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

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

Axel Grothey, MDProfessor of Oncology

Department of OncologyMayo Clinic, College of Medicine

Rochester, Minnesota

RegimenFirst Line

Second Line

FDA Approval Year

5-FU √ √ 1962

Irinotecan (monotherapy) √ 1996

IFLa √ 2000

Capecitabine (monotherapy) √ 2001

Oxaliplatin + infusional 5-FU/LVb √ √Second line 2002

First line 2004

Cetuximab (with or without irinotecan) √ 2004

Bevacizumab + IV 5-FU-based regimensc √ √First line 2004

Second line 2006

Panitumumab (single agent) Salvage 2006

Venook A. Oncologist. 2005;10:250.

New Agents Have Significantly Improved Treatment and Patient Outcomes

More regimens provide more options formultiple lines of therapy to extend survival

a FOLFIRIb FOLFOXc IFL, FOLFIRI, FOLFOX, and FU/LV 5-FU = 5-fluorouracil; IFL = irinotecan+5-FU+leucovorin; LV = leucovorin.

NCCTG/Intergroup Trial N9741Efficacy

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

15

19.5(P = .0001)

6.9

8.7(P = .0014)

0

5

10

15

20

25

IFL FOLFOX IFL FOLFOX

Med

ian

Mo

nth

s

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.

Tournigand Trial (N = 220)

FOLFOXFOLFOX FOLFIRI FOLFIRI FOLFOXFOLFOX (1st line 2nd line) (1st line 2nd line)

111 69 109 81

RR 54% 4% 56%15%

Resection ofhepatic metastases 21%21% 9%

PFS (mo) 8.0 2.5 8.5 4.2

Median OS (mo) 20.6 21.5 Tournigand C, et al. J Clin Oncol. 2004;22:229.

2nd line62%

2nd line74%

No. Patients

FOLFOX = leucovorin + 5-FU + oxaliplatin; FOLFIRI = leucovorin + 5-FU + irinotecan;RR = response rate; PFC = progression-free survival; OS = overall survival.

Different Philosophies…

Piling up

Sequencing

FOLFOXIRIPACCE

FOCUSCAIRO

Courtesy of Dr. A. Grothey.

CAIRO—Trial Design

Arm A Arm B

Randomize

CapecitabineN = 397

Capecitabine +oxaliplatin

N = 143 (36%)

IrinotecanN = 251 (62%)

Capecitabine +oxaliplatin

N = 213 (53%)

Capecitabine +irinotecan

N = 398

1st line

2nd line

3rd line

Courtesy of Dr. C.J. Punt.

CAIRO—Overall Survival

Reprinted from Koopman M, et al. Lancet. 2007;370:135, with permission from Elsevier.

Median OS17.4 vs 16.3 mo

Phase III Trial of FOLFOXIRI vs FOLFIRI as First-Line Therapy of Advanced Colorectal Cancer

FOLFIRIN = 122

FOLFOXIRIN = 122

P-value

RRa (%) 34 60 <.0001

CR+PR+SDa (%) 68 81 N/A

R0 resection (%) (all patients)

6 15 .033

R0 resection (%) (liver limited)

12 36 .017

PFS (mo) 6.9 9.8 .0006

OS (mo) 16.7b 22.6 .032aExternally reviewed; b67% 2nd line FOLFOXRR= Response Rate; CR= Completed Response; PR= Partial Response; SD= Stable Disease

Falcone A, et al. J Clin Oncol. 2007;25:1670.

Concept of “All 3 Drugs”—Update 200511 Phase III Trials, 5768 Patients

OS (mo) = 13.2 + (% 3 drugs x 0.1), R^2 = .85Grothey A, Sargent D. J Clin Oncol. 2005;23:9441.

0 10 20 30 40 50 60 70 80

Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV LV5FU2

FOLFOXIRI

CAIRO

22

21

20

19

18

17

16

15

14

13

12

Med

ian

OS

(m

o)

Patients with 3 Drugs (%)

P = .0001

First-Line Therapy

Multivariate analysis:Effect on OS P

First-line doublet .69All 3 drugs .005

2007

mAbs Target Tumor Cell-Bound EGFR

MetastasisAngiogenesis

Cell survival

Extracellular

Intracellular

Ligand

EGF-R

PI3K

Akt

Ras

Raf

MEK

MAPK

Cell motility

Proliferation

DNA


NCIC CTG CO.17—Cetuximab vs BSCProgression-Free Survival

CETUXIMAB + BSCCENSORED

BSCBSCCENSOREDCENSORED

Pro

po

rtio

n P

rog

ress

ion

-Fre

e

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

Months

00 33 66 99 1212 1515

HR 0.68HR 0.68 (95% CI = 0.57–0.80)

