The Impact of Capecitabine and Oxaliplatin in the Preoperative

Multimodality Treatment of Patients with Carcinoma of the

Rectum: NSABP R-04MS Roh, GA Yothers, MJ O'Connell, RW Beart, HC Pitot, AF Shields, DS Parda, S Sharif, CJ Allegra, NJ Petrelli,

JC Landry, DP Ryan, A Arora, TL Evans, GS Soori,L Chu, RV Landes, M Mohiuddin, S Lopa, N Wolmark

ASCO June 4, 20111 pm

• Preoperative chemoradiotherapy WITH CVI 5FU is the standard of care for T3-4 rectal CANCER

• Distant relapse rate is 24-30%

• Suboptimal compliance to adjuvant therapy

• Deliver effective systemic chemotherapy during radiation therapy

– Better compliance– Early treatment of systemic disease– Decrease local-regional tumor relapse and improve

survival

NSABP R-04 Background

• July 23, 2004 ACTIVATION– 2 arm study comparing 5-FU and Capecitabine

• October 27, 2005 AMENDMENT– Added oxaliplatin – 2 x 2 factorial design– 5-FU and Capecitabine reduced from 7 days per

week to 5 days per week during radiation therapy

• August 16, 2010 CLOSED– 1,608 accrued patients

NSABP R-04

NSABP R-04Surgical Goals

Determine if capecitabine administered concurrently with preoperative radiotherapy is similar to continuous IV infusion of 5-FU administered concurrently with preoperative radiotherapy in attaining

1. local-regional disease control

2. sphincter preservation

1. Compare the rate of local-regional relapse in patients receiving preoperative capecitabine with RT to patients receiving preoperative CVI 5-FU with RT

2. Compare the rate of local-regional relapse in patients receiving preoperative oxaliplatin with those not receiving preoperative oxaliplatin

NSABP R-04 Primary Aims

Evaluate if preop administration of capecitabine with or without oxaliplatin given concurrently with RT is similar to the preop administration of CVI 5-FU with or without oxaliplatin given concurrently with RT by

1.Rate of pathologic CR2.Number of patients undergoing sphincter saving

surgery3.Disease free and overall survival4.Quality of Life5.Toxicity6.Correlating genetic patterns and specific tissue

biomarkers with response and prognosis

NSABP R-04 Secondary Aims

• A collaborative national NCI protocol conducted by NSABP, NCCTG, ECOG, CALGB and SWOG

1.Non-inferiority of capecitabine compared to continuous infusion of 5-FU

2.Superiority FOR the addition of oxaliplatin TO EITHER CAPECITABINE OR 5FU

NSABP R-04Study Design

Group 4Capecitabine 825 mg/m2 PO BID +

Oxaliplatin 50 mg/m2/week X 5+

4600cGy + 540-1080cGy

Adenocarcinoma of rectum amenable to surgical resection located < 12 cm from anal verge

STRATIFICATIONGender

Clinical Tumor Stage II or IIIIntent for Type of Surgery (sphincter saving; non-sphincter saving)

RANDOMIZATION

Group 3Capecitabine 825 mg/m2 PO BID +

4600cGy + 540-1080cGy

Group 25FU (CVI 225mg/m2 5d/week) + Oxaliplatin 50 mg/m2/week X 5

+4600cGy + 540-1080cGy

Group 15FU (CVI 225mg/m2 5d/week)

+4600cGy + 540-1080cGy

SURGERYSURGERY

5-FU(2 Arm)

Cape(2 Arm)

5-FU(4 Arm)

5-FU+ Ox

(4 Arm)

Cape(4 Arm)

Cape+ Ox

(4 Arm)

Age≤ 59≥ 60

59.240.8

52.747.3

56.143.9

61.438.6

57.142.9

61.238.8

SexMaleFemale

68.032.0

67.832.2

67.033.0

68.131.9

67.832.2

67.632.4

Stage**IIIII

49.750.3

46.653.4

61.538.5

61.738.3

62.337.7

61.538.5

Intended Surgery**

Sphincter saving 74.8 71.9 73.6 73.6 74.2 73.3

Non-sphincter

saving25.2 28.1 26.4 26.4 25.8 26.7

Patient Characteristics

** as reported at the time of randomization

Number of Patients

5-FU(2 Arm)

