Translating Clinical Trial Data into the Community Setting: A Case-Based Approach to Metastatic Colorectal Cancer—Overview - PowerPoint PPT Presentation

Loading...

PPT – Translating Clinical Trial Data into the Community Setting: A Case-Based Approach to Metastatic Colorectal Cancer—Overview PowerPoint presentation | free to download - id: 3ba81b-MzFjN



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Translating Clinical Trial Data into the Community Setting: A Case-Based Approach to Metastatic Colorectal Cancer—Overview

Description:

Translating Clinical Trial Data into the Community Setting: A Case-Based Approach to Metastatic Colorectal Cancer Overview Axel Grothey, MD – PowerPoint PPT presentation

Number of Views:174
Avg rating:3.0/5.0
Slides: 79
Provided by: clinicians
Learn more at: http://www.clinicianschannel.com
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Translating Clinical Trial Data into the Community Setting: A Case-Based Approach to Metastatic Colorectal Cancer—Overview


1
Translating Clinical Trial Data into the
Community Setting A Case-Based Approach to
Metastatic Colorectal CancerOverview
  • Axel Grothey, MD
  • Professor of Oncology
  • Department of Oncology
  • Mayo Clinic, College of Medicine
  • Rochester, Minnesota

2
New Agents Have Significantly Improved Treatment
and Patient Outcomes
More regimens provide more options for multiple
lines of therapy to extend survival
a FOLFIRI b FOLFOX c IFL, FOLFIRI, FOLFOX, and
FU/LV 5-FU 5-fluorouracil IFL
irinotecan5-FUleucovorin LV leucovorin.
Venook A. Oncologist. 200510250.
3
NCCTG/Intergroup Trial N9741 Efficacy
25
19.5 (P .0001)
20
15
15
Median Months
8.7 (P .0014)
10
6.9
5
0
IFL
FOLFOX
IFL
FOLFOX
Overall Survival
Progression-Free Survival
Response rate IFL 31, FOLFOX 45 (P .002)
NCCTG North Central Cancer Treatment Group IFL
irinotecan 5-FU leucovorin FOLFOX
leucovorin 5-FU oxaliplatin.
Goldberg RM, et al. J Clin Oncol. 20042223.
4
Tournigand Trial (N 220)
FOLFOX FOLFIRI FOLFIRI FOLFOX
(1st line 2nd line) (1st line 2nd
line) 111 69 109 81
No. Patients
RR 54 4 56 15 Resection of hepatic
metastases 21 9 PFS
(mo) 8.0 2.5 8.5 4.2 Median OS (mo)
20.6 21.5
FOLFOX leucovorin 5-FU oxaliplatin FOLFIRI
leucovorin 5-FU irinotecan RR response
rate PFC progression-free survival OS
overall survival.
Tournigand C, et al. J Clin Oncol. 200422229.
5
Different Philosophies
FOLFOXIRI PACCE
Piling up
Sequencing
FOCUS CAIRO
Courtesy of Dr. A. Grothey.
6
CAIROTrial Design
Courtesy of Dr. C.J. Punt.
7
CAIROOverall Survival
Median OS 17.4 vs 16.3 mo
Reprinted from Koopman M, et al. Lancet.
2007370135, with permission from Elsevier.
8
Phase III Trial of FOLFOXIRI vs FOLFIRI as
First-Line Therapy of Advanced Colorectal Cancer
aExternally reviewed b67 2nd line FOLFOX RR
Response Rate CR Completed Response PR
Partial Response SD Stable Disease
Falcone A, et al. J Clin Oncol. 2007251670.
9
Concept of All 3 DrugsUpdate 2005 11 Phase III
Trials, 5768 Patients
22 21 20 19 18 17 16 15 14 13 12
First-Line Therapy
Infusional 5-FU/LV irinotecan Infusional
5-FU/LV oxaliplatin Bolus 5-FU/LV
irinotecan Irinotecan oxaliplatin Bolus
5-FU/LV LV5FU2 FOLFOXIRI CAIRO
Median OS (mo)
P .0001
0 10 20 30 40 50
60 70 80
Patients with 3 Drugs ()
2007
OS (mo) 13.2 ( 3 drugs x 0.1), R2 .85
Grothey A, Sargent D. J Clin Oncol. 2005239441.
10
mAbs Target Tumor Cell-Bound EGFR
Cell survival
Metastasis
Angiogenesis
Courtesy of Dr. A. Grothey.
11
NCIC CTG CO.17Cetuximab vs BSC Progression-Free
Survival
1.0
0.9
0.8
0.7
HR 0.68 (95 CI 0.570.80) P-value lt .0001
0.6
Proportion Progression-Free
0.5
OS 6.1 vs 4.6 mo HR 0.77, P .0046 (NO
cross-over)
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
Months
CETUXIMAB BSC
BSC
CENSORED
CENSORED
Reprinted from Jonker DJ, et al. N Engl J Med.
2007357(20)2040-2048, with permission from the
Massachusetts Medical Society.
12
CRYSTAL StudyFirst-Line
  • Patients with EFGR mCRCa
  • Randomized to
  • FOLFIRI FOLFIRI
    Cetuximab
  • (n 599)
    (n 599)
  • Primary endpoint PFS (independent
    review)
  • Secondary endpoints RR, DCR, OS, safety, QOL
  • a Stratified by region, ECOG PS
  • Van Cutsem E, et al. ASCO June 1-5, 2007.
    Abstract 4000. Courtesy of Dr. E. Van Cutsem.

