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Niall C. Tebbutt International randomised phase III study of capecitabine, bevacizumab, and...
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Niall C. Tebbutt
International randomised phase III study of capecitabine, bevacizumab,
and mitomycin C in first-line treatment of metastatic colorectal
cancer: Final results of AGITG MAX study
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The MAX study: final results
Authors: Niall C. Tebbutt, Val Gebski, Kate Wilson, Michelle Cummins, YuJo Chua, Bridget Robinson, Adam Broad, David Cunningham, John Simes, Timothy Price; on behalf of the Australasian Gastro-Intestinal Trials Group (AGITG)
Funding: MAX was an investigator-initiated study sponsored by AGITG, supported by Roche Products Pty Ltd, and coordinated independently at the NHMRC Clinical Trials Centre, University of Sydney.
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BackgroundAdding bevacizumab to oxaliplatin- or irinotecan-based doublet chemotherapy has shown benefit for patients with advanced colorectal cancer (CRC). Some patients may not be suitable for oxaliplatin or irinotecan based regimens because of comorbidities. Other patients may not require initial treatment with combination chemotherapy.Capecitabine ± mitomycin C (MMC) is an alternative, convenient chemotherapy regimen with a generally favourable toxicity profile in the Australasian population.This study evaluated the impact of the addition of bevacizumab ± MMC to capecitabine in patients with advanced CRC.
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MAX study objective
To identify a low-toxicity regimen suitable for a broad population of patients with previously untreated metastatic colorectal cancer.
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Study schema
•Age, ≥65 vs <65
•PS, 0,1 vs 2
•Capecitabine dose
•Institution
RANDOMISE
capecitabine*
bevacizumab†
bevacizumab† + mitomycin C‡
d1 d8 d15 d22
* 1.25 or 1 g/m2 bd q3w; † 7.5 mg/kg q3w; ‡7 mg/m2 q 6w max 4 doses
capecitabine*
capecitabine*
C
CBM
CB
bevacizumab†
bevacizumab†
Dis
ease
pro
gres
sion
Metastatic CRC (suitable for capecitabine monotherapy)stratified by:
Interim safety analysis by IDSM after 60 and 150 patients completed 2 cycles.
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EligibilityHistologically confirmed, unresectable metastatic colorectal cancer no prior chemotherapy, other than adjuvant therapy with no relapse for 6 months suitable for capecitabine monotherapy adequate organ functionlife expectancy at least 12 weeksECOG PS 0-2 informed consent
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Primary endpoint
Progression-free survival
The study was designed to detect a difference in median progression-free survival from 5.5 months in arm C to 8 months arm CB or CBM at P<0.025 with 80% power (450 patients required).
Analysis was by intention-to-treat.
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Secondary endpoints
response rate
toxicity
overall survival
quality of life
Response RECIST assessed every 6 weeks.
Toxicity (NCIC CTCAE v 3.0) analyses by treatment received.
Quality of life assessed at 3, 6, 9, 12 weeks, then 6 weekly, with UBQ-C, CAQ, EQ-5D.
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Patient enrolment and progress
No protocol treatment
IneligibleLost to follow-upDid not complete
QOLIncluded in analysis
C CB CBM
156 157 158
156 157 158
271
12
151
16
031
15
471 randomised
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Baseline characteristicsC CB CBM
Median age (range, years) 69 (37–86) 67 (32–85) 67 (33–84)Male (%) 63 65 60Performance status 0–1 (%) 96 92 93Capecitabine 1000 mg/m2 bd (%) 66 67
67Prior adjuvant treatment (%) 22 27 16Liver metastases (%) 72 75 77Lymph node metastases (%) 44 50 44Lung metastases (%) 39 40 39
Peritoneal metastases (%) 21 13 19
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Chemotherapy toxicity (%)C CB CBM
Grade* Grade Grade
Type of toxicity All (3–5) All (3–5) All (3–5)Diarrhoea 62(1165 (17) 71(16)Hand-foot syndrome † 65 (16)77 (26)78(28)Stomatitis 26 (3)48(1) 53(4)Vomiting 31 (5)38(5) 40(4)Nausea 54 (6)67(5) 70(6)Fatigue 74 (10)78 (10)85(13)Febrile neutropenia 2 (2) 3(3) 2(2)Infection, no neutropenia 26 (6)35(10) 35(11)Neutropenia, no infection 10(1)12(0) 21(2)Thrombocytopenia 10(0)15(0) 44(4)High bilirubin 8(3) 6(1) 7(1)† The only toxicity occurring more often in CB and CBM than C was HFS. When the rate was adjusted for duration of treatment (average cycles: C, 8.4; CB, 10.9; CBM, 10.7), the rate of HFS was no higher in CB or CBM than C (unadjusted OR for HFS: CB vs C was 1.85, for CBM v C was 2.02 (P=0.03), and after adjustment, these were 1.30 and 1.39, respectively (P=0.40)).
