Chemotherapy for Chemotherapy for Metastatic Colon CancerMetastatic Colon Cancer

Scott BerryScott Berry

Sunnybrook Health Sciences CentreSunnybrook Health Sciences Centre

Where Were We Until 2000?

NH

HN

O

O

F

5-FU5-FU

FOLFOX

FOLFIRI

IFL

irinotecan

N NC

O

O N

N O

O

O

C 2H

O C 2H

C 3H

H C 3H

oxaliplatinNHNH22

NHNH22

PtPt

OO

OO CC

OO

CC

bevacizumab

cetuximab

PTK 787

CapecitabineCapecitabine

PanitumumabPanitumumab

OS for 1OS for 1stst line Combinations line Combinations

5-FU/LV (Saltz)

5-FU/LV (Douillard)

5-FU/LV (de Gramont)

IFL (Goldberg)

IFL (Saltz)

FOLFIRI (Douillard)

FOLFOX (de Gramont)

FOLFOX (Goldberg)

IFL+ Bevacizumab

0 5 10 15 20 25Median OS (months)

Overview/ObjectivesOverview/Objectives• Review key evidence from randomized trials evaluating the Review key evidence from randomized trials evaluating the

chemotherapies and chemotherapy strategies that have chemotherapies and chemotherapy strategies that have emerged for metastatic colorectal cancer looking at both:emerged for metastatic colorectal cancer looking at both:• EfficacyEfficacy• SafetySafety

• Key Strategies and Questions:Key Strategies and Questions:• Which doublet should be used?Which doublet should be used?• ? Should we be using triplet therapy? Should we be using triplet therapy• Can capecitabine replace infusional 5FU in doublets?Can capecitabine replace infusional 5FU in doublets?• Can sequential monotherapy replace initial doublet therapy?Can sequential monotherapy replace initial doublet therapy?• Can toxicity be reduced and efficacy maintained with “on/off” Can toxicity be reduced and efficacy maintained with “on/off”

chemotherpay strategies? chemotherpay strategies?

Chemotherapy

Case

• 50 yo woman with no history of medical problems presents with bilobar liver and bilateral lung metastases– ECOG 1 – some RUQ pain and cough

• What is the optimal chemotherapy choice for her?

• CAPECITABINE

• FOLFOX

• FOLFIRI

• CAPE IRI

• CAPE OX

• FOLFOXIRI

Efficacy of Chemotherapy in First-Line CRC: Phase III Trial Results

Saltz et al. N Engl J Med. 2000;343:905; Douillard et al. Lancet. 2000;355:1041;de Gramont et al. J Clin Oncol. 2000;18:2938

Regimen RR (%)Median OS (mo)

5-FU/LV

IFL (Saltz trial)

21

39 (P<0.001)

12.6

14.8 (P=0.04)

5-FU/LV

FOLFIRI (Douillard trial)

22

35 (P<0.005)

14.1

17.4 (P=0.031)

5-FU/LV

FOLFOX4 (de Gramont trial)

22

51 (P=0.0001)

14.7

16.2 (P=0.12)

• CAPECITABINE

• FOLFOX

• FOLFIRI

• CAPE IRI

• CAPE OX

• FOLFOXIRI

Phase III Intergroup N9741 Study(Goldberg JCO, 2004)

RRAANNDDOOMMII

Z Z AATTIIOON N

Irinotecan + Oxaliplatin Irinotecan + Oxaliplatin

IFLIFL

FOLFOX 4FOLFOX 4

Phase II Sequential, Randomized CrossoverStudy

Tournigand et al JCO 2004

FOLFIRIFOLFIRI

FOLFOX 6FOLFOX 6

N9741/Tournigand Trial: ResultsN9741 Tournigand

IFL FOLFOX

P-value

FOLFIRI

FOLFOX

P-value

RR %

31 45 .03 56 54 .26

TTP mos

6.9 8.7 .009 8.5 8.0 .26

OS mos

15 19.5 .0002 21.5 20.6 .99

Tournigand Trial: Results

Curative Surgery Rate: 22% FOLFOX , 9% FOLFIRI Curative Surgery Rate: 22% FOLFOX , 9% FOLFIRI

