Jeffrey Meyerhardt, MD, MPH Dana-Farber Cancer Institute Boston, MA

Standard Management of Stage IV Colorectal Cancer:

Start and Stop, Maintenance, Chemotherapy Holidays

Jeffrey Meyerhardt, MD, MPH

Dana-Farber Cancer Institute

Boston, MA

Disclosures

• Consultant: Sanofi-aventis

• Research funding (to DFCI or CALGB) – Pfizer, BMS, Astra Zeneca

• NCI research funding

Outline for this segment

• Continuous treatment for metastatic colorectal cancer – how we got here

• 3 strategies besides continuous– Full chemotherapy holiday– Maintenance – Start and stop (some twist of above 2)

5-Fluorouracil

• First introduced by Heidelberger & colleagues 1957 (J Am Chem Soc 1957; Nature 1957)

• While toxic, it does not have cumulative dose limiting toxicities– Rare patients with relative DPD deficiency have

severe bone marrow suppression – else, most do not bone marrow limitations

N

H

HN

O

O

F

Chemotherapy versus Best Supportive Care

Trial N Treatments Duration Result

NORDIC trial 133 Advanced, asymptomatic

Immediate v delayed MLF

Up to 6 months OS: 14 m v 9 m (p log rank 0.14; p Breslow-Gehan <0.02

Scheithauer

et al

40 Advanced, symptomatic

5-FU, LV, CDDP v BSC only

Up to 6 months OS: 11 v 5 months

Yorkshire GI Tumour Group

57 residual disease after palliative surgery

Methyl CCNU, 5-FU v BSC only

Up to 2 years 1 yr OS: 74 v 57%

RANDOMI

Z e

IrinotecanIrinotecan

IFL(bolus 5-FU/LV/Irinotecan)

IFL(bolus 5-FU/LV/Irinotecan)

5-FU/LV (Mayo Clinic)5-FU/LV (Mayo Clinic)

Saltz LB et al. N Engl J Med. 2000;343:905;

N=226

N=226

N=231

Irinotecan/5-FU/LV(AIO or de Gramont

regimen)

Irinotecan/5-FU/LV(AIO or de Gramont

regimen)

5-FU/LV(AIO or de Gramont

regimen)

5-FU/LV(AIO or de Gramont

regimen)

Douillard JY et al. Lancet. 2000;355:1041.

N=198

N=187

RANDOMI

Z e

First-Line Irinotecan

“Treatment was given until disease progressed, the patient developed unacceptable toxic effects, or consent was withdrawn. “

“Treatment was continued until one of the following occurred: disease progression, unacceptable adverse effects, or the withdrawal of consent by the patient. “

RANDOMI

Z E

De Gramont 5-FU/LVDe Gramont 5-FU/LV

FOLFOXFOLFOX

De Gramont et al. JCO. 2000; 18: 2938-47; Giacchetti et al. JCO. 2000; 18: 136-47;

N=210

N=210

First-Line Oxaliplatin

“Treatment was continued until disease progression or unacceptable toxicity occurred or until a patient chose to discontinue treatment. “

RANDOMI

Z E

Chronomodulated 5-FU/LVChronomodulated 5-FU/LV

Oxaliplatin + Chrono 5-FU/LVOxaliplatin + Chrono 5-FU/LV

N=100

N=100

Treatment continued until toxicity limited, patient became surgical candidate, patient refusal, loss to f/u, death

RANDOMI

Z E

IFLIFL

Irinotecan/OxaliplatinIrinotecan/Oxaliplatin

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

Goldberg JCO 2004.

N=245

N=246

N=250

Response rate

Time to Progress

Median Overall Survival

Grade 3/4 Neutropenia

Grade 3/4 Diarrhea

Grade 3/4

Neuropathy

IFL 33 % 6.9 m 14.8 m 40 % 28 % 3 %

FOLFOX 45 % 8.7 m 19.5 m 50 % 12 % 18 %

IROX 35 % 6.5 m 17.4 m 36 % 24 % 7 %

NCCTG 9741

Goldberg JCO 2004.

NCCTG 9741

IFL 67% ceased treatment due to disease progression or FOLFOX 42%IROX 55%

Log Kill Kinetics

Schmidt C JNCI J Natl Cancer Inst 2004;96:1492-1493

Rate of tumor volume regression is proportional to the rate of growth.

Gompertzian Model of Tumor Growth and Norton–Simon hypothesis

Schmidt C JNCI J Natl Cancer Inst 2004;96:1492-1493

Rate of tumor volume regression is proportional to the rate of growth.

