Topics in Oncology

1
Topics in Oncology

• New Advances in Targeted Therapy for Colorectal
  Cancer

2
Program Overview

• Incidence and epidemiology
• Diagnosis and screening
• Metastatic CRC
• Chemotherapy
• Targeted therapy
• Antiangiogenesis
• EGFR-targeted therapy
• New directions for targeted therapy
• Adjuvant CRC
• Improving outcomes in colorectal cancer
• Quality of care
• Patient management
• Other GI cancers

3
CRC Incidence and Epidemiology
4
2006 Estimated New Cancer Cases in US
Leading Sites by Sex

• Men
• Prostate 33
• Lung and bronchus 13
• Colon and rectum 10
• Urinary bladder 6

Women 31 Breast 12 Lung and bronchus 11 Colon
and rectum 6 Uterine corpus
gt55,000 Total Colorectal Cancer Deaths
Image adapted from http//caonline.amcancersoc.or
g/cgi/content/full/55/1/10 American Cancer
Society. Cancer Facts and Figures 2006. Atlanta
ACS 2006.
5
Colorectal Cancer

• Second leading cause of cancer-related death in
  the US
• 145,000 new cases diagnosed each year in the US
• 75 of new cases in patients with no family
  history of CRC or predisposing illness
• Between 1995-2000, 20 of patients presented with
  metastatic disease at initial diagnosis

American Cancer Society. Colorectal Cancer Facts
Figures Special Edition 2005. 2005 1-24.
6
Gastrointestinal Cancers in the United States
Other digestive organs
Small intestine2
Anus
2
2
Gallbladder
3
Esophagus
6
Liver
7
Colon
41
Stomach
8
Pancreas
13
Rectum
16
American Cancer Society. Cancer Facts and Figures
2006. Atlanta American Cancer Society 2006.
7
Screening for Colorectal Cancer

• Screening methods
• Fecal occult blood testing
• Colonoscopy
• Sigmoidoscopy
• Double-contrast barium enema
• NCCN recommendation for average-risk persons
• FOBT and flexible sigmoidoscopy every 5 years or
• Colonoscopy every 10 years

NCCN Guidelines. Version 2.2006 April 2006.
8
Risk Factors for Colorectal Cancer

• CRC in first-degree family member or in 2
  second-degree
• Genetic1
• Familial adenomatous polyposis (FAP)
• Hereditary nonpolyposis colorectal cancer (HNPCC)
• Nongenetic1
• History of adenomas
• Endometrial or ovarian cancer before age 60
• Inflammatory bowel disease
• Lifestyle factors possibly associated with
  increased risk2
• Western diet, sedentary lifestyle, alcohol,
  smoking

1. NCCN Guidelines. Version 2.2006 April
2006. 2. Ahmed FE. J Environ Sci Health C Environ
Carcinog Ecotoxicol Rev. 20042291-147.
9
Staging of Colorectal Cancer
NCCN Guidelines. Version 2.2006 April 2006.
10
Lymph Node Evaluation in CRC

• Minimum of 12 LN suggested to identify stage II
  CRC according to AJCC, CAP
• Controversy surrounds number of LN needed
• Factors affecting number of LN retrieved
• Age
• Gender
• Tumor grade
• Tumor site

NCCN Guidelines. Version 2.2006 April 2006.
11
Disease Stage at Initial Diagnosis of Colon
Cancer
5
Localized
19
Regional
Distant
39
Unstaged
38
SEER Program (www.seer.cancer.gov) SEERStat
Database Incidence. Released April 2005.
12
Disease-free Survival in Patients with Colon
Cancer
13
Prognostic Factors in CRC

• Poor prognostic factors
• Bowel obstruction, perforation1
• Factors determined retrospectively, not
  prospectively validated
• Thymidylate synthase2
• 18q deletion3
• Number LN examined in colon, rectal surgery4
• Microsatellite instability
• Improved survival in younger patients5

1. Steinberg M, et al. Cancer. 1986571866-1870
2. Johnston PG, et al. J Clin Oncol.
1994122640-2647 3. Jen J, et al. N Engl J Med.
1994331213-221 4. Le Voyer TE, et al. J Clin
Oncol. 2003212912-2919 5. Gryfe R, et al. N
Engl J Med. 200034269-77.
14
Surgical Approaches in the Treatment of
Colorectal Cancer

• Surgery for resectable colon cancer
• Colectomy with en bloc removal of regional LN
• Laparoscopic-assisted surgery may be feasible
• Surgery for rectal cancer
• Transabdominal resection or transanal excision
  for certain patients with T1, T2 lesions
• Abdominal peritoneal resection or low anterior
  resection with TME for all others
• Preoperative or postoperative chemoradiotherapy
  for serosal invasion/regional node involvement

1. Clinical Outcomes of Surgical Therapy Study
Group. N Engl J Med. 20043502050-2059. 2. NCCN
Guidelines. Version 2.2006 November 2005.
15
Metastatic Colorectal Cancer
16
Treatment for Metastatic CRC

• Bolus FU/LV standard of care in US until 2000
• Five agents approved by FDA for mCRC since 1998
• Irinotecan
• Oxaliplatin
• Capecitabine
• Bevacizumab
• Cetuximab
• Median overall survival extended with newer agents

Venook A. Oncologist. 200510250-261.
17
NCCN-recommended Regimens for Metastatic CRC
Venook A. Oncologist. 200510250-261.
18
N9741 IFL vs FOLFOX vs IROX
RANDOMIZE
Irinotecan and bolus 5-FU leucovorin (IFL) (n26
4)

• N792
• Previously untreated mCRC

Oxaliplatin, infused 5-FU leucovorin (FOLFOX) (n
267)
Irinotecan and oxaliplatin (IROX) (n264)
Goldberg RM, et al. J Clin Oncol. 20042223-30.
19
N9741 FOLFOX Increases Overall Survival
Goldberg RM, et al. J Clin Oncol. 20042223-30.
20
N9741 Less Overall Toxicity with FOLFOX vs IFL

• Less diarrhea, vomiting, nausea, febrile
  neutropenia, dehydration with FOLFOX vs IFL1
• More paresthesias, neutropenia with FOLFOX
• More patients discontinued FOLFOX due to toxicity
  than progression
• Caucasians (n1297) vs African Americans (n112)2
• Higher ORR in Caucasians (OR 1.72 P0.012)
• Lower toxicity in AA
• Primarily less diarrhea
• OR for severe toxicity in Caucasians, 1.76
  (P0.006)

1. Goldberg RM, et al. J Clin Oncol.
20042223-30. 2. Goldberg RM, et al. ASCO 2006.
Abstract 3503.
21
N9741 IFL vs FOLFOX vs IROX

• In first-line mCRC, survival longer with FOLFOX
  vs
• IFL (irinotecan and bolus 5-FU leucovorin) or
• IROX (irinotecan and oxaliplatin)
• Median OS
• 19.5 mo, 15.0 mo, 17.4 mo
• Most grade 3/4 adverse events less common with
  FOLFOX
• Only paresthesias, neutropenia more common

Goldberg RM, et al. J Clin Oncol. 20042223-30.
22
FOLFOX4 Maintains Efficacy/ Safety Ratio in
Elderly Patients

• Retrospective analysis of patients receiving
  FOLFOX4
• 3,742 patients 614 aged gt70 years
• Grade 3/4 AEs more frequent in older patients
• Neutropenia (43 vs 49 P0.04)
• Thrombocytopenia (2 vs 5 P0.04)
• No difference in 60-day mortality
• No difference in FOLFOX4 efficacy

