saint agnes medical center oncology symposium october 15, 2011 neoadjuvant, adjuvant and palliative...
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Saint Agnes Medical CenterOncology Symposium
October 15, 2011
Neoadjuvant, Adjuvant and Palliative Management
Marshall Flam, MDHematology, Oncology Medical Group
Age Specific Incidence Rates of Pancreas Cancer,
in California, by Race, 1988-2008
0
20
40
60
80
100
120
140
Age at DX
Rate/100,000
NH White rate
Black rate
Courtesy of Paul Mills, PhD, MPH
Stage at Diagnoses of PAC
Stage at DX % of Patients 5 Yr. Survival
Distant Metastases 50 2%
Locally Advanced Un-resectable 30 7%
Curative Resection of Operated 50 (10) 20%
Metastases Found at Surgery Un-resectable 50 (10)
SINGLE AGENT CHEMOTHERAPY
Overall Survival: Gemcitabine vs 5-FU
Fixed Dose Rate vs. Standard Rate
Toxicity Summary
Grade 3 and 4 Toxicities
(% of Patients)
Toxicity per Patient FDR Standard
Anemia 23.3 18.4
Nausea/vomiting 20.9 14.3
Thrombocytopenia 37.2 10.2
Neutropenia 48.8 26.5
Leukopenia 39.5 22.5
ALT 7.3 2.2
Diarrhea 4.7 8.2
Abbreviation: FDR, fixed dose rate.
Assessment of Clinical Benefit
PAIN PerformanceStatus
STABLE In both Parameters
WEIGHT
ResponderImprovement in both
Parameters. Stable in one parameter, Improvement in
The other parameter
Non-responderWorsening in either
Parameter
Analgesic Consumption
Pain Intensity
Responder> 7% Increase in body weight
ResponderStable or decreased weight
COMBINATION CHEMOTHERAPY
Phase III Trials of Chemotherapyin Advanced Pancreatic Cancer
Regimen OS (mos)5FU OS
(mos) P Value RR (%) 5FU RR %
Gemcitabine + 5FU 6.7 5.4 0.09 9.9 5.6
Gemcitabine + Irinotecan 6.3 6.6 0.789 16.1 4.4
Gemcitabine + Cisplatin 7.5 6 0.15 10.2 8.2
Gemcitabine + Oxaliplatin 9.0 7.1 0.13 26.8 17.3
Gemcitabine + Premetrexed 6.2 6.3 0.848 14.8 7.1
Capecitabine + Gemcitabine 7.4 6 0.026 14.0 7.0
EGOC Trail: Survival – Gemcitabine vs GEMOX
French Trial:
Survival Gemcitabine vs GEMOX
Objective Responses in the Intention-to-Treat Population
Progression-free Survival
Overall Survival
TARGETED THERAPIES
Summary of the CAN-NCIC PA.3 Phase III Trial
Gemcitabine +Erlotinib vs Gemcitabine Alone
in Advanced Pancreatic Cancer
Gemcitabine +
Erlotinib
GemcitabineAlone
HazardRatio
P Value
No. of Patients 285 284 ----- -------Response Rate 8.6% 8.0% ----- -------Median Survival 6.24 mos 5.91 mos 0.82 .0381 Yr. Survival Rate
23% 17% ----- -------
Progression-Free
Survival3.75 mos 3.55 mos 0.77 .004
Data from Moore et al.23,24
Phase III Trial of Bevacizumba + Gemcitabine in Patients with Advanced Pancreatic Cancer:
Median Overall and Progression-Free SurvivalGemcitabine + Bevacizumab
Gemcitabine+ Placebo
P Value Hazard Ratio
Median Overall Survival
5.7 mos 6.0 mos 0.40 1.09
(95% CI) (4.9, 6.5) (5.0, 6.9) ----- -------
Progression-Free Survival
4.8 mos 4.3 mos 0.99 1.0
(95% CI) (4.3, 5.7) (3.8, 5.6) ----- -------
Data from Kindler et al.11
SECOND LINE THERAPIES
Treatment Regimen No. of patients
Metastatic Disease (%)
RR (%)a
DCR (%)a
PFS/TTP (months)
OS (months)
Oxa/5-FU CI/LV vs. BSC14 46 NA NA NA OFF: 5.25BSC: 2.5
OFF: 10BSC: 8.5
Oxa/5-FU CI/LV vs. 5-FU CI/LV36, 27 168 (OFF:77; FF91)
OFF: 85.5FF: 89.2
NA NA OFF: 3.25FF: 2.25
OFF: 6.5FF: 3.25
Oxa/5-FU CI/LV28 30 97 23 53 5.1 5.8
FOLFOX-429 42 83 14 52 4 6.7
Modified FOLFOX(a) vs. modified FOLFIRI.3(b)30
(a) 30(b) 30
NA NA (a) 20(b) 28
(a) 1.4(b) 1.9
(a) 4(b) 4
Oxa/5-FU CI31 18 94.5 0 17 0.9 1.3
Oxa + Gem33 33 64 21 58 4.2 6.0
Oxa + Cap34 39 NA 3 23 NA 5.8
Oxa + Cap36 15 100 7 40 4.1 10
Oxa + irinotecan37 30 100 10 33 4.1 5.9
Oxa + pemetrexed38 16 NA 20 60 3.3 NA
Oxa + ralitrexed39 41 100 24 51 1.8 5.2
L-Cisplatin + Gem40 24 79 8 67 NA 4.0
Cisplatin + irinotecan + Gem + 5-FU + LV41
34 100 34 55 3.9 10.3
Cisplatin + S-142 17 53 29 NA NA 9.0
Cap + Gem + docetaxel43 35 100 29 60 NA 11.2
Mitomycin + docetaxel + Irinotecan44 15 100 0 20 1.7 6.1
Irinotecan + ralitrexed18 19 100 16 47 4.0 6.5
a Intention-to-treat analysis.