PP-value < .0001-value < .0001

Study ArmStudy Arm Med PFS Med PFS 95% CI95% CI

Cetuximab + BSCCetuximab + BSC 1.91.9 1.8–2.11.8–2.1

BSC aloneBSC alone 1.81.8 1.8–1.91.8–1.9

Reprinted from Jonker DJ, et al. N Engl J Med. 2007;357(20):2040-2048, with permission from the Massachusetts Medical Society.

OS 6.1 vs 4.6 moHR 0.77, P = .0046(NO cross-over)

CRYSTAL Study—First-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 RR, DCR, OS, safety, QOL

a Stratified by region, ECOG PSVan Cutsem E, et al. ASCO; June 1-5, 2007. Abstract 4000. Courtesy of Dr. E. Van Cutsem.

CRYSTAL Trial—Primary Endpoint=PFS ITT Population Independent Review

Progression-Free Survival Time (months)

Pro

gre

ssio

n-F

ree

Su

rviv

al E

stim

ate

1.0

0.8

0.9

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 2 4 6 8 10 12 14 16 18 20

8.9 mo

8.0 mo

FOLFIRI

FOLFIRI + cetuximab

1- y PFS rate23% vs 34%

Van Cutsem E, et al. ASCO; June 1-5, 2007. Abstract 4000. Courtesy of Dr. A. Grothey.

HR = 0.851 P = .0479

RR

46.9%

38.7%

P = .0038

mAbs Target Tumor Cell-Bound EGFR

Cell survival

Extracellular

Intracellular

Ligand

EGF-R

PI3K

Akt

Raf

MEK

MAPK

Cell motility

MetastasisAngiogenesis

Proliferation

DNA

Ras


K-ras as Biomarker for Panitumumab Response in Metastatic CRC

Amado RG, et al. ECCO; December 8-11, 2007. Abstract 0007. Courtesy of Dr. RG Amado.

• PFS log HR significantly different depending on K-ras status (P <.0001)• Percentage decrease in target lesion greater in patients with wild-type K-ras receiving panitumumab

Patients with Mutant K-ras

Mean(Wk)

Stratified log rank test: P < .0001

115/124 (93)

Patients with Wild-Type K-ras

1.0

0.9

Pro

po

rtio

n w

ith

PF

S

0.8

0.70.60.50.4

0.3

0.20.1

00 2 4 6 8 10

Events/No. (%)Median

(Wk)

Pmab + BSCBSC alone

114/119 (96)

12.37.3

19.09.3

HR: 0.45 (95% CI: 0.34–0.59)

12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52

Weeks

Pro

po

rtio

n w

ith

PF

S

1.0

0.90.8

0.70.60.50.4

0.30.20.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 2830 32 3436 38 4042 44 46 48 50

Weeks

Pmab + BSCBSC alone Mean

(Wks)

76/84 (90)

Events/No. (%)Median(Wks)

95/100 (95)

7.47.3

9.910.2

HR: 0.99 (95% CI: 0.73–1.36)

52

Anti-VEGF Approaches andAgents—Summary

Reprinted from Kowanetz M, et al. Clin Cancer Res. 2006;12:5018-5022, with permission from the American Association for Cancer Research.

EPC recruitmentMigrationInvasion

Proliferation SurvivalMigration Permeability

LymphangiogenesisVasculogenesis

VEGFR-3VEGFR-2

VEGFR-1

MAPK

MEK

PKC

Akt/PKB

Akt

eNOS

PI3-K

Src

IMC-18F1

BevacizumabVEGF-trap

IMC-1121b

SunitinibVatalanibMotesanib

AxitinibAZD2171

Pazopanib

SunitinibVatalanibSorafenib

VandetanibMotesanib

AxitinibAZD2171

Pazopanib

SunitinibSorafenib

VandetanibMotesanib

AxitinibAZD2171

Pazopanib

Phase III Trial of IFL +/-Bevacizumab in MCRC—Survival

HR = 0.66, P = .00004

Median survival: 15.6 vs 20.3 mo

Duration of survival (mo)

Pro

po

rtio

n s

urv

ivin

g

0.2

200 10 30 400

0.8

1.0

0.4

0.6

Treatment Group

IFL + placeboIFL + bevacizumab

Reprinted from Hurwitz H, et al. N Engl J Med. 2004;350(23):2335-2342, with permission from the Massachusetts Medical Society.