* NCI CTCAE version 3.0
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Bevacizumab toxicity (%)
C CB CBM Grade* Grade
GradeType of toxicity All (3–5) All (3–5) All (3–5) Proteinuria 12 (1) 31 (3) 47 (6)Hypertension 12 (1) 29 (4) 25 (6)Thrombosis or embolism 10 (7) 10 (9) 11 (10)Bowel perforation 1 (1) 3 (3) 1 (1)Haemorrhage 13 (3) 15 (1) 27 (6)
* NCI CTCAE version 3.0
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Tumour response (%)*
Complete response 12 2
Partial response 3036 44
Overall response 3138 46Stable disease 4954 48
Progressive disease 183 3
* C vs CB, P=0.2; C vs CBM, P=0.006
C CB CBM
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Progression-free survival
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Multivariate analysis: progression-free survival
Treatment group C 331.00CB 330.63 (0.50–0.79) <0.001CBM 340.56 (0.44–0.71) <0.001
Performance status 0 561.00≥1 441.52 (1.25–1.85) <0.001
Primary tumour resected No 211.00Yes 790.72 (0.57–0.92) 0.007
Number of metastatic sites <258 1.00≥2 421.28 (1.05–1.55) 0.01
Alkaline phosphatase U/L<140 641.00≥140 361.37 (1.12–1.67) 0.002
Serum bilirubin µmol/L <14 811.00≥14 191.32 (1.03–1.68) 0.03
Variable % HR (95% CI) P
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Quality of life at 3 and 6 weeksCB vs C CBM vs C
favours C favours CB favours C favours CBM
Social
Physical function
Current health
EQ5D utility
0 0.2 0.4-0.2-0.4 0 0.2 0.4-0.2-0.4
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Overall survival
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Multivariate analysis: overall survivalVariable % HR (95% CI) PTreatment group C 331.00
CB 330.88 (0.68–1.13) 0.3CBM 340.94 (0.73–1.21) 0.6
Performance status 0 561 or 2 441.91 (1.54–2.35) <0.001
Neutrophils 109/L <8 85≥8 151.50 (1.12–2.01) 0.007
Alkaline phosphatase U/L <14064≥140 361.68 (1.35–2.10) <0.001
Prior radiotherapy No 87Yes 131.43 (1.05–1.95) 0.02
Primary tumour resected No 21Yes 790.73 (0.57–0.93) 0.01
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Subsequent treatment after progression(%)
C CBCBMAny systemic therapy 6862 61Oxaliplatin 5040 44Irinotecan 4544 35Anti-EGFR 910 13Bevacizumab 41 1Oxaliplatin + irinotecan 3127 25Oxaliplatin + irinotecan + EGFR 96 11
* Rates are not exclusive: that is, patients treated with multiple regimens are also listed under individual regimens. Each row refers to any regimen containing this drug with or without a fluoropyrimidine.
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ConclusionsAll treatment regimens were well tolerated.
Adding bevacizumab, with or without mitomycin C, to capecitabine significantly improves progression-free survival without causing major additional toxicity or impairment of quality of life.
Overall survival results were not significantly different between arms, but are promising for a relatively older patient cohort.
Capecitabine and bevacizumab, with or without mitomycin C, is an active, low-toxicity regimen that may be considered as a treatment option for patients with metastatic colorectal cancer.
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Contact
Dr Niall TebbuttConsultant Medical
OncologistAustin HospitalHeidelberg VIC 3084AustraliaTel: +61 3 9496 5763Fax: +61 3 9457 [email protected]