Axel Grothey, MD Professor of Oncology Mayo Clinic College of Medicine Rochester, MN

transcript

A Report from ASCO-GI 2008and ASCO 2007

Up-to-Date Review of the Treatment of Adjuvant Colorectal Cancer

A Report from ASCO-GI 2008and ASCO 2007

Up-to-Date Review of the Treatment of Adjuvant Colorectal Cancer

Axel Grothey, MDProfessor of Oncology

Mayo Clinic College of MedicineRochester, MN

Axel Grothey, MDProfessor of Oncology

Mayo Clinic College of MedicineRochester, MN

History of Adjuvant Therapy of Colon Cancer

• 5-FU/lev superior to surgery alone

• 5-FU/LV superior to surgery alone

• 5-FU/LV superior to 5-FU/lev

• 6- and 12-month treatment cycles equivalent

• Lev unnecessary

• High-dose and low-dose LV equivalent

• Monthly and weekly treatment equivalent

• LV5FU2 and monthly bolus equivalent

1990 1994 1998 2002

Moertel et al. Ann Intern Med. 1995;122:321.Francini et al. Gastroenterol. 1994;106:899.

Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. AbstractO’Connell et al. J Clin Oncol. 1998;16:295.

Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982.Andre et al. Proc Am Soc Clin Oncol. 2002. Abstract 529.

3 Year DFS vs 5 Year OS

0.5 0.55 0.6 0.65 0.7 0.75 0.8

Disease Free Survival

P = 0.90

5-yr OS = 0.0002 + 0.998* 3-yr DFS

May 05, 2004: ODAC recommends3-yr DFS as new regulatory endpointfor FULL approval in adjuvant colon cancer

Sargent, et al. J Clin Oncol 2005;23:8664–8670.

5-FU: Historical Standardin the Adjuvant Setting

1IMPACT Investigators, Lancet 1995;345:939–44.2Wolmark N, et al. J Clin Oncol 1993;11:1879–87.

3QUASAR Group. Lancet 2000;355:1588–96.4André T, et al. J Clin Oncol 2003;21:2896–903.

3-year disease-free survival (%)

Observation1

5-FU/high-dose LV (Mayo)2

5-FU/low-dose LV (Mayo)3

LV5FU24

Stage II and III colon cancer patients

6 months 5-FU/LV (Mayo)1

55 60 65 70 75

Beyond 5-FU in the Adjuvant SettingBeyond 5-FU in the Adjuvant Setting

Completed studies:

• Oxaliplatin (MOSAIC, NSABP C-07)

• Irinotecan (CALGB 89803, ACCORD-2, PETACC-3)

• Capecitabine (X-ACT)

Ongoing studies:

• CAPOX (XELOXA)

• Bevacizumab (NSABP C-08, AVANT, E5202)

• Cetuximab (N0147, PETACC-8)

Completed studies:

• Oxaliplatin (MOSAIC, NSABP C-07)

• Irinotecan (CALGB 89803, ACCORD-2, PETACC-3)

• Capecitabine (X-ACT)

Ongoing studies:

• CAPOX (XELOXA)

• Bevacizumab (NSABP C-08, AVANT, E5202)

• Cetuximab (N0147, PETACC-8)

MOSAIC: Study DesignMOSAIC: Study Design

Primary end-point: disease-free survival

Secondary end-points: safety, overall survival

Primary end-point: disease-free survival

Secondary end-points: safety, overall survival

LV5FU2

FOLFOX4(LV5FU2 + oxaliplatin 85 mg/m²)

(N =1,123)

LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days;

FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1

N = 2,246

Enrollment:Oct 1998–Jan 2001 (146 centres; 20 countries)

• Completely resected colon cancer

• Stage II, 40%; Stage III, 60%

• Age 18–75 years

• KPS ≥60

• No prior chemotherapy

Disease-free Survival: ITTDisease-free Survival: ITT

Data cut-off: June 2006Disease-free survival (months)

FOLFOX4

LV5FU2

0 6 12 18 24 6030 36 42 48 54

Events

FOLFOX4 304/1,123 (27.1%)

LV5FU2 360/1,123 (32.1%)

HR [95% CI]: 0.80 [0.68–0.93]

P = 0.0035.3%

De Gramont A, et al. ASCO 2007. Abstract #4007.