Goldberg RM, et al. 2006 ASCO GI. Abstract 228.
23
FOLFIRI Equivalent to FOLFOX4

• Phase III randomized trial compared FOLFIRI to
  FOLFOX4 in first-line advanced CRC
• Survival, response rates similar between groups
• Toxicity mild but differed by treatment
• FOLFOX
• Thrombocytopenia
• Neurosensory toxicities
• FOLFIRI
• Alopecia
• GI disturbances

Colucci G, et al. J Clin Oncol. 2005234866-4875.
24
UGT1A1 and Irinotecan Toxicity

• Individuals homozygous for UGT1A128 allele at
  increased risk of neutropenia
• Gilberts syndrome
• Allele detectable by molecular assay (Invader
  UGT1A1 Molecular Assay)
• Consider reduced initial irinotecan dose for
  these patients

Camptosar (irinotecan HCL injection) Prescribing
Information. New York, NY Pfizer, Inc. July
2005 Invader UGT1A1 Molecular Assay Product
Information. Madison, WI Third Wave
Technologies, Inc. August 12, 2005.
25
Phase III GERCOR Study FOLFOX6/FOLFIRI Sequence
RANDOMIZE
Folinic acid, FU, irinotecan (FOLFIRI) (n109)
Folinic acid, FU, oxaliplatin (FOLFOX6) (n81)

• N220
• Previously untreated mCRC

Folinic acid, FU, oxaliplatin (FOLFOX6) (n111)
Folinic acid, FU, irinotecan (FOLFIRI) (n69)
Tournigand C, et al. J Clin Oncol.
200422229-237.
26
FOLFOX6/FOLFIRI Sequences Equivalent

• FOLFIRI more grade 3/4 mucositis, grade 2
  alopecia
• FOLFOX6 more grade 3/4 neutropenia, neurosensory
  toxicity

In first-line In second-line. Tournigand C,
et al. J Clin Oncol. 200422239-237.
27
Importance of Individualizing Treatment Approach

• Optimal sequence of chemotherapy regimens unknown
• Important to consider patient factors
• Tolerability for different toxicities
• More bowel dysfunction ? may prefer oxaliplatin
• Performance status
• Patient wishes

28
FOLFOXIRI vs FOLFIRI
RANDOMIZE
FOLFIRI Irinotecan (180 mg/m2 d1) I-LV (100
mg/m2 d1,2) bolus 5FU (400 mg/m2 d1,2) 5FU
(600 mg/m2 22 h inf on d1,2) (n122)
N244 Previously untreated mCRC
Repeat q2 wk until progression
Repeat q2 wk until progression
FOLFOXIRI Irinotecan (165 mg/m2 d1) Oxaliplatin
(85 mg/m2 d1) I-LV (200 mg/m2 d1) 5FU (3200
mg/m2 48 h inf starting on d1) (n122)
Falcone A, et al. ASCO GI 2006. Abstract 227.
29
FOLFOXIRI More Effective Than FOLFIRI

• Overall response rate significantly higher with
  FOLFOXIRI
• 66 vs 41 with FOLFIRI (P0.0002)
• At median FU of 14.0 months, PFS longer with
  FOLFOXIRI
• Median PFS, 9.8 vs 6.8 months P0.0003)
• FOLFOXIRI associated with significantly more
  grade 2/3 neurotoxicity (20 vs 0 Plt0.0001)

Falcone A, et al. ASCO GI 2006. Abstract 227.
30
Survival Correlates with Availability of All
Effective Drugs
3 drugs 5-FU/LV, irinotecan, oxaliplatin. Grothey
A, et al. J Clin Oncol. 2005239441-9442.
31
Targeted Therapies in Metastatic Colorectal Cancer
32
Introduction to Targeted Therapy

• Agent targets specific pathway in the
  growth/development of malignant cells
• Current types of biologic therapy
• Tyrosine kinase receptor inhibitors
• Antibodies, small molecule inhibitors
• Angiogenesis inhibitors
• Proteasome inhibitors
• Immunotherapy
• Others

33
VEGF Primary Mediator of Angiogenesis

• Promotes endothelial cell viability and
  proliferation
• Chemotaxis
• Increases expression of collagenase, tPA, and uPA
• Increases vascular permeability and vasodilation
• Inhibits maturation of antigen-presenting
  dendritic cells

tPA, tissue plasminogen activator uPA, urokinase
plasminogen activator.
34
VEGF Family and Its Receptors
VEGF-A
VEGF-B
VEGF-C
VEGF-D
PIGF
0
0
0
0
0
VEGFR-2 (Flk-1/KDR)
NRP-1 (Neuropilin)
VEGFR-3 (Flt-4)
VEGFR-1 (Flt-1)
Unclear, but likely involved in tumor
growth (non-RTK)
Angiogenesis, lymphangiogenesis (RTK)
Angiogenesis (RTK)
Lymphangiogenesis (RTK)
RTK, receptor tyrosine kinase. Dvorak HF. J Clin
Oncol. 2002204368 Ferrara N, et al. Nat Med.
20039669.
35
Inhibition of VEGF

• Inhibits metastasis
• Blocks VEGF-induced peritumor lymph drainage1
• Blocks VEGF(A)-induced dysfunctional
  angiogenesis2
• Inhibits invasion of circulation by the tumor3
• Decreases vascular density of tumor
• Increases killing of established tumors
• Improves chemotherapy delivery to tumor

1. Dafni H, et al. Cancer Res. 2002626731-6739.
2. Nagy JA, et al. J Exp Med. 20021961497-1506.
3. Weis S, et al. J Cell Biol. 2004167223-229.
36
Mechanisms of Inhibiting VEGF
Ligand sequestration mAbs, soluble
receptors (eg, bevacizumab)
VEGF
Tyrosine kinase inhibition TKIs (eg, SU11248)
Receptor-blockingmAbs (eg, IMC-1121)
p85
VEGFR
ras
GRB2
SOS
PLCg
Transcription factor inhibition
36
37
Phase III Trial Bevacizumab IFL
RANDOMIZE
Irinotecan, bolus FU, leucovorin (IFL) 5 mg/kg
bevacizumab q2 wk (n402)
N813 Previously untreated mCRC
Stratified by study center, ECOG PS, colon vs
rectal disease, no. metastatic sites
Irinotecan, bolus FU, leucovorin (IFL)
Placebo (n411)
Hurwitz H, et al. N Engl J Med.
20043502335-2342.
38
Survival Benefit When Bevacizumab Added to IFL
Hurwitz H, et al. N Engl J Med.
20043502335-2342.
39
Bevacizumab IFL Safety
Hurwitz H, et al. N Engl J Med.
20043502335-2342.
40
Bevacizumab Safety Issues Thromboembolic Events

• Potential events
• Stroke, MI, TIA, angina, other arterial
  thromboembolic events
• Older patients at particular increased risk
• Age gt65 years
• 8.5 vs 2.9 on chemotherapy alone
• Age lt65 years
• 2.1 vs 1.4
• Permanently discontinue bevacizumab in patients
  who develop severe arterial thromboembolic event
  during treatment

Avastin (bevacizumab) Prescribing Information.
So. San Francisco, CA Genentech, Inc. February
2004.
41
Bevacizumab Safety Issues GI Perforation

