Asco 04 in perspective gi highlights
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ASCO ‘04 in Perspective GI Highlights. George A. Fisher M.D. Ph.D. Stanford University School of Medicine. ASCO ‘03 GI Highlights A Tough Act to Follow. First (+) adjuvant colon trial in >10 years Mosaic Trial: LV5FU2 vs. FOLFOX4 “Targeted” therapies in metastatic colon

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ASCO ‘04 in Perspective GI Highlights

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Asco 04 in perspective gi highlights

ASCO ‘04 in PerspectiveGI Highlights

George A. Fisher M.D. Ph.D.

Stanford University School of Medicine


Asco 03 gi highlights a tough act to follow

ASCO ‘03 GI HighlightsA Tough Act to Follow

  • First (+) adjuvant colon trial in >10 years

    • Mosaic Trial: LV5FU2 vs. FOLFOX4

  • “Targeted” therapies in metastatic colon

    • First line: IFL + Bevacizumab

    • Second line: Cetuximab + Irinotecan

  • Encouraging early results Phase III pancreas

    • GemOx vs Gem: response and DFS improvements


Gem vs gemox louvet et al 4008 the gercor pancreatic trial

GEM vs GEMOX (Louvet et al #4008)The GERCOR Pancreatic Trial

R

A

N

D

O

M

I

Z

A

T

I

O

N

Gemcitabine 1000 mg/m2 over 30 min

Weekly x 7, then 3 weeks of 4

Gemcitabine 1000 mg/m2 (10 mg/m2/min) day 1

Oxaliplatin 100 mg/m2 2 hour infusion day 2

Every 2 weeks


Gem vs gemox efficacy

GEM vs GEMOX Efficacy


Current ecog trial metastatic pancreas cancer

Current ECOG TrialMetastatic Pancreas Cancer

R

A

N

D

O

M

I

Z

A

T

I

O

N

Gemcitabine 1000 mg/m2 over 30 min

Weekly x 7, then 3 weeks of 4

Gemcitabine 1000 mg/m2 (10 mg/m2/min)

Gemcitabine 1000 mg/m2 (10 mg/m2/min) day 1

Oxaliplatin 100 mg/m2 2 hour infusion day 2

Every 2 weeks


Rectal cancer astro 03 the german pre op vs post op trial

Rectal Cancer ASTRO ‘03The German pre-op vs. post-op trial

50.4 Gy

CI 5-FU Surgery 5-FU x 4

R

A

N

D

O

M

I

Z

A

T

I

O

N

T3Nx

Rectal

Surgery 50.4 Gy 5-FU x 4

CI 5-FU


Rectal cancer astro 03 the german pre op vs post op trial1

Rectal Cancer ASTRO ‘03The German pre-op vs. post-op trial


Capecitabine vs infusional 5 fu concurrent with neoadjuvant xrt randomized phase iii nsabp r 04

Capecitabine vs. Infusional 5-FU Concurrent with Neoadjuvant XRT[Randomized Phase III NSABP R-04]

R

A

N

D

O

M

I

Z

A

T

I

O

N

  • Endpoints:

  • path response

  • local relapse

  • - down staging

  • - sphincter sparing

  • - quality of life

  • - biomarkers

S

U

R

G

E

R

Y

Capecitabine (825/m2 bid)

+ radiation

T3-4

or

N1

Rectal

5-FU infusion (225/m2 daily)

+ radiation


Preoperative chemoradiotherapy a phase i ii rectal trial kuo et al stanford university

Preoperative Chemoradiotherapy: A Phase I/II Rectal TrialKuo et al.Stanford University

Endpoints:

-toxicity

-op morbidity

-path response

-downstaging

-sphincter

-molecular, imaging and circulating cell correlates

S

U

R

G

E

R

Y

Radiation therapy

Cetuximab q week

Capecitabine M-F

Oxaliplatin q 2wks

US T3/4

or N1

Rectal

Cancer

Biopsy

Day 0

Biopsy

Day 8

PET

PET


Origin of folfox

Origin of FOLFOX

Bolus 400

Bolus 400

LV5FU2

(1984)