Disease-free Survival:Stage II and Stage III Patients

Data cut-off: June 2006

HR [95% CI] P - value

Stage II 0.84 [0.62–1.14] 0.258

Stage III 0.78 [0.65–0.93] 0.005

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Months

0 6 12 18 24 6030 36 42 48 54 66 72

P = 0.258

P = 0.005

MOSAIC: Disease-free Survival –Final Update

5-year DFS %

HR [95% CI] P - value FOLFOX4 LV5FU2

ITT (overall population) 73.3 67.4 0.80

[0.68–0.93]

Stage III 66.4 58.9 0.78

[0.65–0.93]

Stage II 83.7 79.9 0.84

[0.62–1.14]

High-risk stage II N = 576 82.1 74.9 0.74

[0.52–1.06]

Low-risk stage II N = 323 86.3 89.1 1.22

[0.66–2.26]

Data cut-off: June 2006

“High-risk” Stage II Colon Cancer“High-risk” Stage II Colon Cancer

• Clinico-pathological parameters (MOSAIC)

- T4 tumors

- Obstruction/perforation

- Lymphatic or vascular invasion

- Undifferentiated histology

- Less than 10 (12) Ln examined

• Molecular parameters

- LOH 18q

- Other?

• Clinico-pathological parameters (MOSAIC)

- T4 tumors

- Obstruction/perforation

- Lymphatic or vascular invasion

- Undifferentiated histology

- Less than 10 (12) Ln examined

- LOH 18q

- Other?De Gramont A, et al. ASCO 2007. Abstract #4007.

Long-term SafetyLong-term Safety

(% patients)

FOLFOX

LV5FU2

DuringTx

6months

1-year 2-year 3-year 4-year

Grade 1

Grade 2

Grade 3

Data cut-off: January 2007

Second cancer

Peripheral Sensory Neuropathy

Evaluable patients

N = 811

Grade 0 84.3%

Grade 1 12.0%

Grade 2 2.8%

Grade 3 0.7%

Overall Survival: ITTOverall Survival: ITT

Overall survival (months)

FOLFOX4

LV5FU2

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

Events

FOLFOX4 243/1,123 (21.6%)

LV5FU2 279/1,123 (24.8%)

HR [95% CI]: 0.85 [0.72–1.01]

P = 0.057

6 yrs: 78.6% vs. 76.0%

Overall Survival: Stage II and Stage IIIOverall Survival: Stage II and Stage III

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Overall survival (months)

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

HR [95% CI]

Stage II 1.00 [0.71–1.42]

Stage III 0.80 [0.66–0.98]

P = 0.996

P = 0.029

Take-Home Messages MOSAICTake-Home Messages MOSAIC

• DFS benefit for FOLFOX is maintained over 5 years

• Significant OS benefit for stage III, but NOT for unselected stage II patients

• “High-risk” stage II with trend toward better DFS with FOLFOX, but clinical consequence unclear

• No increased rate of secondary cancers, but more deaths of cancer in FOLFOX group (21 vs. 11)

• Even 4 years after FOLFOX, 3.5% of patients still have grade 2/3 neurotoxicity (+12% grade 1)

FOLFOX is standard adjuvant therapy for stage III and can be considered for high-risk stage II CC

• DFS benefit for FOLFOX is maintained over 5 years

• Significant OS benefit for stage III, but NOT for unselected stage II patients

• “High-risk” stage II with trend toward better DFS with FOLFOX, but clinical consequence unclear