• GI perforation, wound dehiscence can result in
  death
• GI perforation occurred in 2 of patients
  receiving bevacizumab plus bolus IFL
• Typical presentation
• Abdominal pain with constipation/vomiting
• Discontinue bevacizumab permanently if bowel
  perforation or wound dehiscence requiring medical
  intervention
• Proper interval between bevacizumab treatment and
  surgery occurs is unknown

Avastin (bevacizumab) Prescribing Information.
So. San Francisco, CA Genentech, Inc. February
2004.
42
Bevacizumab Safety Issues Hypertension

• 1.7 of patients developed HT resulting in
  hospitalization or treatment discontinuation
• Temporarily stop BEV if uncontrolled severe HT
  develops
• Permanently discontinue BEV if hypertensive
  crisis develops
• Monitor BP at least every 2 to 3 weeks
• More frequently in those who develop hypertension

Across all clinical studies (N1032). Avastin
(bevacizumab) Prescribing Information. So. San
Francisco, CA Genentech, Inc. February 2004.
43
Bevacizumab Safety Issues Hemorrhage

• Bevacizumab linked to infrequent cases of
  hemoptysis, GI hemorrhage, subarachnoid
  hemorrhage, and hemorrhagic stroke
• Grade 1 epistaxis occurred in 35 of patients
  receiving BEV IFL
• Generally mild and resolved spontaneously
• CNS bleeding risk in patients with CNS metastases
  unknown
• Patients with serious hemorrhage should
  discontinue BEV
• Those with recent hemoptysis should not receive
  BEV

Avastin (bevacizumab) Prescribing Information.
So. San Francisco, CA Genentech, Inc. February
2004.
44
E3200 High-dose BEV FOLFOX4 Study Design
FOLFOX4 Bevacizumab (BEV 10 mg/kg q2 wk)
(n289)
RANDOMIZE
N822 Previously treated mCRC
FOLFOX4 (n290)
Bevacizumab (10 mg/kg q2 wk) (n243)
Stratified by study center, ECOG PS, prior XRT
Giantonio BJ, et al. ASCO 2005. Abstract 2.
45
Improved Survival with High-dose Bevacizumab
FOLFOX4
P-value compares BEV FOLFOX4 vs
FOLFOX4. Giantonio BJ, et al. ASCO 2005.
Abstract 2.
46
E3200 High-dose Bevacizumab FOLFOX4 Safety

• Grade 3/4 AEs significantly more frequent with
  adding bevacizumab
• Hypertension
• Bleeding
• Neuropathy
• Vomiting
• Grade 3/4 arterial, venous thromboses equivalent
• Bowel perforation occurred in 1 of BEV-treated
  patients

Giantonio BJ, et al. ASCO 2005. Abstract 2.
47
Benefit of Adding Bevacizumab to FOLFOX4

• Adding bevacizumab to FOLFOX4 lengthened overall
  survival by 24
• Hypertension, bleeding, vomiting more common with
  bevacizumab FOLFOX4
• Bowel perforation occurred at rate of 1 with
  bevacizumab
• Bevacizumab not active as single agent

Giantonio BJ, et al. ASCO 2005. Abstract 2.
48
TREE-1/2 Bevacizumab Oxaliplatin
Fluoropyrimidine
mFOLFOX6 BEV q2 wk Bevacizumab (5 mg/kg d1)
Oxaliplatin (85 mg/m2) LV (fixed dose 350
mg) 5-FU (400 mg/m2 IV bolus followed by 2400
mg/m2 IV inf over 46 h d1) (n71)
RANDOMIZE

• N213
• Previously untreated mCRC
• Unresectable
• Adequate organ function

bFOL BEV q28 d Bevacizumab (5 mg/kg d1,
15) Oxaliplatin (85 mg/m2 d1, 15) LV (20 mg/m2
IV bolus d1, 8, 15) 5-FU (500 mg/m2 IV bolus d1,
8, 15) (n71)
CapeOx BEV q21 d Bevacizumab (7.5 mg/kg
d1) Oxaliplatin (130 mg/m2 d1) Capecitabine (850
mg/m2 bid d1-15 d1 PM only, d15 AM only) (n71)
Hochster H, et al. ASCO 2006. Abstract 3510.
49
Addition of Bevacizumab Improves Efficacy of All
Three Regimens
TTP, time from randomization to objective tumor
progression or death. Hochster H, et al. ASCO
2006. Abstract 3510.
50
TREE-2 Conclusions

• No significant additive toxicities when
  bevacizumab combined with any regimen
• Bevacizumab improved RR, TTP, OS of all regimens
  (over TREE-1 results)
• CapeOx tolerability improved when CAPE dose
  reduced to 850 mg/m2 bid

Hochster H, et al. ASCO 2006. Abstract 3510.
51
BRiTE Trial Bevacizumab Safety in Community
Setting

• BRiTE Trial
• Safety in 1968 patients taking BEV
• 12 had related SAEs after median 10 mo
• Arterial thromboembolic events, 2.1
• Grade 3/4 bleeding, 1.9
• GI perforation, 1.7
• Postop bleeding/wound healing complications, 1.2
• New hypertension requiring medication, 8.9
• Worse hypertension in patients already treated at
  baseline, 6.2

Hedrick E, et al. ASCO 2006. Abstract 3536.
52
CONCEPT Continuous Oxaliplatin Neurotoxicity
Prevention Trial
RANDOMIZE
mFOLFOX7 bevacizumab (continuous) /- IV
Calcium/magnesium

• Previously untreated mCRC
• (initiated 2/05)

mFOLFOX7 bevacizumab (intermittent
oxaliplatin) /- IV Calcium/magnesium
Study Director, Gilbert Jirau-Lucca, MS,
Bridgewater, NJ Sanofi-Aventis.
53
OPTIMOX2 Maintenance vs Chemotherapy-free
intervals
RANDOMIZE
mFOLFOX7 No maintenance until baseline
progression mFOLFOX7 reintroduction (n102)
N202 Previously untreated mCRC
mFOLFOX7 sLV5FU2 until baseline
progression mFOLFOX7 reintroduction (n100)
Maindrault-Goebel F, et al. ASCO 2006. Abstract
3504.
54
Chemotherapy-free Intervals Feasible in Some
Patients after FOLFOX

• Suggests break in therapy feasible in patients
  responding to first- line FOLFOX

Maindrault-Goebel F, et al. ASCO 2006. Abstract
3504.
55
Bevacizumab Demonstrates Value of Targeted Therapy

• Bevacizumab is the first targeted agent to show
  survival benefit in metastatic CRC
• Ongoing trials investigating optimal use of
  bevacizumab
• EGFR pathway represents another attractive target
• Involved in tumor cell growth, resistance to
  apoptosis, and metastasis

56
EGF-induced Signal Transduction and Tumorigenesis
EGF

• EGFR
• A large tyrosine kinase growth factor receptor
• Natural ligands
• TGF-?, EGF
• Potential to block multiple steps in the signal
  transduction process
• Extracellular surface
• Intracellular targets

()
EGFR
X
Anti-EGFR
K
K
PI3-K
pY
pY
MEK
pY
STAT
PTEN
AKT
MAPK
Gene transcription Cell-cycle progression
p27
X
X
X
X
Proliferation
Invasion/ metastasis
Survival/ anti-apoptosis
Angiogenesis
Perez-Soler R. Oncologist. 2004958-67.
57
Incidence of EGFR Expression in Solid Tumors
SCCHN, squamous cell carcinoma of the head and
neck. Arteaga C. Semin Oncol. 200330(suppl
7)3-14.
58
Anti-EGFR Strategies
Toxin conjugates
mAbs
TKIs
Ligand
Antisense
Cetuximab
Panitumumab
Ligand
Ligand
Ligand
mAb
Gefitinib Erlotinib
TKI
K
K
K
K
K
K
K
K
Survival and metastasis
Signal transduction
Protein synthesis
Cell death
Adapted from Raymond E, et al. Drugs.
200060(suppl 1)15-23.
59
Cetuximab Chimeric Anti-EGFR

