slide 1 of 50. slide 2 of 50 case study 62-year-old woman presents with intermittent bright red...

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Case Study

• 62-year-old woman presents with intermittent bright red blood per rectum for the past 3 weeks. Sought attention from PCP

• Medical history– Type 2 diabetes mellitus for 20

years

– Obesity (BMI: 32)

• Lifestyle issues– Exercises <30 minutes per week

– Diet with 4–5 servings of red meat per week

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Risk Factors for Developing Colorectal Cancer

Decreases Risk Increases Risk Uncertain Impact

Screening Family history Statins

Exercise IBD Fiber

Calcium/vitamin D

Diabetes Glycemic index

Aspirin Obesity Fruits/vegetables

Postmenopausal estrogen

Red meatWestern diet

Folic acid Alcohol

SmokingIBD = irritable bowel disease.

Courtesy of Jeffrey A. Meyerhardt, MD, MPH.

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Case Continues

• CT of chest, abdomen, and pelvis shows no metastases

• Colonoscopy reveals a sigmoid colon cancer

• Patient undergoes a laparoscopic-assisted sigmoid colectomy. Pathology report:– 4.5-cm poorly differentiated adenocarcinoma

– Penetrates to subserosa

– 2 of 16 lymph nodes positive

– T3 N1 M0 (stage IIIB)

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a) 5-FU/leucovorin/oxaliplatin (FOLFOX)

b) Capecitabine

c) Intravenous 5-FU/leucovorin

d) FOLFOX + bevacizumab

e) FOLFOX + cetuximab

Question 1What would you recommend for adjuvant

therapy in this patient?

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Rationale for Adjuvant Treatmentof Stage III Colon Cancer

Reprinted from Greene FL, et al. Ann Surg. 2002;236:416, with permission from Lippincott Williams & Wilkins.

Surgery Alone Surgery + Adjuvant Chemotherapy

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Adjuvant CapecitabineX-ACT Trial

Capecitabine 1250 mg/m BID days 1–14, q3wk24 weeks

Stage III colon cancer N = 1987

RANDOMIZE

Courtesy of Christopher Twelves, MD.

Mayo Clinic regimen IV 5-FU/LV6 cycles

Primary endpoint: equivalence in disease-

free survival (DFS)

5-FU/LV Capecitabine P Value

Overall DFS (5 y) 57% 61% .07

Overall survival (5 y) 68% 71% .06

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FOLFOX4 LV5FU2 P Value

Overall DFS (5 y) 73% 67% .003

Stage III 66% 59% .005

Stage II 84% 80% .26

Overall survival (6 y) 79% 76% .06

Stage III 73% 69% .03

Stage II 87% 87% .99

Courtesy of Aimery de Gramont, MD.

MOSAIC Adjuvant Oxaliplatin

FOLFOX4

Stage II (40%) and III (60%)colon cancerN = 2246

RANDOMIZE LV5FU2

Primary endpoint:

Disease-free survival (DFS)

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Targeted Biologic Treatments as Adjuvant Therapy

• Currently no data regarding efficacy of bevacizumab, cetuximab, or panitumumab in adjuvant therapy

• Bevacizumab trials– NSABP C-08 (stage II and III)—pending results

– AVANT (stage II and III)—pending results

– ECOG (stage II colon)—accruing

• Cetuximab trials– NCCTG (stage III colon)—accruing

– PETACC-8 (stage III colon)—accruing

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Clinical Challenges Associated with Treating this Patient

• Diabetes mellitus– Predisposition for developing chemotherapy-induced

neuropathy has been observed in patients whose nerves have been damaged by diabetes mellitus1

– 1 study showed higher risk of recurrence with diabetes mellitus2

• Obesity

– Increased central adiposity prior to diagnosis of colorectal cancer associated with poorer overall and disease-specific survival3

– Do not dose cap

1.Quasthoff S, et al. J Neurol. 2002;249:9. 2. Meyerhardt JA, et al. J Clin Oncol. 2003;21:433.3. Haydon AM, et al. Gut. 2006;55:62.