b KPS 80-100%
Clinical Trials Investigating second-line combination chemotherapy in gemcitabine-pretreated patients with advanced pancreatic cancer
CONKO 003
Phase II trial of capecitabine + erlotinib in gemcitabine-refractory advanced pancreatic
cancer
ADJUVANT THERAPY
FOLLOWING RESECTION OF PAC
Key Trials of Adjuvant Therapy in Resectable Pancreatic Cancer
Trial Regimen # of PatientsMedian Survival
(mos)
GITSG (1985) 5FU + 40GY XRT 21 20
Surgery Only 22 11
GITSG (1987) 5FU + 40GY XRT 30 18
EORTC (1999) 5FU + 40GY XRT 110 17.1
Surgery Only 108 12.6
ESGCP (2004) Chemoradiotherapy 145 15.9
ESGCP (2004) No Chemoradiotherapy 144 17.9
Maintenance Chemotherapy 142 20.1
No Maintenance Chemotherapy 147 15.5
RTOG (2006) 5FU + 50.4Gy 270 16.7
Gemcitabine + 5FU + 50.4Gy 268 18.8*
CONKO-001 (2007) Gemcitabine 179 22.1
Surgery Only 177 20.2
* Statistically Significant
NEO-ADJUVANT
(PRE-OPERATIVE) THERAPY
Advantages Pre-operative Chemo radiation over Post-operative
Chemo radiation More effective chemotherapy delivery with an intact blood supply Avoidance of hypoxia related chemo radiation resistance Avoidance of late radiation toxicity by surgical removal of irradiated duodenum and use
of unirradiated jejunum use in reconstruction Immediate use of systemic therapy for a disease that is systemic at diagnosis in
the majority of patients Improved patient selection for pancreatic surgery Pancreatic surgery is safer following chemo radiation due to reduced risk of
pancreatic anastomotic leak due to pancreatic fibrosis Timely access to therapy. No delays due to post-operative recovery complications Increases R0 (complete) resection rates in patients with borderline resectable
tumors
Operability Classification of Localized PAC based on high-quality cross-sectional imaging Resectable
Borderline Resectable
Locally Advanced
Metastatic
Selected Trials of Neoadjuvant Chemoradiation for Patients with
Potentially Resectable Pancreatic Cancer
Author EvaluablePatients
Resected EBRTDose (Gy)
Chemotherapy Regimen
Median SurvivalAll Patients (Mo)
Median Survival Resected Patients (Mo)
Evans et al. (119) 28 17 (61%) 50.4 + IORT CI 5-FU NA 18
Hoffman et al. (121) 53 24 (45%) 50.4 Bolus 5-FU 9.7 15.7
Pisters et al. (120 35 20 (57%) 30 + IORT PVI 5-FU 7 25
White et al. 53 resectable 28 (53%) 45 PVI 5-FU NR NR
Moutardier et al (261) 19 15 (79%) 30 or 45 Bolus 5-FU + CDDP
20 30
Arnoletti et al (262) 26 14 (54%) 59.4 5-FU and/or MMC or Gem
NA 34
Pisters et al. (123) 35 20 (57%) 30 and 10 IORT Paclitaxel 12 19
Wolff et al. (125) 86 64 (75%) 30 Gem 22 36
Magnin et al. (263) 32 19 (59)% 30 or 45 PVI 5-FU + CDDP 16 30
Talamonti et al. (126) 20 17 (85%) 36 Gy Gem NA NA
Kaplan-Meier curves compare overall survival in patients according to timing of
systemic therapy. MS indicate medial survival.
Kaplan Meier curves compare overall survival in patients with extra pancreatic disease (ie, T3 or T4 Disease) according to timing of sytematic therapy.
MS indicates median survival.
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Need Title
Survival adjusted for age, sex, and comorbidity for patients receiving treatment versus untreated patients.
Need Title
Kaplan-Meier overall survival curves in patients with good Karnofsky performance score (90 to 100). Gem, gemcitabine; GemCap, Gemcitabine plus capecitabine.