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Pancreatic Cancer Ali Shamseddine MD Proessor of Medicine AUBMC
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Transcript of Pancreatic Cancer Ali Shamseddine MD Proessor of Medicine AUBMC
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
Pancreatic Cancer
Ali Shamseddine MDProessor of Medicine
AUBMC
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
GITSG1
Survival advantage for chemoradiation followed by 5-FU for 1 year, but
Early termination, andSlow accrual (43 patients in 8 years)
EORTC2
No survival benefit for chemoradiation, but no maintenance chemotherapy
1. Kaiser MH, et al. Arch Surg. 1985;120:899-903.2. Klinkenbijl JH. Ann Surg. 1999;230:776-782.
Adjuvant Therapy: Historical Lack of Consensus
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
1. Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.2. Oettle H, et al. J Am Med Assoc. 2007;297:267-277.
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%
Adjuvant Chemotherapy
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
ESPAC-1: SurvivalCONKO-001: Disease-Free Survival
Oettle H, et al. J Am Med Assoc. 2007;297:267-277.
Adjuvant Chemotherapy:Outcomes
Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.Oettle H, et al. J Am Med Assoc. 2007;297:267-277.
Months
Cu
mu
lati
ve D
isea
se F
ree
Su
rviv
al
100%
75%
50%
25%
0%0
100%
75%
50%
25%
0%12 24 36 48 60 72
Chemotherapy
No chemotherapy
Months
Su
rviv
al (
%)
847260483624120
observation
gemcitabine
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
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;297:267-277.
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. OettleCharitè - 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
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
Disclosure
I have Consultant or Advisory Role to disclose:Lilly OncologyRocheSanofi-Aventis
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Study Design and Patient Disposition
* 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
Resected pancreatic cancer 368 patients enrolled 7/98 - 12/04
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
Date of Analysis: March 2008
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Endpoints
Primary Endpoint Disease free survival (DFS)
Secondary Endpoint Overall survival (OS) Toxicity
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
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
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Treatment Schedule
Gem
Obs
Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks
Observation: d1; q 4 weeks
Randomisati
on
Follow up every 8weeks
Gem
Ultrasoundafter week 8
Ultrasoundafter week 16
CT Scanafter week 32
Obs
Gem
Obs
Gem
Obs
Gem
Obs
Gem
Obs
Gem
Obs
4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Patient Characteristics
Characteristic Chemotherapy(N=179)
Observation(N=175)
Days to randomisation
Median (interquartile range) 22 (15 - 32) 24 (15 - 34)
Age - years
Median (range) 62 (34 - 82) 61 (36 - 81)
Sex – no. (%)
Female 74 (41%) 77 (44%)
Male 105 (59%) 98 (56%)
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Tumor Characteristics
Characteristic Chemotherapy(N=179)
Observation(N=175)
1 + 2 25 (14%) 24 (14%)T
3 + 4 154 (86%) 151 (86%)
negative 52 (29%) 48 (27%)N
positive 127 (71%) 129 (73%)
1 10 (6%) 9 (5%)
2 103 (58%) 95 (54%)
3 63 (35%) 68 (39%)G
unknown 3 (2%) 3 (2%)
R0 145 (81%) 149 (85%)R
R1 34 (19%) 28 (15%)
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
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 2005H. Oettle et al., JAMA 2007
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 DFS
Gemcitabine Median: 13.4 months (95% CI. 11.3-15.4) (21.2% censored)
Observation Median: 6.9 months (95% CI. 6.2-7.5) (7.4% censored)
Log Rank P<0.001(14.4% censored)
Median DFS (months)Arm A Arm B P*
All pts n=179 n=17513.4 6.9 <.001
R0 n=145 n=14813.1 7.3 <.001
R1 n=34 n=2715.4 5.5 <.001
N– n=52 n=4822.4 10.4 <.006
N+ n=127 n=12712.1 6.3 <.001
T1-2 n=25 n=2427.5 10.0 <.05
T3-4 n=154 n=15113.1 6.6 <.001
*Log-rank test
Date of Analysis: March 2008
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 DFS Hazard Ratios
0.59 [0.46, 0.76] 0.33 [0.18, 0.58]
Test for heterogeneity: Chi² = 3.54, df = 1 (P = 0.06), I² = 71.7%
0.53 [0.34, 0.84] 0.53 [0.41, 0.69]
Test for heterogeneity: Chi² = 0.00, df = 1 (P = 0.96), I² = 0%
0.52 [0.27, 1.00] 0.55 [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% CISub-category
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Overall Survival (OS)
Gemcitabine Median: 22.8 months (95% CI. 18.5-27.2) (23.5% censored)
ObservationMedian: 20.2 months (95% CI. 17.7-22.8) (10.9% censored)
Log Rank P=0.005(17.2% censored)
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Longterm Survival
ITT OS 1 year (%) 2 years (%) 3 years (%) 5 years (%)
Gemcitabine 72.0 48.5 36.5 21.0
Observation 72.5 40.0 19.5 9.0
Δ Gem-Obs -0.5 8.5 17.0 12.0
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 OS Resection Margin
R0 n=293
Gemcitabine Median: 22.8 months (95% CI. 18.0-27.6) (24.8% censored)
ObservationMedian: 20.3 months (95% CI. 17.9-22.7) (11.5% censored)
Log Rank P=0.018(18.1% censored)
R1n=61
Gemcitabine Median: 22.1 months (95% CI. 9.4-34.9) (17.6% censored)
ObservationMedian: 14.1 months (95% CI. 12.2-16.0) (7.4% censored)
Log Rank P=0.088 n.s.(13.1% censored)
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 OS Primary Tumor
T1+T2n=49
Gemcitabine Median: 40.6 months (95% CI. 26.6-54.5) (44.0% censored)
Observation Median: 27.0 months (95% CI. 21.4-32.7) (20.8% censored)
Log Rank P= 0.12 n.s.(32.7% censored)
T3+T4n=305
Gemcitabine Median: 21.0 months (95% CI. 16.2-25.8) (20.1% censored)
Observation Median: 19.0 months (95% CI. 16.3-21.7) (9.3% censored)
Log Rank P= 0.018(14.8% censored)
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 OS Hazard Ratios
OS (fixed) 95% CI
Hazard ratio 95% CISub-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
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
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