13
CRYSTAL TrialPrimary EndpointPFS ITT
Population Independent Review
1.0
RR
FOLFIRI cetuximab
46.9
FOLFIRI
38.7
P .0038
Progression-Free Survival Estimate
8.9 mo
1- y PFS rate 23 vs 34
8.0 mo
HR 0.851 P .0479
Progression-Free Survival Time (months)
Van Cutsem E, et al. ASCO June 1-5, 2007.
Abstract 4000. Courtesy of Dr. A. Grothey.
14
mAbs Target Tumor Cell-Bound EGFR
Cell survival
Courtesy of Dr. A. Grothey.
15
K-ras as Biomarker for Panitumumab Response in
Metastatic CRC
  • PFS log HR significantly different depending on
    K-ras status (P lt.0001)
  • Percentage decrease in target lesion greater in
    patients with wild-type K-ras receiving
    panitumumab

Patients with Mutant K-ras
Patients with Wild-Type K-ras
Pmab BSC
1.0
Mean (Wk)
Median (Wk)
1.0
BSC alone
Pmab BSC
Events/No. ()
0.9
Mean (Wks)
Median (Wks)
0.9
BSC alone
Events/No. ()
0.8
19.0
12.3
115/124 (93)
0.8
9.3
7.3
0.7
114/119 (96)
9.9
7.4
0.7
76/84 (90)
0.6
10.2
7.3
95/100 (95)
0.6
HR 0.45 (95 CI 0.340.59)
Proportion with PFS
0.5
Stratified log rank test P lt .0001
Proportion with PFS
0.5
HR 0.99 (95 CI 0.731.36)
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
0
40
44
40
44
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
42
46
48
50
52
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
42
46
48
50
52
Weeks
Weeks
Amado RG, et al. ECCO December 8-11, 2007.
Abstract 0007. Courtesy of Dr. RG Amado.
16
Anti-VEGF Approaches and AgentsSummary
Bevacizumab VEGF-trap
VEGFR-1
IMC-1121b
VEGFR-2
IMC-18F1
VEGFR-3
Sunitinib Vatalanib Sorafenib Vandetanib Motesanib
Axitinib AZD2171 Pazopanib
Sunitinib Sorafenib Vandetanib Motesanib Axitinib
AZD2171 Pazopanib
Sunitinib Vatalanib Motesanib Axitinib AZD2171 Paz
opanib
Src
PI3-K
PKC
Akt
Akt/PKB
MEK
eNOS
EPC recruitment Migration Invasion
Lymphangiogenesis Vasculogenesis
MAPK
Permeability
Migration
Proliferation
Survival
Reprinted from Kowanetz M, et al. Clin Cancer
Res. 2006125018-5022, with permission from the
American Association for Cancer Research.
17
Phase III Trial of IFL /- Bevacizumab in
MCRCSurvival
1.0
HR 0.66, P .00004 Median survival 15.6 vs
20.3 mo
0.8
0.6
Proportion surviving
0.4
Treatment Group
0.2
IFL placebo IFL bevacizumab
0
20
0
10
30
40
Duration of survival (mo)
Reprinted from Hurwitz H, et al. N Engl J Med.
2004350(23)2335-2342, with permission from the
Massachusetts Medical Society.
18
BICC-CSummary
NR not reached.
Fuchs CS, et al. J Clin Oncol. 2007254779.
19
XELOX vs FOLFOX /- Bevacizumab Roche
NO16966Study Design
Recruitment June 2003May 2004
Recruitment Feb 2004Feb 2005
XELOX placebo n 350
XELOX bevacizumab n 350