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Case Continues

• The patient receives FOLFOX adjuvant therapy for 9 cycles but develops grade 2 persistent neuropathy

• She continues adjuvant therapy with capecitabine for 2 additional months

• Neuropathy diminishes to grade 1 after 6 months and is nearly resolved at 12 months after last dose of oxaliplatin

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Incidence of Neurosensory Symptoms During FOLFOX and Follow-up

Evaluable Patients n = 811 at 4 Years

Grade 0 84.3%

Grade 1 12.0%

Grade 2 2.8%

Grade 3 0.7%

0

10

20

30

40

50

60

DuringTreatment

6 Months 1 Year 2 Years 3 Years 4 Years

Grade 1Grade 2Grade 3

Inci

denc

e of

Neu

rose

nsor

y S

ympt

oms

(%)

Courtesy of Aimery de Garamont, MD.

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a) Surveillance with intermittent clinic visits, colonoscopies, and CT scans

b) Increasing physical activity

c) Avoidance of diet high in red meat, sugary desserts, and refined grains

d) All of the above

Question 2 What other recommendations would you

make after completion of adjuvant therapy?

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Exercise and Colon Cancer Recurrences

Meyerhardt et alJAMA 2007

1

0.87 0.9

0.51 0.55

00.10.20.30.40.50.60.70.80.9

1

< 3 3-8.9 9-17.9 18-26.9 >27

Metabolic Equivalent Task [MET]-H/Wk of Physical Activity

Rec

urre

nce,

Haz

ard

Rat

io

Meyerhardt JA, et al. J Clin Oncol. 2006;24:3535.

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Diet and Colon Cancer Recurrences

Quintile of Western Pattern Diet

1 2 3 4 5 P Trend

Disease-free survival

Energy-adjusted only

Ref 0.95(0.66–1.36)

1.51(1.06–2.15)

1.75 (1.19–2.58)

3.28 (2.15–2.07)

<.0001

Multivariate adjusted

Ref 0.98(0.68–1.43)

1.51(1.05–2.17)

1.64(1.09–2.46)

3.25(2.04–5.19)

<.0001

Western pattern: high intakes of red meat, processed meat, refined grains, sweets and dessert, french fries, and high-fat dairy products

Adapted from Meyerhardt JA, et al. JAMA. 2007;298:754-764, with permission from the American Medical Association.

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Case Continues

• Patient increased her exercise level to walking 6 days per week for approximately 1 hour daily

• A CT scan 3 months after therapy is read NED

• The patient is followed every 3 months with clinic visits and carcinoembryonic antigen (CEA) testing

• At 14 months, CEA rose from 2.0 to 7.4

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Case Continues

• CT of chest, abdomen, and pelvis shows 5 total lesions in her liver (bilobar); no lesions identified elsewhere

• Patient’s neuropathy has fully resolved

• She is evaluated by a liver surgeon who does not believe she is resectable at this point

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a) FOLFOX or FOLFIRI alone

b) FOLFOX + bevacizumab

c) FOLFIRI + bevacizumab

d) FOLFIRI + cetuximab

e) FOLFOX + bevacizumab + panitumumab

f) Clinical trial

Question 3What treatment would you offer the patient

now?

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RANDOMI

Z E

IFL (irinotecan/5-FU/LV)IFL (irinotecan/5-FU/LV)

IROX (irinotecan/oxaliplatin)IROX (irinotecan/oxaliplatin)

FOLFOX (5-FU/LV/oxali)FOLFOX (5-FU/LV/oxali)

Goldberg JCO 2004.

n = 264

n = 267

n = 264

Response Rate (%)

Time to Progress

(Mo)

Median Overall Survival

(Mo)

Grade 3/4 Neutropenia

(%)

Grade 3/4 Diarrhea

(%)

Grade 3/4 Paresthesias

(%)

IFL 31 6.9 15.0 40 28 3

FOLFOX 45 8.7 19.5 50 12 18

IROX 35 6.5 17.4 36 24 7

FOLFOX 1st-Line Standard for Metastatic Colorectal Cancer

NCCTG 9741

Goldberg RM, et al. J Clin Oncol. 2004;22:23.