• No increased rate of secondary cancers, but more deaths of cancer in FOLFOX group (21 vs. 11)

• Even 4 years after FOLFOX, 3.5% of patients still have grade 2/3 neurotoxicity (+12% grade 1)

FOLFOX is standard adjuvant therapy for stage III and can be considered for high-risk stage II CC

FU RestLV 500

FU 500

RestLV 500

OHP 8585 2hr2hr

Week 1 2 3 4 5 6 7 8

NSABP C-07

N = 2,407

Endpoint3yr DFS

Accrual 02/00 - 11/02

Kuebler JP, et al. J Clin Oncol 2007;25:2198–2204.

Ev # 3yr DFSFLOX 272 76.5%FULV 332 71.6%

P < 0.004HR: 0.79 [0.67 – 0.93]

21 % risk reduction

C-07: DFS

0 1 2 3 4

Kuebler JP, et al. J Clin Oncol 2007;25:2198–2204.

3y DFS Δ HR

C-07 76.5 % 4.9 % 0.79

MOSAIC 77.9 % 5.1 % 0.77

C-07 and MOSAIC - Oxaliplatin benefit

De Gramont A, et al. ASCO 2007. Abstract #4007.Kuebler JP, et al. J Clin Oncol 2007;25:2198–

Cross-Study ComparisonToxicity: MOSAIC / C-07Cross-Study ComparisonToxicity: MOSAIC / C-07

FOLFOX 4

(MOSAIC)

(C-07)

Gr 3-4 Neutropenia41%

(2% neut. fever)4% (?)

Gr 3-4Diarrhea

11% 38%

Gr 3 Neuro(cum oxali)

12.4%(1,020 mg/m2)

8%(765 mg/m2)

All Cause Mortality 0.5% 1%

De Gramont A, et al. ASCO 2007. Abstract #4007.Kuebler JP, et al. J Clin Oncol 2007;25:2198–

Abstract 347

Ramanathan RK, André T, Rothenberg ML, de Gramont A,

Tournigand C, Goldberg RM, Gupta S

Diabetes Mellitus and the Incidence and Time to Onset of Oxaliplatin-Induced

Peripheral Sensory Neuropathy (PSN) in Patients with Colorectal Cancer: A Pooled

Analysis of Three Randomized Studies

Pooled AnalysisPooled Analysis

• Data from 3 randomized clinical trials including FOLFOX4

• EFC3313 (MOSAIC): 5-FU and LV (LV5–FU2) + oxaliplatin as adjuvant therapy in CRC

• EFC4584: Three-arm study of LV5–FU2, LV5–FU2 with oxaliplatin, or oxaliplatin alone as second-line therapy of metastatic CRC

• EFC2962: Phase II/III study of LV5FU2 + oxaliplatin first-line

• PSN data from the overall study population with or without diabetes were analyzed for:

• Incidence and time to onset of PSN

• Trends indicating clinically relevant differences in the incidence and severity of PSN

• Data from 3 randomized clinical trials including FOLFOX4

• EFC3313 (MOSAIC): 5-FU and LV (LV5–FU2) + oxaliplatin as adjuvant therapy in CRC

• EFC4584: Three-arm study of LV5–FU2, LV5–FU2 with oxaliplatin, or oxaliplatin alone as second-line therapy of metastatic CRC

• EFC2962: Phase II/III study of LV5FU2 + oxaliplatin first-line

• PSN data from the overall study population with or without diabetes were analyzed for:

• Incidence and time to onset of PSN

• Trends indicating clinically relevant differences in the incidence and severity of PSN

Ramanathan 2008 ASCO GI abstract # 347

Incidence and Severity of PSNIncidence and Severity of PSN

PSNAll Patients

(N = 1,585)

DM Patients

(N = 135)

