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The Impact of Capecitabine and Oxaliplatin in the Preoperative Multimodality Treatment of Patients with Carcinoma of the Rectum: NSABP R-04. - PowerPoint PPT Presentation
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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
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