Cape(2 Arm)

5-FU(4 Arm)

5-FU+ Ox

(4 Arm)

Cape(4 Arm)

Cape+ Ox

(4 Arm)

Randomized 147 146 330 329 326 330

Ineligible 1 5 2 2 0 1

Average time on study (mos.)*

64.0 64.1 29.0 29.1 29.3 29.0

NSABP R-04Patient Entry

*as of November 30, 2010

Surgical Complications

Complication 5FU%

5FU+Ox%

Cape%

Cape+Ox%

Any Complication 34.92 37.00 36.89 40.20

Urinary Complication 9.91 9.32 8.79 7.12

Bowel Obstruction/ Ileus 7.27 7.72 7.47 9.06

Re-operation Necessary 5.47 6.00 6.70 5.32

Urinary Retention 5.73 4.82 6.59 4.85

Perineal Wound Infection 4.85 5.47 3.30 5.18

Gastrointestinal Toxicity5-Fu or CAPE vs addition of Oxaliplatin

GI Toxicity** No Oxali Oxali Total

< Grade 3 diarrhea 581 534 1115

Grade 3/4 diarrhea 41 97 138

Total Patients 622 631 1253

Incidence (%) 6.6 15.4P-value0.0001

Oxali

No Oxali

0.04 0.08 0.12 0.16 0.2

**CTCAE Version 3.0

Surgical Downstaging (SD) by Treatment5-FU vs Capecitabine

SD Status 5-FU Cape Total

without SD 149 144 293

with SD 39 43 82

Total Patients* 188 187 375

SD Rate (%)95% CI

20.715.2-27.2

23.017.2-29.7

P-value.62

*Restricted to patients without pre-trial intent for SSS

5-FU

Cape

0.15 0.2 0.25 0.3

Surgical Downstaging (SD) by TreatmentOxaliplatin vs None

SD Status No Oxali Oxali Total

without SD 117 122 239

with SD 35 29 64

Total Patients* 152 151 303

SD Rate (%)95% CI

23.016.6-30.5

19.213.3-26.4

P-value.48

*Restricted to patients without pre-trial intent for SSS

No OxaliOxali

0.1 0.15 0.2 0.25 0.3 0.35

Sphincter Saving Surgery by Treatment5-FU vs Capecitabine

SSS Status 5-FU Cape Total

without SSS 282 265 547

with SSS 445 445 890

Total Patients 727 710 1437

SSS Rate (%)95% CI

61.257.6-64.8

62.759.0-66.2

P-value.59

5-FUCape

0.56 0.58 0.6 0.62 0.64 0.66 0.68

Sphincter Saving Surgery by TreatmentOxaliplatin vs None

SSS Status No Oxali Oxali Total

without SSS 212 231 443

with SSS 370 353 723

Total Patients 582 584 1166

SSS Rate (%)95% CI

63.659.5-67.5

60.456.3-64.4

P-value.28

No Oxali

Oxali

0.56 0.58 0.6 0.62 0.64 0.66 0.68

Pathologic Complete Response by Treatment5-FU vs Capecitabine

pCR Status 5-FU Cape Total

without pCR 584 550 1134

with pCR 135 157 292

Total Patients 719 707 1426

pCR Rate (%)95% CI

18.816.0-21.8

22.219.2-25.5

P-value.12

5-FU

Cape

0.14 0.16 0.18 0.2 0.22 0.24 0.26

Pathologic Complete Response by TreatmentOxaliplatin vs None

pCR Status No Oxali Oxali Total

without pCR 469 457 926

with pCR 111 121 232

Total Patients 580 578 1158

pCR Rate (%)95% CI

19.116.0-22.6

20.917.7-24.5

P-value0.46

No Oxali

Oxali

0.16 0.18 0.2 0.22 0.24 0.26

NSABP R-04Conclusions

• Administration of capecitabine with preoperative RT achieved rates similar to continuous infusion 5-FU for

– Surgical downstaging– Sphincter saving surgery– Pathologic complete response

• Addition of oxaliplatin did not improve outcomes and added significant toxicity

• Longer follow up will be needed to assess local-regional tumor relapse, DFS and OS