Duration of Adjuvant Therapy for Colon Cancer Anthony F. Shields, - - PowerPoint PPT Presentation

Duration of Adjuvant Therapy for Colon Cancer

Anthony F. Shields, M.D., Ph.D. Karmanos Cancer Institute Wayne State University Detroit, Michigan

Standard therapy after surgery for:

Stage III with + nodes Stage II with high risk features (T4, obstruction, perforation)

Also considered for:

Stage II without added risk factors Stage IV resected metastatic disease Options: FOLFOX, CAPOX, Capecitabine, 5FU

Adjuvant Therapy for Colon Cancer

Observed 5-year Survival by TN Category

LL Gunderson, J Clin Oncol, 2010

MOSAIC 2007: Stage III Adjuvant

• Study now presented with > 5 years follow-up
• 6.6% DFS benefit maintained HR = 0.8, p = 0.003

Prob OS 6 years

5FU FOLFOX p Overall 76% 78.6% 0.057 Stage II 86.8% 86.9% 0.996 Stage III 68.6% 73% 0.029

MOSAIC 2009: Stage III Adjuvant

Peripheral Sensory Neuropathy

• T. Andre et al., J Clin Oncol, 2009

12 Weeks of ci 5-FU vs 6 Months

• f 5-FU/LV

RFS OS

Chau et al., Ann Oncol 2005

5 Year (%) 12 wks Ci 5-FU 6 months 5-FU/ LV HR (95% CI) p-value RFS 73.3 66.7 0.8 (0.62-1.04) p=0.10 OS 75.7 71.5 0.79 (0.61-1.03) p=0.08

Likelihood of ci 5-FU being inferior: P<0.005

N=801

– SCOT (UK, Denmark, Spain, Australia, Sweden, New Zealand), TOSCA (Italy), Alliance/SWOG 80702 (US, Canada), IDEA France, ACHIEVE (Japan), HORG (Greece)

• Total of 12,834 patients with stage III disease included in analysis

Duration of Adjuvant Chemotherapy for Stage III Colon Cancer

• A. Grothey, A.F. Sobrero, A.F. Shields, T. Yoshino, J. Paul, J. Taieb, J. Souglakos, Q. Shi, R. Kerr, R. Labianca,

J.A. Meyerhardt, D. Vernerey, T. Yamanaka, I. Boukovinas, J.P. Meyers, L.A. Renfro, D. Niedzwiecki, T. Watanabe,*

• V. Torri, M. Saunders, D.J. Sargent,* T. Andre, and T. Iveson

Study Overview

• Objective:

Reduce side-effects of therapy without giving up (too much) anti- cancer efficacy of therapy

• Non-inferiority design:

As agreed upon by patient advocates and oncologists, shorter duration of therapy should not sacrifice more than 12% of benefit of adjuvant therapy In statistical terms: upper 95% confidence interval of Hazard Ratio (HR) of disease free survival (DFS) should not exceed 1.12

Stage III Colon Cancer Patients R

3 months 6 months FOLFOX*

• r CAPOX*

*Investigator’s choice,

no randomization

12,834 patients

Non-inferiority Hypothesis Testing

Hazard Ratio 1.12 3m TRT better 6m TRT better Superiority Non-inferiority Not proven Inferiority Piaggio et al. JAMA 2012;308(24):2594-2604 1.0 Non-Inferiority Margin

One-sided Type I Error Rate = 0.025 Power = 90% Require 3390 DFS Events

Statistical Conclusions Under Different Scenarios

TRT: treatment

Patient Characteristics by Study

Patient Characteristics TOSCA (N=2402) SCOT (N=3983) IDEA France (N=2010) C80702 (N=2440) HORG (N=708) ACHIEVE (N=1291) Median Age, years 64 65 64 61 67 66 ECOG PS* 95% 71% 74% 71% 82% 96% 1 5% 29% 25% 28% 18% 4% T Stage T1-2 13% 12% 12% 18% 8% 15% T3 75% 59% 70% 67% 78% 57% T4 12% 29% 18% 15% 14% 28%

