margaret tempero professor of medicine university of california, san francisco therapeutic...

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!