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

Long term results of a randomized phase III trial

R. Hofheinz, F. Wenz, S. Post, A. Matzdorff, S. Laechelt, J. Hartmann, L. Müller, H. Link, M. H. Moehler, E. Kettner, E. Fritz, U. Hieber,

H. W. Lindemann, M. Grunewald, S. Kremers, C. Constantin, M. Hipp, D. Gencer, I. Burkholder, A. Hochhaus,on behalf of the German MARGIT study group

Background

• Capecitabine (Cape), an oral fluoropyrimidine derivative, has been shown to be equieffective with 5-fluorouracil (5-FU) / leucovorin in the adjuvant treatment of stage III colon cancer. [Twelves et al. N Engl J Med 2005]

• Cape was non-inferior to infusional 5-FU in combination with oxaliplatin as first-line treatment for metastatic colorectal cancer.[Cassidy et al. J Clin Oncol 2008]

• Cape has radiosensitizing properties. Several phase I and II trials investigated combined modality treatment using Cape in the perioperative treatment of rectal cancer. [e.g. Dunst et al. J Clin Oncol 2002]

• The present phase-III trial sought to compare Cape with 5-FU in the perioperative treatment of locally advanced rectal cancer.

Study design

• Primary aim To determine whether 5-year overall survival rate (SR5) was non-inferior in arm A (Cape) vs. arm B (5-FU) with non-inferior margin of 12.5%.

• Assumption: SR55-FU = 57.5%. Sample size calculation performed with β = 20%, α = 5% and a drop-out rate of 5%.

• Study was designed as a two-arm, two-strata multicenter, randomized, open phase III trial.

• N = 372 evaluable patients (186 per arm) required to evaluate non-inferiority with a follow-up time of 4 years.

Main inclusion & exclusion criteria

• Patients ≥18 years• Histologically proven rectal cancer (0 – 16 cm ab ano)• No distant metastases• Adequate hematological parameters: Leukocytes > 3,500/µl,

thrombocytes > 100,000/µl, hemoglobin > 10g/dl.• Adequate liver & renal function

Patients treated in adjuvant stratum• Total mesorectal resection performed (R0-resection)• Tumor stages pT3/4 Nany M0 or pTany N+ M0

Patients treated in neoadjuvant stratum

• uT3/4 uNany M0 or uTany uN+ M0 (staging with EUS)

• Total mesorectal excision mandatory

Treatment regimen

Arm A Chemoradiotherapy50.4 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 Chemoradiotherapy50.4 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

Treatment regimen Adjuvant stratum S IArm A

Arm B

1 5 9 13 17 21

Radiotherapy 50.4 Gy

Capecitabine 2,500mg/m²/day (during radiotherapy 1,650mg/m²/day)

Week

5-FU 500mg/m² day 1 – 5 (during radiotherapy 225 mg/m²/day)

Radiotherapy 50.4 Gy

Treatment regimen Neodjuvant stratum S IArm A

Arm B

1 5 16 24 28

Week

10 20

Surgery

Surgery

Capecitabine 2,500mg/m²/day (during radiotherapy 1,650mg/m²/day)

5-FU 500mg/m² day 1 – 5 (during radiotherapy 1000 mg/m² d 1 – 5, d 29 – 33)

Radiotherapy 50.4Gy

Radiotherapy 50.4Gy

Patients recruitment (n = 392)

2007

Baseline characteristics

Capecitabinen = 197

5-FU n = 195

Age, years Median (Range) 64.6 (29.6 – 84.8) 64.0 (32.8 – 86.3)Gender, n (%) Male Female

129 (65.5) 68 (34.5)

131 (67.2) 64 (32.8)

Stratum, n (%) Adjuvant Neoadjuvant

116 (58.9) 81 (41.1)

115 (59.0) 80 (41.0)

Tumor category (cT or pT), n (%) T1 or T2 T3 T4 Missing data

29 (14.7)150 (76.1) 15 (7.7) 3 (1.5)

36 (18.5)140 (71.8) 14 (7.2) 5 (2.6)

Nodal category (cN or pN), n (%) Node negative Node positive Missing data

78 (39.6)112 (56.9) 7 (3.6)

69 (35.4)120 (61.5) 6 (3.1)

Adjuvant stratum – % of patients receiving schedules cycles

Neoadjuvant stratum – % of patients receiving schedules cycles

Hematological and liver toxicity – NCI-CTC grades (v. 2.0)

Capecitabinen = 197

5-FU n = 195

p-value²

Total1 1/2 3/4 Total1 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.