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Irinotecan vs Oxaliplatin–Phase II/III DataReference Regimen N RR (%) TTP (Mo) OS (Mo)

Tournigand1 FOLFIRI 109 56 8.5 21.5

FOLFOX 111 54 8.1 20.6

Gruppo Oncologico Dell’Italia2

FOLFIRI 164 31 7 14

FOLFOX 172 34 7 15

Hellenic Oncology Group3

IFL 147 33 8.9 17.6

FLOX 148 32 7.6 17.4

CALGB 802034 FOLFIRI 58 36 8.4 18.5

FOLFOX 58 40 9.8 20.81. Tournigand C, et al. J Clin Oncol. 2004;22:229. 2. Colucci G, et al. J Clin Oncol. 2005;23:4866. 3. Kalofonos HP, et al. Ann Oncol. 2005;16:869. 4. Venook A, et al. 42nd ASCO; June 2-6, 2006. Abstract

3509.

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Targeted Biologic Therapies in Metastatic Colorectal Cancer

Targeted monoclonal antibodies representsome of the newest developments incolorectal cancer treatment

• Bevacizumab: anti-VEGF

• Cetuximab: EGFR inhibitor

• Panitumumab: EGFR inhibitor

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........................

.... ..... .... .....

........................

.... .....

........................

........................

........................

Maturation factors present

Normal and Tumor Vasculature

Normal Blood Vessels Tumor Blood Vessels

Reduced integrin expression

Less dependent on cell survival factors

.... ..... Less permeable

Leaky

Preferential expression of v3 v5 &

51 integrins

Fewer pericytes

Growth and survival factors (eg, VEGF)

present

.... .....

Supporting pericytes present

Slide courtesy of A. Venook, MD. Illustration courtesy of Genentech BioOncology.

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Bevacizumab3 Proposed Mechanisms of Action

Regression

Normalization

1

2

Inhibition3

Early effect Later effect

Slide courtesy of A. Venook, MD. Illustration courtesy of Genentech BioOncology.

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RANDOMI

Z E

IFLIFL

IFL + bevacizumabIFL + bevacizumab

Hurwitz H, et al. N Engl J Med. 2005;350:2335-2342. Copyright © 2005 Massachusetts Medical Society. All rights reserved.

Bevacizumab in Metastatic Colorectal Cancer Pivotal 1st-Line Trial

Bevacizumab + IFL (n = 402)

IFL (n = 411)

Hazard Ratio P Value

Median OS (mo) 20.3 15.6 0.66 <.001

Median PFS (mo) 10.6 6.2 0.54 <.001

Response rate (%) 44.8 34.8 .004

Median duration response (mo)

10.4 7.1 0.62 .001

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Phase III Study of XELOX or FOLFOX4 ± Bevacizumab in 1st-Line MCRC

XELOX-1/NO16966

0 5 10 15 20 25

Months

Pro

gre

ssio

n-F

ree

Su

rviv

al E

stim

ate

HR = .83 [97.5% CI .72–.95]P = .0023

9.48.0

1.0

0.8

0.6

0.4

0.2

0

XELOX/FOLFOX4 + bevacizumab n = 699 (513 events)

XELOX/FOLFOX4 + placebo n = 701 (547 events)

Courtesy of Leonard Saltz, MD.

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6.2

9.4

7.6

11.2

5.9

8.38.0

10.6

0

2

4

6

8

10

12

IFL IFL + BevXELOX/FOLFOXXELOX/FOLFOX/BevFOLFIRIFOLFIRI + BevmIFL mIFL + Bev

1st-Line Bevacizumab in Metastatic Colorectal Cancer

Progression-Free Survival

1. Hurwitz H, et al. N Engl J Med. 2004;350:2335. 2. Saltz L, et al. 43rd ASCO; June 1-5, 2007. Abstract 4028.3. Fuchs C, et al. 43rd ASCO; June 1-5, 2007. Abstract 4027.

