Adjuvant Chemotherapy

for Colorectal Cancer

Ronald L. Burkes, M.D.

Historic Synopsis in the Treatment of Colorectal Cancer

• 5-FU has anti-tumor activity 1958

• Biochemical modulation of 5-FU with LV 1989

• HAI with FUDR RR 1993• Responses seen post bolus 5-FU with infusional 5-FU 1993• Adjuvant CT (5-FU/Lev or 5-FU/LV) for colon cancer 1994

• Adjuvant CT + RT for rectal cancer 1995

• New drugs - CPT-11/Tomudex/Oxaliplatin 1993-2002• MTD – Cetuximab; Bevacizumab; 2000-2008

Panitumumab

Adjuvant Therapy for

Stage II Colon Cancer:

Yes, No and Maybe So

Why is the Situation in Stage II Colon Cancer Less Clear than Stage III

DFS and survival difference is small – relatively low activity of adjuvant treatment

High patient numbers required to show a difference

Stage II is a heterogeneous disease for

Clinical factors

Pathological factors

Molecular factorsMost trials were not stratified for these factors

Why is Adjuvant Therapy Effective in Stage III but not Stage II Disease:

The Numbers

To detect a 2% survival difference between Rx and controls (90% power with significance level of .05) would require a sample size of 9680 pts per group

To detect an absolute risk reduction of 2.5% at 3 yrs and 4% at 5 (85% & 75% survival) would require a study of 8000 and 4700 pts respectively

Benson JCO 22:3408, 2004

Stage II Colon Cancer: Poor Prognostic factors

• Inadequate staging

• Clinical/pathological features

• Molecular/enzymatic factors

Poor Prognostic Factors: Inadequate Staging

• Variability of the number of lymph nodes sampled

• Recent reports have independently recommended that >10 lymph nodes (ideally >12) be examined to classify a colon cancer as truly N0Intergroup adjuvant trialNational Cancer Data Base

JCO, 2003Ann Surg Oncology, 2003

Clinical/Pathological Features: Subset Analysis for B2 Intergroup Study

(7 year survival)

Covariate Observation 5-FU/Lev

Adhesion 70% 82%

Invasion 64% 86%

Obstruction 58% 70%

Perforation 51% 67%

Stage II a Heterogeneous Disease: Molecular Factors

• Microsatellite instability – MSI-Hi > MSS (stg for stg)

• MSI-H vs MSS with CT – ND

• MSS with CT - ↑ survival

• MSI-H with CT – ND (trend to survival)

• 18q LOH

• DNA ploidy

• EGFR+

• P53

• Microarray gene expression profiling

• ???KRAS

Gryfe NEJM 342:69, 2000Ribic NEJM 349:247, 2003Watanabe NEJM 344:1196, 2001Barrier JCO 24:4685, 2006

Other Prognostic Pathological Variables

• Grade

• Lymphovascular invasion

• Perineural invasion

• ?Immune response – lymphocytic infiltrate confers a better prognosis; fibrosis a worse prognosis

Pooled Analysis of Fluorouracil-Based Adjuvant Therapy for Stage II and III

Colon Cancer

• 3 factors predict prognosis

- nodal status – N0 vs N1-4 vs >5

- depth of invasion – T1/2 vs T3 vs T4

- grade – low vs high

• www.mayoclinic.com/calcs

• Stage II - 17% relative reduction in risk of recurrence (4% ↑ in 5 yr DFS; 72% vs 76% but overall survival was 80% vs 81%)

Gill JCO 22:1797, 2004

Adjuvant on Line

• Depth of invasion• Histologic grade• # of nodes involved• # of nodes examined• Derived tumor stage• Age• General health (# of comorbid conditions)• Treatment

5-FU + Levamisole for Stage II/Dukes’ B2 Colon

Cancer Obs 5-FU/Lev

n 159 159

RFS (7 yr) 71% 79% p=.1

OS (7 yr) 72% 72% p=.83

recurrence by 31% (p=.1)• disparity secondary to: - higher rates of non-colon ca deaths with CT - salvage surgery