• Mousehuman chimeric mAb
• Active alone or in combination with irinotecan in
  irinotecan-refractory patients
• Currently approved for patients with
  irinotecan-refractory metastatic CRC

Cunningham D, et al. N Engl J Med.
2004351337-345. Shitara K, et al. Cancer
Immunol Immunother. 199336373-380.
60
BOND I Cetuximab /- Irinotecan
RANDOMIZE
Cetuximab irinotecan Cetuximab (initial dose,
400 mg/m2 then weekly infusion 250 mg/m2)
irinotecan (same as prestudy therapy) (n218)

• N329
• Patients with mCRC who progressed during or
  within 3 mo after irinotecan

Cetuximab (initial dose, 400 mg/m2 then weekly
infusion 250 mg/m2) (n111)
Histamine receptor antagonist premedication given
before at least the first cetuximab infusion.
Cunningham D, et al. N Engl J Med.
2004351337-345.
61
Cetuximab Irinotecan Active in
Irinotecan-refractory Tumors
Cunningham D, et al. N Engl J Med.
2004351337-345.
62
EGFR Expression and Responses to Cetuximab

• EGFR expression did not correlate with responses
  to cetuximab

Cunningham D, et al. N Engl J Med.
2004351337-345.
63
Cetuximab Active in EGFR-negative CRC

• 16 irinotecan-refractory, EGFR-negative CRC
  patients received cetuximab in nonstudy setting
  at MSKCC
• ORR, 25 (95 CI, 4-46)
• Indicates EGFR analysis by currently available
  IHC not predictive
• Suggests against selecting, excluding patients
  based on EGFR expression as measured by currently
  available IHC

Chung KY, et al. J Clin Oncol. 2005231803-1810.
64
Predictive Value of EGFR Inhibitor-associated Rash

• Rash associated with superior responses to
  treatment
• Indicates rash can be surrogate marker of
  activity
• Presence of any rash conferred significant
  survival benefit (P0.02)
• Trend toward improved survival with increasing
  severity of rash
• Cause of correlation currently unknown

Cunningham D, et al. N Engl J Med.
2004351337-345.
65
EGFR Inhibitor-associated Rash
Acneform rash on face
Paronychial inflammation
Acneform rash on chest
Segaert S, Van Cutsem E. Ann Oncol.
2005161425-1433.
66
BOND II Bevacizumab Cetuximab /- Irinotecan
Bevacizumab Cetuximab Bevacizumab (5 mg/kg q2
wk) Cetuximab (400 mg/m2 initial dose then 250
mg/m2 weekly) (n40)
RANDOMIZE

• N81
• Patients with CRC who progressed on irinotecan
• EGFR expression not required
• No prior bevacizumab or cetuximab

Bevacizumab Cetuximab Irinotecan Bevacizumab
(5 mg/kg q2 wk) Cetuximab (400 mg/m2 initial dose
then 250 mg/m2 weekly) Irinotecan (same dose as
prev therapy) (n41)
Saltz LB, et al. ASCO 2005. Abstract 3508.
67
BOND II Cetuximab/Bevacizumab /- Irinotecan
Efficacy
Saltz LB, et al. ASCO 2005. Abstract 3508.
68
BOND II Cetuximab/Bevacizumab /- Irinotecan
Safety
Saltz LB, et al. ASCO 2005. Abstract 3508.
69
CALGB 80203 FOLFIRI or FOLFOX Cetuximab in mCRC
FOLFIRI Cetuximab (n58)
RANDOMIZE

• N224
• Patients with previously untreated mCRC
• Tissue available for EGFR testing

FOLFIRI (n55)
FOLFOX Cetuximab (n53)
FOLFOX (n58)
Venook A, et al. ASCO 2006. Abstract 3509.
70
Improved Responses with Cetuximab Added to
FOLFOX, FOLFIRI

• Overall OS at 16-month FU
• 16.9 months without cetuximab vs not reached with
  cetuximab
• No unexpected toxicities
• FOLFOX and FOLFIRI appear equivalent

Venook A, et al. ASCO 2006. Abstract 3509.
71
CALGB/SWOG 80405 Cetuximab, Bevacizumab, and
FOLFOX/FOLFIRI
RANDOMIZE
FOLFOX or FOLFIRI Cetuximab

• First-line mCRC
• Planned accrual 2300

FOLFOX or FOLFIRI Cetuximab Bevacizumab
FOLFOX or FOLFIRI Bevacizumab
Physician-selected chemotherapy. Stratification
based on chemotherapy, prior adjuvant
chemotherapy, prior pelvic RT. Study Chairs,
Alan P. Venook MD, University of California, San
Francisco and Charles D. Blanke, MD, FACP, Oregon
Health and Science University.
72
Unanswered Questions About Cetuximab

• Must it be used with irinotecan?
• First-line or refractory disease?
• Adjuvant therapy?
• Combinations of HER-1/HER-2 inhibitors?

73
Newest mAbs Are Fully Human
Matuzumab
Panitumumab
Cetuximab
Chimeric 34 mouse
Humanized 10 mouse
100 human
100 mouse
Developments in Hybridoma Technology
74
Possible Advantages of Fully Humanized Antibody

• May reduce likelihood of generating antibodies
  against therapeutic antibody
• Could maximize efficacy over long treatment
  period
• May reduce risk of developing infusion reactions

75
Panitumumab Proposed Mechanism of Action
Not FDA approved for the treatment of
CRC. Weiner LM, et al. ASCO 2005. Poster
presentation available at http//www.abgenix.com/d
ocuments/ASCO20200520Weiner20Poster20FINAL.pdf
. Accessed 8/24/05.
76
Panitumumab Human Anti-EGFRPhase II Study

• Patients with mCRC failing multiple standard
  chemotherapy regimens (N148)
• Prior treatment failure
• Fluoropyrimidine leucovorin
• Irinotecan, oxaliplatin, or both
• EGFR overexpression by IHC required
• Patients with brain metastases ineligible
• 2.5 mg/kg IV panitumumab given weekly over 1-h
  infusion in 8-wk cycles

Malik I, et al. ASCO 2005. Abstract 3520.
77
Panitumumab Activity

• Results comparable to cetuximab
• PR, 9
• SD, 29
• Median PFS, 13.6 weeks (95 CI, 8.3-16.1 weeks)
• Median OS, 37.6 weeks (95 CI, 25.6-42.4 weeks)
• Responses observed in patients with up to 4 prior
  regimens
• Response rates not affected by EGFR expression

Malik I, et al. ASCO 2005. Abstract 3520.
78
Panitumumab Phase II Monotherapy Safety

• Skin toxicity in 95 of patients
• Grade 3 AEs
• Skin toxicity, 7
• Fatigue, 3
• Vomiting, nausea, dyspnea, diarrhea
• 1 each
• One infusion-related grade 3 event on second
  infusion
• Grade 4 pulmonary embolism, 1
• No HAHA in 107 patients tested at baseline,
  postbaseline

