Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial.
BACKGROUND
In the non-curative setting, the sequence in which anticancer agents are used, singly or in combination, may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects. We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer, who were regarded as not potentially curable irrespective of response.


METHODS
We studied patients with advanced colorectal cancer, starting treatment with non-curative intent. 2135 unpretreated patients were randomly assigned to three treatment strategies in the ratio 1:1:1. Strategy A (control group) was single-agent fluorouracil (given with levofolinate over 48 h every 2 weeks) until failure, then single-agent irinotecan. Strategy B was fluorouracil until failure, then combination chemotherapy. Strategy C was combination chemotherapy from the outset. Within strategies B and C, patients were randomly assigned to receive, as the combination regimen, fluorouracil plus irinotecan (groups B-ir and C-ir) or fluorouracil plus oxaliplatin (groups B-ox and C-ox). The primary endpoint was overall survival, analysed by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 79877428.


RESULTS
Median survival of patients allocated to control strategy A was 13.9 months. Median survival of each of the other groups was longer (B-ir 15.0, B-ox 15.2, C-ir 16.7, and C-ox 15.4 months). However, log-rank comparison of each group against control showed that only C-ir--the first-line combination strategy including irinotecan--satisfied the statistical test for superiority (p=0.01). Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1.18 or less (HR=1.06, 90% CI 0.97-1.17).


CONCLUSIONS
Our data challenge the assumption that, in this non-curative setting, maximum tolerable treatment must necessarily be used first-line. The staged approach of initial single-agent treatment upgraded to combination when required is not worse than first-line combination, and is an alternative option for discussion with patients.
Seymour
Matthew T
MT
Cookridge Hospital, Leeds, UK. Electronic address: matt.seymour@leedsth.nhs.uk.
Maughan
Timothy S
TS
Velindre Hospital, Cardiff, UK.
Ledermann
Jonathan A
JA
UCL Hospitals, London, UK.
Topham
Clare
C
St Luke's Cancer Centre, Guildford, UK.
James
Roger
R
Mid-Kent Oncology Centre, Maidstone, UK.
Gwyther
Stephen J
SJ
East Surrey Hospital, Redhill, UK.
Smith
David B
DB
Clatterbridge Centre for Oncology, Wirral, UK.
Shepherd
Stephen
S
Cheltenham General Hospital, Cheltenham, UK.
Maraveyas
Anthony
A
Princess Royal Hospital, Hull, UK.
Ferry
David R
DR
New Cross Hospital, Wolverhampton, UK.
Meade
Angela M
AM
Medical Research Council Clinical Trials Unit, London, UK.
Thompson
Lindsay
L
Medical Research Council Clinical Trials Unit, London, UK.
Griffiths
Gareth O
GO
Medical Research Council Clinical Trials Unit, London, UK.
Parmar
Mahesh Kb
MK
Medical Research Council Clinical Trials Unit, London, UK.
Stephens
Richard J
RJ
Medical Research Council Clinical Trials Unit, London, UK.
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D016019:Survival Analysis
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin