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