Malik I, et al. ASCO 2005. Abstract 3520.
79
Panitumumab Active in EGFR Low/Negative mCRC

• Phase II study of treatment-refractory patients
  with mCRC with low or negative EGFR expression1
• 88 patients enrolled to receive 6 mg/kg
  panitumumab q2 wk
• Interim analysis of efficacy (n23), safety
  (n80)
• Week 16 PR13 (EGFR-neg vs low, 18 vs 8)
• Skin toxicity, 93 (15 grade 3)
• Infusion reactions, 5 (grade 3, 1)
• Similar findings in interim analysis of 39
  patients with EGFR expression gt10 (8 PR rate,
  21 SD)2

1. Hecht JR, et al. ASCO 2006. Abstract 3547. 2.
Berlin J, et al. ASCO 2006. Abstract 3548.
80
Phase III Study Panitumumab vs Best Supportive
Care
RANDOMIZE
Panitumumab (6 mg/kg q2 wk) BSC (n231)
PD

• N463
• Patients third-line mCRC
• EGFR expression required

Stratification based on ECOG score, geographic
region
Optional Panitumumab Crossover study
Best Supportive Care (n232)
PD
Peeters M, et al. AACR 2006. Abstract CP-1.
81
Panitumumab Improves PFS Over Best Supportive Care

• PFS significantly longer with panitumumab vs BSC
• Hazard ratio, 0.54 (95 CI, 0.44-0.66
  Plt0.000000001)
• No correlation between EGFR expression, responses
• No grade 3/4 infusion reactions

Plt0.0001 Peeters M, et al. AACR 2006. Abstract
CP-1.
82
Panitumumab vs Best Supportive Care Results

• Crossover study
• 1 CR, 9 PR, 32 SD
• At interim analysis (n250), OS equivalent
• OS after censoring BSC patients who responded in
  crossover
• HR with panitumumab0.78 (95 CI, 0.61-1.01)
• Severity of skin toxicity correlated with overall
  survival
• Grade 2-4 vs grade 1, HR0.61 (95 CI, 0.40-0.95
  P0.0278)
• No anti-panitumumab Abs detected after treatment
  in 185 patients tested

Peeters M, et al. AACR 2006. Abstract CP-1.
83
Panitumumab vs Best Supportive Care in mCRC
Safety
Treated with IV magnesium replacement 2
developed 2o hypercalcemia. Peeters M, et al.
AACR 2006. Abstract CP-1.
84
PACCE Panitumumab Advanced CRC Evaluation Study
RANDOMIZE
Panitumumab Oxaliplatin- or irinotecan-based
chemotherapy bevacizumab (q2 wk)

• First-line mCRC
• No CNS metastases
• No CV risk factors

Oxaliplatin- or irinotecan-based chemotherapy
bevacizumab (q2 wk)
Trial supported by Amgen, Inc.
85
Small Molecule Inhibitors Gefitinib, Erlotinib,
PTK/ZK

• Considered inactive as single agent in refractory
  patients
• Small phase II data of standard chemotherapy with
  erlotinib or gefitinib suggest possible
  incremental benefit vs historical control
• GERCOR trial in Europe testing FOLFOX/bevacizumab
  vs XELOX/bevacizumab /- erlotinib in first line
  (2x2 design)
• Large phase III trial showed no improvement
  adding PTK/ZK to FOLFOX4 in first-line mCRC

Kuo T, et al. J Clin Oncol. 2005235613-5619
Meyerhardt JA, et al. J Clin Oncol.
2006241892-1897 Hecht JR, et al. ASCO 2005.
Abstract 3.
86
NCCN Guidelines Advanced/mCRC
Recommendations for Patients with Good Tolerance
to Intensive Therapy
NCCN Guidelines. Version 2.2006 April 2006.
87
NCCN Guidelines Advanced/mCRC
Recommendations for Patients with Poor Tolerance
to Intensive Therapy
NCCN Guidelines. Version 2.2006 April 2006.
88
Special Consideration for Liver Metastases

• Liver is the most common site of distal
  metastases
• 25 of patients with liver metastases have no
  other metastases, can be treated with regional
  therapy
• Regional therapies being investigated
• Cryosurgery
• Hepatic artery infusion of floxuridine (FUDR)
• Radiofrequency ablation
• Systemic chemotherapy often best option for
  metastases beyond the liver

Yoon SS, Tanabe KK. Oncologist. 19994197-208.
89
Survival after Primary or Secondary Resection of
Liver Metastases
1
Resectable (N425) Initially nonresectable
(N95)
0.9
0.8
0.7
54
0.6
0.5
Proportion surviving
34
0.4
27
50
0.3
34
0.2
29
19
0.1
0
10
8
6
4
2
0
Survival time (years)
Topham C, Adam R. Semin Oncol. 2002293.
90
LiverMetSurvey Prognostic Factors in Liver
Metastases

• International internet registry evaluating
  prognostic factors
• In 2,122 evaluable patients
• 5 y OS42
• 10 y OS26
• Independent poor prognostic factors
• gt3 metastases (Plt0.0001)
• Bilateral metastases (P0.0002)
• Largest metastasis gt5 cm (P0.03)
• Preoperative chemotherapy improved survival only
  in patients with gt5 metastases

Adam R, et al. ASCO 2006. Abstract 3521.
91
Adjuvant Treatment of Colon Cancer
92
Adjuvant Treatment According to Stage

• Stage I
• No adjuvant treatment
• Stage II
• Treatment controversial
• Stage III
• Consensus for treatment

93
Recent Advances in Adjuvant Therapy

• FOLFOX4 recommended for early stage colon cancer1
• Irinotecan not beneficial in multiple trials
• Capecitabine active as single agent2
• Continuous infusion of 5-FU less toxic, as
  effective as bolus FU or FU/LV3
• Current studies investigating targeted agents
• Cetuximab, bevacizumab

1. Andre T, et al. N Engl J Med.
20043502343-2351. 2. Twelves C, et al. N Engl J
Med. 2005352(26)2696-2704. 3. Meta-analysis
Group in Cancer. J Clin Oncol. 199816301-308.
94
MOSAIC FOLFOX4 vs LV5FU2
RANDOMIZE
FOLFOX4 oxaliplatin, leucovorin, fluorouracil
(bolus infusion) (n1123)
N2246 Patients with resected stage II/III colon
cancer
LV5FU2 leucovorin, fluorouracil (bolus
infusion) (n1123)
Andre T, et al. N Engl J Med. 20043502343-2351.
95
Superior DFS with FOLFOX4 vs LV5FU2

• Stage III patients
• Significant 25 DFS risk reduction at 4.7 y
• Stage II patients
• No significant DFS risk reduction at 4.7 y

Plt0.001. 1. Andre T, et al. N Engl J Med.
20043502343-2351. 2. de Gramont A, et al. ASCO
2005. Abstract 3501.
96
Toxicity with FOLFOX4 vs LV5FU2

• All-cause mortality, 0.5 each arm

Late recovery from sensory neuropathy was
observed. de Gramont A, et al. ASCO 2005.
Abstract 3501.
97
MOSAIC FOLFOX4 vs LV5FU2

• In 2,246 patients with resected stage II/III
  colon cancer, FOLFOX provided 24 relative risk
  reduction in 4-y DFS
• More neutropenia, sensory neuropathy with FOLFOX4
• Late recovery from neuropathy observed
• All-cause mortality equivalent between arms (0.5)