FOLFIRIFOLFIRI

FOLFOXFOLFOX

00

1010

2020

3030

F. neu

tropen

ia

F. neu

tropen

ia

Nause

a

Nause

a

Vomiti

ng

Vomiti

ng

Diarrh

ea

Diarrh

ea

Pares

thes

ia

Pares

thes

ia

%

7%7%

13%13%

0%0%3%3%

14%14%

11%11% 10%10%

3%3% 3%3%

34%34%4040

TournigandTournigandToxicity Toxicity ggrade rade >>33

P>>0.05 for0.05 forComparisons marked Comparisons marked

by arrowsby arrows

AlopeciaAny grade 60% vs 28%

60-day Mortality:4% vs 3%

Combination Chemotherapy - Summary

• Combination chemotherapy with FOLFIRI or FOLFOX are both acceptable first line chemotherapy regimens for people with metastatic colorectal cancer

• Follow by alternate combination (or single agent Irinotecan after FOLFOX)

• Considerations:– Toxicity profile– ? Considering surgery : FOLFOX based on “circumstantial” evidence

• CAPECITABINE

• FOLFOX

• FOLFIRI

• CAPE IRI

• CAPE OX

• FOLFOXIRI

Overall survival

Integrated CRC

Capecitabine (n=603)

5-FU/LV (n=604)

13.1 13.1

0 5 10 15 20 25 30

Time (months)

Est

imat

ed p

rob

abil

ity 1.0

0.8

0.6

0.4

0.2

0

What About Capecitabine As a Partner?

Capecitabine + Irinotecan

BICC-C studyFOLFIRI +/- celecoxib

CAPIRI (Cape 1000mg/m2 d1-14) +/- celecoxib

n=430

1st line mCRC

mIFL +/- celecoxib

FOLFIRI mIFL CAPIRI

Median OS (mos) 23.1 17.6 (p=0.1) 18.9 (p=0.42)

Median PFS (mos) 8.2 6.0 (p=0.01) 5.7 (p=0.01)

g3/4 nausea 6.6 6.6 18.4

g3/4 vomiting 5.8 6.6 15.6

g3/4 diarrhea 13.9 16.8 47.5

g3/4 dehydration 5.8 6.6 19.1

G3/4 HFS 0 0 9.9

Febrile neutropenia 3.6 12.4 7.1

Slide Courtesy D Jonker from data presented at ASCO 2007Slide Courtesy D Jonker from data presented at ASCO 2007

EORTC 40015 studyFOLFIRI +/- celecoxib

CAPIRI (Cape 1000mg/m2 bid x14d)+/- celecoxib

n=85 1st line CRC

FOLFIRI CAPIRI

Req dose adjustment (%) 33% 53%

g3/4 diarrhea 13% 37%

Median number cycles 5 (10w) 3 (9w)

Dose intensity irinotecan 85% 83%

Median OS (mos) 19.9 14.8

Median PFS (mos) 9.6 5.9

Celecoxib vs Placebo : No Survival differenceCelecoxib vs Placebo : No Survival difference

Slide Courtesy D JonkerSlide Courtesy D Jonker

What About Capecitabine As a Partner?