BICC-C—Summary

Period 1 (No BEV) Period 2 (+ BEV)

EfficacyFOLFIRIN = 144

mIFLN = 141

CapIriN = 145

FOLFIRIN = 57

mIFLN = 60

RR (%) 46.6 41.9 38 57.9 53.3

PFS (mo) 7.6 5.9 5.8 11.2 8.3

OS 23.1 17.6 18.9 NR 19.2

G 3/4 (%)

Diarrhea 14 19 48 11 12

Dehydr. 6 7 19 5 2

MI/stroke 0.7 4.4 0 1.8 0

60-d mort. 3.4 5.1 3.5 1.8 6.8

NR = not reached.Fuchs CS, et al. J Clin Oncol. 2007;25:4779.

XELOX + placebo n = 350

FOLFOX4 + placebo n = 351

XELOX + bevacizumab

n = 350

FOLFOX4 + bevacizumab

n = 350

XELOX n = 317

FOLFOX4 n = 317

Initial 2-armopen-label study

(n = 634)

Protocol amended to 2x2 placebo-controlled design after bevacizumab

phase III data became available(n = 1401)

RecruitmentJune 2003–May 2004

RecruitmentFeb 2004–Feb 2005

XELOX vs FOLFOX +/- Bevacizumab Roche NO16966—Study Design

Cassidy J, et al. ASCO; June 1-5, 2007. Abstract 4026. Courtesy of Dr. J. Cassidy.

PFS Chemotherapy + Bevacizumab Primary Objective Met

0 5 10 15 20 25

Months

Pro

gre

ssio

n-F

ree

Su

rviv

al E

stim

ate

HR = 0.83 [97.5% CI 0.72–0.95] (ITT)P =.0023

9.48.0

1.0

0.8

0.6

0.4

0.2

0

FOLFOX+placebo/XELOX+placebo (n = 701; 547 events) FOLFOX+bevacizumab/XELOX+bevacizumab (n = 699; 513 events)

Saltz L, et al. ASCO. June 1-5, 2007. Abstract 4028. Courtesy of Dr. L. Saltz.

NO16966 Study Drug ExposureMedian Months of Treatment

FOLFOX+ Placebo

(n = 336)

FOLFOX+ Bev

(n = 341)

XELOX+ Placebo

(n = 339)

XELOX+ Bev

(n = 353)

Oxaliplatin 6.0 6.0 5.5 5.8

Fluoropyrimidine 6.3 6.7 5.6 6.3

Placebo or bev 6.3 6.0 5.5 6.0

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.

OPTIMOX Studies

OPTIMOX-1n = 620

FOLFOX 4 until TF

FOLFOX 7 FOLFOX 7

sLV5FU2

OPTIMOX-2n = 202

mFOLFOX 7 mFOLFOX 7

sLV5FU2

mFOLFOX 7 mFOLFOX 7

CFIMaindrault-Goebel F, et al. ASCO. June 1-5, 2007. Abstract 4013. Courtesy of Dr. A. Grothey.

Tournigand C, et al. J Clin Oncol. 2006; 22:229.

0 10 20 30 40 500.0

0.2

0.4

0.6

0.8

1.0

26 months

19 months

Maintenance

CFI

P = .0549

Months

OPTIMOX-2—Overall Survival

Lesson from OPTIMOX-2—Don’t stop treatment before progression


PACCE StudyRandomized, Open-Label, Controlled Phase 3b Trial

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.

Panitumumab 6 mg/kg q2wk

Ox-CTBevacizumab

Ox-based CT(eg, FOLFOX)

N = 800Inv choice

Iri-basedCT(eg, FOLFIRI)

N = 200Inv choice

Ox-CTBevacizumab

Panitumumab Panitumumab 6 mg/kg q2wk6 mg/kg q2wk

Iri-CTIri-CTBevacizumabBevacizumab

Iri-CTBevacizumab

RANDOMIZE

1:1

1:1

SCREENING

Courtesy of Dr. J. Hecht.

PACCE = Panitumumab Advanced Colorectal Cancer Evaluation.