PF

S o

r T

TP

(M

on

ths)

Saltz2 (NO16966)

Hurwitz1 Fuchs3 (BICC-C)

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Bevacizumab Safety and Usage Guidelines

• Cardiovascular events

– Hypertension (60%–67%; severe, 7%–10%)1

ACE inhibitors, beta blockers, diuretics, calcium channel blockers

Discontinue permanently for severe crisis

Discontinue temporarily if severe hypertension uncontrolled with medications

– Thromboembolic (TE) events (3.8%)2

Do not use if arterial TE <6 mo, or if active cardiovascular disease

Give to >65 years of age (a relative risk)

1. Avastin (bevacizumab). Package insert. Genentech BioOncology; 2004.

2. Skillings J, et al. ASCO; May 13-17, 2005. Abstract 3019.

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• Bleeding (grade 3/4 in 4% of patients with resected primary)1

– Avoid in patients with central nervous system metastases, lung metastases with central cavitation or hemoptysis, bleeding diathesis/coagulopathy

– Safe in patients with primary colorectal cancer in place without active bleeding

1. Kopetz J, et al. GI ASCO; January 26-28, 2006. Abstract 243.

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• Gastrointestinal (GI) perforations (1% with resected primary; 6% with unresected primary)1

– Careful use in patients with abdominal carcinomatosis, GI perforation/abdominal fistula/intra-abdominal abscess <6 mo

– Use with caution in patients with acute diverticulitis, obstruction, history of abdominal/pelvic XRT

– Wait >6–8 weeks after major surgery/invasive GI procedure before using

• Surgical wound healing complications – Careful use in patients <28–56 days after surgery, nonhealing

wound/ulcer/fracture, anticipated major surgery

– Delay elective surgical procedures (hold bevacizumab >6 weeks preoperatively)

1. Kopetz J, et al. GI ASCO;January 26-28, 2006. Abstract 243.

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EGFR Activation Mediates Several Processes

Available at http://commons.wikimedia.org/wiki/Image:EGFR_signaling_pathway.png

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1st-Line Cetuximab in Metastatic Colorectal Cancer

CRYSTALRANDOMI

Z E

FOLFIRIFOLFIRI

FOLFIRI + CetuximabFOLFIRI + Cetuximab

n = 599

n = 599

FOLFIRIFOLFIRI + Cetuximab

Hazard/ Odds Ratio

P Value

Median PFS (mo) 8.0 8.9 0.85 .048

1-year PFS (%) 23 34

Response rate (%) 39 47 .004

% underwent surgery with curative intent

2.5 6 3.0 .003

Van Cutsem E, et al. 43rd ASCO; June 1-5, 2007. Abstract 4000.

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Randomized, Open-Label, Controlled Phase IIIb Trial of Panitumumab in MCRC–PACCE

Stratification factors: ECOG score, prior adjuvant therapy, disease site, oxaliplatin doses/irinotecan regimen, number of metastatic organs

Tumor assessments: q12wk until disease progression or intolerability

Panitumumab 6 mg/kg q2wk +

ox-CT +bevacizumab

Ox-CT(eg, FOLFOX)

Iri-CT(eg, FOLFIRI)

Ox-CT +bevacizumab

Panitumumab 6 mg/kg q2wk +

iri-CT +bevacizumab

Iri-CT +bevacizumab

RANDOMIZE

1:1

1:1

Investigator’s choice of

oxaliplatin- or

irinotecan-based

chemotherapy

Courtesy of Randy Hecht, MD.

n = 413

n = 410

n = 115

n = 115

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PACCE Trial of PanitumumabEfficacy by Central Review

Pmab+ Bev + Ox-CT

(n = 413)%

Bev + Ox-CT

(n = 410)%

Pmab+ Bev + Iri-CT

(n = 115)%

Bev + Iri-CT

(n = 115)%

Best ORR 45 46 40 37

Complete response 0 <1 0 0

Partial response 45 45 40 37

Stable disease 29 34 26 36

Median PFS 9.5 m 11 m 10.6 m 10.7 m

Courtesy of Randy Hecht, MD.

Pmab = panitumumab; Bev = bevacizumab; Ox-CT = oxaliplatin-based chemotherapy (eg, FOLFOX); Iri-CT = irinotecan-based chemotherapy (eg, FOLFIRI); ORR = overall response rate; PFS = progression-free survival.