Capecitabine + Oxaliplatin

Capecitabine + Oxaliplatin Randomized Trials : EfficacyRegimen RR (%)

Median OS (mo)

Capecitabine (1000 bid) +

Ox (130 q 3wks)

FOLFOX 6 (oxali 100 q 2wks)

(Ducreux ASCO 2007 N=306)

42

46

Non-Inferior

19.9

20.5 (p=NS)

Capecitabine + Ox

FOLFOX 4

(Cassidy ASCO 2007 N=2034)

NR 19.6

19.8 (p=NS)

Capecitabine+ Ox

FOLFOX 4

(Rothenberg ASCO 2007 N= 627)

15

12

13.2

12.8 (p=NS)SecondSecondLineLine

FirstFirstLineLine

Capecitabine + Oxaliplatin Randomized Trials : Toxicity

Regimen Toxicity

Capecitabine (1000 bid) + Ox (130 q 3wks)

FOLFOX 6 (oxali 100 q 2wks)

(Ducreux ASCO 2007 N=306)

FOLFOX arm had significantly more Gr 3/4:

Neuropathy (25 v 11%), Feb Neut (6 v 0%)

Capecitabine + Ox

FOLFOX 4

(Cassidy ASCO 2007 N=2034)

FOLFOX arm had more Gr 3/4:

Feb Neut (5 v <2%)

CapeOx arm had more Gr 3/4:

Diarrhea (20 v 12%) and HFS (6 v 1%)

Capecitabine + Ox

FOLFOX 4

(Rothenberg ASCO 2007 N= 627)

FOLFOX arm had more Gr 3/4:

Feb Neut

CapeOx arm had more Gr 3/4:

Diarrhea (20 v 7) and HFS (4 v <2%)

SecondSecondLineLine

FirstFirstLineLine

Can Capecitabine Replace Infusional 5FU in mCRC?

• Capecitabine and Irinotecan– At doses studied CapeIri is more toxic and less effective

than FOLFIRI

• Capecitabine and Oxaliplatin– CapeOx has same efficacy as FOLFOX – Differential toxicity profile between CapeOx and FOLFOX

• CAPECITABINE

• FOLFOX

• FOLFIRI

• CAPE IRI

• CAPE OX

• FOLFOXIRI

Triplet Therapy

5-FU/IRI vs FOLFOXIRI: 5-FU/IRI vs FOLFOXIRI: Falcone et al Falcone et al

N = 244N = 244

FOLFOXIRI

5-FU/Iri

Douillard Randomization

Slide Courtesy of R GoldbergSlide Courtesy of R Goldberg

FOLFOXIRI ScheduleFOLFOXIRI ScheduleFOLFOXIRI ScheduleFOLFOXIRI Schedule

5FU flat continuous infusion3200mg/m2

L-LV 200 mg/m2

Oxaliplatin 85 mg/m2

2 hours

Repeated every 14 days

CPT-11165 mg/m2

48 hours

Day 1 Day 2 Day 3

1 hour

Slide Courtesy of R GoldbergSlide Courtesy of R Goldberg

EfficacyEfficacy

5-FU/IRI5-FU/IRI

N=122N=122FOLFOXIRIFOLFOXIRI

N=122N=122P-valueP-value

Response Response rate (%)rate (%)

41%41% 66%66% ??

PFS PFS (mos)(mos)

6.96.9

(BICC = (BICC = 8.3)8.3)

9.99.9 0.00090.0009

OS (mos)OS (mos) 16.716.7 23.623.6 0.0420.042

Slide Courtesy of R GoldbergSlide Courtesy of R Goldberg

FU/IRIFU/IRI(42 pts)(42 pts)

FOLFOXIRIFOLFOXIRI(39 pts)(39 pts)

R0R0 12%*12%*(5 pts)(5 pts)

36%*36%*(14 pts)(14 pts)

* p=0.017

Post-ChemoRx Resections(patients with liver mts only)

Post-ChemoRx Resections(patients with liver mts only)

Slide Courtesy of R GoldbergSlide Courtesy of R Goldberg

28%

3% 1% 1%

50%

5% 2% 3%

0%

25%

50%

75%

100%

Neutropenia Febrile Neutropenia Thrombocytopenia Anemia

FOLFIRI

FOLFOXIRI

5

Grade 3-4 ToxicityGrade 3-4 ToxicityGrade 3-4 ToxicityGrade 3-4 Toxicity

(N=122)

(N=122)

12%

2% 3% 3% 0%

20%

7% 5% 6%

20%

0%

25%

50%

75%

100%

Diarrhea Vomiting Stomatitis Asthenia Neurotoxicity

p =0.0006

Slide Courtesy of R GoldbergSlide Courtesy of R Goldberg

Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442.