N Stage

N1 73% 69% 75% 73% 67% 74% N2 27% 31% 25% 27% 33% 26%

Chemotherapy CAPOX 35% 67% 10% 0% 58% 75% FOLFOX 65% 33% 90% 100% 42% 25% Median follow-up time, m 62 37 51 35 48 37

*1% of PS 2 in IDEA France and C80702 trials

T4 12% 29% 18% 15% 14% 28%

CAPOX 35% 67% 10% 0% 58% 75%

Median follow-up time, m 62 37 51 35 48 37

1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 6 Months 3 Months Duration 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 6424 5446 4464 3000 1609 826 321 6410 5530 4477 3065 1679 873 334

Primary Outcomes Analysis

Duration 3-yr DFS 3m 74.6 % 6m 75.5 %

3-yr DFS diff. = -0.9%, 95% CI, (-2.4 to 0.6%)

N Patients At risk

DFS HR = 1.07 95% CI, 1.00 to 1.15

Adverse Events

FOLFOX CAPOX

Adverse Events 3m Arm 6m Arm p-value1 3m Arm 6m Arm p-value1

Overall G2 G3-4 32% 38% 32% 57%

<.0001

41% 24% 48% 37%

<.0001

Neurotoxicity

G2 G3-4 14% 3% 32% 16%

<.0001

12% 3% 36% 9%

<.0001

Diarrhea G2 G3-4 11% 5% 13% 7%

<.0001

10% 7% 13% 9%

0.0117

1Chi-squared test for trend; Total of 19 grade 5 events; adverse events only collected on first 617 patients enrolled to SCOT trial

6 mo 3 mo Average PSN Grade Time from Randomization

Neuropathy (PSN) Time Course: Japanese Study

Ø At 36 mo: Ø Grade 2-3 2.8% in 6 mo arm 0% in 3 mo arm Ø ANY Grade 24.3% in 6 mo arm 9.7% in 3 mo arm

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 M 1 M 2 M 3 M 4 M 5 M 6 M 9 M 1 2 M 1 5 M 1 8 M 2 1 M 2 4 M 2 7 M 3 M 3 3 M 3 6 M

Analysis of Risk Groups by Regimen

• Large difference in overall prognosis observed

between (T1-3 N1) and (T4 or N2) cancers – 3 year DFS ∆ 20% ØAnalysis of 3m vs 6m adjuvant therapy for these groups

• Two different adjuvant regimens used,

FOLFOX and CAPOX – Preplanned analysis of 3m vs 6m based on regimen

1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 2554 2219 1903 1175 488 193 30 2517 2222 1844 1185 529 207 25 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 3870 3227 2561 1825 1121 633 291 3893 3308 2633 1880 1150 666 309

DFS Comparison by Regimen

Duration 3-yr DFS 3m 73.6 % 6m 76.0 %

3-yr DFS diff. = -2.4% 95% CI, (-4.3 to -0.5%)

Duration 3-yr DFS 3m 75.9 % 6m 74.8 %

3-yr DFS diff. = 1.1% 95% CI, (-1.3 to 3.5%)

FOLFOX CAPOX

Interaction p-value = 0.0051

N Pts At risk

DFS Comparison by Risk Group and Regimen

2308 2030 1669 1215 745 433 203 2311 2013 1642 1198 751 411 195 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 2311 2013 1642 1198 751 411 195 2308 2030 1669 1215 745 433 203 1531 1242 937 648 396 228 103 1523 1189 900 612 360 216 94 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 1523 1189 900 612 360 216 94 1531 1242 937 648 396 228 103 1419 1306 1119 734 336 133 18 1433 1300 1154 736 313 116 16 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 1433 1300 1154 736 313 116 16 1419 1306 1119 734 336 133 18 1091 909 718 446 190 73 7 1111 910 740 432 171 76 13 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 1 2 3 4 5 6 Years from Randomization 10 20 30 40 50 60 70 80 90 100 Percent Without Event 6 Months 3 Months Duration 1111 910 740 432 171 76 13 1091 909 718 446 190 73 7