Grade 1 45.2 46.7

Grade 2 28.4 26.7

Grade 3 13.0 12.6

Probability of PSN by Cumulative Dose

EFC3313: any grade EFC3313: grade ≥ 3

EFC4584: any grade EFC4584: grade ≥ 3Ramanathan 2008 ASCO GI abstract # 347

Conclusions FOLFOX in DiabeticsConclusions FOLFOX in Diabetics

• In CRC trials with FOLFOX4 no difference in:

- the probability of developing PSN nor

- the severity of grade between all treated patients

and the subset with diabetes mellitus was observed

• This data suggests patients with diabetes mellitus have no increased risk of developing cumulative neurotoxicity

• In CRC trials with FOLFOX4 no difference in:

- the probability of developing PSN nor

- the severity of grade between all treated patients

and the subset with diabetes mellitus was observed

• This data suggests patients with diabetes mellitus have no increased risk of developing cumulative neurotoxicity

CALGB 89803: DFS and OS Not Improvedwith IFL in Stage III Colon Cancer

Saltz L, et al. J Clin Oncol 2007;25:3456–61

OS = overall survival; IFL = irinotecan, 5-FU plus leucovorin

g0 1 2 3 4 5 6 7

Years0 1 2 3 4 5 6 7

N Events

FU/LV 629 227IFL 635 248

P (stratified) = 0.85 (1-sided)

N Events

FU/LV 629 171IFL 635 181

P (stratified) = 0.74 (1-sided)

FU/LVIFL

ACCORD-02Irinotecan in High-risk Stage III Colon Cancer

• 400 patients with resected high risk stage III colon cancer (N2 or N1 with occlusion/perforation)

• Accrual completed in Spring 2002

• Stratified:- Center- N stage- Delay to chemotherapy- Age

• 400 patients with resected high risk stage III colon cancer (N2 or N1 with occlusion/perforation)

• Accrual completed in Spring 2002

• Stratified:- Center- N stage- Delay to chemotherapy- Age

RANDOMIZE LV5FU2

FOLFIRI:• LV5FU2• CPT-11 180 mg/m2

on day 1

12 cycles planned

Ychou M, et al. J Clin Oncol 2005;(Suppl. 16):246s (Abstract 3502)

ACCORD-02: DFS Not Improved with FOLFIRI in High-risk Colon Cancer

Ychou M, et al. J Clin Oncol 2005;(Suppl. 16):246s (Abstract 3502)

00 1 2 3 4 5 6

y HR = 1.19 (95% CI: 0.90–1.59)P = 0.22

LV5FU2 60FOLFIRI 51

3-year DFS (%)

Stratification:

• Stage II vs. III

• Center

RANDOMIZATION

Day 1 Day 2

FA 200 mg/m2

5-FU bolus 400 mg/m2

5-FU CI 600 mg/m2

Day 1 Day 2

Irinotecan 180 mg/m2

LV5FU2

LV5FU2 as above

IFRepeat q 2 weeks

for 12 Cycles

PETACC-3: Study Design

210 pts treated with AIO regimen ± irinotecan within given centers will be presented later.

Van Cutsem E, et al. J Clin Oncol 2005; 23:(Suppl. 16):3s (Abstract LBA8)

PETACC-3: Results Stage IIIPETACC-3: Results Stage III

HR (95% CI)

P-value

DFS 0.89 0.091(0.77-1.11)

RFS 0.86 0.045(0.75-1.00)

PETACC-3: DFS not significantly improved with FOLFIRI in stage IIIPETACC-3: DFS not significantly improved with FOLFIRI in stage III

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48Months

FOLFIRI 1,044 63.35-FU/LV 1,050 60.3

HR=0.89 (95% CI: 0.77–1.11)

P = 0.091

3-year DFS (%)

DFS = disease free survivalHR = hazard ratio; CI = confidence interval

X-ACT Trial - DesignX-ACT Trial - Design

Endpoints- DFS- RFS- overall survival (OS)- tolerability (NCIC CTG)- pharmacoeconomics- quality of life (QoL)