Gastrointestinal Toxicity – NCI-CTC grades (v. 2.0)

Capecitabinen = 197

5-FU n = 195

p-value²

Total1 1/2 3/4 Total1 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 < 0.001

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.

Diarrhea – NCI-CTC grades (v. 2.0)

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 (Cycle 3 in adjuvant strata & cycle 1 in neoadjuvant strata)

Other Toxicity – NCI-CTC grades (v. 2.0)

Capecitabinen = 197

5-FU n = 195

p-value²

Total1 1/2 3/4 Total1 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.

Neoadjuvant stratum – CONSORT diagram

Informed consent withdrawn, n = 1Refused port implantation, n = 1

Protocol violation (sigma CA), n = 1Primary resection, n = 2No start (worsening renal function), n = 1

No surgery (refusal, n = 2; PD, n = 1)

Deep anterior resection, n = 58Abdominoperineal resection, n = 16

Not resectable, n = 1

No surgery (pCR n = 1, PD n = 1)Died during RChT (accident, n = 1; heart attack, n = 1)

Deep anterior resection, n = 53Abdominoperineal resection, n = 19Local excision, n = 1

Randomized n = 161

Capecitabine, n = 815-Fluorouracil, n = 80

Commenced RChT, n = 78 Commenced RChT, n = 77

Surgery, n = 75

Died ≤ 30 days post surgery, n = 3

Surgery, n = 73

Died ≤ 30 days post surgery, n = 1

Neoadjuvant stratumComparison Arm A & Arm B

Capecitabine 5-FU p-value (² test)

Type of resection, % Deep anterior Abdominoperineal Local excision

n = 7372.626.0 1.4

n = 7478.421.6

0p = 0.56

Resection status, % R0 R1/R2 Unknown

n = 7295.8 4.2

0

n = 7491.9 2.7 5.4

p = 1.00

ypT- status, % ypT 0 ypN 0 (pCR) ypT 0 – 2 ypT 3 – 4

n = 7313.555.444.6

n = 74 5.439.260.8

p = 0.16p = 0.07

pCR: pathological complete remission

Neoadjuvant stratumComparison Arm A & Arm B

Capecitabine 5-FU

Clinical staging Pathohistology Clinical staging Pathohistology

T status

0, 1, 2

3, 4

n = 80

8.8%

91.2%

n = 73

55.4%

44.6%

n = 76

5.3%

94.7%

n = 74

39.2%

60.8%

N status

0, X

1, 2, 3

n = 75

48.0%

52.0%

n = 73

71.2%

28.8%

n = 75

52.0%

48.0%

n = 74

56.8%

43.2%

Neoadjuvant stratum – 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

Disease related events

Localization of recurrence and death

Capecitabinen = 197

5-FUn = 195

p-value ² test

Local recurrence 12 (6.1) 14 (7.2) p = 0.7795

Distant metastases 37 (18.8) 54 (27.7) p = 0.0367

Deaths, n (%)

Disease related

Other causes

Unknown

38 (19.3)

26 (13.2)

12 (6.1)

0

55 (28.2)

37 (19.0)

15 (7.7)

3 (1.5)

p = 0.0380

Disease free survival (DFS)Secondary endpoint (Median Follow-up 52 mon.)

Overall survival (OS)Primary endpoint (Median Follow-up 52 mon.)

Hand-foot skin reaction (HFS) and survivalComparison 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)

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.