Moertel JCO 13: 2936, 1995

IMPACT B2 Adjuvant Trials (n=1016)(GIVI0, NCIC, FFCD, NCCTG, Siena)

Pooled Analysis

5-FU/FA Control (370/200)

EFS (5 yrs) 76% 73%

OS (5 yrs) 82% 80%

JCO 17:1356, 1999 (Lancet 345:939,1995)

NSABP Colon Trials5 Year Survival

C-01 MOF OP

C-02 PVI OP

C-03 FU-LV MOF

C-04 FU-LV FU-LEV

• All Patients 67 60 74 67 76 66 75 70

• Dukes B 75 72 88 76 92 84 85 81

• Dukes C 59 50 58 56 70 59 67 63

Benefit for stage II same or greater as for stage III

mortality, recurrence or DFS event rate from CT irrespective of stage

30% less mortality for Dukes’ B 18% less mortality for Dukes’ C

Mamounas JCO 17: 1349,1999

Cancer Care Ontario Practice Guidelines for Stage II Colon Cancer

August, 1997• 31 RCT’s• 3 meta-analysis• 1 evidence-based consensus

statement

Update: April, 2000• 4 meta-analysis• New or updated reports on 19 RCT’s

Cancer Care Ontario Practice Guidelines for Stage II Colon Cancer

• Adjuvant therapy is not recommended

• Patients with high risk factors have a poorer prognosis and adjuvant CT could be considered

- bowel obstruction

- tumor adhesion

- invasion

- perforation

- aneuploidyFigueredo Ca Prev Control 1: 379, 1997

CCOPGI: Full Report – April, 2000

Systematic Review from the CCO Program in Evidence-Based Care’s GI

Disease Site Group: Conclusions

• No compelling evidence to use systemic adjuvant therapy.

• There probably is a small benefit that present trials have yet to detect as significant.

• Additional investigation of newer therapies and more mature data from the available trials should be pursued.

Figueredo JCO 22:3395, 2004

Conclusions Regarding Adjuvant Therapy: ASCO Guidelines

• Adjuvant therapy for low-risk stage II colon cancer is not supported by randomized controlled trials.

• Adjuvant therapy for hi-risk stage II disease is recommended - ? regimen.

Benson JCO 22:3408, 2005

FULV vs FLOX for Stage II or III Colon Cancer: NSABP C-07

Wolmark PASCO 23&26: 246s/179s (3500/4005), 2005/2008

FULV FLOX 1209 1200

N0 28.8% 28.9%N1-3 45.7% 44.8%N>3 25.3% 25.6%Neuro - all gr - 85% (29% @ 1 yr) - gr 3 - 8% (.5% @ 1 yr) Oxali dose - 765 mg/m2

(1020 in MOSAIC)

FULV vs FLOX for Stage II or III Colon Cancer: NSABP C-07

Wolmark PASCO 26:179s (4005)2008

FULV FLOX

DFS - 3 yr

- 5 yr

71.5%

64.2%

76.1%

69.4%

OS - 5 yr

- 6 yr

78.3%

73.5%

80.3% (p=.06)

77.7% (HR=.85)

Surv after recur

22.2 mo 17.6 mo

Global test for interaction between stage and Rx was not significant (p = .7)

Adjuvant Oxaliplatin + 5-FU + Leucovorin: MOSAIC Trial

Andre NEJM 350:2343, 2004; de Gramont PASCO 23:246 (3501), 2005 and PASCO 25:#4007, 2007