Chemo-naïve stage III colon cancer,resection 8 weeks

Capecitabine1 250mg/m2 twice daily,

d1–14, q21d N = 1,004

Bolus 5-FU / LV5-FU 425mg/m2 plus

LV 20mg/m2, d1–5, q28dN = 983

Recruitment1998–2001

24 weeks

Twelves et al., N Engl J Med 2005

X-ACT: 5-year DFS (median follow-up 6.8 years)

5-year

DFS (%)

Capecitabine 1, 004 60.8

5-FU/LV 983 56.7

00 6 42 48 78 96

Months

HR = 0.88 (95% CI: 0.77–1.01)NI margin 1.20

12 18 24 30 36 54 60 66 72 84 90

ITT population

ITT (intent-to-treat) population; NI = non-inferiority

Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

Test of non-inferiority P < 0.0001Test of superiority P = 0.0682

X-ACT: 5-year OS (median follow-up 6.8 years)

HR = 0.86 (95% CI: 0.74–1.01)NI margin 1.14

ITT population

0 6 42 48 78 96

Months

12 18 24 30 36 54 60 66 72 84 90 102

Test of non-inferiority P = 0.000116Test of superiority P = 0.06

5-year

OS (%)

Capecitabine 1, 004 71.4

5-FU/LV 983 68.4

Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

Neutropenia

Nausea/

vomitin

Stomatitis

Diarrhea

Febrile

neutropenia HFS

Scheithauer W, et al. Ann Oncol 2003;14:1735–43

*P < 0.001HFS = hand foot syndrome

Capecitabine (N = 993)

5-FU/LV (N = 974)

Grade 3/4 adverse events

X-ACT: Improved Safety with CapecitabineX-ACT: Improved Safety with Capecitabine

Chemo/radiotherapy-naïve

stage III colon cancer

Bolus 5-FU/LVMayo Clinic or Roswell Park

CAPOXCapecitabine 1,000mg/m2 b.i.d. days 1–15

Oxaliplatin 130mg/m2 day 1 q3w

Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23

XELOXA: Phase III Trial of CAPOX in the Adjuvant Setting

• Primary endpoint: disease-free survival• Primary endpoint: disease-free survival

N = 944

N = 942

RANDO MISATION

Duration of therapy: 24 weeks

Grade 3/4 Adverse Events

CAPOX1 (N = 938)

FOLFOX42 (N = 1,108)

FLOX3 (N = 1,200)

Cross-trial comparison*Not reported

Neutropenia

Nausea

Stomatitis

Diarrhea

Febrile

neutropenia HFS

Vomiting

Neurose

1Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034)2André T, et al. N Engl J Med 2004;350:2343–51

3Wolmark N, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500)

Adjuvant CAPOX: Toxicity Compared with FOLFOX and FLOX

Ongoing US Cooperative Group Trials Adjuvant Therapy of Colon Cancer

Stage III colon cancer (N = 2,300)

Stage II/III colon cancer (N = 2,400)

mFOLFOX6 6m

mFOLFOX6 6m +Bevacizumab 12m

Intergroup N0147

NSABP C-08

mFOLFOX6 6m

mFOLFOX6 6m +Cetuximab 6m

Accrual completed

Should Patients with Stage II Colon Cancer Receive Adjuvant Therapy?Should Patients with Stage II Colon Cancer Receive Adjuvant Therapy?

• Direct evidence of randomized trials

• Meta-analyses

• Identification of “high-risk” patients

• Direct evidence of randomized trials

• Meta-analyses

• Identification of “high-risk” patients

Approximate Number of Patients Needed to Detect a Realistic Treatment Benefit*

Dukes’ B Dukes’ C

No. of No. of Survival ARR Patients Survival ARR Patients

At 3-years 85% 2.5% 8,000 65% 5.2% 3,400

At 4-years 80% 3.3% 5,800 58% 6.0% 2,800

At 5-years 75% 4.0% 4,700 50% 6.6% 2,400

Abbreviation: ARR = absolute risk reduction

• For 90% power of detecting the treatment benefit using two-tailed significance tests at the 5% level, assuming the true relative risk reduction is 18% for both Dukes’ B and Dukes’ C.