T4 or N2 FOLFOX T1-3, N1 FOLFOX T1-3, N1 CAPOX T4 or N2 CAPOX 3 yr DFS, 3 m Rx: -1.6 (-3.8 to 0.6) 3 m Rx: +1.9 (-0.8 to 4.6) 3 m Rx: -3.2 (-6.6 to 0.2) 3 m Rx: 0.1 (-3.9 to 4.1) HIGH RISK LOW RISK

3 yr DFS rate (%) and HR by Regimen and Risk Group

Regimen

CAPOX FOLFOX CAPOX/FOLFOX Combined 3 yr DFS, % (95% CI)

HR (95% CI)

3 yr DFS, % (95% CI) HR

(95% CI)

3 yr DFS, % (95% CI) HR

(95% CI)

3 m 6 m 3 m 6 m 3 m 6 m Risk Group

Low-risk (T1-3 N1) ~60% 85.0 (83.1-86.9) 83.1 (81.1-85.2) 0.85 (0.71-1.01) 81.9 (80.2-83.6) 83.5 (81.9-85.1) 1.10 (0.96-1.26) 83.1 (81.8-84.4) 83.3 (82.1-84.6) 1.01 (0.90-1.12) High-risk (T4 and / or N2) ~40% 64.1 (61.3-67.1) 64.0 (61.2-67.0) 1.02 (0.89-1.17) 61.5 (58.9-64.1) 64.7 (62.2-67.3) 1.20 (1.07-1.35) 62.7 (60.8-64.4) 64.4 (62.6-66.4) 1.12 (1.03-1.23) Risk Groups Combined 75.9 (74.2-77.6) 74.8 (73.1-76.6) 0.95 (0.85-1.06) 73.6 (72.2-75.1) 76.0 (74.6-77.5) 1.16 (1.06-1.26) P-value Interaction Test: Regimen: 0.0051 Risk Group: 0.11

Non-inferior Not Proven Inferior

Predicted 5-yrs DFS with Surgery Alone, 5FU, Oxaliplatin x 3 or 6 months

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 T 1 N 1 a T 1 N 1 b T 1 N 2 a T 1 N 2 b T 2 N 1 a T 2 N 1 b T 2 N 2 a T 2 N 2 b T 3 N 1 a T 3 N 1 b T 3 N 2 a T 3 N 2 b T 4 N 1 a T 4 N 1 b T 4 N 2 a T 4 N 2 b OXA6 OXa3 Surg+FUFA Surgalone

• A. Sobrero

Stage III Colon Cancer Treatment Question 1:

• For most patients with LOW risk stage III colon cancer (T1-3 N1)

which of the following is your preferred adjuvant treatment regimen?

– 1: FOLFOX for 3 months – 2: FOLFOX for 6 months – 3: CAPOX for 3 months – 4: CAPOX for 6 months

Stage III Colon Cancer Treatment Question 2:

• For most patients with HIGH risk stage III colon cancer

(T4 N1-2 or T any N2 ) which of the following is your preferred adjuvant treatment regimen?

– 1: FOLFOX for 3 months – 2: FOLFOX for 6 months – 3: CAPOX for 3 months – 4: CAPOX for 6 months

If you only had FOLFOX, 3 or 6 months in low risk T1-3 N1? Red X for fighters, Blue X for fatalists

FOLFOX 3 FOLFOX 6 Sobrero I TOSCA X X Cervantes E ESMO X X Grothey US IDEA X X Iveson UK SCOT X X Andre F IDEA FRANCE X X Labianca I TOSCA X X Yoshino J ACHIEVE X X Shields US SWOG X X Souglakos G HORG X X Meyerhardt US Alliance X X Maughan UK

clinical discussant

X X

A Sobrero et al., Ann Oncol, 2018

Now you are free to decide FOLFOX or CAPOX: What do you advise to high risk? Red X for fighters, Blue X for fatalists