Lung Cancer Experience

• Continuation of 2 and 3 drug combinations beyond 4-6 cycles does not improve survival

Socinski M A et al. JCO 2002;20:1335-1343

Lung Cancer Experience

• Maintenance with non-cross resistant agents likely helpful– Docetaxel – PFS significant; OS trend– Pemetrexed – PFS and OS significant– EGFR TKIs – PFS significant; OS mixed data

Continuous v Intermittent Therapy: MRC Trial

Maughan et al The Lancet. 2003. 361: 457-64.

Responding or stable disease after 12 weeks


• Median off-treatment duration with intermittent therapy was 4.3 months– Significantly fewer adverse events

• Overall survival was similar in both groups


PFS HR1.20 (0.96-1.49) favor continuous


• Selection bias – randomization after known disease control to therapy– Included and not included patients similar baseline

characteristics

• Only 37% in intermittent group resumed scheduled treatment at progression


Continuous v Intermittent Therapy:2nd Line Irinotecan

Lal R et al. JCO 2004;22:3023-3031

Progressed on fluoropyrimidine therapy

Continuous v Intermittent Therapy:2nd Line Irinotecan

• No differences in failure-free survival (P = .999) or overall survival (P = .11)

• No difference in mean global health status QOL score

Lal R et al. JCO 2004;22:3023-3031

FOLFIRI x 2 m

EVALUATION

PD

STOPx 2 m

A

B

2nd Line(OHP)

CR, PR, SDRANDOM

FOLFIRI x 2 m

FOLFIRI x 2 m

FOLFIRI x 4 m

Every 4 m until PD

EVALUATION

Continuous v Intermittent Therapy:GISCAD Trial

Labiana ASCO 2006


Labianca R et al. Ann Oncol 2011;22:1236-1242


Labianca R et al. Ann Oncol 2011;22:1236-1242

Median OS17 v 18 monthsHR 0.88 (0.69–1.14)

Median PFS6 v 6 monthsHR 1.03 (0.81–1.29)

Median chemo-free interval 3.5 months

OPTIMOX 1: Trial of Maintenance

Tournigand et al. JCO 2006;24:394-400

FOLFOX7 x 6 cyclessLV5FU2 x up to 12 cycles

FOLFOX7 x 6 cycles

FOLFOX7 x 6 cyclessLV5FU2 x up to 12 cycles

FOLFOX7 x 6 cycles

FOLFOX4 until Progression

FOLFOX4 until Progression N=311

N=309

RANDOMI

Z e

Only 40%reintroduced oxaliplatin

18.5% early progression/death18.4% toxicity (including neuropathy)5.5% surgery17.5% unknown





Duration of Disease Control



PFS OS



Grade 3 / 4 Toxicity

Grade 3 Neurotoxicity

OPTIMOX 2: Go and Full Stop

Chibaudel B et al. JCO 2009;27:5727-5733


A

FOLFOX7 x 6 cy

A A A A A

FOLFOX7 x 6sLV5FU2

Baseline progression

FOLFOX7 x 6 cy

A A A A

FOLFOX7 x 6Chemotherapy-free interval

Baseline progression

LV 400 5-FU 3000

mFOLFOX7

Oxali 100

H0 H2 H24 H48

LV 400 5-FU 3000

sLV5FU2

H0 H2 H24 H48

5FUb 400

Cycles every 14 days, dose mg/m²

OPTIMOX 1

OPTIMOX 2

A

A

Maindrault-Goebel ASCO Presentation 2006


t

T size

FOLFOX FOLFOX

Progression Baseline progression

Progressionat reintroduction

Chemotherapy-free Interval

Maindrault-Goebel ASCO Presentation 2006



HR= 0.71 (95% CI, 0.51 to 0.99; P = .046

Median duration of maintenance therapy = 4.8 months in the arm 1Median duration of CFI = 3.9 months in arm 2.



PFSHR = 0.61; P = .0017

OSHR = 0.88; P = 0.42

CaMg = 1 g calcium gluconate and 1 g magnesium sulfate over 30 min pre- and post-oxaliplatin

CONcePT Trial Primary endpoint: TTF for CO vs IO schedule

First-line mCRC, 532 patientsPrimary endpoint: time to failure (TTF)Randomization (2x2):

mFOLFOX7 + bevacizumabCO until Treatment Failure

mFOLFOX7 + bevacizumabIntermittent oxaliplatin

+/- IV CaMgR

270 pts

Grothey et al ASCO 2008

2400

x 8

Cumulative oxaliplatin

680 mg/m2

Months

42400

x 8

8680 mg/m2

2400

200855

2005

200855

x 8 1360 mg/m2 12

etc.