Adjuvant Oxaliplatin + 5-FU + Leucovorin: MOSAIC Trial

Andre NEJM 350:2343, 2004; deGramont PASCO 23:246 (3501), 2005

LV5FU2 FOLFOX4

1123 1123

Stage II/III 40%/60% 40%/60%

Mean # cycles 11.3 10.7

DI - 5-FU 97.7% 84.4%

- Oxali - 80.5%

MOSAIC Trial: 5 Year DFSde Gramont PASCO 25:#4007, 2007

LVFU2 FOLFOX4

All pts 67.4% 73.3%

Stage III 58.9% 66.4%

Stage II 79.9% 83.7%

Hi-risk stage II

(576)

74.9% 82.1%

Low-risk stage II

(323)

86.3% 89.1%

MOSAIC Trial: 6 Year Survivalde Gramont PASCO 25:#4007, 2007

LV5FU2 FOLFOX4

All pts 76% 78.6%

HR = .85; p = .057

Stage III 68.6% 73%

HR = .8; p = .029

Stage II 86.8% 86.9%

HR = 1; p = .996

MOSAIC Trial: Conclusions

• DFS benefit seen at 3 yrs is maintained at 5 yrs

• At 6 years there is no survival benefit for stage II pts

• Despite a DFS benefit with F4 for hi-risk stage II pts this did not translate into a survival benefit

• There was no increase in 2nd cancers

• There is continued recovery in peripheral neuropathy but 15% of pts still had residual PN at 4yrs (.7% gr 3; 2.8% gr 2; 12% gr 1)

DFS (3 yr) vs OS (5 yr) as a Primary Endpoint for

Adjuvant Therapy for CRCSargent PASCO 23:249s (3512), 2005/JCO 23:8564, 2005

• 43 Rx arms; n = 20,898 pts• M:F = 54:46• Stg II:III = 34:66• 74% of recurrences in 1st 3 yrs• 3 yr DFS & 5 yr OS – cc = .92 for stg III but

only .65 for stg II• DFS excellent predictor of OS at 5 yrs (stg III)• ODAC voted 15 to 0 to accept as a surrogate

marker (Pazdur)

Microsatellites

• Short, tandemly repeated DNA sequences

• Detected at the molecular level using genomic DNA from either fresh or paraffin-fixed CRC tissues

• Insertion or deletions of nucleotides within repeated sequences of DNA = Microsatellite Instability

• Frequent alterations in DNA sequence length = MSI-H

• MSI is due to defective mismatch repair genes

dMMR as a Predictive Marker for Lack of Benefit from 5-FU based Adjuvant Chemotherapy

Sargent PASCO 26:180s (#4008), 2008

Summary of Adjuvant Therapy for

Stage II Colon Cancer: DFS

Moertel IMPACT Gray Mosaic

7 yr 5 yr 5 yr 6 yrObs CT Obs CT Obs CT LV5FU2 F4

71% 79% 73% 76% 73.8% 77.8% 86.8% 86.9%

Conclusions: Stage II

• Prospective clinical trials and meta-analyses have not yet shown a benefit for adjuvant chemotherapy.

• Present guidelines have recommended against the use of such treatment in “standard risk” patients.

• The use of adjuvant therapy in subsets of stage II pts with ominous clinical, pathological or molecular characteristics appears reasonable although the value of this strategy has not been prospectively validated and the regimen to use is controversial.

Stage III Disease

Intergroup Trial of Levamisole/5-FU for Stage III Colon Carcinoma

(F/U > 5 yrs, med 6.5)

Obs. Lev. Lev/5-FU

n 315 310 304

Recurrence 177 172 119 p<.0001

Deaths 168 158 121 p=.0007

• decrease recurrence by 40% • decrease death rate by 33%

Moertel Ann Int Med 122: 321, 1995

IMPACT Trial: Adjuvant 5-FU/FA(GIVI0, NCIC, FFCD)

5-FU/FA (370/200)

Control

736 757

Dukes’ B – 56% 56.8% 55.9%

Dukes’ C – 44% 43.2% 45.1%

EFS (3 yrs) 71% 62% p<.0001

OS (3 yrs) 83% 78% p=.029

Dukes’ B–EFS/OS (%) 79/88 76/90

Dukes’ C-EFS/OS (%) 62/76 44/64

IMPACT Trial: Adjuvant 5-FU/FA(GIVI0, NCIC, FFCD) - cont’d.