XELOX n 317
FOLFOX4 placebo n 351
FOLFOX4 bevacizumab n 350
FOLFOX4 n 317
Protocol amended to 2x2 placebo-controlled design
after bevacizumab phase III data became
available (n 1401)
Initial 2-arm open-label study (n 634)
Cassidy J, et al. ASCO June 1-5, 2007. Abstract
4026. Courtesy of Dr. J. Cassidy.
20
PFS Chemotherapy Bevacizumab Primary Objective
Met
1.0 0.8 0.6 0.4 0.2 0
HR 0.83 97.5 CI 0.720.95 (ITT) P .0023
Progression-Free Survival Estimate
9.4
8.0
0 5 10 15 20 25
Months
Saltz L, et al. ASCO. June 1-5, 2007. Abstract
4028. Courtesy of Dr. L. Saltz.
21
NO16966 Study Drug Exposure Median Months of
Treatment
Per protocol, patients discontinuing
oxaliplatin could continue with a
fluoropyrimidine placebo or bevacizumab.
Patients could also remain on a fluoropyrimidine
alone or placebo or bevacizumab alone but not
oxaliplatin alone.
Saltz L, et al, Proc Am Soc Clin Oncol. 2007
Abstract 4028. Courtesy of Dr. L. Saltz.
22
OPTIMOX Studies
FOLFOX 4 until TF
OPTIMOX-1 n 620
FOLFOX 7
FOLFOX 7
sLV5FU2
Tournigand C, et al. J Clin Oncol. 2006 22229.
Maindrault-Goebel F, et al. ASCO. June 1-5, 2007.
Abstract 4013. Courtesy of Dr. A. Grothey.
23
OPTIMOX-2Overall Survival
Lesson from OPTIMOX-2Dont stop treatment before
progression
Months
Courtesy of Dr. A. Grothey.
24
PACCE Study Randomized, Open-Label, Controlled
Phase 3b Trial
Panitumumab 6 mg/kg q2wk Ox-CT Bevacizumab
Ox-based CT (eg, FOLFOX) N 800 Inv choice
R A N D O M I Z E
S C R E E N I N G
11
Ox-CT Bevacizumab
Panitumumab 6 mg/kg q2wk Iri-CT Bevacizumab
Iri-basedCT (eg, FOLFIRI) N 200 Inv choice
11
Iri-CT Bevacizumab
Stratification factors ECOG score, prior
adjuvant tx, disease site, Ox doses/Iri regimen,
number of metastatic organs. Tumor assessments
q12wk until disease progression or intolerability.
PACCE Panitumumab Advanced Colorectal Cancer
Evaluation.
Courtesy of Dr. J. Hecht.
25
Limited Update of PFSOx-CT Cohort (Central
Review, Apr 2007 Data Cutoff)
Pmabbev/Ox-CT Bev/Ox-CT
HR 1.29 (95 CI, 1.051.58)
M
o
n
t
h
s
0
5
1
0
1
5
2
0
P
a
t
i
e
n
t
s

a
t

r
i
s
k

P
m
a
b

b
e
v
/
O
x
-
C
T


N
4
1
3
2
6
7
9
2
2
1
3
4
1
0
2
9
8
9
6
2
1
1
b
e
v
/
O
x
-
C
T


N
ITT set
Courtesy of Dr. J. Hecht.
26
PACCEGrade 3/4 AEs of Interest Ox-CT Cohort
MedDRA v9.0 preferred terms Graded per NCI CTCAE
v3.0 aGrade 5 infections occurred in 2 (1) pmab
bev/Ox-CT pts and 3 (1) bev/Ox-CT pts. bGrade
5 pulmonary embolism occurred in 2 (1) pmab
bev/Ox-CT pts.
Courtesy of Dr. J. Hecht.
27
CALGB/SWOG Intergroup Trial 80405 (n 2289)
  • Dealers Choice
  • FOLFOX or FOLFIRI
  • Randomize to
  • Bevacizumab Cetuximab Bevacizumab

