RTOG 9704: Correlation of Survival Results With Radiotherapy Compliance

1. RTOG 9704: Correlation of Survival Results With Radiotherapy Compliance RA Abrams, KA Winter, WF Regine, H Safran, JP Hoffman, AA Konski, AB Benson, JS MacDonald, TA Rich, CG Willett A U.S. GI INTERGROUP TRIAL

2. Localized AdenoCa of the pancreas S/P gross total 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

3. 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

4. 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]

5. RTOG 9704 / US INTERGROUP Phase III Study (Schema)1998 – 2002 Nodal Inv Neg. vs. Pos. Tumor Diam < 3cm vs. >3 cm Margins Neg. vs. Pos. Vs. Unknown ARM 1: Pre-CRT 5 – FU + 5-FU + XRT (CRT) + Post – CRT 5 – FU* ARM 2: Pre-CRT GEM + 5-FU + XRT (CRT) + Post – CRT GEM STRATIFY RANDOMIZE AdenoCa of the Pancreas S/P “Potentially” Curative Resection

6. Entry Criteria RTOG 9704 / US Intergroup Phase III Postop Adjuvant Study Quality Assurance of Radiation Therapy Performed *First Phase III Adjuvant Pancreas Trial to Do So

7. Variation In Radiotherapy Execution As Compared To Protocol Requirements Is Well Documented ( RTOG – Ortiz et al.. 1985; EORTC - Schaake-Koning et al. 1991) Experience In GI Intergroup Gastric Adjuvant Trial: 35% Major Deviations In Radiotherapy Planning In Pretreatment Screening ( Macdonald et al. – 2001) A Major Concern In Interpreting Results Of ESPAC-1 Was The Absence Of A Defined Radiotherapy QA Process Therefore, This Analysis Undertaken To See If A Correlation Between Radiotherapy Compliance And Survival Could Be Identified For Patients On This Trial. Background: Why a Radiotherapy QA Component For This Pancreatic Trial?

8. Criteria: Section 6.1. And 6.3 Correct Treatment Volumes Dose W/i 5%, W/i 10%, Or > 10% Deviation From Protocol Duration: < 7 Days Of Break, 8-14 Days Of Break, >14 Days Of Break Physical Factors: >4 MV; > 80cm SAD Critical Normal Organ Tolerance Liver At Least 40% To Get < Than 30 Gy Cord Max Dose < 45 Gy At Any Point Kidney At Least 2/3rds Of 1 Kidney < 20 Gy RTOG XRT Guidelines In 9704

9. Specified In Detail (Sections 6.1.8, 6.1.9, 6.2, and 6.3) Conceptually: Per Protocol Variation Acceptable – No Significant Impact On Toxicity Or Potential Tumor Control Anticipated Variation Unacceptable – Significant Risk Of Increased Toxicity Or Compromise Of Tumor Control Potential Incomplete/Not Evaluable – Xrt Not Started Or Not Completed; These Pts Excluded from Further Analysis Requested – GTV and PTV for Cone Down on Sim Film RTOG XRT QA Guidelines

10. Simulation W/i 14 Days Of Registration Sim Films To Be Reviewed Prior To Start Of XRT (Pre-op GTV, Renal Volumes Drawn In) Preliminary Review; Feedback To Investigator For Concerns Problem: Not All Data Available- Forms, Op Note, Path Report, Diagnostic CT (Requested, Not Always Sent) Final Review Later (After Treatment) When All Data Available Scores < Per Protocol agreed by Both WR & RA Data Presented Here Based On Final Review QA Schema

11. RTOG 9704 US / Intergroup Phase III Adjuvant Study Cases Eligible For QA Review- All Pts Actually analyzed 211 205 416 “Head of Pancreas” 186 173 359

12. RTOG 9704 / US Intergroup Phase III Adjuvant Study Overall Survival – All Eligible Patients by RTQA Per Protocol vs. < Per Protocol Total Dead MST Per Protocol 216 152 1.74 < Per Protocol 200 167 1.47 p = 0.019 Patients at Risk Per Protocol Unaccept, Accept 216 200 153 144 92 71 57 43 37 30 19 16

13. ALL PTS By Rx Arm ALL PTS By RT QA ALL PTS By QA Score HEAD PTS By Rx Arm HEAD PTS By QA Score

14. Multivariate Analysis: Impact of Nodal Involvement, Treatment, And QA Score On Survival All Eligible Patients (n=416) HR > 1 Indicates Increased Risk of Death For The Second Variable HR < 1 Indicates Decreased Risk of Death For The Second Variable

15. Median Survival By Rx Arm And RT Compliance—All Patients

16. Median Survival By Rx Arm And RT Compliance—Head Patients

17. Multivariate Analysis: Impact of Nodal Involvement, Treatment Arm And QA Score On Survival All Eligible PancreaticHead Patients (n=359) HR > 1 Indicates Increased Risk of Death For The Second Variable HR < 1 Indicates Decreased Risk of Death For The Second Variable

19. Prospective QA Requires Availability Of All Relevant Data To Be Successful For Patients Whose RT was scored as “Per Protocol”: Survival Was Significantly Better (p=0.019) Than the Survival of Patients Whose RT Was Scored as < Per Protocol In MVA: RT QA Score significantly impacted on survival for both “all patients” and “pancreatic head” patients. Treatment arm significantly impacted survival for only “pancreatic head” patients When adjusted for nodal involvement and RTQASc, the demonstrated superiority of gemcitabine over 5-FU for pancreatic head patients was increased. In This Context, RT QA Scoring Needs To Be Considered In The Design of Future Co-Operative Group Adjuvant Trials For Pancreatic Cancer Conclusions

20. Ms. Bernadine Dunning –ACR Phila. - For Exemplary Assistance With The RT QA Review Process Mr. Miguel Garcia – RTOG Statistics - For Assistance With Data Analysis And Presentation ACKNOWLEDGEMENTS