Buyse, Piedbois, 2001

QUASAR: Study DesignQUASAR: Study Design

Clear indication for chemotherapy

(N = 4,320)

2 x 2 randomization to 5-FU with low- or high-dose LV and

Lev or placebo

Chemotherapy(N = 1,622)*

Observation(N = 1,617)No clear indication

for chemotherapy(mainly stage II)

(N = 3,239)

RANDOMIZE

Colon or rectal cancer

• Stage I-III• Complete resection

with no evidence of residual disease

* Prior to 10/1997 chemotherapy patients were randomized as in clear indication arm; after 10/1997 patients received 5-FU/low-dose LV.

QUASAR Group, Lancet 2007

tsQUASAR: Overall Survival in Patients with

“no clear indication for chemo”QUASAR: Overall Survival in Patients with

“no clear indication for chemo”

P = .025-year OS, Observation = 77.4% vs Chemotherapy = 80.3%Relative risk = 0.83 (95% CI, 0.71-0.97)

YearsQUSAR group, Lancet 2007

0 1 2 3 4 5 6 7 8 9 100

100Observation (N = 1,622)

Chemotherapy (N = 1,617)

5-yr OS difference: 2.9%

ASCO Guidelines 2004ASCO Guidelines 2004

• Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer.

• Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease.

• The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences.

• Patients with stage II disease should be encouraged to participate in randomized trials.

• Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer.

• Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease.

• The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences.

• Patients with stage II disease should be encouraged to participate in randomized trials.

Benson et al. J Clin Oncol. 2004

“High-risk” Stage II Colon Cancer“High-risk” Stage II Colon Cancer

• Clinico-pathological parameters

• T4 tumors

• Obstruction/perforation

• Lymphatic or vascular invasion

• Undifferentiated histology

• Less than 10 (12) Ln examined

• LOH 18q

• MSS

• Other?

• Clinico-pathological parameters

• T4 tumors

• Obstruction/perforation

• Lymphatic or vascular invasion

• Undifferentiated histology

• Less than 10 (12) Ln examined

• LOH 18q

• MSS

• Other?

Analysis of Molecular Markers in Patients with Stage III Colon Cancer

Watanbe T, et al. N Engl J Med 344(16);1196-1206, 2001

Colon Stage II – AdjuvantE5202: High Risk Stage IIColon Stage II – AdjuvantE5202: High Risk Stage II

Register

Tumor block assessmentfor 18q/MSI

High Risk• MSS + 18q LOH• MSI-L + 18q LOH

Low Risk• MSS, no 18q LOH• MSI-L, no 18q LOH• MSI-H +/- 18q LOH

Observation

mFOLFOX6

mFOLFOX6+ bevacizumab

Expect 2 weeks for tissue review

N = 3,610

What is the Standard Adjuvant Therapy in Colon Cancer ?

• FOLFOX is the standard adjuvant therapy in stage III and high-risk stage II colon cancer

• Capecitabine (UFT,S1?) for patients who are not considered candidates for oxaliplatin

• Irinotecan-based combinations are NOT options in the adjuvant setting

• XELOX data eagerly awaited

• Bevacizumab and Cetuximab are under investigation

• FOLFOX is the standard adjuvant therapy in stage III and high-risk stage II colon cancer

• Capecitabine (UFT,S1?) for patients who are not considered candidates for oxaliplatin

• Irinotecan-based combinations are NOT options in the adjuvant setting

• XELOX data eagerly awaited

• Bevacizumab and Cetuximab are under investigation

Axel Grothey, MD Professor of Oncology Mayo Clinic College of Medicine Rochester, MN

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