  • Cetuximab

Primary endpoint overall survival HR
1.25 (22 vs 27.5 months)
http//www.cancer.gov protocol ID CALGB-80405
28
BRiTE RegistryPatients with Bevacizumab Beyond
Progression (BBP)
Evaluable patients (n 1953)
BRiTE N 1953 1445 pts with 1st progression
932 deaths (1/21/07 cut-off) Median follow-up
19.6 mo
1st progression (n 1445)
Physician decisionno randomization
BBP (n 642)
No BBP (n 531)
No Post-progression treatment (n 253)
Grothey A, et al. J Clin Oncol. 2008 (in press).
29
BRiTEPatient Outcome Based on Treatment Post 1st
PD
BBP (n 642)
No BBP (n 531)
No Post-PD Treatment (n 253)
PD progression BBP bevacizumab beyond
progression OS overall survival.
Grothey A, et al. J Clin Oncol. 2008 (in press).
30
Multivariate Analysis of Pre- and Post-Treatment
Variables on Survival
Grothey A, et al. J Clin Oncol. 2008 (in press).
31
SWOG/NCCTG/NCIC 2nd-Line Trial S0600/iBET
(Intergroup BEV Continuation Trial)
Open since June 2007
(FOLF)IRI/C225
MCRC pretreated with FOLFOX BEV or CAPOX
BEV or OPTIMOX BEV
(FOLF)IRI/C225 BEV 5 mg/kg
(FOLF)IRI/C225 BEV 10 mg/kg
n 1260 Primary endpoint OS (HR 1.30 12 ? 15.6
mo) Principal Investigators Gold P, Grothey A
Courtesy of Dr. A. Grothey.
32
Courtesy of Dr. A. Grothey.
33
Case Study Stage IV Metastatic Colon Cancer in
a Patient with Ulcerative Colitis
  • J. Philip Kuebler, MD, PhD
  • Principal Investigator
  • Columbus Community Clinical Oncology Program
  • Columbus, Ohio

34
(No Transcript)
35
Martin
  • A 71-year-old man presented with chronic
    abdominal pain and recent blood in his stool
  • There were no changes in bowel habits
  • He had a history of ulcerative colitis and
    associated symptoms
  • There was no family history of cancer
  • He was moderately overweight but has no other
    medical problems
  • Physical exam revealed abdominal tenderness

36
Martin
  • An abdominal CT scan showed a large mass in the
    ascending colon
  • The CT scan also showed bilateral masses in his
    liver
  • Abdominal and retroperitoneal lymph nodes, as
    well as pulmonary nodules, were also present
  • A liver biopsy was positive for metastatic
    adenocarcinoma consistent with a colon primary
  • After being told surgery was not an option due to
    the extent of his disease, he was referred to a
    medical oncologist