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Phase III Trial of Cetuximab, Bevacizumab, and FOLFOX/FOLFIRI

CALGB/SWOG 80405

RANDOMIZE

FOLFOX or FOLFIRIFOLFOX or FOLFIRIaa + cetuximab + cetuximab• 1st-line 1st-line

metastatic metastatic colorectal colorectal cancercancer

• Planned Planned accrual: 2289accrual: 2289 FOLFOX or FOLFIRIFOLFOX or FOLFIRIaa + +

cetuximab + bevacizumabcetuximab + bevacizumab

FOLFOX or FOLFIRIFOLFOX or FOLFIRIaa + + bevacizumabbevacizumab

aPhysician-selected chemotherapy.Stratification based on chemotherapy, prior adjuvant chemotherapy, prior pelvic RT.

US NIH Clinical Trials Database. http://www.clinicaltrials.gov/ct2/show/NCT00265850?term=80405&rank=1.

EGFR Inhibitor–Induced Skin Reactions

1 2 3 4 5 6 7 89

Descriptionof severe cases

THERAPY SUGGESTIONS

Postinflammatory effectsAcne-like rash

Paronychia

Dry skin

Topical anti-acne creams (drying effect)

+/- tetracyclines

+/- antihistamines

Pruritus

Pulse dye laser

Emollients Hydrocolloid dressing

or

Propylene glycol+/-acetylsalicylate

Antiseptic soaks

Silver nitrate (pyogenic granuloma)

Fissures

Slide courtesy of Eric Van Cutsem, MD, PhD.

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Case Continues

• The patient enrolls in CALGB/SWOG 80405

• Her physician chooses FOLFOX, and she is randomized to bevacizumab-only arm– She tolerates it fairly well

• Her initial scans show stable disease

• After 7 months, her disease shows progression with increased liver metastases and several <1-cm lung nodules

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a) FOLFIRI + bevacizumab

b) Irinotecan + cetuximab

c) Irinotecan + cetuximab + bevacizumab

d) Clinical trial

Question 4What treatment would you offer the

patient now?

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BBP(n = 642)

No BBP(n = 531)

No post-PD Rx

(n = 253)

Evaluable patientson 1st-line bevacizumab

(n = 1953)

1st Progression(n = 1445)

BRiTE Registry—Patients with Bevacizumab Beyond Progression (BBP)

Courtesy of Axel Grothey, MD.

Physician decision—no randomization

BBP(n = 642)

No BBP(n = 531)

No post-PD Rx

(n = 253)

Number of deaths (%)

168(66%)

306(58%)

260(41%)

Median OS (mo)

12.6 19.9 31.8

1-year (%) survival rate

52.5 77.3 87.7

Median survival beyond 1st PD (mo)

3.6 9.5 19.2

PD = progressive disease; BBP = bevacizumab beyond 1st progression.

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RANDOMI

Z E

CetuximabCetuximab

Irinotecan + cetuximabIrinotecan + cetuximab

Cunningham D, et al. N Engl J Med. 2004;351:337.

n = 111

n = 218

2nd-Line CetuximabBOND Trial

Patients progressed on or within 3 months of irinotecan

Response(%)

TTP Median OS

Grade 3/4 Rash (%)

Grade 3/4 Diarrhea

(%)

Cetuximab 11 1.5 m 6.9 m 9 2

Irinotecan + cetuximab

23 4.1 m 8.6 m 5 22

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RANDOMI

Z E

Panitumumab + best supportive care (BSC)

n = 231

Panitumumab + best supportive care (BSC)

n = 231

Panitumumab Registration Trial

Patients progressed on fluoropyrimidine,oxaliplatin, and irinotecan BSC

n = 232BSC

n = 232Panitumumab

n = 176Panitumumab

n = 176

Reprinted from Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664, with permission from the American Society of Clinical Oncology.

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RANDOMI

Z E

Cetuximab + bevacizumabCetuximab + bevacizumab

Irinotecan + cetuximab + bevacizumab

Irinotecan + cetuximab + bevacizumab

n = 40

n = 43

Antibody CombinationBOND-2

Patients progressed on or within 3 months of irinotecan

No prior bevacizumab

Response Rate (%)

Time to Progress

Grade 3/4 Rash (%)

Grade 3/4 Diarrhea

(%)

Cetuximab + bevacizumab

20 4.9 m 20 0

Cetuximab + bevacizumab + irinotecan

37 7.3 m 21 28

Saltz LB, et al. J Clin Oncol. 2007;25:4557.

