1. Pancreatic Cancer Ali Shamseddine MD Proessor of Medicine AUBMC

2. Adjuvant Therapy: Historical Lack of Consensus
GITSG1
Survival advantage for chemoradiation followed by 5-FU for 1 year, but
Early termination, and
Slow accrual (43 patients in 8 years)
EORTC2
No survival benefit for chemoradiation, but no maintenance chemotherapy
5-FU, 5-fluorouracil; EORTC, European Organisation for the Research and Treatment of Cancer; GITSG, Gastro-Intestinal Study Group.
1. Kaiser MH, et al. Arch Surg. 1985;120: Klinkenbijl JH. Ann Surg. 1999;230:

3. Adjuvant Chemotherapy
Two recent randomized clinical trials demonstrated benefit
ESPAC-11
N = 289 (4-arm study also evaluating chemoradiation)
Observation vs 5-FU/LV (Mayo)
5-year survival: 8% vs 21% (P = .009)
CONKO-0012
N = 368
Observation vs gemcitabine (Days 1, 8, and 15 of 4-week cycle x 6 months)
Disease-free survival: 6.9 vs 13.4 months
5-year disease-free survival: 5.5% vs 16.5%
5-FU/LV, 5-fluorouracil/leucovorin; CONKO, Charite Onkologie; ESPAC, European Study Group for Pancreatic Cancer.
1. Neoptolemos JP, et al. NEJM. 2004;350: Oettle H, et al. J Am Med Assoc. 2007;297:

4. Adjuvant Chemotherapy: Outcomes
CONKO-001: Disease-Free Survival
ESPAC-1: Survival
100%
75%
100%
75%
Cumulative Disease Free Survival
50%
Survival (%)
50%
gemcitabine
25%
Chemotherapy
25%
observation
No chemotherapy 0% 0% 12 24 36 48 60 72 84 12 24 36 48 60 72
Months
Months
Neoptolemos JP, et al. NEJM. 2004;350:
Oettle H, et al. J Am Med Assoc ;297:
Oettle H, et al. J Am Med Assoc ;297:

5. CONKO-001: Previous Analysis
Previously reported data indicated that the median DFS was 13.4 and 6.9 mos in the gemcitabine and control groups, respectively
Estimated DFS at 3 and 5 yrs was 23.5% and 16.5% in the gemcitabine group and 7.5% and 5.5% in the control group, respectively
Subgroup analyses showed the effect of gemcitabine on DFS was significant in patients with either R0 and R1 resection
No difference in OS between the gemcitabine and control groups
Oettle H, et al. JAMA. 2007;297:

6. *CHARITÉ ONKOLOGIE:Clinical studies in GI cancers
CONKO*-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC)
U.P. Neumann
P. Neuhaus, H.Riess, S. Post, K. Gellert, K. Ridwelski, H. Schramm, C. Zülke, G. Fahlke, J. Langrehr, H. Oettle Charitè - Universitätsmedizin Berlin - Campus Virchow Klinikum; Ruprecht-Karls-Universität, Mannheim; Oskar-Ziethen-Krankenhaus, Berlin; Otto-von-Guericke-Universität, Magdeburg; Wald-Klinikum, Gera; Universität Regensburg, Regensburg; AIO; CAO; Deutsche Krebsgesellschaft e.V.
*CHARITÉ ONKOLOGIE:Clinical studies in GI cancers

7. Disclosure I have Consultant or Advisory Role to disclose:
Lilly Oncology
Roche
Sanofi-Aventis

8. CONKO-001 Study Design and Patient Disposition
Resected pancreatic cancer
368 patients enrolled 7/ /04
Stratification R; T; N
182 pts. for Observation
179 eligible* pts. (96%)
for Intent-to-Treat Analysis
175 eligible* pts. (96%) for Intent-to-Treat Analysis
186 pts. for Gemcitabine
* 7 excluded Patients:
4 pts. withdrew consent
1 pt. no histologic verification
1 pt. persistent disease after resection
1 pt. another malignant disease
* 7 excluded Patients:
4 pts. withdrew consent
3 pts. another malignant disease
Date of Analysis: March 2008

9. CONKO-001 Endpoints Primary Endpoint Secondary Endpoint
Disease free survival (DFS)
Secondary Endpoint
Overall survival (OS)
Toxicity

10. CONKO-001 Inclusion Criteria
Histologically proven resected pancreatic carcinoma
Standard operation
No measurable disease
No prior chemo- or radiotherapy
No active infection
Karnofsky performance status  50%
Adequate hematologic, renal and hepatic function
CA 19-9, CEA < 2.5 ULN
Start with adjuvant therapy within 6 weeks after resection
Written informed consent