37
Advances in the Treatment of Colorectal Cancer
1980
1985
1990
1995
2000
2005
Oxaliplatin

Cetuximab
Targeted therapies
Panitumumab
Therapeutic concepts
5-FU 5-fluorouracil CT chemotherapy. Courtesy
of Dr. J. Kuebler.
38
First-Line Chemotherapy in MCRC Phase III
TrialsProgression-Free Survival
Saltz
Douillard
de Gramont
N9741a
Tournigandb
d
c
c
d
c
PFS or TTP (mo)
aUpdate After a median follow-up of 4.3 years,
median TTP was significantly longer in the FOLFOX
arm, 9.2 mo vs 6.5 mo for IROX (P.001) and 6.0
mo for IFL (P.001) bIn first-line therapy
cP.001 dP.01. MCRC metastatic colorectal
cancer PFS progression-free survival TTP
time to progression. de Gramont A, et al. J
Clin Oncol. 2000182938 Douillard JY, et al.
Lancet. 20003551041 Goldberg RM, et al. J Clin
Oncol. 20042223 Saltz LB, et al. N Engl J Med.
2000343905 Sanoff HKK, et al. 43rd ASCO June
15, 2007. Abstract 4067 Tournigand C, et al. J
Clin Oncol. 200422229. Courtesy of Dr. J.
Kuebler.
39
First-Line Bevacizumab in MCRC Progression-Free
Survival
aPlt.001 bPlt.005 cP.004 vs mIFL. Fuchs CS, et
al. J Clin Oncol. 2007254779 Hochster HS, et
al. ASCO June 15, 2006. Abstract 3510 Hurwitz
H, et al. N Engl J Med. 20043502335 Saltz LB,
et al. ASCO GI January 1721, 2007. Abstract
238. Courtesy of Dr. J. Kuebler.
40
First-Line Cetuximab in MCRC Phase III
TrialsProgression-Free Survival
CALGB 80203a
CRYSTAL
b
PFS or TTP (mo)
a16 months follow-up bPlt.05. Conclusions on
overall survival await further follow-up. Van
Cutsem E, et al. 43rd ASCO June 15, 2007.
Abstract 4000 Venook A, et al. 42nd ASCO June
26, 2006. Abstract 3509. Courtesy of Dr. J.
Kuebler.
41
Correlation Between Survival and Percentage of
Patients Receiving 3 Drugs in Phase III Trials
3 drugs 5-FU/LV, irinotecan, oxaliplatin. Reprin
ted from Grothey A, et al. J Clin Oncol.
2005239441,with permission from the American
Society of Clinical Oncology.
42
Managing Side Effects of ChemotherapyDiarrhea
  • Treat diarrhea aggressively and promptly with
    antidiarrheals
  • Fluid/electrolyte replacement for grade gt3
    diarrhea
  • Hospitalization/antibiotics for diarrhea with
    febrile neutropenia
  • Delay chemotherapy until bowel function back to
    grade 01 with no antidiarrheals
  • Consider dose reduction if diarrhea grade gt3
  • Anticholinergic therapy for diarrhea due to
    irinotecan

Kuebler JP, et al. Cancer. 20071101945.
43
Managing Side Effects of ChemotherapyNeurotoxicit
y
  • Distal paresthesias/dysethesias triggered by cold
  • Educate patients to breathe in warm air, drink
    warm fluids
  • Acute paresthesias tend to last longer with each
    cycle and may increase as duration of infusion
    increases
  • Efficacy of calcium and magnesium still being
    evaluated
  • Evaluate neurotoxicity prior to each treatment
  • Stop oxaliplatin when paresthesias begin to
    interfere with activities of daily living
  • Residual paresthesias can last up to 2 years

Land SR, et al. J Clin Oncol. 2007242205.
44
Managing Side Effects of ChemotherapyBevacizumab
  • Treat hypertension (blood pressure persistently
    gt140/90) with oral agents
  • Stop chemotherapy if blood pressure uncontrolled
    on oral agents
  • Monitor dipstick urine assays
  • Interrupt treatment if proteinuria gt2 gm/24 hours
  • Risk for arterial thrombotic events greater in
    patients aged gt65 years or with arteriosclerosis
  • Mild epistaxis common, major bleeding rare
  • Avoid surgery 1 month prior to and 68 weeks
    after bevacizumab
  • GI perforation in 1.5 of patients

Gordon MS, Cunningham D. Oncology. 200569(suppl
3)25 Kozloff M, et al. ASCO GI January 1721,
2007. Abstract 364 Rosiak J, Sadowski L. Clin J
Oncol Nurs. 20059407 Scappaticci FA, et al. J
Natl Cancer Inst. 200799232 Ellis LM, et al. J
Clin Oncol. 2005234853 Sugrue M, et al. 42nd
ASCO June 26, 2006. Abstract 3535.
45
Managing Side Effects of ChemotherapyCetuximab
  • Treat grade 1 acneiform skin rash with topical
    anti-inflammatory agents
  • Treat pruritis with oral antihistamines
  • Treat grade gt2 skin rash with oral tetracycline
    (minocycline at 100 mg/day)
  • Treat paronychia with topical antiseptics/antibiot
    ics
  • Due to severe infusion reactions in 3 of
    patients, premedicate with antihistamines
  • Monitor patients for 1 hour posttreatment