200

600

600

200

1997 (De Gramont et al. JCO): Better response rate with less toxicity than bolus 5-FU (Mayo regimen)

Bolus 400

Bolus 400

FOLFOX4

(1995)

200

600

200

600

85

2000 (De Gramont et al. JCO):Better response rate and DFS than LV5FU2

2004 (Goldberg et al. JCO): Better response rate / DFS / OS with less toxicity than IFL (Saltz regimen)


Asco 04 in perspective gi highlights

Evolution of FOLFOX Regimens

Bolus 400

Bolus 400

FOLFOX4

(1995)

200

600

200

600

85

Bolus 400

FOLFOX6

(1997)

2400-3000

400

100

FOLFOX7

(1998)

400

2400

130

24 hr

48 hr

Doses mg/m2: 5-FU,oxaliplatin,leucovorin


Folfox4 reasons for discontinuation

FOLFOX4Reasons for Discontinuation

  • Reanalysis of Intergroup Study N9741

    • 43% patients off study due to progressive disease

    • 57% for “other” reasons”

      • 23%neurotoxicity

      • 23%myelosuppression

      • 7%hypersensitivity

      • 9%Complete response or secondary resection of mets

      • 29%Patient refusal: unspecified

      • 9%Other

Axel Grothey et al


Optimox i de gramont 3525 optimizing oxaliplatin concept of intermittent therapy

Optimox I [De Gramont #3525]Optimizing Oxaliplatin:Concept of Intermittent Therapy

R

A

N

D

O

M

I

Z

A

T

I

O

N

FOLFOX4 to progressive disease or intolerance

Bolus 400

Bolus 400

200

600

200

600

85

FOLFOX7 x 6 LV5FU2 to PD FOLFOX7

400

2400

130


Optimox 1 de gramont 3525 optimizing oxaliplatin concept of intermittent therapy

Optimox 1 [De Gramont #3525]Optimizing OxaliplatinConcept of Intermittent Therapy

FOLFOX4 FOLFOX7

Response rate58.5%58.3%

PFS (mos)9.0 9.2

OS (mos)20.021.6

G3/4 N-Tox18.7%13.3%

-more acute thrombocytopenia, N / V, cold sensitivity with FOLFOX 7 vs. FOLFOX 4

-variable adherence to protocol by center (resuming FOLFOX7)

-protocol adherence correlated with improved survival


Optimox 2 trial using mfolfox7

Optimox 2 Trial [using mFOLFOX7]

FOLFOX7

400

2400

130

mFOLFOX7

400

3000

100

R

A

N

D

O

M

I

Z

A

T

I

O

N

mFOLFOX7 x 6 no rx until PD mFOLFOX7

mFOLFOX7 x 6 LV5FU2 mFOLFOX7


Oxaliplatin neuropathy possible protection by ca mg

Oxaliplatin NeuropathyPossible Protection by Ca/Mg

  • Ca2+ gluconate + Mg2+ sulfate 1 gram each before and after oxaliplatin

  • Post-hoc analysis of 161 patients

    • Gamelin et al, Clin Cancer Research 2004

    • % pts stopping due to neurotoxicity

      • 35% controls vs 5% for Ca / Mg treated

      • No decrement in response rate


Concept optimization of folfox bevacizumab 2 x 2 randomization 532 patients

CONcePT: Optimization of FOLFOX + Bevacizumab2 x 2 randomization: 532 patients

mFOLFOX7 + Bevacizumab Continued until treatment failure + placebo

mFOLFOX7 + Bevacizumab Continued until treatment failure + Ca/Mg

mFOLFOX7 + Bevacizumab Intermittent oxali therapy + placebo

mFOLFOX7 + Bevacizumab Intermittent oxali therapy + Ca/Mg

400 (LV)

*mFOLFOX7

3000 (5-FU)

85 (Ox)

5 (Bev)


Integrating parallel successes bevacizumab role in first line

Integrating Parallel SuccessesBevacizumab: Role in first line

FOLFOX >> IFL

IFL + Bevacizumab > IFL

??FOLFOX + Bev > FOLFOX

FOLFOX ~ FOLFIRI

??FOLFIRI + Bev > FOLFIRI


Bevacizumab current cooperative group trials

Bevacizumab: CurrentCooperative Group Trials

Second Line ECOG Trial completed; results ASCO ‘05

FOLFOX4 + Bev

Results expected fall/winter ‘04; ASCO ‘05

First Line SWOG Trial: (underway)

[mFOLFOX6 vs. CAPOX] + Bevacizumab

Adjuvant NSABP Trial: (activation 10/04?)

