saint agnes medical center oncology symposium october 15, 2011 neoadjuvant, adjuvant and palliative...

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.

Add Title

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.