decrease recurrence by 33%decrease mortality by 22%borderline EFS & none for OS

for Dukes’ B

Lancet 345: 939, 1995

5-FU/LV vs FU/Lev vs 5-FU/LV/Lev: Low dose vs Hi-dose and

6 months vs 12 months

6 months of 5-FU + Leucovorin (LD/HD) became the standard

adjuvant treatment

Capecitabine vs Mayo in Stage III CRC: X-ACT StudyTwelves NEJM 352: 2696, 2005; GI ASCO #274, 2008

Cape Mayo1004 983

T1/2 10% 10% T3 76% 76% T4 14% 14%

3 yr - DFS 60.8% 56.7% - RFS 65.5% 61.9% - OS 71.4% 68.4%

Toxicity - H/F ↑ - Diarrhea ↓

- Stomatitis ↓ - Neutr ↓

Conclusions:• ↑ RFS• Trend to ↑ DFS & OS benefit• ↑ safety

X-ACT Trial: Survival Data

UFT vs FULV (Roswell) in Stage II & III CRC: NSABP CO6

Wolmark PASCO 23:#3508, 2004

Roswell UFT 777 784

II 46% 47%III 54% 54%N1 38% 37%N2 16% 16%RFS 76.4% 74.5%DFS 68.3% 66.9%OS 78.7% 78.7%Diarrhea 28% 29%QOL NDSx distress ↓

Conclusion• Equitoxic• Equivalent• UFT not available in N.A.

Adjuvant Oxaliplatin + 5-FU + Leucovorin: MOSAIC Trial

Andre NEJM 350:2343, 2004; de Gramont PASCO 23:246 (3501), 2005 and PASCO 25:#4007, 2007

Adjuvant Oxaliplatin + 5-FU + Leucovorin: MOSAIC Trial

Andre NEJM 350:2343, 2004; deGramont PASCO 23:246 (3501), 2005

LV5FU2 FOLFOX4

1123 1123

Stage II/III 40%/60% 40%/60%

Mean # cycles 11.3 10.7

DI - 5-FU 97.7% 84.4%

- Oxali - 80.5%

MOSAIC Trial: 5 Year DFSde Gramont PASCO 25:#4007, 2007

LVFU2 FOLFOX4

All pts 67.4% 73.3%

Stage III 58.9% 66.4%

Stage II 79.9% 83.7%

Hi-risk stage II

(576)

74.9% 82.1%

Low-risk stage II

(323)

86.3% 89.1%

MOSAIC Trial: 6 Year Survivalde Gramont PASCO 25/26:#4007, 2007/08

LV5FU2 FOLFOX4

All pts 76% 78.6%

HR = .85; p = .057

Stage III 68.6% 73%

HR = .8; p = .029

Stage II 86.8% 86.9%

HR = 1; p = .996

Alive with Recurrence

7.8% 6.1%

Time from Recur to Death

24 mo 21 mo

MOSAIC Trial: Conclusions

• DFS benefit seen at 3 yrs is maintained at 5 yrs

• There is a 6 yr OS benefit for stage III pts

• There was no increase in 2nd cancers

• There is continued recovery in peripheral neuropathy but 15% of pts still had residual PN at 4yrs (.7% gr 3; 2.8% gr 2; 12% gr 1)

FULV vs FLOX for Stage II or III Colon Cancer: NSABP C-07

Wolmark PASCO 26:179s (4005)2008

FULV FLOX

DFS - 3 yr

- 5 yr

71.5%

64.2%

76.1%

69.4%

OS - 5 yr

- 6 yr

78.3%

73.5%

80.3%

77.7%

Surv after recur

22.2 mo 17.6 mo

Global test for interaction between stage and Rx was not significant (p = .7)