Months

413 267 92 21 3

410 298 96 21 1

0 5 10 15 20

Pmab+bev/Ox-CT Nbev/Ox-CT N

Patients at risk:

Limited Update of PFS—Ox-CT Cohort(Central Review, Apr 2007 Data Cutoff)

# PFS Events (%)

Median95% CI (mo)

206 (50) 9.0 (8.5–10.4)

172 (42) 10.5 (9.7–11.6)

Pmab+bev/Ox-CT

Bev/Ox-CT

HR = 1.29 (95% CI, 1.05–1.58)

Pro

po

rtio

n P

rog

ress

ion

-Fre

e 100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

ITT setCourtesy of Dr. J. Hecht.

PACCE—Grade 3/4 AEs of InterestOx-CT Cohort

Pmab+bev/Ox-CT, % (n = 401)

bev/Ox-CT, %(n = 392)

Adverse Effects Gr 3 Gr 4 Gr 3 Gr 4

Skin toxicity 33 <1 1 0

Diarrhea 21 2 12 1

Dehydration 14 2 4 1

Hypokalemia 8 2 3 1

Hypomagnesemia 3 1 0 0

Neutropenia 12 10 17 7

Neuropathy 9 <1 10 <1

Nausea 10 0 4 <1

Infectionsa 16 2 7 2

Deep venous thrombosis 6 0 7 0

Pulmonary embolismb 0 6 0 4MedDRA v9.0 preferred terms; Graded per NCI CTCAE v3.0aGrade 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.

CALGB/SWOG Intergroup Trial 80405(n = 2289)

“Dealer’s Choice”

FOLFOX or FOLFIRI

Randomize to

Bevacizumab Cetuximab Bevacizumab+

Cetuximab

Primary endpoint: overall survivalHR 1.25 (22 vs 27.5 months)

http://www.cancer.gov protocol ID CALGB-80405

http://www.cancer.gov/

http://www.cancer.gov/

BBP(n = 642)

No BBP(n = 531)

No Post-progression

treatment(n = 253)

Evaluablepatients

(n = 1953)

1st progression(n = 1445)

BRiTE Registry—Patients withBevacizumab Beyond Progression (BBP)

BRiTEN = 1953 1445 pts with 1st progression 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo

Grothey A, et al. J Clin Oncol. 2008 (in press).

Physician decision—no randomization

BRiTE—Patient Outcome Based on Treatment Post 1st PD

BBP(n = 642)

No BBP(n = 531)

No Post-PD Treatment(n = 253)

Number of deaths (%)

168(66%)

306(58%)

260(41%)

Median OS (mo) 12.6 19.9 31.8

1-year OS rate (%)

52.5 77.3 87.7

OS after 1st PD (mo)

3.6 9.5 19.2


PD = progression; BBP = bevacizumab beyond progression; OS = overall survival.

Multivariate Analysis of Pre- and Post-Treatment Variables on Survival


Hazard Ratio (HR) (95% Cl) P value

Age at 1st PD (per 10 years) 1.04 (0.98, 1.11) .235

ECOG PS0 (n = 632)1 (n = 598) ≥2 (n = 87)

1.0 (reference)1.29 (1.09, 1.52)1.58 (1.20, 2.09)

.003

.001

Albumin, (per g/dL) 0.73 (0.64, 0.32) <.001

Alkaline phosphatase, per (100 U/L) 1.18 (1.12, 1.23) <.001

Site of primary tumor, %

Colon (n = 1137) Rectum (n = 293)

1.0 (reference)0.79 (0.66, 0.97) .024

Exposure to EGFR inhibitors (cetuximaband/or other EGFR monoclonal antibodies) No (n = 884) Yes (n = 542)

1.0 (reference)0.97 (0.81, 1.16) .724

Exposure to all 3 active CT agentsb

No (n = 681) Yes (n = 745)

1.0 (reference)0.93 (0.77, 1.12) .447

Time-To-1st PD, per month 0.91 (0.89, 0.93) <.001

Best 1st-line response CR (n = 156) PR (n = 468) SD (n = 488) PD (n = 314)

1.0 (reference)1.64 (1.14, 2.35)1.62 (1.13, 2.33)1.32 (0.88, 1.97)

.007

.008

.173

Post-1st progression therapy

No BBP (n = 531) BBP (n = 642) No Post-PD treatment (n = 253)

1.0 (reference)0.48 (0.41, 0.57)2.01 (1.61, 2.51)

<.001<.001

SWOG/NCCTG/NCIC 2nd-Line Trial S0600/iBET (Intergroup BEV Continuation Trial)

(FOLF)IRI/C225

MCRC pretreated with

FOLFOX + BEV or CAPOX + BEV orOPTIMOX + BEV

(FOLF)IRI/C225+ BEV 10 mg/kg

n = 1260Primary endpoint: OS (HR 1.30; 12 15.6 mo)Principal Investigators: Gold P, Grothey A

(FOLF)IRI/C225+ BEV 5 mg/kg

Open since June 2007


Patient Potentially Curable?