Survival improves with availability Survival improves with availability of three active drugsof three active drugs

*FOLFOXIRI

P=0.0001

Is FOLFOXIRI more active than Is FOLFOXIRI more active than 5-FU/IRI?5-FU/IRI?

Yes, including better resection Yes, including better resection ratesrates But is comparator arm inferior?But is comparator arm inferior?

More toxicMore toxic

Monotherapy

Overall survival

Integrated CRC

Capecitabine (n=603)

5-FU/LV (n=604)

13.1 13.1

0 5 10 15 20 25 30

Time (months)

Est

imat

ed p

rob

abil

ity 1.0

0.8

0.6

0.4

0.2

0

Monotherapy versus

doublets

• ? Have 3 active chemo agents in mCRC

• Lead with combination

• ? Can we use agents sequentially and maintain efficacy and reduce toxicity

• FOCUS and CAIRO– Do both have fatal flaws?

FOCUS

Lancet, 2008

2,135 Untreated Stage IV patients 2,135 Untreated Stage IV patients

A: 5 FU/LV (de Gramont)A: 5 FU/LV (de Gramont)

C: FOLFOX vs FOLFIRIC: FOLFOX vs FOLFIRI

B: 5 FU/LV (de Gramont)B: 5 FU/LV (de Gramont)

RANDOMISATION

RANDOMISATION

FOCUS UK MRC CR08

IRIIRI

FOLFOX orFOLFIRI

FOLFOX orFOLFIRI

FOCUS UK MRC CR08

• Breaks allowed – Not before 3 mos– Only 4 weeks in 2nd 3 mos– After that – allowed with re-start of previous

regimen as long as progression hadn’t occurred within 12 weeks of stopping

FOCUS UK MRC CR08

• Up to Dec 02 , recommended salvage in all groups Infusional 5FU and Mit-C

• Since Dec 02, "balanced salvage" with CapOx or CapIri

• Primary Endpoint: Survival

Survival

OS (mos)

5FU TO IRI 13.9

5FU TO FOLFOX 15.2

5FU TO FOLFIRI 15.0

FOLFOX 15.4

FOLFIRI16.7

(p=0.01)

Table 4

FOCUS

QOL

• Mean overall QOL : varied little between arms and regimens

• In particular, no differences seen at 3 and 6 mos

FOCUS

• Conclude that sequential strategy is a valid option

• Median Survivals of all arms inferior to FOLFOX arm of N9741 and both arms of Tournigand trial

• ? Seeing an effect of restricting access to all 3 drugs

Percentage of Patients Receiving All 3 Active Drugs

OS (mos)

A 5FU TO IRI 16%

B

5FU TO FOLFOX

19%5FU TO FOLFIRI

CFOLFOX

33%FOLFIRI

FOCUS

Grothey, JCO, 2004Grothey, JCO, 2004

CAIRO

Randomized study of sequential versus combination chemotherapy with capecitabine,

irinotecan and oxaliplatin in advanced colorectal cancer

a study of the Dutch Colorectal Cancer Group (DCCG)

CJA Punt, M Koopman, J Douma, J Wals, AH HonkoopFLG Erdkamp, RS de Jong, CJ Rodenburg,