Segaert S, Van Cutsem E. Ann Oncol. 2005161425.
46
(No Transcript)
47
Martin
  • The patient had a marked initial response to
    FOLFOX bevacizumab, documented by CT scan and
    drop in CEA
  • After 11 cycles of chemotherapy, he was still in
    response, but he was beginning to have problems
    with fine motor control
  • His wife had to help button his shirts and he had
    difficulty holding a pen to write his name
  • He discussed options for further therapy
    (maintenance vs observation) with his medical
    oncologist

48
OPTIMOX Studies
OPTIMOX-1 maintenance therapy1 (N 620)
sLV5FU2
OPTIMOX-2 CT-free interval2 (N 202)
sLV5FU2
CT-free interval
1. Tournigand C, et al. J Clin Oncol.
200422229. 2. Maindrault-Goebel F, et al.
43rd ASCO June 15, 2007. Abstract
4013. Courtesy of Dr. A. Grothey.
49
Chemotherapy-Free Intervals of mFOLFOX in
Patients With MCRC (OPTIMOX-2)OS
OS
P .0549
Probability
Months
MCRC metastatic colorectal cancer OS overall
survival. Maindrault-Goebel F, et al. 43rd ASCO
June 15, 2007. Abstract 4013. Courtesy of Dr. F.
Maindrault-Goebel.
50
Martin
  • The patient was placed on maintenance treatment
    with infusional 5-FU leucovorin
  • The neurotoxicity improved quickly but did not
    resolve entirely
  • After 4 months, his CEA began to rise and a
    follow-up CT scan confirmed progressive disease
  • Options for second-line chemotherapy were
    discussed as the patients performance status had
    not changed

51
Second/Third-Line Therapy Options in MCRC
  • If FOLFOX bevacizumab used as first-line,
    consider FOLFIRI or irinotecan, /- cetuximab, as
    second-line treatment
  • IF FOLFIRI bevacizumab used as first-line,
    consider FOLFOX, CAPOX or cetuximab irinotecan
    as second-line
  • If 5-FU/LV bevacizumab used as first-line (not
    preferred), consider FOLFOX, CAPOX, FOLFIRI, or
    irinotecan as second-line
  • For third-line therapy, consider cetuximab,
    panitumumab, or cetuximab irinotecan
  • Avoid single-agent bevacizumab or oxaliplatin
  • Consider going back to FOLFOX or FOLFIRI

52
FOLFIRI Cetuximab Bevacizumab in Patients
with Relapsed MCRC (S0600/iBET)Phase III Trial
Design
FOLFIRI cetuximab placebo (q2w)
RANDOM I Z A T I ON
Previously treated patients with MCRCa N 1250
FOLFIRI cetuximab bevacizumab (5 mg/kg q2w)
FOLFIRI cetuximab bevacizumab (10 mg/kg q2w)
Primary end point Overall Survival
(OS) Secondary end point Progression-Free
Survival (PFS)
MCRC metastatic colorectal cancer iBET
Intergroup Bevacizumab Continuation
Trial. aPatients progressed on FOLFOX, OPTIMOX,
or CAPEOX bevacizumab as first-line
regimen. http//clinicaltrials.gov/ct/show/NCT004
99369?order1. Accessed August 27, 2007.
53
Summary
  • First-line treatment regimen should be based on
    the disease and patient situation
  • mFOLFOX, FOLFIRI, CAPOX, or 5-FU/LV with
    bevacizumab or cetuximab are all reasonable
    choices for first-line therapy
  • Maintenance therapy after response is reasonable
    but there are no randomized data
  • Bevacizumab is an option for maintenance and with
    second-line therapy
  • Cetuximab plus irinotecan is an option for
    second- or third-line therapy
  • Overall survival of patients with metastatic
    unresectable disease has been steadily increasing
    with the use of regimens in sequence or in
    combination (FOLFOXIRI)

54
Case Study Surgically Resectable Metastatic
Colorectal Cancer
  • Cathy Eng, MD
  • Assistant Professor
  • Department of Gastrointestinal Medical Oncology
  • The University of Texas M. D. Anderson Cancer
    Center
  • Houston, Texas