98
Adjuvant Therapy for Stage II Disease Where Do
We Stand?

• FDA approved FOLFOX4 for stage III disease only
• Main limitation for stage II clinical trials
• Absolute benefit expected is about half the
  benefit in stage III
• Twice as many patients are needed
• Available studies not powered to detect a
  statistically significant benefit in this
  subgroup of patients

99
Adjuvant Chemotherapy in Stage II Disease

• Important to discuss potential risks/benefit with
  patient
• Factors to consider
• Number of LN analyzed
• Poor prognostic features
• Comorbidities
• Anticipated life expectancy
• Chemotherapy not appropriate for all patients

100
Irinotecan Negative in Adjuvant Setting
1. Saltz L, et al. ASCO 2004. Abstract 3500. 2.
Van Cutsem E, et al. ASCO 2005. Abstract 8. 3.
Ychou M, et al. ASCO 2005. Abstract 3502.
101
NSABP C-07 FLOX vs 5-FU/LV
RANDOMIZE
FLOX Weekly LV-modulated 5-FU/LV
Oxaliplatin (n1200)
N2407 Patients with stage II/III colon cancer
FULV Weekly LV-modulated bolus 5-FU/LV (n1207)
Wolmark N, et al. ASCO 2005. Abstract 3500.
102
Superior DFS with FLOX vs FULV
1
0.9
0.8
DFS probability
0.7
Plt0.004 HR 0.79 95 CI, 0.67-0.93
0.6
0.5
0
1
2
3
4
Wolmark N, et al. ASCO 2005. Abstract 3500.
103
Toxicity with FLOX vs FULV

• Symptoms more often reported by patients on FLOX
  vs FULV 18 mo after treatment (n395)
• Ringing in ears (OR, 2.4) foot discomfort (OR,
  4.4) foot numbness/tingling (OR, 6.0) hand/foot
  pain in cold (OR, 2.9)

Due to bowel wall thickening. Wolmark N, et al.
ASCO 2005. Abstract 3500. Land SR, et al. ASCO
2006. Abstract 3564.
104
X-ACT Capecitabine vs 5-FU/LV
24 wk
RANDOMIZE
Oral capecitabine (1250 mg/m2 bid on d1-14 q21
d) (n1004)
N1987 Patients with resected stage III colon
cancer
Bolus 5-FU leucovorin (Mayo Clinic
Regimen) (n983)
Twelves C, et al. N Engl J Med.
20053522696-2704.
105
Capecitabine As Effective As Monthly Bolus of
5-FU/LV
1.0 0.8 0.6 0.4
3-year DFS Capecitabine (n1
004) 64.2 5-FU/LV (n983) 60.6
Estimated probability
HR0.87 (95 CI, 0.75-1.00)P0.0528
0 1 2 3 4 5 6
Years
Twelves C, et al. N Engl J Med.
2005352(26)2696-2704.
106
Improved Safety with Capecitabine vs Monthly
Bolus 5-FU/LV
Treatment-related Grade 3/4 AEs
100 80 60 40 20 0
Capecitabine (n993) Bolus 5-FU/LV (n974)
Patients ()






Diarrhea Stomatitis Hand-foot Neutropenia
Nausea/ Alopecia syndrome vomiting
Plt0.001. Cassidy J, et al. ASCO 2004. Abstract
219.
107
X-ACT Study Conclusions

• Capecitabine at least equivalent to IV 5-FU/LV
• Fewer adverse events with capecitabine
• Dose used (1250 mg/m2 bid x 14 d) is higher than
  most oncologists would use in patients with
  advanced disease

Twelves C, et al. N Engl J Med.
2005352(26)2696-2704. Cassidy J, et al. ASCO
2004. Abstract 219.
108
NSABP C-08 mFOLFOX6 Bevacizumab
RANDOMIZE
Bevacizumab q14 d for 6 mo (in absence of PD)
mFOLFOX6 Bevacizumab q14 d for 12 courses

• Patients with resected stage II/III colon cancer
• Target enrollment, 2632

mFOLFOX6 q14 d for 12 courses
Trial opened Sept 2004.
Study Chair, Carmen J. Allegra, MD, Network for
Medical Communication and Research.
109
AVANT Trial FOLFOX vs FOLFOX/BEV vs XELOX/BEV
Temporarily Suspended due to Deaths on
XELOX/Bevacizumab Arm Independent DSMB
Recommended Resuming Recruitment in May 2006
RANDOMIZE
FOLFOX4

• Patients with stage II/III colon cancer
• Target enrollment, 3450

FOLFOX4 Bevacizumab
XELOX Bevacizumab
de Gramont A. Hôpital Saint- Antoine, Paris,
France.
110
N0147 Adjuvant Cetuximab
RANDOMIZE
FOLFOX4 Cetuximab

• Patients with resected stage III colon cancer
• Target enrollment, 2300

(FOLFOX then FOLFIRI) Cetuximab
FOLFIRI Cetuximab
Study by NCCTG/NCI/ECOG. Principal Investigator,
Frank Sinicrope, MD, Mayo Clinic.
111
NCCN Guidelines for Adjuvant Therapy

• For stage III patients
• 6 months of 5-FU/LV, capecitabine, or
  5-FU/LV/oxaliplatin (FLOX, FOLFOX4, mFOLFOX6)
• Same recommendation for stage II patients with no
  high-risk features
• For high-risk stage II patients
• Consider same regimens
• Consider radiation therapy for patients with T4
  penetration to a fixed structure

Category 2B (nonuniform consensus). NCCN
Guidelines. Version 2.2006 April 2006.
112
Preoperative vs Postoperative ChemoRT in Rectal
Cancer

• 823 patients received preoperative or
  postoperative chemoradiotherapy
• Less toxicity with preoperative CMT no survival
  difference

Sauer R, et al. N Engl J Med. 20043511731-1740.
113
Long-term Outcomes after CMT Followed by TME for
Rectal Cancer

• 297 consecutive patients with locally advanced
  rectal cancer received preoperative CMT followed
  by TME
• Estimated 10-year OS, 58
• Estimated 10-year RFS, 62
• OS significantly improved among patients with
  gt95 pathologic response

Guillem JG, et al. Ann Surg. 2005241829-838.
114
Moving Forward Topics of Ongoing Research in CRC

• Determine best setting for different agents
• Optimize sequence of therapies
• Evaluate new agents and regional therapeutic
  approaches
• Define molecular mechanisms of CRC to identify
• Novel ways of approaching known targets
• New therapeutic targets
• Patients most likely to benefit from targeted
  therapies
• Methods of monitoring response to therapy

115
Improving Outcomes in Colorectal Cancer
116
Treatment Choices and Challenges

• Incorporate discussions across disciplines
• Improve early detection and appropriate adjuvant
  therapy
• Further define predictors of response
• Define lengths of treatment
• Ensure on-time delivery and full, planned dose of
  chemotherapy to optimize outcomes
• Can we return to therapy previously used?
• Cost/benefit analyses must continue
• Continue development of newer agents

117
Factors beyond Treatment Selection Are Central to
Outcomes

• Other factors in treatment have significant
  impact on clinical outcomes
• Quality of care
• Management of side effects
• Patient education, involvement, and communication
• Effective therapies given in the proper disease
  setting with a high quality of care will produce
  the best clinical outcomes

118
Quality of Cancer Care Is an Important Component
of Treatment

• Many patients believe they are receiving
  suboptimal care
• Benefits of measuring quality of care
• Focuses us to improve quality
• Identifies areas that need improving
• Quality Oncology Practice Initiative (QOPI)
• Coordinated by ASCO
• Promotes self-examination, improvement
• Every 6 months measures developed by oncologists
  are collected
• Practice identities concealed, data entered into
  database
• Allows practices to compare their progress