CAPOX 3 FOLFOX 3 CAPOX 6 FOLFOX 6

Sobrero I TOSCA X X Cervantes E ESMO X X Grothey US IDEA X X Iveson UK SCOT X X Andre F IDEA FRANCE X X Labianca I TOSCA X X Yoshino J ACHIEVE X X Shields US SWOG X X Souglakos G HORG X X Meyerhardt US Alliance X X X Maughan UK

clinical discussant

X X X X

A Sobrero et al., Ann Oncol, 2018

Clinical Decision Making in Stage III Colon Cancer

• FATALIST

– always 3 months of CAPOX (11/11), even high risk

• FIGHTERS:

– low risk (T1-3 N1): always 3 months of CAPOX (11/11) – high risk N2: usually 3 months CAPOX (8/11); 6 months (3/11) – high risk T4: usually 6 months CAPOX (8/11) or FOLFOX (2/11); 3 mo (1/11)

Clinical Decision Making Adjuvant Treatment of Colon Cancer

Roles of Age, Gender, and Performance Status (PS)

• Cox proportional hazard models used with

IDEA cohort by age (< 70 or > 70), gender, and PS (0 v 1/2)

• Overall age, gender, and PS didn’t modify the

comparison of 3 v 6m Rx.

• Subgroups of note:

– Patients < 70 on FOLFOX – High-risk males

Age and 3 vs. 6 Months

• f Adjuvant Therapy
• Age ≤ 70 CAPOX: 3m Rx is as good as 6m
• Age ≤ 70 FOLFOX: 6m Rx is required
• Age>70 Either regimen: 6m may be needed

Events/Total HR (3 vs. 6m) 95% CI Pi 2-way Age <=70 FOLFOX 1439/5845 1.16 1.05-1.29 0.0022 CAPOX 917/3759 0.9 0.79-1.03 Age>70 FOLFOX 505/813 1.12 0.94 -1.33 0.701 CAPOX 380/1290 1.19 0.97 – 1.46 AF Shields et al.

Gender and 3 vs. 6 Months

• f Adjuvant Therapy

Events/Total HR (3 vs. 6m) 95% CI Pi 2-way Male T1-3N1 789/4220 0.94 0.82-1.08 0.015 T4 or N2 1126/2964 1.18 1.05-1.33 Female T1-3N1 523/3247 1.09 (0.91 – 1.29) 0.738 T4 or N2 809/2290 1.04 (0.91 – 1.20) AF Shields et al.

• Low risk male:, 3m Rx is as good as 6m
• High risk males: 6m Rx is required
• Any risk Women: 3m Rx is as good as 6m

Capecitabine Issues

• Patients who are poor capecitabine candidates:
• Unable to swallow pills
• Concerns about compliance
• Capecitabine available in 500 mg and 150 mg tablets
• Do we use only 500 mg tabs?
• Cost responsibility for patient (5FU vs. capecitabine)
• Poor renal function (estimated clearance < 30 mL/min)
• PPI use may interfere with absorption

Capecitabine Dosing Issues: US vs Other Countries

• Retrospective analysis of randomized trials with

fluoropyrimidines

• N=1864 receiving adjuvant treatment
• Overall grade 3/4 AEs RR 1.47 in US vs. non-US
• CAPOX Grade 3/4 GI (diarrhea, nausea, vomiting,

stomatitis) – 37% in US; 23% rest of the world

• D. Haller et al., J Clin Oncol 2008

Suggest start Capecitabine 1500 – 1700 mg/m2/d

Stage III Colon Cancer Treatment Summary

• IDEA data provides a framework for discussions on risks and

benefits of individualized adjuvant therapy approaches

• Shorter duration of therapy associated with remarkable

reduction in (neuro)toxicity

• For low-risk cancers (~60% of stage III) 3 months duration of
• xaliplatin-based therapy is adequate
• Yet unexplained finding that shorter duration of CAPOX is

adequate, whereas for FOLFOX a longer duration might be required, in particular, in high-risk cancers

• The roles of age and gender, along with tumor size and other

factors need further examination