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Phase III Trial of Irinotecan/FOLFIRI + Cetuximab ± Bevacizumab

in Patients with Relapsed MCRC S0600/iBET

iBET = Intergroup Bevacizumab Continuation Trial.aPatients progressed on FOLFOX, OPTIMOX, or XELOX + bevacizumab in 1st-line.

Primary endpoint: OS

Secondary endpoint: PFS

http://clinicaltrials.gov/ct/show/NCT00499369?order=1. Accessed May 2008.

RANDOMI

Z E

Previously treated patients with metastatic colorectal cancera

(N = 1260)

Irinotecan or FOLFIRI + cetuximab +

placebo (q2–3wk)


bevacizumab (5 mg/kg q2–3wk)


bevacizumab (10 mg/kg q2–3wk)

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a) EGFR staining by immunohistochemistry

b) K-ras mutational analysis

c) VEGF levels in the blood

d) EGFR mutational analysis

Question 5The patient was favoring irinotecan and

cetuximab but read in the newspaper that her tumor should be tested first to see if it

will respond to cetuximab.

Which of the following markers may predict a response to EGFR monoclonal antibody therapy?

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• Patients with tumors that have K-ras mutations may not benefit from cetuximab or panitumumab

• Other potential predictors– Skin toxicity

– Amphiregulin and epiregulin

• Not predictors– EGFR staining on immunohistochemistry

– EGFR mutations (rare in colorectal cancer)

Predictors of Response to Monoclonal EGFR Inhibitors

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K-ras and Cetuximab

1. Reprinted from Khambata-Ford S, et al. J Clin Oncol. 2007;25:3230-3237, with permission from theAmerican Society of Clinical Oncology.

2. Reprinted from Lievre A, et al. J Clin Oncol. 2008;26:374-379, with permission from the American Society of Clinical Oncology.

Progression-free survival with single-agent cetuximab in later-line metastatic colorectal cancer1

Cetuximab + irinotecan after irinotecan progression2

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K-ras and Panitumumab

K-ras Mutation Wild-Type K-ras

Courtesy of Eric Van Custem, MD, Segaert and Van Cutsem. Ann Oncol. 2005.

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1st-Line Cetuximab and K-ras Status

CRYSTAL Trial

RANDOMIZ E

FOLFIRIFOLFIRI

FOLFIRI + CetuximabFOLFIRI + Cetuximab

n = 599

n = 599

Van Cutsem E, et al. ASCO 2008. J Clin Oncol. 2008;26(suppl):abstract 2.

All patients

FOLFIRI 8.0 m

FOLFIRI + Cetuximab 8.9 m

P value .046

K-ras wildtype

K-ras mutant

8.7 m 8.1 m

9.9 m 7.6 m

.02 .47

Median Progression-Free Survival

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Phase III Trial of Cetuximab, Bevacizumab, and FOLFOX/FOLFIRI

CALGB/SWOG 80405

RANDOMIZE

FOLFOX or FOLFIRIFOLFOX or FOLFIRIaa + cetuximab + cetuximab

• 1st-line 1st-line metastatic metastatic colorectal colorectal cancercancer

• Wt K-rasWt K-ras

• Planned Planned accrual: 2600accrual: 2600

FOLFOX or FOLFIRIFOLFOX or FOLFIRIaa + + cetuximab + bevacizumabcetuximab + bevacizumab

FOLFOX or FOLFIRIFOLFOX or FOLFIRIaa + + bevacizumabbevacizumab

aPhysician-selected chemotherapy.Stratification based on chemotherapy, prior adjuvant chemotherapy, prior pelvic RT.

US NIH Clinical Trials Database. http://www.clinicaltrials.gov/ct2/show/NCT00265850?term=80405&rank=1.

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Conclusions

• Lifestyle adjustments may impactoutcome from colorectal cancer

• Biologic agents have a role in advanced disease but their place in the adjuvant setting remains to be determined

• The era for individualized colorectal cancer treatments is approaching

slide 1 of 50. slide 2 of 50 case study 62-year-old woman presents with intermittent bright red...

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