119
Components of Quality of Cancer Care

• Resources
• Staff, equipment
• Clinical outcomes
• Are results meeting expected targets?
• Process
• Proper timing, use of screenings, prescribing
  medications, vaccinations

120
Patient Issues in Colorectal Cancer

• Symptom management key to success of therapy
• Careful monitoring allows early intervention
• Assess AE risk at baseline
• Comorbidities, current medications, risk of
  bleeding/clotting, family history, etc
• Educate patients on importance of monitoring for
  symptoms, complications
• Example blood pressure monitoring

121
Delivered Chemotherapy Dose Intensity and
Treatment Outcomes

• Positive relationship between dose intensity,
  tumor response rate demonstrated in many common
  cancers, including CRC
• Achieving improved clinical outcomes may depend
  on delivering chemotherapy above a certain
  threshold of dose intensity

Chu E, DeVita VT Jr. In DeVita VT, et al.
Cancer Principles Practice of Oncology.
2001289-306.
122
Ways to Enhance Chemotherapy Dose Delivery

• Effective tools for evaluation important
• Develop performance improvement tool(s) to help
  track current practices in chemotherapy
  administration
• Adequate and proactive risk assessment
• Active reviews
• Study rate of toxicities and determine if
  preventive methods are being appropriately used
• Education
• Educate personnel, including physicians, about
  RDI
• Advocacy
• Use RN advocate to keep patients on track
• Proactive attitude and prevention
• Use preventive measures to avoid cancellations,
  reduce complications and enhance RDI

123
Managing Side Effects in Colorectal Cancer
124
Fatigue Affects Most Cancer Patients

• Physiologic predisposing factor/etiologies
• Underlying disease
• Treatment (anemia, infection, malnutrition, etc)
• Sleep disorders
• Immobility, lack of exercise
• Chronic pain
• Use of centrally acting drugs
• Psychosocial factors

125
Patient-reported Areas Negatively Affected by
Fatigue
Ability to work
61
Physical well-being
60
Ability to enjoy lifein the moment
57
Emotional well-being
51
Intimacy with partner
44
Ability to take care of family
42
Relationships with family and friends
38
Concerns about mortality and survival
33
0
10
20
30
40
50
60
70
Patients ()
Vogelzang NJ, et al. Semin Hematol. 199734(suppl
2)4-12.
126
Cancer-related Fatigue an Important Issue

• Patients reported that fatigue had greater impact
  on daily life than pain
• 80 of oncologists considered fatigue to be
  undertreated or overlooked
• 50 of patients discussed treatment options for
  fatigue with oncologists
• 27 of oncologists recommended any treatment
• Treatments for fatigue generally successful when
  used

Vogelzang NJ, et al. Semin Hematol. 199734(suppl
2)4-12.
127
Managing Fatigue in Patients with Colorectal
Cancer

• Patient education is key
• Correct potential etiologies if possible
• Treat anemia, sleep disorders, etc
• Antidepressants for fatigue-associated major
  depression
• Pharmacologic treatments
• Psychostimulants, low-dose corticosteroids
• Nonpharmacologic strategies
• Exercise, stress management, nutrition, activity
  modification

Portenoy RK, Itri LM. Oncologist. 199941-10.
128
Anemia Highly Prevalent in Colorectal Cancer

• Prevalence increases from 44 to 63 with
  radiation

100
90
80
70
61.49
60
58.25
Percentage of cancer patients with anemia
507
50
49.66
40
39.511
32.48
30
2910
25.94
22.43
20.512
20
122
10
7.91
0
Lung
Prostate
Ovarian
Colon
Head and
Larynx
neck
Adapted from http//www.anemia.org/professionals/r
esources/slides/cancer.ppt388,19,Slide 19. 1.
Rassam JW, et al. Thorax. 19753086-90 2. Song
SZ, et al. Chin Med J (Engl). 198710097-102 3.
Dunphy EP, et al. Int J Radiat Oncol Biol Phys.
1989161173-1178 4. Obermair A, et al. Oncol
Rep. 20007639-644 5. Cappell MS, et al. J
Clin Gastroenterol. 199214227-235 6. Foti CE,
et al. Am Surg. 197036129-135 7. Twine RW, et
al. J Natl Med Assoc. 198678187-192 8. Fass L,
et al. Am J Med Sci. 1966251255-259 9. Lee
WR, et al. Int J Radiat Oncol Biol Phys.
1998421069-1075 10. Dubray B, et al.
Radiology. 1996201553-558 11. Von Knorring,
et al. Scand J Urol Nephrol. 198115279-283 12.
Grant KL. P and T. 199318191.
129
Negative Consequences of Anemia in CRC

• Fatigue
• Decreased quality of life
• Increased mortality
• Decreased treatment efficacy

130
NCCN Clinical Practice Guidelines Algorithm for
Cancer and Treatment-related Anemia
Asymptomatic (risk factors)
Asymptomatic (no risk factors)
Symptomatic
Transfuse as indicated and/or consider
erythropoietic therapy
Observation and periodic re-evaluation
Consider erythropoietic therapy
Conduct iron studies (serum iron, total
iron-binding capacity, serum ferritin)
Epoetin alfa
Darbepoetin alfa
Hb 10-11 g/dL consider erythropoietic therapy
Hblt10 g/dL strongly consider erythropoietic
therapy NCCN. Clinical Practice Guidelines in
Oncology v.2.2006-Cancer and Treatment-related
Anemia Available at http//www.nccn.org/physician
_gls/f_guidelines.html. Accessed June 24, 2006.
131
Darbepoetin alfa in CIA in GI Cancers

• 2 studies enrolled 671 patients with GI cancers
  and anemia
• Study 2 regimen effective with lower mean weekly
  dose

Without imputation. Blayney D, et al. ASCO GI
2005. Abstract 251.
132
Every-3-Week Darbepoetin alfa Noninferior to
Weekly Dosing

• Double-blind, randomized, active-control phase
  III trial of 705 patients (16 CRC) with anemia
  receiving chemotherapy
• Study compared two DA doses (N705)
• Weekly (2.25 mg/kg) or q3 wk (500 mg) for 15
  weeks
• q3 wk dose noninferior to weekly dose
• Fewer transfusions with q3 wk (unadjusted, 23 vs
  30)
• Target Hb with q3 wk vs weekly
• 84 vs 77
• Safety comparable

Canon JL, et al. J Natl Cancer Inst.
200698273-284.
133
2006 NCCN Anemia Guidelines Erythropoietic
Therapy Options
Epoetin alfa 150 U/kg tiw
Increase to 300 U/kg tiw
or Epoetin alfa 40,000 U q wk
Increase to 60,000 U q wk
or Darbepoetin alfa 2.25 µg/kg q wk
Increase to 4.5 µg/kg q wk
or Darbepoetin alfa 500 µg q3 wk
Decrease to 300 µg/kg q3 wk Darbepoetin
alfa 3 µg/kg q2 wk Increase to 5 µg/kg q2 wk
or Darbepoetin alfa 200 µg q2 wk Increase to
300 µg q2 wk
Package Insert Dosing
Commonly Used Regimens
Boccia R, et al. Oncologist. 200611(4)409-417.
NCCN. Clinical Practice Guidelines in Oncology
v.2.2006-Cancer and Treatment-related Anemia.
Available at http//www.nccn.org/physician_gls/f_
guidelines.html. Accessed May 15, 2006.
134
Treatment-specific Side Effects in Colorectal
Cancer
135
Managing Irinotecan Side Effects

• Early diarrhea, other cholinergic symptoms
• Prevent or treat with atropine (0.25-1 mg IV or
  SC)
• Late diarrhea
• Treat promptly with loperamide
• Fluid, electrolyte replacement
• Antibiotics for ileus, fever, severe neutropenia
• Delay chemotherapy until bowel function returns
  to pretreatment level for 24 hours with no
  anti-diarrhea medication
• Grade 2-4 late diarrhea ? decrease irinotecan dose

Camptosar (irinotecan) Prescribing Information.
New York, NY Pfizer, Inc. July 2005
136
Managing Irinotecan Side Effects (cont.)

