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Margaret Tempero
Professor of Medicine
University of California, San Francisco
Therapeutic Landscapes
In
Pancreatic Cancer
Acinar secretory
cell
Ductal epithelial
cell
Bile Duct
Duodenum
Main Duct Islets ofLangerhans
Acinus
Duct
Anatomy of the pancreas
PanIN-1BPanIN-1ANormal PanIN-2 PanIN-3
Pancreatic cancer progression
Oncogene activation
Loss of tumor suppressor genes
Hruban et al
Because of early invasion and metastasis, effective systemic
therapy will have the most impact following surgery for patients with
invasive ductal cancer
The best proving ground for new systemic treatment is
metastatic disease
Efficacy in Pancreatic Cancer
•Objective response
•Symptom assessment/QOL
•survival
Objective response can not be adequately measured!
•Technically difficult to measure dimensions of the primary tumors radiographically
•Much of the mass effect can result from associated desmoplasia
CA19-9 by QuartileGroup Percentage of
patientsMedian survival
(mos)
Median time to treatment
failure (mos)No decline in CA19-9 42.3% 7.60 3.90
0-25% decline 11.5% 8.30 5.95
26-50% decline 19.2% 12.85 7.25
51-75% decline 11.5% 11.05 6.90
75% decline 15.4% 10.35 5.30
p-value 0.075 0.37
Factors Impacting Survival
• PS
• Extent of disease
• Crossover
Does Chemotherapy Improve Survival?
Natural History
SMS pa LAR vs. Placebo
92 patients (59% with mets) on placebo
Median survival 16.9 weeks (3.9 mos.)
Pederzoli et al, ASCO 1998
Chemotherapy vs. Supportive Care
Mallinson, 1980 5FU, CTX, VCN 11 vs. 2.25 mos* MTX, Mito
Frey, 1981 5FU and CCNU 3 vs. 3.9 mos
Palmer, 1994 5FU, Adria, Mito 8.25 vs. 3.75 mos*
Glimelius, 1996 5FU, leucovorin, 6 vs. 2.5mos*
± etoposide
Regimen Median Survival
*significant difference noted
Overall survival
Strategies for Optimizing Therapy
• Gemcitabine fixed dose rate infusion
• Selection of synergistic drug combinations with gemcitabine
• Find more effective drugs
Gemcitabine(2’2’-difluorodeoxycytidine, dFdC)
• Nucleoside analogue with 2 fluorine atoms in deoxyribofuranosyl ring
• Prodrug metabolized intracellularly
• Phosphorylated by deoxycytidine kinase
• Active metabolites: dFdCDP, dFdCTP
• Rate of dFdCTP formation is dose and dose-rate dependent - exceeding plasma [C] of 20mM can saturate activation process
JHFN: A Randomized Phase II Study Comparison of Two Different Infusion Rates of Gemcitabine Therapy
in Patients with Locally Advanced or Metastatic Adenocarcinoma of the Pancreas
Primary Objective: to determine TTF in patients with measurable metastatic pancreatic adenocarcinoma
Secondary Objective: PK, survival
Randomized
2200 mg/m2 over 30’ weekly x3 q 4 wks
1500 mg/m2 over 150’ weekly x3 q 4wks
Tempero et al, JCO, 2003
Intracellular Gemcitabine Pharmacokinetics
0.00.10.20.30.40.50.60.70.80.91.0
0 6 12 18 24 30 36Survival Time in Months
ProportionSurviving
Standard
Fixed Dose Rate
Figure 2a.
Overall Survival
Randomized Phase II
ProportionSurvival
Fixed Dose Rate
Standard
Survival Time in Months
Median survival 8.6 monthsEstimated 1-year survival 33%
UCSF Trial: FDR Gemcitabine + Low Dose Cisplatin
Ko et al, ASCO 2004
Phase 2 trial in metastatic pancreatic cancer - early analysis
The Lifeline
Supportive Care
1996
Std gem 1997
FDR gem 2000
FDR gem/cis
2004
Next?
010 months
Gemcitabine and Platinum
TTP (mos)
Heineman, 2003 2.5 4.6
Reni, 2004** 3.3 5.3
Louvet, 2004 3.0 4.6(M)
5.3 7.4 (LAD)
gem gem/cis or oxali*
*all statistically significant
**gem/cis plus epirubicin and 5-FU
Gemcitabine and Platinum
Median Survival (mos)
Heineman, 2003 6.0 7.6
Reni, 2004* 9.0 9.0
Louvet, 2004 6.7 8.5(M)
10.3 10.3 (LAD)
gem gem/cis or oxali
*gem/cis plus epirubicin and 5-FU
Gemcitabine and Platinum
1 year survival
Heineman, 2003 ~30 ~30
Reni, 2004** 21.3 38.5
Louvet, 2004 27.8 34.7
**gem/cis plus epirubicin and 5FU
gem gem/cis or oxali
Previous reports for gem: 17-24%
Analysis Options
• gem/platinum is not superior OR• gem/platinum is modestly superior and
survival endpoint was affected by crossover (> 50% in Louvet trial)
Other Issues
• interruption of treatment for radiation for LAD could have handicapped the experimental arm
• we can’t conclude anything about FDR gem or about which platinum
• LAD and metastatic disease - different natural history?