Induction Ctx (3–4 mo)Eg, FOLF?? + BEV/C225

Surgery with curative intent

“Adjuvant” Ctx

Yes

Yes

Yes

Re-evaluation of resectability

Observation

RRInduction Ctx (3–4 mo)

eg, FOLF?? + BEV

Maintenance

Re-induction Ctx

“All 5 drugs”

No

Evaluation oftumor biology

CFI ??

Time, QOL

Treatm

ent C

on

tinu

umC

ura

tive

Ap

pro

ach


Case Study: Stage IV Metastatic Colon Cancer in a Patient with

Ulcerative Colitis

J. Philip Kuebler, MD, PhDPrincipal Investigator

Columbus Community Clinical Oncology ProgramColumbus, Ohio

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

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

Advances in the Treatment of Colorectal Cancer

1980 1985 1990 1995 2000 2005

Therapeutic concepts

Palliative CT

Adjuvant CT

Neoadjuvant CT

CapecitabineOxaliplatin

CetuximabBevacizumab

Irinotecan5-FU

PanitumumabTargeted therapies {

5-FU = 5-fluorouracil; CT = chemotherapy.Courtesy of Dr. J. Kuebler.

6.2

4.4

6.7

4.3

7.0 6.96.5

8.78.0

8.59.0

012

3456

789

10

1112

5-FU/LVFOLFOX4 5-FU/LVFOLFIRI 5-FU/LVIFL IFL IROX FOLFOX4 FOLFOX6FOLFIRI

First-Line Chemotherapy in MCRC Phase III Trials—Progression-Free Survival

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. 2000;18:2938; Douillard JY, et al. Lancet. 2000;355:1041; Goldberg RM, et al. J Clin Oncol. 2004;22:23; Saltz LB, et al. N Engl J Med. 2000;343:905; Sanoff HKK, et al. 43rd ASCO; June 1–5, 2007. Abstract 4067; Tournigand C, et al. J Clin Oncol. 2004;22:229.Courtesy of Dr. J. Kuebler.

SaltzDouillardde Gramont N9741a Tournigandb

PF

S o

r T

TP

(m

o) c

cd

d c

First-Line Bevacizumab in MCRC Progression-Free Survival

aP<.001; bP<.005; cP=.004 vs mIFL.

Fuchs CS, et al. J Clin Oncol. 2007;25:4779; Hochster HS, et al. ASCO; June 1–5, 2006. Abstract 3510; Hurwitz H, et al. N Engl J Med. 2004;350:2335; Saltz LB, et al. ASCO GI; January 17–21, 2007. Abstract 238.Courtesy of Dr. J. Kuebler.

6.2

8.0

9.4

7.6

11.2

5.9

8.3

10.6

0

2

4

6

8

10

12

IFL IFL + BevFOLFOX/CapeOxFOLFOX/CapeOxFOLFIRIFOLFIRI + BevmIFL mIFL + Bev

+ Bev

PF

S o

r T

TP

(m

o)

NO16966AVF2107g

Phase III

b

a

BICC-C

c

9.8

8.2 8.4

10.6

8.08.9b

0

2

4

6

8

10

12

FOLFOX FOLFOX + CetFOLFIRI FOLFIRI + CetFOLFIRI FOLFIRI + Cet

First-Line Cetuximab in MCRCPhase III Trials—Progression-Free Survival

a16 months’ follow-up; bP<.05.Conclusions on overall survival await further follow-up.Van Cutsem E, et al. 43rd ASCO; June 1–5, 2007. Abstract 4000; Venook A, et al. 42nd ASCO; June 2–6, 2006. Abstract 3509.Courtesy of Dr. J. Kuebler.

b

CALGB 80203a CRYSTAL

PF

S o

r T

TP

(m

o)

Correlation Between Survival and Percentage of Patients Receiving 3 Drugs*

in Phase III Trials

*3 drugs: 5-FU/LV, irinotecan, oxaliplatin.Reprinted from Grothey A, et al. J Clin Oncol. 2005;23:9441,with permission from the American Society of Clinical Oncology.