LVOXBEV

5-FU

CONcePT Trial: IO Arm


Early reintroduction of oxaliplatin if progression

a log rank test

Unstratified (IO relative to CO), p=0.002a

Stratified by CaMg (IO relative to CO), p=0.003a

Proportionof patients

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 2 4 6 8 10 12 14 16 17

TTF months

COIO

Censored data

N at riskCO:IO:

1 3 5 7 9 11 13 15

6871

5861

3652

2032

621

412

210

14

01

6365

4656

2843

1128

418

412

27

11

TTF (mos)

95% CI

CO 4.2 3.7 - 5.5

IO 5.6 4.7 - 7.0

CONcePT Trial


CONcePT Trial

a log rank test

Unstratified (IO relative to CO), p=0.044a

Stratified by Ca/Mg (IO relative to CO), p=0.030a

Proportionof patients

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 2 4 6 8 10 12 14 16 17

PFS months

COIO

Censored data

N at riskCO:IO:

1 3 5 7 9 11 13 15

6871

4655

2943

1327

318

310

08

02

01

6464

3951

2438

724

315

19

03

01

PFS (mos)

95% CI

CO 7.3 6.9 - NE

IO 12.0 8.2 - NE


N pts (%) with >1 NTE leading to

CO (n=68)

IO(n=71)

Placebo(n=33)

CaMg(n=35)

Placebo(n=36)

CaMg(n=35)

Discontinuation8 (24) 7 (20) 3 (8) 4 (11)

15 (22) 7 (10)

Delay 1 (3) 0 1 (3) 0

Dose reduction 7 (21) 6 (17) 2 (6) 2 (6)

Delay and dose reduction 0 1 (3) 1 (3) 1 (3)

Delay or dose reduction

8 (24) 7 (20) 3 (8) 3 (9)

15 (22) 6 (8)

CONcePT Trial


N016966

Saltz et al. JCO. 2008; 26: 2013-2019

Treatment d/c due to PD in 29% in the bevacizumab-containing arms and 47% in the placebo-containing arms

Prespecified secondary analysis, median on-rx PFS = 10.4 vs 7.9 months (HR, 0.63 [ 0.52 to 0.75 ] )

MACRO Trial

ProgressionRCapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

Bevacizumabuntil progression

N=480

N=239

N=241

CapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

CapecitabineOxaliplatin

Bevacizumabuntil progression

Taberno et al ASCO 2010

Non-inferiority design Sample Size: 470 patients; 235 per arm

Assuming 10 months as median PFS Non-inferiority limit of 7.6 m (HR=1.32)One sided alpha = 0.025, one side; Power = 80%

LNI: 1.32

Patients at risk

MACRO Trial


Patients at risk

MACRO Trial


Some Ongoing Trials• AIO-Studien-gGmbH (n = 760)

– FOLFOX / Bevacizumab x 24 week then maintenance with fluoropyrimdine / bevacizumab OR bevacizumab alone OR full treatment holiday

• Dutch Colorectal Cancer Group (n = 635)– XELOX / Bevacizumab x 6 months then capecitabine / bevacizumab OR

full treatment holiday

• Spanish Cooperative Group (n = 192)– FOLFOX / Cetuximab x 18 weeks then continuation OR cetuximab only

• Swiss Group (n = 238)– Chemotherapy / Bevacizumab x 16-24 weeks then bevacizumab OR full

treatment holiday

Some Ongoing Trials

• FFCD (n = 188)– FOLFIRI / Bevacizumab x 24 week then maintenance

bevacizumab alone OR full treatment holiday

• Lund University Hospital (n = 240)– Chemotherapy / Bevacizumab x 4 months then

bevacizumab / erlotinib OR bevacizumab only

• DREAM / OPTIMOX 3 (n = 640)– FOLFOX or XELOX / Bevacizumab then

bevacizumab / erlotinib OR bevacizumab only

What To Do?• Data can be seen as favoring any approach

– Continuing combination therapy til progression– Maintenance with some of the agents– Full treatment holidays

• Don’t forget about surgery if inoperable operable

• One size (or at least strategy) doesn’t fit all– Patient preferences, goals, quality of life– Low burden disease / asymptomatic versus symptomatic or high burden of disease– Consider initial response to therapy

• Consider a clinical trial for your patient

Documents

Jeffrey Meyerhardt, MD, MPH Dana-Farber Cancer Institute Boston, MA