1. RTOG 9704: A Phase III Study of Adjuvant Pre and Post Chemoradiation 5-FU vs. Gemcitabine for Resected Pancreatic Adenocarcinoma
A U.S. GI INTERGROUP TRIAL
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

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
Main Objective
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)

4. 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

5. 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]

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

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

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

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

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

13. RTOG 9704 US / Intergroup Phase III Adjuvant Study
Status of Cases
CRT + 5-FU
CRT + Gemcitabine
Total
Total patients entered
270
268
538
Ineligible 44 46
90 (17%)
Withdrew consent 1
No follow-up info 3
No on-study info 2
Analyzable
221
442

14. RTOG 9704 / US Intergroup Phase III Adjuvant Study
442/538 pts Eligible and Analyzable
Reasons for Ineligibilty
Ineligibility reasons
Frequency
CA 19-9 not submitted 20
Protocol Rx started > 8 weeks after surgery 19
Incomplete/Ineligible staging 18
Caloric intake is ineligible 14
Ineligible primary 10
Unable to confirm any eligibility/No FU 5
Previous RT/Cancer 3
Unable to confirm KPS 1
TOTAL
90 (17%)

15. RTOG 9704 / US Intergroup Phase III Adjuvant Study
Pretreatment Patient Characteristics
CRT + 5-FU
(n = 221)
CRT + Gemcitabine
p-value
Age (Median) 62 61
GENDER
Male
60%
53%
0.12
Female
40%
47%
LOCATION
Head
88%
85%
0.33
Non-Head
12%
15%
TUMOR DIAM.
< 3 cm
44%
39%
0.29
> 3 cm
56%
61%

16. RTOG 9704 / US Intergroup Phase III Adjuvant Study
Pretreatment Patient Characteristics
CRT + 5-FU
(n = 221)
CRT + Gemcitabine
p-value
N - STAGE N0
35%
32%
0.48 N1
65%
68%
T - STAGE
0.0062
T1/2
30%
19%
T3/4
70%
81%
SURGICAL MARGINS
Negative
44%
39%
Positive
33%
Unknown*
23%
26%
* 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
CRT+ 5-FU
p = 0.033
Median: 20.6 vs 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
CRT+ 5-FU
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
Variable
Comparison
Adjusted HR
(95% CI)
p-value
Treatment
CRT+5-FU vs. CRT+Gemcitabine
0.76
(0.61, 0.97)
0.025
Nodal
Involvement
No vs. Yes
1.42
(1.10, 1.85)
0.003
Tumor
Diameter
<3cm vs. ≥3cm
1.27
(0.99, 1.62)
0.03

20. RTOG 9704 / US Intergroup Phase III Adjuvant Study
Overall Survival – All Eligible Patients
Total Dead MST
CRT + Gemcitabine
CRT+ 5-FU
p = 0.15
Patients at Risk
RT + GEM
RT + 5FU
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
Toxicity
CRT + 5-FU
(n = 221)
CRT + Gemcitabine
p-value
Worst Hematologic
10%
58%
p<0.0001
Grade 4 * 2%
14%
Worst non-hematologic
0.94
Worst overall
62%
79.5%
0.0006
* No difference in febrile neutropenia or infection

23. RTOG 9704 / US Intergroup Phase III Adjuvant Study
Ability to Complete Therapy as per Study
CRT + 5-FU
(n = 221)
CRT + Gemcitabine
ChemoRx
88%
90% RT
86%

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