Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic...
-
Upload
stephanie-horton -
Category
Documents
-
view
223 -
download
0
Transcript of Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic...
![Page 1: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/1.jpg)
Margaret Tempero
Professor of Medicine
University of California, San Francisco
Therapeutic Landscapes
In
Pancreatic Cancer
![Page 2: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/2.jpg)
Acinar secretory
cell
Ductal epithelial
cell
Bile Duct
Duodenum
Main Duct Islets ofLangerhans
Acinus
Duct
Anatomy of the pancreas
![Page 3: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/3.jpg)
PanIN-1BPanIN-1ANormal PanIN-2 PanIN-3
Pancreatic cancer progression
Oncogene activation
Loss of tumor suppressor genes
Hruban et al
![Page 4: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/4.jpg)
Because of early invasion and metastasis, effective systemic
therapy will have the most impact following surgery for patients with
invasive ductal cancer
![Page 5: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/5.jpg)
The best proving ground for new systemic treatment is
metastatic disease
![Page 6: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/6.jpg)
Efficacy in Pancreatic Cancer
•Objective response
•Symptom assessment/QOL
•survival
![Page 7: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/7.jpg)
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
![Page 8: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/8.jpg)
![Page 9: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/9.jpg)
![Page 10: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/10.jpg)
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
![Page 11: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/11.jpg)
Factors Impacting Survival
• PS
• Extent of disease
• Crossover
![Page 12: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/12.jpg)
Does Chemotherapy Improve Survival?
![Page 13: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/13.jpg)
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
![Page 14: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/14.jpg)
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
![Page 15: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/15.jpg)
Overall survival
![Page 16: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/16.jpg)
Strategies for Optimizing Therapy
• Gemcitabine fixed dose rate infusion
• Selection of synergistic drug combinations with gemcitabine
• Find more effective drugs
![Page 17: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/17.jpg)
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
![Page 18: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/18.jpg)
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
![Page 19: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/19.jpg)
![Page 20: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/20.jpg)
Intracellular Gemcitabine Pharmacokinetics
![Page 21: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/21.jpg)
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
![Page 22: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/22.jpg)
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
![Page 23: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/23.jpg)
The Lifeline
Supportive Care
1996
Std gem 1997
FDR gem 2000
FDR gem/cis
2004
Next?
010 months
![Page 24: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/24.jpg)
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
![Page 25: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/25.jpg)
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
![Page 26: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/26.jpg)
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%
![Page 27: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/27.jpg)
Analysis Options
• gem/platinum is not superior OR• gem/platinum is modestly superior and
survival endpoint was affected by crossover (> 50% in Louvet trial)
![Page 28: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/28.jpg)
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?
![Page 29: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/29.jpg)
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
![Page 30: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/30.jpg)
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
![Page 31: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/31.jpg)
Randomized Phase II trial: Germany
•gemcitabine plus oxaliplatin
•gemcitabine plus capecitabine
•capecitabine plus oxaliplatin
Heinemann/ASCO, 2004
![Page 32: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/32.jpg)
The Future?
Phase I Best chemotherapy platform plus targeted therapeutics (bevacizumab, cetuximab, erlotinib, etc)
Phase II “Tailored” therapy based on genomic/proteomic profile
![Page 33: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/33.jpg)
Managing Locally Advanced
and
Resectable Pancreatic Cancer
![Page 34: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/34.jpg)
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
![Page 35: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/35.jpg)
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
![Page 36: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/36.jpg)
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)
![Page 37: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/37.jpg)
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)
![Page 38: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/38.jpg)
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
![Page 39: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/39.jpg)
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
![Page 40: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/40.jpg)
Neoadjuvant Therapy
• Everyone can be treated
• Results not inferior
• “Selects” for more indolent disease
Spitz et al, JCO, 1997
![Page 41: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/41.jpg)
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
![Page 42: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/42.jpg)
Klinkenbijl, 1999
![Page 43: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/43.jpg)
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
![Page 44: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/44.jpg)
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)
![Page 45: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/45.jpg)
RTOG 97-04
Is the systemic treatment component “too little, too late”?
![Page 46: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/46.jpg)
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
![Page 47: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/47.jpg)
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
![Page 48: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/48.jpg)
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?
![Page 49: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/49.jpg)
ESPAC 3
Surgery
5FU & leucovorin
gemcitabine
Without chemoradiation, it’s a simple platform
![Page 50: Margaret Tempero Professor of Medicine University of California, San Francisco Therapeutic Landscapes In Pancreatic Cancer.](https://reader036.fdocuments.in/reader036/viewer/2022062314/56649ec65503460f94bd1d62/html5/thumbnails/50.jpg)
The End
We Are Making Progress!