Cj allegra g yothers mj o connell ms roh rw beart nj petrelli s lopa s sharif and n wolmark
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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. CJ Allegra, G Yothers, MJ O ’ Connell, MS Roh, RW Beart, NJ Petrelli, S Lopa, S Sharif, and N Wolmark. Disclosures.

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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-04A Collaborative National NCI Protocol Conducted by NSABP, NCCTG, ECOG, CALGB, and SWOG

CJ Allegra, G Yothers, MJ O’Connell, MS Roh, RW Beart,

NJ Petrelli, S Lopa, S Sharif, and N Wolmark


Disclosures

Disclosures

  • I have no relevant conflicts of interest to disclose


Goals of nsabp r 04

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


Cj allegra g yothers mj o connell ms roh rw beart

NSABP R-04

  • July, 2004 ACTIVATION

    • 2-arm study comparing 5-FU and Cape

  • October, 2005AMENDMENT

    • Added oxaliplatin

    • 2 x 2 factorial design

    • 5-FU and Cape reduced from 7 days/wk to 5 days/wk during RT

  • August, 2010CLOSED

    • 1,608 accrued patients; 1595 (99.2%) Eligible


Cj allegra g yothers mj o connell ms roh rw beart

NSABP R-04

Rectal AdenoCa < 12 cm from anal verge

STRATIFICATION

Gender; Clinical Stage II/III; Intent for Type of Surgery (sphincter saving v. APR)

Group 1

5-FU (CIV 225mg/m2 5d/wk) +

RT (46Gy over 5 wks + boost)

Group 2

5-FU (CIV 225mg/m2 5d/wk) + Oxaliplatin 50 mg/m2/wk X 5 + RT

RANDOMIZATION

Group 3

Capecitabine 825 mg/m2 PO BID + RT

Group 4

Capecitabine 825 mg/m2 PO BID + Oxaliplatin 50 mg/m2/wk X 5 + RT


Nsabp r 04 primary endpoint

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

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 04 statistical design

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


Cj allegra g yothers mj o connell ms roh rw beart

Patient Demographics


Nsabp r 04 pcr rates

NSABP R-04 pCR Rates (%)

P = 0.14

P = 0.42

* No significant fluoropyrimidine by oxaliplatin interaction


3 y ear overall l r recurrences

3 Year Overall & L-R Recurrences

P = 0.98

P = 0.70

P = 0.52

P = 0.22

* No significant fluoropyrimidine by oxaliplatin interaction


Cj allegra g yothers mj o connell ms roh rw beart

5 year Outcomes (%)

P = 0.70

P = 0.34

P = 0.61

P = 0.38

* No significant fluoropyrimidine by oxaliplatin interaction


Cj allegra g yothers mj o connell ms roh rw beart

NSABP R-04

Primary Endpoint: Local-Regional Control

5-FU vs. Cape

No Oxali vs. Oxali

100

100

80

80

60

60

5-FU 782 Pts, 95 L/R Recurrence

No Oxali 641 Pts, 81 L/R Recurrence

L/R Recurrence Free (%)

L/R Recurrence Free (%)

Cape 785 Pts, 97 L/R Recurrence

Oxali 643 Pts, 76 L/R Recurrence

40

40

HR = 1.00, 95% CI (0.75-1.32)

HR = 0.94, 95% CI (0.67-1.29)

P = 0.98

P = 0.70

20

20

0

0

0

1

2

3

4

5

6

0

1

2

3

4

5

6

Years from Randomization

Years from Randomization


Cj allegra g yothers mj o connell ms roh rw beart

NSABP R-04

Overall Survival

5-FU vs. Cape

No Oxali vs. Oxali

100

100

80

80

60

60

No Oxali 641 Pts, 116 deaths

5-FU 782 Pts, 141 deaths

Alive (%)

Alive (%)

Cape 785 Pts, 138 deaths

Oxali 643 Pts, 103 deaths

40

HR = 1.00, 95% CI (0.74-1.19)

40

HR = 0.94, 95% CI (0.68-1.16)

P = 0.61

P = 0.38

20

20

0

0

0

1

2

3

4

5

6

0

1

2

3

4

5

6

Years from Randomization

Years from Randomization


Treatment compliance

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

NSABP R-04 Mortality & Adverse Events (%)


Nsabp r 04 summary

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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