55
(No Transcript)
56
Case PresentationAnn
  • Ann is a 49-year-old female with newly diagnosed
    metastatic colorectal cancer who presents for
    treatment recommendations
  • Six weeks earlier, she presented to the ER with
    weakness, nausea and vomiting, and abdominal pain
  • She denies any prior constitutional symptoms or
    change in bowel habits until the past month
  • Physical exam revealed a young, thin female in
    moderate distress with 8/10 right-sided abdominal
    pain
  • Her ECOG PS was 1
  • Diagnostic studies included blood work,
    obstruction series, and CT scan of the chest,
    abdomen, and pelvis
  • Findings Hb 10.1 g/dL, MCV 73 fL, LFTs WNL
  • Obstruction series of the abdomen demonstrated
    air fluid levels and dilated small bowel loops
    consistent with small bowel obstruction

ER Emergency Room ECOG PS Eastern
Cooperative Group performance status CT
computed tomography Hb hemoglobin MCV mean
corpuscular volume LFTs liver function tests
WNL within normal limits.
57
CT Scan at Baseline
2 coalescent lesions 4.8 cm in greatest diameter
Carcinoma of the cecum
Courtesy of Dr. C. Eng.
58
Case Presentation
  • Preoperative carcinoembryonic antigen (CEA)
    38 ng/mL (normal, lt5 ng/mL)
  • No known family history of colon cancer
  • Emergent right hemicolectomy performed due to
    bowel obstruction
  • Palpation of the liver revealed no additional
    hepatic lesions, a finding confirmed by
    intraoperative ultrasound
  • The surgeon elected to resect the hepatic lesions
    at a later date
  • Postoperative pathology revealed a moderately
    differentiated adenocarcinoma of the colon
    penetrating through the muscularis propria, with
    5 of 22 lymph nodes positive
  • AJCC staging T3N2M1 right-sided colon cancer

59
(No Transcript)
60
Case Presentation Postoperative state
  • Ann has recovered fully
  • ECOG PS 0
  • She has only lost 5 lbs since the surgery
  • She has 12 bowel movements daily
  • Postoperative CEA 16 ng/mL
  • LFTs within normal limits
  • Postoperative CT scan reveals no new lesions
  • She is anxious to initiate therapy
  • She desires to know what her options are to be
    cancer-free in the future
  • What is the best approach to address her
    metastatic disease in the liver?

61
Options in Management of Hepatic Metastasis from
Colorectal Cancer
  • Prioritize multidisciplinary discussion with the
    liver surgeon
  • Options
  • Surgical resection
  • Neoadjuvant systemic chemotherapy
  • Conversion chemotherapy
  • Hepatic arterial infusion therapyfallen out of
    favor

62
Immediate Hepatic Resection
  • Resectable disease
  • Role of adjuvant chemotherapy is unknown
  • Duration of adjuvant chemotherapy is unknown
  • To date, no randomized trial of surgical
    resection followed by observation vs adjuvant
    chemotherapy has been completed

63
Neoadjuvant Systemic Chemotherapy
  • Majority of prior studies have been retrospective
  • Ideal for surgically resectable or borderline
    resectable disease
  • Allows indirect measure of chemotherapy
    responsiveness
  • Be wary of chemotherapy-induced hepatic
    toxicities
  • Do not treat until best response
  • Radiologic complete response ? pathologic
    complete response

64
Phase III EORTC 40983 Perioperative FOLFOX for
Resectable Hepatic Metastases
Randomize N 364
Surgery
FOLFOX4 6 cycles (3 months)
  • Primary endpoint progression-free survival
  • Eligibility criteria lt 4 liver lesions
  • (metachronous or synchronous),
  • surgically resectable, no extrahepatic disease

Surgery
FOLFOX4 6 cycles (3 months)
Only prospective trial to date.
Nordlinger B, et al. 43rd ASCO June 1-5, 2007.
Abstract LBA5.
65
Complications of Surgery
P .04
Courtesy of Dr. B. Nordlinger.
66
Final Results of EORTC 40983
Statistically significant only in those patients
surgically resected.
Courtesy of Dr. B. Nordlinger.
67
Conversion Chemotherapy
  • Defined as systemic chemotherapy provided to
    decrease tumor burden and improve likelihood of
    surgical resection
  • Previously conducted studies
  • FOLFOXIRI
  • CRYSTAL
  • NO16966