L Mol, NF Antonini

ASCO 2007

CAIRO study CKTO 2002-07

Arm A Arm B

Randomize

capecitabine

capecitabine +oxaliplatin

irinotecancapecitabine +

oxaliplatin

capecitabine +irinotecan1st line

2nd line

3rd line

Dose/schedule of drugsall cycles given 3 weekly

• Capecitabine monotherapy: 1250 mg/m2 b.i.d. day 1-14

• Irinotecan monotherapy: 350 mg/m2 day 1

• CAPIRI1: capecitabine 1000 mg/m2 b.i.d. day 1-14 + irinotecan 250 mg/m2 day 1

• CAPOX2: capecitabine 1000 mg/m2 b.i.d. day 1-14 + oxaliplatin 130 mg/m2 day 1

1 Rea et al. Ann Oncol 20052 Borner et al. J Clin Oncol 2002

Trial profile

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

Median overall survival

Combination treatment 17.4 months (15.2-19.2)

----------- Sequential treatment 16.3 months (14.3-18.2)

p = 0.33

Efficacy results

Sequential

N=401

Combination

N=402

p value

Median overall survival (months) 16.3 17.4 0.33

Hazard ratio for death 1.08

One-year survival rate (%) 64 67

Median PFS (months) 1st line 5.8 7.8 0.0002

Overall response rate (CR + PR)*

1st line

2nd line

3rd line

77 (20%)

23 (10%)

5 (4%)

139 (41%)

24 (12%)

-

Disease control rate (CR + PR + SD)*

1st line

2nd line

3rd line

280 (74%)

162 (71%)

72 (57%)

297 (87%)

121 (63%)

* Percentages are based on patients evaluable for response

Grade 3-4 toxicities in first line

Toxicity

Arm Acapecitabine

N = 397

Arm B capiri

N = 398p value

Hand-foot syndrome 12% 6% 0.002

Diarrhea 11% 26% <0.001

Nausea 4% 10% 0.004

Vomiting 3% 9% 0.0002

Stomatitis <1% 2% 0.16

Thrombosis/embolism * 7% 10% 0.20

Febrile neutropenia <1% 7% <0.001

* All grades

Quality of life

• Participation to this part of the study was proposed to the first 620 patients entered in the study (QLQ-C30 questionnaire of the EORTC)

• 403 patients were evaluable for quality of life

• Quality of life scores were comparable between the two arms, except for diarrhoea which was reported more frequently in combination treatment

Conclusions

• Combination treatment is not superior in terms of efficacy to sequential treatment in patients with advanced colorectal cancer

• Our results on median overall survival for sequential treatment are the highest reported when a fluoropyrimidine is administered as monotherapy in 1st line

• Sequential treatment is a useful alternative for combination treatment

• Our results may be useful for strategies in which chemotherapy is combined with targeted agents

What about use of CapeIri?

62

Back to CAIRO

• PFS Capeiri in CAIRO similar to FOLFIRI in BICC-C– But OS of 17 mos is less than we’ve come to expect in

sequential doublets– Cross trial comparisons– CapeIri in CAIRO better tolerated than CapeIri in BICC-C

or EORTC trial except for high rates of diarrhea (~ double that seen with FOLFIRI in Tournigand or BICC-C)

• Would Combination arm in CAIRO have done better if FOLFIRI used?– No one knows.

63

? Reasons for Results

• ? Geographic differences in capecitabine metabolism

– Similar results in Europe

• ? Celecoxib

– Results not published for BICC-C

• ? Different dose of cape do better

– Maybe but not used in this trial

64

Summary

• Both CAIRO and FOCUS validate a sequential approach within the context of their study parameters

• ? Would they have done so if FOCUS had allowed better access to all 3 chemo drugs and CAIRO had used FOLFIRI?

65

Is Less Chemo More?

Case

• 50 yo woman with no history of medical problems presents with bilobar liver and bilateral lung metastases– ECOG 1 – some RUQ pain and cough

She agrees to chemotherapy but asks if there is anyway she can take a break during chemo without reducing the benefits of chemo?

Which of the following strategies has been shown to reduce toxicity without impacting on efficacy?