MOSAIC vs CO.7: 5 year Survival: Stages II/III

Study DFS ∆ HR

MOSAIC 81.3% 2.2% .85

CO.7 80.3% 2.0% .85

Comparison of Adjuvant Trials

Moertel IMPACT X-ACT MOSAIC

Regimen Lev/5-FU LV/5-FU Cape FOLFOX

DFS (3yr) 63% 62% 64.2% 72.2%

Role for Adjuvant Irinotecan

• Adjuvant FL (Roswell) vs IFL in Stage III CRC: CALGB 89803 (CO.15)

• FOLFIRI vs LV5FU2 in Stage III Colon Cancer: PETACC 3

• Adjuvant LV5FU2 vs FOLFIRI for Stage III (hi-risk) Colon Cancer: ACCORD-2

All negative studies – no role for adjuvant irinotecan

Saltz PASCO 23: 246 (3500), 2004van Cutsem PASCO 23:3 (8), 2005Ychou PASCO 23: 246s (3502), 2005

DFS (3 yr) vs OS (5 yr) as a Primary Endpoint for

Adjuvant Therapy for CRCSargent PASCO 23:249s (3512), 2005

• 43 Rx arms; n = 20,898 pts• M:F = 54:46• Stg II:III = 34:66• 74% of recurrences in 1st 3 yrs• 3 yr DFS & 5 yr OS – cc = .92 for stg III but

only .65 for stg II• DFS excellent predictor of OS at 5 yrs (stg III)• ODAC voted 15 to 0 to accept as a surrogate

marker (Pazdur)

Time-Dependent Patterns of Failure and Treatment Benefit from Adjuvant Therapy for Resectable Colon

Cancer: Lessons from the 20,800-pt ACCENT databaseSargent PASCO 25:#4008, 2007

ACCENT: Conclusions

ACCENT: Survival from RecurrenceO’Connell PASCO 25:#4009, 2007

PASCO 26:179s (#4007), 2008

MOSAIC:Long Term Follow Up

DFS OS Difference

3 yr 5.3 1.1 4.2

4 yr 6.6 1.6 5

5/6 yr 5.9 2.6 3.3

Extended survival after recurrence ’s the DFS and OS relationship

How to Follow Patients Post Adjuvant Therapy

Examine and do BW including CEA every 3 months (pre-op CEA)

CT chest, abdomen and pelvis every 6 months x 3 years and then annually x 2 years

Colonoscopy at 1 year post op and then every 3 years if no polyps

ASCO guidelines (Desch JCO 23:8512, 2005)

Adjuvant Therapy of Stage III Colon Cancer: 3 year DFS

(equates with 5 year survival)

44%

63% 63% 64.20%

72.20%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Surgery

Lev/5FU

Leuc/5FU

Cape

FOLFOX

Rectal Cancer

Standard of Care for Most Patients with Stage II/III Rectal Cancer

CI 5-FU 225 mg/m2/day or Xeloda

+ RT

Surgery

FOLFOX x 8 cycles

Future Adjuvant Trials

CRC.2 (N0147)

Stage III FOLFOX6 x 12 + Cetuximab

CRC.3 in Canada

NCIC CRC.4/E5204

Stage II/III Rectal Cancer

Pre-op CT/RT

FOLFOX FOLFOX +

Bevacizumab

Conclusions Regarding Adjuvant Therapy

• Adjuvant therapy for low-risk stage II colon cancer is not supported by randomized controlled trials (Benson JCO 22:3408, 2005).

• Adjuvant therapy for hi-risk stage II disease is recommended - ? Xeloda/FOLFOX.

• Adjuvant CT with either FOLFOX or Xeloda for stage III colon cancer is standard practice.

• Pre-op CT/RT for stage II & III rectal cancer followed by FOLFOX is the usual practice. In the post-op setting pts usually receive FOLFOX x 4 CT/RT FOLFOX x 4.