68
FOLFIRI vs FOLFOXIRI Phase III (Gruppo Oncologico
Nord Ovest)
Randomize untreated MCRC N244
FOLFOXIRI x 12
FOLFIRI X 12
Falcone A, et al. J Clin Oncol. 2007251670.
69
FOLFOXIRI vs FOLFIRI Results
Investigators assessment
Patients with liver metastases only
Falcone A, et al. J Clin Oncol. 2007251670.
70
Role of Biologics in Hepatic Resection?
71
CRYSTAL Trial Liver Resection with Cetuximab
FOLFIRI Alone Cetuximab FOLFIRI
ITT Population
Liver-MetastasesOnly Population
P .0034
No Residual Tumor in Patients with Liver
Metastases
n 134/n 122
n 599/Group
n 599/Group
Courtesy of Dr. E. Van Cutsem.
72
Lucrative Points in the Management of Hepatic
Resection
73
Duration of Chemotherapy
  • Chemotherapy may induce hepatic toxicities
  • At a median of 4 months of chemotherapy with
    fluoruracil and irinotecan or oxaliplatin, many
    patients developed
  • Sinusoidal dilatation
  • Steatosis
  • Steatohepatitis
  • Associated with increased 90-day postoperative
    mortality
  • Shorter duration of chemotherapy (e.g. 2-3 months
    may be optimal)
  • Biologic therapy
  • Bevacizumab recommended to be held 4-8 weeks
    prior to surgical resection

Vauthey JN, et al. J Clin Oncol. 2006242065.
74
Radiologic CR Pathologic Cure?
  • 19982004
  • 586 consecutive patients treated for up to 10
    hepatic metastases
  • 38 patients had radiologic CR of gt1 hepatic
    lesion
  • Surgery was conducted 4 weeks after start of
    neoadjuvant treatment
  • Number of neoadjuvant cycles 9 5
  • Types of chemotherapy
  • 5-FU/LV 9
  • FOLFOX 17
  • FOLFIRI 12

Nordlinger B, et al. 42nd ASCO June 2-6, 2006.
Abstract 3501.
75
Radiological CR Cure?
  • 66 liver lesions had a radiologic CR
  • 20 (9 pts) had macroscopic residual disease
  • Mean size 12 7 mm
  • Viable cancer cells at biopsy
  • 15 (15 pts) had microscopic disease
  • No visible tumor was seen surgically or by IOUS
  • Site was resected
  • Viable cancer cells were seen in 12 of 15 liver
    mets
  • 31 lesions in 14 pts showed no evidence of
    disease surgically or by IOUS
  • Site was not resected
  • One year follow-up 23 of 31 mets had in situ
    recurrences
  • Findings 55 of 66 (83) of the lesions were not
    pathologically cured
  • Conclusions Consider pursuing surgical resection
    regardless of no radiographic evidence of
    disease.

Nordlinger B, et al. 42nd ASCO June 2-6, 2006.
Abstract 3501.
76
Case Presentation
  • Ann received 5 cycles of FOLFOX bevacizumab,
    followed by 1 cycle of FOLFOX without bevacizumab
  • Except for mild cold hypersensitivity, she
    tolerated her chemotherapy well
  • In the interim, genetics counseling showed that
    she is microsatellite-stable
  • Her CEA concentration is now 7.2 ng/mL
  • CT of her chest, abdomen, and pelvis all showed
    response to therapy
  • Her PET/CT scan is negative for extrahepatic
    disease

77
Postchemotherapy CT Scan
  • The patient undergoes right hepatic resection
    without complications
  • Minimal lt5 steatosis was noted
  • Due to her excellent response to chemotherapy,
    the patient opted for an additional 46 months of
    adjuvant FOLFOX bevacizumab

Courtesy of Dr. C. Eng.
78
Conclusions
  • Multidisciplinary management is crucial for a
    patient with resectable hepatic metastases
  • Resection of the primary tumor is patient
    dependent based on presenting symptoms
  • Be wary of duration of neoadjuvant therapyDo not
    treat a patient to cure for hepatic metastases
    but treat until surgically resectable
  • Radiolologic CR is not equivalent to pathologic
    CR and must still be evaluated if possible
  • Challenge identifying the original site of
    disease intraoperatively
  • To date, the role of biologic therapy in
    conjunction with chemotherapy as neoadjuvant
    treatment has not been defined in a large
    randomized phase II or phase III trial
About PowerShow.com