. RTOG 9704 US / Intergroup Phase III Adjuvant Study Statistical Considerations Study Extension Proposed to NCI and Approved • Increase accrual to 518; increasing statistical power • Power of 85% to detect HR of .71 (18 mos vs. 25 mos) • Two-sided Significance level of 0.05, 2 interim tests • Allowed 80% power to evaluate difference among • ‘Pancreatic Head’ pts as a Prospective Primary Endpoint

  12. Accrual RTOG 9704 US / Intergroup Phase III Adjuvant Study • Study closed July 2002 @ 538pts: • RTOG* –370, ECOG –86, SWOG -82 *Includes Canadian Affiliates

  13. RTOG 9704 US / Intergroup Phase III Adjuvant Study Status of Cases

  14. 442/538 pts Eligible and Analyzable RTOG 9704 / US Intergroup Phase III Adjuvant Study Reasons for Ineligibilty

  15. RTOG 9704 / US Intergroup Phase III Adjuvant Study Pretreatment Patient Characteristics

  16. RTOG 9704 / US Intergroup Phase III Adjuvant Study Pretreatment Patient Characteristics * Not mentioned/commented on pathology report

  17. RTOG 9704 / US Intergroup Phase III Adjuvant Study Overall Survival – ‘Pancreatic Head’ Pts Only Total Dead MST CRT + Gemcitabine 187 134 1.72 CRT+ 5-FU 194 156 1.41 p = 0.033 Median:20.6vs 16.9mos 3-Year:32%vs 21% Patients at Risk RT + GEM RT + 5FU 187 194 134 132 77 63 46 31 24 19

  18. RTOG 9704 / US Intergroup Phase III Adjuvant Study Disease-Free Survival – ‘Pancreatic Head’ Pts Only Total Failed MDFST CRT + Gemcitabine 187 155 0.95 CRT+ 5-FU 194 166 0.84 p = 0.10 Patients at Risk RT + GEM RT + 5FU 187 194 87 81 52 36 30 19 18 11

  19. RTOG 9704 / US Intergroup Phase III Adjuvant Study Multivariate Analysis – OS -‘Pancreatic Head’ Pts Only

  20. RTOG 9704 / US Intergroup Phase III Adjuvant Study Overall Survival – All Eligible Patients Total Dead MST CRT + Gemcitabine 221 163 1.57 CRT+ 5-FU 221 175 1.41 p = 0.15 Patients at Risk RT + GEM RT + 5FU 221 221 152 151 87 74 52 39 27 24

  21. RTOG 9704 US / Intergroup Phase III Adjuvant Study Salvage Therapy CRT + 5-FU Arm (n=221) • 111/221 (50%) received salvage chemotherapy • 92/221 (42%) Crossed Over to receive Gemcitabine

  22. RTOG 9704 / US Intergroup Phase III Postop Adjuvant Study Toxicity- All Eligible Patients > Grade 3 Toxicity

  23. RTOG 9704 / US Intergroup Phase III Adjuvant Study Ability to Complete Therapy as per Study

  24. RTOG 9704 / US Intergroup Phase III Adjuvant Study Conclusions • The addition of Gemcitabine to postop adjuvant 5-FU CRT • improves survival in pts with pancreatic Head adenoCa • The increased hematologic toxicity seen with Gemcitabine • is manageable with > 88% of pts able to complete • chemo/RT as per study • Postop adjuvant Gemcitabine + 5-FU CRT defines a new • standard which will serve as the platform for • developing/future Phase III studies

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