• Manage neutropenic complications with antibiotics
• Temporarily omit irinotecan during cycle if
• Neutropenic fever
• ANC lt1000/mm3
• After ANC gt1000/mm3, reduce irinotecan dose
• Consider CSF if neutropenia significant

Camptosar (irinotecan) Prescribing Information.
New York, NY Pfizer, Inc. July 2005.
137
NCI Recommendations for Managing IFL-induced
Diarrhea
Benson AL, et al. J Clin Oncol. 2004222918-2926.
138
Managing Oxaliplatin Side Effects

• Common
• Acute neurotoxicity (in 1st 2 wk of therapy)
• Distal paresthesias (numbness, tingling) or
  dysesthesias (pain) often triggered by cold
• Reversible by warming hands
• Rare (lt1)
• Pharyngolaryngeal dysesthesia
• Educate patients to breathe in warm air, drink
  warm fluids
• Chronic neurotoxicity (cumulative- after several
  cycles)
• Reversible- usually gone within 1 year

139
Managing Oxaliplatin Side Effects (cont.)

• Calcium gluconate (1 g) and magnesium sulfate (1
  g) 15 min before, after oxaliplatin
• Small retrospective study showed substantial
  reduction in any neuropathy1
• Increase duration of infusion (up to 6 hours)
• Oral calcium and magnesium (anecdotal)

1. Gamelin E, et al. ASCO 2002. Abstract 624.
140
Xaliproden Reduces Oxaliplatin-related Neuropathy

• 18-20 of patients on oxaliplatin develop grade
  3/4 PSN
• Xaliproden
• An oral neurotrophic agent
• Double-blind, randomized, controlled, phase III
  trial
• 649 patients with first-line mCRC received
  FOLFOX4 xaliproden or placebo
• Xaliproden reduced grade 3/4 PSN by 39
  (P0.0203)
• No effect on FOLFOX4 efficacy

Cassidy J, et al. 2006 ASCO Gastrointestinal
Cancers Symposium. Abstract 229.
141
Managing Capecitabine Side Effects

• Patient education key for this home-based therapy
• Capecitabine can produce 5-FU-like side effects
• Most symptoms less common than with IV 5-FU
• Only hand-foot syndrome more common
• Treatment modification only proven relief
• Temporary interruption, dose modification will
  likely resolve symptoms without adversely
  affecting outcomes

Marse H, et al. Eur J Oncol Nurs.
20048(suppl1)S16-30.
142
Managing Bevacizumab Side Effects

• Hypertension common with bevacizumab
• Suggest lifestyle modifications
• New or additional hypertensive therapy may be
  needed
• Monitor blood pressure at least every 2-3 wk
• More frequently in those who develop hypertension
• Monitor patients for bleeding

143
Managing Bevacizumab Side Effects (cont.)

• Assess for signs of potential thrombosis
• Initiate treatment promptly if thromboembolic
  event occurs
• Infusion-related symptoms
• Usually mild and self-limited
• Most often occur during first few infusions
• If symptoms develop
• Stop infusion until symptoms improve
• Use medications according to protocol
  (antihistamines, corticosteroids, acetaminophen,
  etc)

144
Treating EGFR-associated Rash
Segaert S, Van Cutsem E. Ann Oncol.
2005161425-1433.
145
Rash Management Recommendations for Patients

• Hydrating measures
• Bath oils instead of gel/soap
• Wash in tepid water
• Emollients
• Limit sun exposure use sunscreens
• Avoid tight shoes to prevent paronychia
• Explain to patient link between rash, response
  rate

Segaert S, Van Cutsem E. Ann Oncol.
2005161425-1433.
146
Cetuximab Infusion Reactions

• 3 of patients have severe reactions 90 at
  first infusion
• Administer prophylactic H1 antagonist prior to
  infusion
• Grade 1/2
• Permanently reduce infusion rate by 50
• Grade 3/4
• Immediately, permanently discontinue cetuximab
• Management strategies
• Monitor patient vigilantly
• Have readily available resources
• Initiate protocols per institution or practice

Erbitux (cetuximab) Prescribing Information.
ImClone Systems and BMS, Inc. March 2006.
147
Appendix

• Other GI Cancers

148
Pancreatic Cancer
149
Current State of Pancreatic Cancer

• Fourth leading cause of cancer-related death in
  US
• 1-y survival lt20 5-y survival lt5
• Surgery only potential curative option only 15
  of patients are candidates
• Systemic therapy with gemcitabine standard
  therapy since 1997
• Continued investigations into combination therapy

Jemal A, et al. CA Cancer J Clin.
20055510-30. Lillemoe KD. Ann Surg.
1995221133-148.
150
Agents Evaluated with Gemcitabine Showing No
Overall Survival Benefit
1. Riess H, et al. ASCO 2005. Abstract 4009 2.
Herrmann R, et al. ASCO 2005. Abstract 4010 3.
Rocha Lima CM, et al. J Clin Oncol. Abstract
3776 4. Heinmann V, et al. ASCO 2003. Abstract
1003 5. OReilly E, et al. ASCO 2004. Abstract
4006 6. Richards DA, et al. ASCO 2004. Abstract
4007 7. Louvet C, et al. ASCO 2004. Abstract
4008.
151
Gemcitabine Capecitabine in Pancreatic Cancer
RANDOMIZE
Gemcitabine Capecitabine Gemcitabine 1000 mg/m2
weekly x 3 q4 wk Capecitabine 1660 mg/m2/d for 21
days then 7 days rest (n267)
N553 Patients with previously untreated
advanced/ metastatic pancreatic cancer
Gemcitabine (1000 mg/m2 weekly x 7 q8 wk then 1
wk rest thereafter weekly x 3 q4 wk) (n266)
Cunningham D, et al. European Cancer Conference
(ECCO) 2005. Abstract PS11.
152
Superior Survival with Gemcitabine Capecitabine
in Pancreatic Cancer

• 20 improvement in overall survival with
  combination

P0.026. Cunningham D, et al. European Cancer
Conference (ECCO) 2005. Abstract PS11.
153
Gemcitabine Erlotinib Approved for Advanced
Pancreatic Cancer

• Based on phase III trial of 569 patients
• Addition of erlotinib to gemcitabine
  significantly improved survival vs gemcitabine
  alone
• Superior OS ? HR, 0.81 (95 CI, 0.67-0.97
  P0.025)
• Longer 1-year survival (24 vs 17)
• Longer PFS ? HR, 0.76 (P0.003)
• Incidence of grade 3/4 toxicity equivalent
  between groups

Moore MJ, et al. J Clin Oncol. 20052316s.
Abstract 1.
154
Gem Platin A