E 6201: Phase III Trial of Gemcitabine and Oxaliplatin in Pancreatic Carcinoma
Arm A:
Gemcitabine 1000 mg/m2/30 minutes qw x 3 every 4 weeksArm B:
Gemcitabine 1500 mg/m2/150 minutes qw x 3 every 4 weeks
Arm C:
Gemcitabine 1000 mg/m2/100 minutes
Oxaliplatin 100 mg/m2/120 minutes q 14 days
R
A
N
D
O
M
I
Z
E
Accrual Goal: 791
Other Gemcitabine Drug Combinations
Agent median survival (mos)
Bolus 5FU (Berlin)* 6.7
PVI 5FU (Hidalgo) 10.3
Irinotecan (Roche-Lima)* 5.7
Docetaxel (Ryan, Lutz) 8.9, 7.6
Pemetrexed (Kindler)* 6.5
Capecitabine (Scheitauer) 9.5
*Phase III
Randomized Phase II trial: Germany
•gemcitabine plus oxaliplatin
•gemcitabine plus capecitabine
•capecitabine plus oxaliplatin
Heinemann/ASCO, 2004
The Future?
Phase I Best chemotherapy platform plus targeted therapeutics (bevacizumab, cetuximab, erlotinib, etc)
Phase II “Tailored” therapy based on genomic/proteomic profile
Managing Locally Advanced
and
Resectable Pancreatic Cancer
Locally Unresectable Pancreatic Cancer
chemoRT vs. RT
GITSG Study
RX Median Survival
6000 cGy 5.5
4000 cGy + 5FU bolus* 10
6000 cGy + 5FU bolus 10
*recommended for standard of care
Moertel et al, Cancer 48:1705, 1981
What do we really do?Patterns of care have changed!
• RT dose closer to 6000 cGy
• Continuous infusion 5FU
• Variable use of additional systemic chemotherapy
Locally Advanced Disease
Is there a better radiation sensitizer than 5FU? Gemcitabine, taxol, cisplatin, a combination?
• No Phase III trials• MDACC retrospective analysis suggests
comparable survival with gemcitabine but more toxicity (Crane et al, Int J Radiation Oncology Biol. Phys. 52:1293-1302, 2002)
Locally Advanced Disease
Do we need “full dose” RT with gemcitabine?
“Full dose” gemcitabine can be given with about 3900 cGy delivered over 3 weeks (McGinn et al, JCO Nov 15:4202-4208, 2001)
Is radiation really that important?
The majority of recent phase II and III
chemotherapy trials have included patients with
locally advanced disease (LAD).
Louvet et al gem/oxali 47% 10.5 mos.
Reni et al PEF-G 37% 18.5 mos.
Colucci et al Gem or gem/cis 44%
Median survival%LAD
Beware: some patients went on to receive chemoRT off study
Adjuvant Therapy of Pancreatic CancerGITSG Study
n Med.surv.(mos)
surgeryobservation 22 11
4000 cGy/5Fu 21 20
registered 24 19
Arch.Surgery 120:899, 1985
Cancer 5:2006, 1987
p = 0.03
+ 5FU for 2 years
Neoadjuvant Therapy
• Everyone can be treated
• Results not inferior
• “Selects” for more indolent disease
Spitz et al, JCO, 1997
EORTC Adjuvant Study
• Adenocarcinoma of pancreas and ampullary carcinoma (apples and oranges)
• Randomized to observation vs. “standard” split course RT with bolus 5FU - no maintenance 5FU
Klinkenbijl, 1999
Possible reasons for conflicting results Possible reasons for conflicting results between GITSG and EORTC studiesbetween GITSG and EORTC studies
• Substantial proportion of patients (20-24%) randomized to treatment arm on both studies never received treatment due to prolonged postoperative course
• EORTC study included very early stage (T1N0) patients which might skew results in favor of no difference
• GITSG study included 2 additional years of 5-FU after chemoradiation; EORTC study did not
• Small sample size/insufficient power
RTOG 97-04
Title: A Phase III Study of Pre and Post Chemoradiation 5FU vs. Pre and Post Chemoradiation Gemcitabine for
Postoperative Adjuvant Treatment of Resected Pancreatic Adenocarcinoma
Surgery
S
T
R
A
T
I
F
Y
Nodes
Size
Margins
R
A
N
D
O
M
I
Z
E
D
c.i. 5FU 5FU chemoRT c.i. 5FU
(1 cycle) (2 cycles, 12 weeks)
gemcitabine 5FU chemoRT gemcitabine
(1 cycle) (3 cycles, 12 weeks)
RTOG 97-04
Is the systemic treatment component “too little, too late”?
ESPAC 1541 patients randomized:• no therapy• chemoRT with 5FU• 5FU + leucovorin (L)• chemoRT followed by 5FU/L
chemoRT 15.1 mos chemo 19.7 mos
vs. p = 0.24 vs.
no chemoRT 16.1 mos no chemo 14.0 mos
P = 0.0005
median survival median survival
Neoptolemos et al, Lancet 358: 1576-85, 2001
Overall Survival by CTOverall Survival by CT
Survival rates 2-year 5-yearNo CT: 28.7% 9.9%CT: 43.3% 23.3%HR=0.64 (0.52, 0.78), p<0.001
Neoptolemos et al, NEJM, 2004
ESPAC I Analysis
• chemo RT results inconclusive
• chemotherapy results suggest “chemo component” of adjuvant treatment is important - remember the old GITSG trial mandated 2 years treatment with 5FU
• hypothesis generating - is chemo RT an essential component of adjuvant therapy?
ESPAC 3
Surgery
5FU & leucovorin
gemcitabine
Without chemoradiation, it’s a simple platform
The End
We Are Making Progress!
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