cj allegra, g yothers, mj o ’ connell, ms roh, rw beart,
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CJ Allegra, G Yothers, MJ O’Connell, MS Roh, RW Beart,
NJ Petrelli, S Lopa, S Sharif, and N Wolmark
Neoadjuvant Therapy For Rectal Cancer: Mature Results From NSABP Protocol R-04
A Collaborative National NCI Protocol Conducted by NSABP, NCCTG, ECOG, CALGB, and SWOG
Disclosures
• I have no relevant conflicts of interest to disclose
Goals of NSABP R-04• Designed at the start of the millennium to address the questions:
– Can the oral fluoropyrimidine, capecitabine be substituted for the standard of care in the curative setting of Stage II & III rectal cancer namely, CIV 5-FU, during neoadjuvant RT?• CIV 5-FU became the SoC based on a US cooperative group study (O’Connell et al; NEJM
August, 1994) showing superiority over bolus administrations of 5-FU
• Capecitabine was shown to be non-inferior to 5-FU in the palliative & adjuvant colon settings and does not require a central venous catheter or infusion pump
• Small retrospective studies support similar outcomes with 5-FU and capecitabine in the rectal neoadjuvant setting
– Can the addition of oxaliplatin enhance the activity of fluoropyrimidine sensitized RT?• Oxaliplatin was shown to have radiation sensitizing properties in preclinical models
• Oxaliplatin was shown to enhance the activity of 5-FU in the palliative and adjuvant colon settings
• July, 2004 ACTIVATION– 2-arm study comparing 5-FU and Cape
• October, 2005 AMENDMENT– Added oxaliplatin – 2 x 2 factorial design– 5-FU and Cape reduced from 7 days/wk to 5 days/wk during RT
• August, 2010 CLOSED– 1,608 accrued patients; 1595 (99.2%) Eligible
NSABP R-04
Group 4Capecitabine 825 mg/m2 PO BID + Oxaliplatin 50 mg/m2/wk X 5 + RT
NSABP R-04
STRATIFICATION Gender; Clinical Stage II/III; Intent for Type of Surgery (sphincter saving v. APR)
RANDOMIZATIONGroup 3Capecitabine 825 mg/m2 PO BID + RT
Group 25-FU (CIV 225mg/m2 5d/wk) + Oxaliplatin 50 mg/m2/wk X 5 + RT
Group 15-FU (CIV 225mg/m2 5d/wk) +RT (46Gy over 5 wks + boost)
Rectal AdenoCa < 12 cm from anal verge
NSABP R-04– Primary Endpoint –
• Local-regional control with 3 years minimum follow-up– Time from randomization to first L-R failure– Inoperable patients or those with positive margins are
considered L-R failures at the time of surgery– Patients without documented clinical CR who do not
undergo surgery will be considered a L-R failure at the time they should have had surgery
• “Local” – Anastomotic and pelvis
• “Regional” – Pelvic or retroperitoneal LNs at or below L5
NSABP R-04 – Secondary Endpoints –
– Rate of pathologic CR
– Number of pts undergoing sphincter-saving surgery
– Disease free and overall survival
– Quality of Life
– Toxicity
– Correlating genetic patterns and specific tissue biomarkers with response and prognosis
NSABP R-04Statistical Design
• Comparison of cape and 5-FU
Comparable if 0.86 < HazRatio < 1.17
Roughly corresponds to 3yr L-R rate of +/- 2%
• Superiority for the addition of oxaliplatin to fluoropyrimidines
>80% power for HazRatio = 0.59
Roughly corresponds to 4% increase in L-R 3yr rate
Regimen# Eligible Pts
FU461
FU+Ox321
Cape463
Cape+Ox322
Total1567
Age (%)≤ 59≥ 60
5644
6139
5644
6139
5842
GenderMaleFemale
6733
6832
6832
6832
6832
Clinical StageIIIII
5941
6238
5842
6238
6040
SS Surg 74 74 73 74 74
Non-SS Surg 26 26 27 26 26
Patient Demographics
NSABP R-04 pCR Rates (%)
P = 0.42P = 0.14
* No significant fluoropyrimidine by oxaliplatin interaction
3 Year Overall & L-R Recurrences P = 0.70P = 0.98
P = 0.52 P = 0.22
* No significant fluoropyrimidine by oxaliplatin interaction
P = 0.34P = 0.70 P = 0.61 P = 0.38
* No significant fluoropyrimidine by oxaliplatin interaction
5 year Outcomes (%)
NSABP R-04Primary Endpoint: Local-Regional Control
5-FU vs. Cape
Years from Randomization
L/R
Rec
urr
ence
Fre
e (
%)
0 1 2 3 4 5 6
020
4060
8010
0
5-FU 782 Pts, 95 L/R Recurrence Cape 785 Pts, 97 L/R Recurrence HR = 1.00, 95% CI (0.75-1.32)P = 0.98
No Oxali vs. Oxali
Years from Randomization
L/R
Rec
urr
ence
Fre
e (%
)
0 1 2 3 4 5 6
020
4060
8010
0
No Oxali 641 Pts, 81 L/R Recurrence Oxali 643 Pts, 76 L/R Recurrence HR = 0.94, 95% CI (0.67-1.29)P = 0.70
NSABP R-04Overall Survival
Years from Randomization
Aliv
e (%
)
0 1 2 3 4 5 6
020
4060
8010
0
5-FU 782 Pts, 141 deathsCape 785 Pts, 138 deathsHR = 1.00, 95% CI (0.74-1.19)P = 0.61
Years from Randomization
Aliv
e (%
)
0 1 2 3 4 5 6
020
4060
8010
0
No Oxali 641 Pts, 116 deathsOxali 643 Pts, 103 deathsHR = 0.94, 95% CI (0.68-1.16)P = 0.38
5-FU vs. Cape No Oxali vs. Oxali
Treatment Compliance
• At least 80% of treatment completed per protocol
–FU – 90% alone; 84% with Oxali
–Cap – 97% alone; 96% with Oxali
–Oxali – 69% with FU; 62% with Cap
–RT – 96-98% depending on the arm
NSABP R-04 Mortality & Adverse Events (%)
Toxicity (Grade) 5-FU Capecitabine5-FU +
OxaliplatinCapecitabine + Oxaliplatin
Overall (3+) 26.5 30.1 39.9 42.2
Diarrhea (3/4) 7 7 16 16
Death (5) 0.3 1.3 0.3 1.6
NSABP R-04 Summary• Capecitabine with preop RT achieved rates similar to CIV 5-FU for:
– L-R Failure – Primary Endpoint
– pCR
– DFS
– OS
• Oxaliplatin did not improve outcomes but added significant toxicity (diarrhea) and is therefore not indicated in combination with RT in the preop rectal setting
• Establishes capecitabine as a standard of care in the preop rectal setting
• NSABP R-04 supports pCR & neoadjuvant rectal cancer (NAR) score as surrogates for overall survival (Yothers G ASCO GI, 2014; Abst #384)
• Fully annotated tissue samples available for molecular studies
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