Stage II / III colon cancer

mFOLFOX6 + Bevacizumab


Egfr inhibition with first line folfox chemotherapy

EGFR Inhibition with First Line FOLFOX Chemotherapy

*Gefitinib at 500 mg; higher GI toxicity c/w FOLFOX

**Eligibility required EGFR(+) tumors


Proposed intergroup trial

Proposed Intergroup Trial

+ Bevacizumab

R

A

N

D

O

M

I

Z

A

T

I

O

N

Investigator’s Choice:

mFOLFOX6

CAPOX

FOLFIRI

[CAPIRI]

+ Cetuximab

+ Bevacizumab + Cetuximab


Reasonable options for metastatic disease

First line therapy

Good performance status

FOLFOX (n) vs CAPOX

+ Bevacizumab

FOLFIRI vs CAPIRI

+ Bevacizumab

Poor KPS

Capecitabine or 5-FU

+ Bevacizumab

Liver mets only

Consider resection of responders

Second line therapy

If first line irinotecan

Capecitabine

CAPOX or FOLFOX

Cetuximab (if EGFR +)

Cetuximab + irinotecan

If first line oxaliplatin

Irinotecan

Irinotecan + cetuximab

“Reasonable” Options for Metastatic Disease

ALWAYSCONSIDER CLINICAL TRIALS


Recently completed adjuvant trials for colon cancer

Recently Completed Adjuvant Trials for Colon Cancer

  • Intergroup Stage III:

    • IFL vs Roswell Park 5-FU/LV (Saltz #3500)

  • NSABP Stage II/III:

    • *Bolus 5-FU/oxali vs Roswell Park 5-FU/LV

  • European Trials Stage II/III

    • *FOLFIRI vs LV5-FU2

    • UK Study: Continuous infusion 5-FU x 3 mos vs bolus 5-FU/LV x 6 months

    • FOLFOX vs LV5-FU2

  • Capecitabine vs bolus 5-FU Stage III (Cassidy #3509)

*no efficacy data available to date


Bolus 5 fu mayo vs capecitabine for stage iii x act trial cassidy 3509

Bolus 5-FU (Mayo) vs Capecitabine for Stage IIIX-ACT Trial (Cassidy # 3509)

Standard Mayo Clinic bolus 5-FU regimen x 6

versus

Capecitabine (1250 mg/m2 bid x 14 d q 3wks) x 8

Median follow-up 3.8 years

  • Significantly decreased gr 3/4 diarrhea, stomatitis and neutropenia

  • 3 year DSF [HR = 0.87; p = 0.0526]

  • 3 year Overall survival [HR = 0.84; NS]


Reasonable options for adjuvant therapy

Stage II

Assess risk

Clinical parameters

Molecular markers

High risk

FOLFOX vs CAPOX vs. Capecitabine

Low risk

Observation vs. capecitabine

Stage III

Good performance status

FOLFOX vs. CAPOX

Poor performance status

Capecitabine vs. observation

“Reasonable” Options for Adjuvant Therapy

ALWAYS CONSIDER CLINICAL TRIALS


Asco 03 04 implications

ASCO ‘03-04: Implications

  • No role for IFL / Vanishing role for bolus 5-FU

  • “Acceptable”, even “recommended” options include regimens with no Phase II data

    • FOLFOX or FOLFIRI + Bevacizumab first line colon

    • Irinotecan + cetuximab after FOLFOX failure

  • Consistently high activity with EGFR inhibitors and fluoropyrimidine /oxali regimens

    • Three phase II studies with > 75% response rates 1st line

  • The Stage II dilemma continues

    • Less toxic adjuvant options may shift risk-benefit

  • Back to the drawing board:

    • pancreas, gastric, esophageal and hepatocellular


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