12

13

14

15

16

17

18

19

20

21

22

0 10 20 30 40 50 60 70 80

Patients receiving 3 drugs (%)

Median OS (mo)

Managing Side Effects ofChemotherapy—Diarrhea

• Treat diarrhea aggressively and promptly with antidiarrheals

• Fluid/electrolyte replacement for grade >3 diarrhea• Hospitalization/antibiotics for diarrhea with febrile

neutropenia• Delay chemotherapy until bowel function back to

grade 0–1 with no antidiarrheals• Consider dose reduction if diarrhea grade >3• Anticholinergic therapy for diarrhea due to irinotecan

Kuebler JP, et al. Cancer. 2007;110:1945.

Managing Side Effects of Chemotherapy—Neurotoxicity

• 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. 2007;24:2205.

Managing Side Effects of Chemotherapy—Bevacizumab

• Treat hypertension (blood pressure persistently >140/90) with oral agents

• Stop chemotherapy if blood pressure uncontrolled on oral agents

• Monitor dipstick urine assays• Interrupt treatment if proteinuria >2 gm/24 hours• Risk for arterial thrombotic events greater in patients

aged >65 years or with arteriosclerosis• Mild epistaxis common, major bleeding rare• Avoid surgery 1 month prior to and 6–8 weeks after

bevacizumab• GI perforation in ~1.5% of patients

Gordon MS, Cunningham D. Oncology. 2005;69(suppl 3):25; Kozloff M, et al. ASCO GI; January 17–21, 2007. Abstract 364; Rosiak J, Sadowski L. Clin J Oncol Nurs. 2005;9:407; Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:232;Ellis LM, et al. J Clin Oncol. 2005;23:4853; Sugrue M, et al. 42nd ASCO; June 2–6, 2006. Abstract 3535.

Managing Side Effects of Chemotherapy—Cetuximab

• Treat grade 1 acneiform skin rash with topical anti-inflammatory agents

• Treat pruritis with oral antihistamines• Treat grade >2 skin rash with oral tetracycline (minocycline

at 100 mg/day)• Treat paronychia with topical antiseptics/antibiotics • 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. 2005;16:1425.

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

OPTIMOX Studies

OPTIMOX-1: maintenance therapy1

(N = 620)

FOLFOX4 until progression

FOLFOX7 FOLFOX7

sLV5FU2

OPTIMOX-2: CT-free interval2

(N = 202)

mFOLFOX7 mFOLFOX7

sLV5FU2

mFOLFOX7 mFOLFOX7

CT-free interval1. Tournigand C, et al. J Clin Oncol. 2004;22:229. 2. Maindrault-Goebel F, et al. 43rd ASCO; June 1–5, 2007. Abstract 4013.


Chemotherapy-Free Intervals of mFOLFOX in Patients With MCRC (OPTIMOX-2)—OS

MCRC = metastatic colorectal cancer; OS = overall survival.Maindrault-Goebel F, et al. 43rd ASCO; June 1–5, 2007. Abstract 4013. Courtesy of Dr. F. Maindrault-Goebel.

0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40 50

Pro

bab

ility

Months

OPTIMOX-1 (median 26 mo)OPTIMOX-2 (median 19 mo)

OS

P = .0549

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 patient’s performance status had not changed

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

FOLFIRI + Cetuximab ± Bevacizumab in Patients with Relapsed MCRC

(S0600/iBET)—Phase III Trial Design

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/NCT00499369?order=1. Accessed August 27, 2007.

Primary end point: Overall Survival (OS)

Secondary end point: Progression-Free Survival (PFS)

Previously treated patients with MCRCa

N = 1250

FOLFIRI + cetuximab +

bevacizumab (5 mg/kg q2w)


bevacizumab (10 mg/kg q2w)


placebo (q2w)

RANDOMIZATION

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)

Case Study: Surgically Resectable Metastatic Colorectal Cancer

Cathy Eng, MDAssistant Professor

Department of Gastrointestinal Medical OncologyThe University of Texas M. D. Anderson Cancer Center

Houston, Texas

Case Presentation—Ann• 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.