• Induction of FOLFOX for 3 mos followed by infusional 5FU maintanence then reintroduce FOLFOX

• Induction of FOLFOX for 3 mos followed by no maintanence (complete chemo break) then reintroduce FOLFOX

• FOLFIRI on for 2 mos, off for 2 mos

Stop and Go concept - OPTIMOX1

Tournigand et al, JCO 2006

6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7

FOLFOX4

620 pts

R

Cum. Oxali 780 1560

(%) FOLFOX4 FOLFOX7

RR 58.5 58.3PFS 9.0 8.7DDC 9.0 10.6OS 19.3 21.2G3/4 NTox 17.9 13.3

Primary endpoint

F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro,

P.Artru, C. Louvet, A. de Gramont

OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals

(CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC).

A GERCOR study.

OPTIMOX Studies

OPTIMOX-1

FOLFOX 4 until TF

FOLFOX 7 FOLFOX 7

sLV5FU2

OPTIMOX-2

mFOLFOX 7 mFOLFOX 7

sLV5FU2

mFOLFOX 7 mFOLFOX 7

CFI

Baseline Progression

t

T size

FOLFOX FOLFOX

Progression Baseline progression

Progressionat reintroduction

Chemotherapy-free Interval

Duration of Disease Control

t

T size

FOLFOX FOLFOX

PFS 1

Progression Baseline progression

PFS 2

Progressionat reintroduction

DDC = PFS 1 + PFS 2 (if no PD)

ASCO 2001, 146a

Neuropathy

Grade 1 8 %

2 21.2 % 3 2 %

Grade 1 29.4 % 2 35.3 % 3 5.9 %

Grade 1 6.8 % 2 15.5 % 3 3.9 %

Grade 1 36.8 % 2 19.2 % 3 7 %

Optimox 1 Optimox 2

After the first reintroduction

2 months after FOLFOX

Grade 1 70.7 % 2 18.1 % 3 0 %

Grade 1 70.8 % 2 16.5 % 3 0 %

During C1-C6

Chemotherapy-free IntervalChemotherapy-free interval

0 10 20 30 40 50 60 70 80 90 1000.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX2 median 17 weeks

R0 surgery excluded

weeks

Probability

Duration of Disease ControlDuration of Disease Control

0 10 20 30 40 50 60 70 80 90 1000.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX1 median 52 weeks

OPTIMOX2 median 39 weeks

p=0.39

weeks

Probability

Overall SurvivalOverall Survival

0 10 20 30 40 500.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX1 median 26 months

OPTIMOX2 median 19 months

p=0.0549

months

Probability

Alternating vs continuous FOLFIRI in advanced Alternating vs continuous FOLFIRI in advanced colorectal cancer (ACC): colorectal cancer (ACC):

a randomized GISCAD triala randomized GISCAD trial

Roberto LabiancaOspedali Riuniti – Bergamo, Italy

Floriani I, Cortesi E, Isa L, Zaniboni A, Marangolo M, Frontini L, Barni S, Beretta GD, Sobrero A

GISCAD-Trial: Design

• Primary endpoint: OS

R

FOLFIRIFOLFIRIFOLFIRIFOLFIRI

Evaluation

4 mos

N=336

PFSMedian f-up: 30 m

Median time to PD:Arm A 6.2 mArm B 6.5 m

Cox analysis (after adjustment for gender, age and site): HR: 1.01 (0.78-1.27)

OS Median f-up: 30 m

Median survival time:Arm A 16.9 mArm B 17.6 m

Cox analysis (after adjustment for gender, age and site): HR: 1.03 (0.78-1.35)

Toxicity

• Grade 3/4 toxicities similar in both arms– This paradigm of toxicity measurement is not

appropriate for this type of trial

• No QOL analysis

Summary

• GISCAD– Equivalent DFS, OS, toxicity – ? Rationale clinical strategy

• OPTIMOX2

• ? Longer induction needed

• ? Shorter break before re-introduction

• ? Different maintenance strategy

From OPTIMOX to DREAM

OPTIMOX-1

OPTIMOX-2

Efficacy =Toxicity

Efficacy decresedToxicity =

DREAMBevacizumab

ErlotinibBevacizumab