Authors: Hofheinz et al Reviewed By: Scott Berry Date posted: June 2011

www.OncologyEducation.ca

Capecitabine versus 5-fluorouracil-based (neo-)adjuvant chemo-radiotherapy for locally advanced rectal cancer:

Long term results of a randomized phase III trial

Authors: Hofheinz et al

Reviewed By: Scott Berry

Date posted: June 2011


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N=392Resectable Stage II/II

Rectal CancerPrimary Outcome: 5 Yr OS (non-inferiority)

Study Design

Mar 2002-July2005Post-Op

Treatment


N=392Resectable Stage II/II

Rectal CancerPrimary Outcome: 5 Yr OS (non-inferiority)

Study Design

Post July 2005

After Publication of Sauer TrialNeoadjuvant

TreatmentArms Added


Study Design

Arm A Chemoradiotherapy

50.4 Gy + Cape 1,650 mg/m² days 1 – 38

plus

5 cycles of Cape 2,500 mg/m² d 1 – 14, rep. d 22 S I: 2 x Cape CRT 3 x Cape

S II: CRT TME surgery (4 – 6 weeks after CRT) Cape x 5

Arm B Chemoradiotherapy

50.4 Gy + 5-FU 225 mg/m² c.i. daily [S I] or

5-FU 1,000 mg/m² c.i. d 1 – 5 and 29 – 33 [S II]

plus

4 cycles of bolus 5-FU 500mg/m² d 1 – 5, rep. d 29 S I: 2 x 5-FU CRT 2 x 5-FU

S II: CRT TME surgery (4 – 6 weeks after CRT) 5-FU x 4 Cape: capecitabine; CRT: chemoradiotherapy; TME: total mesorectal excision; 5-FU: 5-fluorouracil


Study Design


RESULTS

% of Patients Receiving All Scheduled Cycles

Cape 5FU

Adjuvant Group 77.6% 80.0%

Neoadjuvant Group

45.7% 40.0%


RESULTS

Cape 5FU p-value

5 Yr DFS

67.8% 54.1% P=0.035

5 Yr OS 75.7% 66.6%

P<0.001

(non-inferiority)

P=0.053

(exploratory for superiority

Distant Mets

(%)18.9% 27.7% P=0.0367

Local Recurrence (%) 6.1% 7.2% p = 0.7795


Neoadjuvant Group – Trend of Improved Downstaging with

Capecitabine

Patients receiving capecitabine exhibited

• less ypN-positive tumors (p = 0.09)

• improved T-downstaging (i.e. ypT0 – 2) (p = 0.07)

• more pCR (ypT0 ypN0): 13.2 % vs. 5.4% (p = 0.16)

Comparison (² test)

Clinical staging Pathohistology

T status p = 0.5 p = 0.07

N status p = 0.7 p = 0.09


Hand-foot skin reaction (HFS) Comparison of 3-y DFS and 5-y OS

CapecitabineAny grade HFS

n = 62

CapecitabineNo HFS

n = 135

5-FUAll patients

n = 195

3-y DFS 83.2%1 71.4% 66.6%

95%-CI (%) 71.0 – 90.6 62.6 – 78.4 59.1 – 73.0

5-y OS 91.4%2 68.0% 66.6%

95%-CI (%) 80.5 – 96.3 56.6 – 77.0 57.7 – 74.0

1 Test for superiority: p = 0.031 versus Cape no-HFS (n = 135) & p = 0.004 versus remaining population (n = 330)2 Test for superiority: p = 0.001 versus Cape no-HFS (n = 135) & p < 0.0001 versus remaining population (n = 330)


TOXICITY

Capecitabinen = 197

5-FU n = 195

p-value

Total1 1/2 3/4 Total 1/2 3/4

Hemoglobin 62 58 – 52 49 2 0.32

Leukocytes 50 47 3 68 50 16 0.047

Platelets 23 23 – 32 29 1 0.19

GGT 5 5 – 7 6 – 0.57

Bilirubin 8 6 1 2 1 1 0.10

1 CTC-grade is missing in some pts.2 p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.


TOXICITY

Capecitabinen = 197

5-FU n = 195

p-value

Total 1/2 3/4 Total 1/2 3/4

Nausea 36 33 2 32 30 – 0.69

Vomiting 14 11 1 9 8 1 0.39

Diarrhea 104 83 17 85 76 4 0.07

Mucositis 12 11 1 17 15 2 0.34

Stomatitis 8 8 – 12 11 – 0.37

Abdominal pain

23 19 1 14 11 – 0.17

Proctitis 31 26 1 10 9 1 < 0.0011 CTC-grade is missing in some pts.2 p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.


Diarrhea

Capecitabinen = 197

5-FU n = 195

p-value

Diarrhea 47 43 0.72

Capecitabinen = 197

5-FU n = 195

p-value

Diarrhea 88 62 < 0.001

Cycles without radiotherapy

Cycles with radiotherapy


TOXICITY

Capecitabinen = 197

5-FU n = 195

p-value

Total 1/2 3/4 Total 1/2 3/4

Fatigue 55 50 – 29 27 2 0.002

Anorexia 13 13 – 6 5 1 0.16

Alopecia 4 4 – 11 10 – 0.07

Hand-foot skin reaction

62 56 4 3 3 – < 0.001

Radiation dermatitis 29 22 2 35 32 1 0.41

Thrombosis / Embolism

10 2 7 11 5 2 0.83

1 CTC-grade is missing in some pts.2 p-value resulted from Chi-Square test comparing the total number of events between both treatment arms.


Author’s Conclusions

• Both treatment regimens were well tolerated. Cape patients had more all grade HFS, proctitis, diarrhea and fatigue, while alopecia and leukopenia were more frequently observed with 5-FU.

• In the neo-adjuvant stratum Cape led by trend to improved downstaging and a numerical higher rate of pCR.

• Cape was non-inferior to 5-FU regarding 5-year survival. – Exploratory test for superiority was borderline significant.

• 3-year DFS was significantly better with Cape.

• HFS indicated superior 3-year DFS and 5-year OS.

• Capecitabine may replace 5-FU in the perioperative treatment of locally advanced rectal cancer.


Bottom Line For

Canadian Medical Oncologists

• Many Canadian oncologists have already started using capecitabine as the systemic therapy component of neo-adjuvant and adjuvant therapy of rectal cancer based on

• Extrapolation from adjuvant colon cancer trials for the chemotherapy component

• Based on the results of phase II trials, population based outcome studies and interim results of phase III trials for the chemorads component

• This results of this study affirm that practice

Documents

Authors: Hofheinz et al Reviewed By: Scott Berry Date posted: June 2011