11. CONKO-001 Treatment Schedule
Ran domi sa t i on
Ultrasound
after week 8
Ultrasound
after week 16
CT Scan
after week 32
Gem
Gem
Gem
Gem
Gem
Gem
Follow up every 8
weeks
Obs
Obs
Obs
Obs
Obs
Obs
4 weeks
4 weeks
4 weeks
4 weeks
4 weeks
4 weeks
Gem
Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks
Obs
Observation: d1; q 4 weeks

12. CONKO-001 Patient Characteristics

13. CONKO-001 Tumor Characteristics

14. CONKO-001 Disease Free Survival (DFS)
We already demonstrated safety data and superior DFS for adjuvant treatment with gemcitabine as compared to observation in patients with resected pancreatic cancer P. Neuhaus et al., ASCO H. Oettle et al., JAMA 2007

15. Date of Analysis: March 2008
CONKO-001 DFS
Date of Analysis: March 2008
Gemcitabine Median: 13.4 months (95% CI ) (21.2% censored)
Observation Median: 6.9 months (95% CI ) (7.4% censored)
Log Rank P<0.001 (14.4% censored)

16. CONKO-001 DFS Hazard Ratios
0.59 [0.46, 0.76] [0.18, 0.58]
Test for heterogeneity: Chi² = 3.54, df = 1 (P = 0.06), I² = 71.7%
0.53 [0.34, 0.84] [0.41, 0.69]
Test for heterogeneity: Chi² = 0.00, df = 1 (P = 0.96), I² = 0%
0.52 [0.27, 1.00] [0.43, 0.70]
Total (95% CI)
0.55 [0.44, 0.69]
Test for heterogeneity: Chi² = 0.02, df = 1 (P = 0.87), I² = 0%
0.2
0.5 1 2 5
Favours gemcitabine
Favours control
R Status R0 R1
N stage N- N+
T stage T1-2 T3-4
DFS (fixed) 95% CI
Hazard ratio 95% CI
Sub-category

17. CONKO-001 Overall Survival (OS)
Gemcitabine Median: 22.8 months (95% CI ) (23.5% censored)
Observation Median: 20.2 months (95% CI ) (10.9% censored)
Log Rank P=0.005 (17.2% censored)

18. CONKO-001 Longterm Survival

19. CONKO-001 OS Resection Margin
R0 n=293
Gemcitabine Median: 22.8 months (95% CI ) (24.8% censored)
Observation Median: 20.3 months (95% CI ) (11.5% censored)
Log Rank P=0.018 (18.1% censored)
R1 n=61
Gemcitabine Median: 22.1 months (95% CI ) (17.6% censored)
Observation Median: 14.1 months (95% CI ) (7.4% censored)
Log Rank P=0.088 n.s. (13.1% censored)

20. CONKO-001 OS Primary Tumor
T1+T2 n=49
Gemcitabine Median: 40.6 months (95% CI ) (44.0% censored)
Observation Median: 27.0 months (95% CI ) (20.8% censored)
Log Rank P= 0.12 n.s. (32.7% censored)
T3+T4 n=305
Gemcitabine Median: 21.0 months (95% CI ) (20.1% censored)
Observation Median: 19.0 months (95% CI ) (9.3% censored)
Log Rank P= (14.8% censored)

21. CONKO-001 OS Hazard Ratios
OS (fixed) 95% CI
Hazard ratio 95% CI
Sub-category
R Status R0 R1
0.74 [0.57, 0.95]
0.62 [0.36, 1.08]
Test for heterogeneity: Chi² = 0.30, df = 1 (P = 0.59), I² = 0%
N stage N- N+
0.57 [0.36, 0.91]
0.80 [0.61, 1.04]
Test for heterogeneity: Chi² = 1.50, df = 1 (P = 0.22), I² = 33.5%
T stage T1-2 T3-4
0.58 [0.29, 1.16]
0.74 [0.58, 0.95]
Total (95% CI)
0.72 [0.57, 0.91]
Test for heterogeneity: Chi² = 0.44, df = 1 (P = 0.50), I² = 0%
Test for overall effect: Z = 2.74 (P = 0.005)
0.2
0.5 1 2 5
Favours gemcitabine
Favours control

22. CONKO-001 Conclusions
Treatment with gemcitabine as compared to observation in patients with resected pancreatic cancer results in improved disease free survival and overall survival
Adjuvant treatment with gemcitabine doubles the longterm survival rate after 5 years compared to observation
Gemcitabine should be the standard of care for adjuvant treatment of pancreatic cancer