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

2. RTOG 9704 / US Intergroup Phase III Adjuvant Study
Entry Criteria
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)

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

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

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

7. Background: Why a Radiotherapy QA Component For This Pancreatic Trial?
Variation In Radiotherapy Execution As Compared To Protocol Requirements Is Well Documented ( RTOG – Ortiz et al ; 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.

8. RTOG XRT Guidelines In 9704 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

9. RTOG XRT QA Guidelines 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

10. QA Schema 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

11. RTOG 9704 US / Intergroup Phase III Adjuvant Study
Cases Eligible For QA Review- All Pts
CRT + 5-FU
CRT + Gemcitabine
Total
Potentially Analyzable
RT Incomplete /
Not evaluable
230 19
221 16
451 35
Actually analyzed
“Head of Pancreas”

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
< Per Protocol
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
QA Score
ALL PTS By
RT QA
HEAD PTS By
Rx Arm
HEAD PTS By
QA Score

14. HR > 1 Indicates Increased Risk of Death For The Second Variable
Multivariate Analysis: Impact of Nodal Involvement, Treatment, And QA Score On Survival All Eligible Patients (n=416)
Endpoint
Adjustment
Variable
Comparison
Adjusted HR
(95% CI) P
Value
Nodal Involvement
No vs. Yes
1.62
(1.27, 2.06 )
0.0001
Overall Survival
Treatment
Gemcitabine vs.
5-FU
1.15
(0.92, 1.43)
0.22
RT QA Score
<Per Protocol
Vs.
Per Protocol
0.77
(0.62, 0.96)
0.02
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
Treatment Arm
Per protocol
Variation Acceptable
Variation
Unacceptable
p-value for trend
(1 sided)
5FU Arm
(95% CI) n
1.50 yrs
(1.28, 1.90)
117
1.52 yrs
(1.21,1.91) 82
1.18 yrs
(1.06,1.84) 12
0.08
0.03
Gem Arm
( 95% CI)
1.89 yrs
(1.54, 2.48) 99
1.41 yrs
(1.24, 1.73) 94
1.37 yrs
(1.18, 2.37)

16. Median Survival By Rx Arm And RT Compliance—Head Patients
Treatment Arm
Per protocol
Variation Acceptable
Variation
Unacceptable
p-value for trend
(1 sided)
5FU Arm
(95% CI) n
1.47 yrs
(1.26, 1.89)
104
1.34 yrs
(1.17, 1.91) 72
1.18 yrs
(0.71, 1.92) 10
0.14
0.12
Gem Arm
1.91 yrs
(1.54, 2.48) 81
(1.26, 1.85) 84
1.72 yrs
(1.37, 3.14) 8

17. HR > 1 Indicates Increased Risk of Death For The Second Variable
Multivariate Analysis: Impact of Nodal Involvement, Treatment Arm And QA Score On Survival All Eligible Pancreatic Head Patients (n=359)
Endpoint
Adjustment
Variable
Comparison
Adjusted HR
(95% CI) P
Value
Nodal Involvement
No vs. Yes
1.65
(1.27, 2.15 )
0.0002
Overall Survival
Treatment
Gemcitabine vs.
5-FU
1.30
(1.03, 1.67)
0.03
RT QA Score
<Per Protocol
Vs.
Per Protocol
0.78
(0.62, 0.99)
0.04
HR > 1 Indicates Increased Risk of Death For The Second Variable
HR < 1 Indicates Decreased Risk of Death For The Second Variable

19. Conclusions
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

20. ACKNOWLEDGEMENTS
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