CT Scan at Baseline

2 coalescent lesions 4.8 cm in greatest diameter

Carcinoma of the cecum

Courtesy of Dr. C. Eng.

Case Presentation

• Preoperative carcinoembryonic antigen (CEA) = 38 ng/mL (normal, <5 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

Case PresentationPostoperative state

• Ann has recovered fully • ECOG PS = 0

– She has only lost 5 lbs since the surgery– She has 1–2 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?

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 therapy–fallen out of favor

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

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

Phase III EORTC 40983

Perioperative FOLFOX for ResectableHepatic Metastases*

RandomizeN = 364

Surgery

FOLFOX46 cycles

(3 months)

Nordlinger B, et al. 43rd ASCO; June 1-5, 2007. Abstract LBA5.

• Primary endpoint: progression-free survival

• Eligibility criteria: < 4 liver lesions

(metachronous or synchronous),

surgically resectable, no extrahepatic disease

Surgery

*Only prospective trial to date.

FOLFOX46 cycles

(3 months)

Complications of SurgeryPeri-op CT Surgery

Postoperative complications*

40 /159 (25.2%)

27 / 170 (15.9%)

Cardiopulmonary failure 3 2

Bleeding 3 3

Biliary fistula 122 5

Includes output >100 mL/d, >10 d (9) (2)

Hepatic failure 11 8

Includes bilirubin >10 mg/dL, >3 d (10) (5)

Wound infection 4 4

Intra-abdominal infection 8 2

Needed to re-operate 5 3

Other 25

16

Includes postoperative death 1 patient 2 patients

*P = .04Courtesy of Dr. B. Nordlinger.

Final Results of EORTC 40983No. Pts

CTN Pts

SurgeryAbsolute

Differencein 3-Year PFS

(95.66% Confidence

Interval)

HazardRatio

(95.66% Confidence

Interval)

P-value

All patients (ITT)

182 182 +7.3% (28.1%–35.4%)

0.79(0.62–1.02)

P = .058

All eligiblepatients

171 171 +8.1% (28.1%–36.2%)

0.77 (0.60–1.00)

P = .041

All resectedpatients

151 152 +9.2% (33.2%–42.4%)

0.73(0.55–0.97)

P = .025*

Courtesy of Dr. B. Nordlinger.

*Statistically significant only in those patients surgically resected.

Conversion Chemotherapy

• Defined as systemic chemotherapy provided to decrease tumor burden and improve likelihood of surgical resection

• Previously conducted studies– FOLFOXIRI – CRYSTAL – NO16966

FOLFIRI vs FOLFOXIRIPhase III

(Gruppo Oncologico Nord Ovest)

Randomize untreated MCRC N=244

FOLFIRI X 12

FOLFOXIRI x 12


FOLFOXIRI vs FOLFIRIResults

FOLFIRI(n = 122)

FOLFOXIRI(n = 122)

CR* 6% 8%

PR* 35% 58%

RR* 41%[95%: 0.32-0.50]

66% [95%: 0.56-0.74]

R0 (hepatic resection)†

12% (n = 42) 36% (n = 39)P = .017


* Investigators assessment † Patients with liver metastases only

Role of Biologics in Hepatic Resection?

CRYSTAL TrialLiver Resection with Cetuximab

Courtesy of Dr. E. Van Cutsem.

4.5

9.8

0

1

2

3

4

5

6

7

8

9

10

Percentage (%)

2.5

1.5

6

4.3

0

1

2

3

4

5

6

7

Surgery withCurative Intent

No Residual TumorAfter Resection

Percentage (%)

n = 599/Group n = 599/Group n = 134/n = 122

P = .0034*

No Residual Tumor in Patients with Liver Metastases

ITT Population Liver-Metastases–Only Population

FOLFIRI Alone Cetuximab + FOLFIRI

Lucrative Points in the Management of Hepatic

Resection

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. 2006;24:2065.

Radiologic CR = Pathologic Cure?

• 1998–2004– 586 consecutive patients treated for up to 10 hepatic

metastases 38 patients had radiologic CR of >1 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.

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.

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

Postchemotherapy CT Scan

• The patient undergoes right hepatic resection without complications

• Minimal <5% steatosis was noted

• Due to her excellent response to chemotherapy, the patient opted for an additional 4–6 months of adjuvant FOLFOX + bevacizumab

Courtesy of Dr. C. Eng.

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 therapy—Do 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

Documents

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