Articles

Different strategies of sequential and combination

chemotherapy for patients with poor prognosis advanced
colorectal cancer (MRC FOCUS): a randomised controlled trial
Matthew T Seymour, Timothy S Maughan, Jonathan A Ledermann, Clare Topham, Roger James, Stephen J Gwyther, David B Smith, Stephen Shepherd,
Anthony Maraveyas, David R Ferry, Angela M Meade, Lindsay Thompson, Gareth O Griffiths, Mahesh K B Parmar, and Richard J Stephens, for the
FOCUS Trial Investigators* and the National Cancer Research Institute Colorectal Clinical Studies Group

Summary
Background In the non-curative setting, the sequence in which anticancer agents are used, singly or in combination, may Lancet 2007; 370: 143–52
be important if patients are to receive the maximum period of disease control with the minimum of adverse effects. We See Comment page 105
compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic See Articles page 135
colorectal cancer, who were regarded as not potentially curable irrespective of response. *Collaborators listed at end of
report
Methods We studied patients with advanced colorectal cancer, starting treatment with non-curative intent. Cookridge Hospital, Leeds, UK
2135 unpretreated patients were randomly assigned to three treatment strategies in the ratio 1:1:1. Strategy A (control (Prof M T Seymour MD);
Velindre Hospital, Cardiff, UK
group) was single-agent fluorouracil (given with levofolinate over 48 h every 2 weeks) until failure, then single-agent
(Prof T S Maughan MD); UCL
irinotecan. Strategy B was fluorouracil until failure, then combination chemotherapy. Strategy C was combination Hospitals, London, UK (Prof
chemotherapy from the outset. Within strategies B and C, patients were randomly assigned to receive, as the combination J A Ledermann MD); St Luke’s
regimen, fluorouracil plus irinotecan (groups B-ir and C-ir) or fluorouracil plus oxaliplatin (groups B-ox and C-ox). The Cancer Centre, Guildford, UK
(C Topham MD); Mid-Kent
primary endpoint was overall survival, analysed by intention to treat. This study is registered as an International Standard Oncology Centre, Maidstone,
Randomised Controlled Trial, number ISRCTN 79877428. UK (Prof R James MD); East
Surrey Hospital, Redhill, UK
Results Median survival of patients allocated to control strategy A was 13·9 months. Median survival of each of the other (S J Gwyther MBBS);
Clatterbridge Centre for
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 Oncology, Wirral, UK
against control showed that only C-ir—the first-line combination strategy including irinotecan—satisfied the statistical (D B Smith MD); Cheltenham
test for superiority (p=0·01). Overall comparison of strategy B with strategy C was within the predetermined non- General Hospital, Cheltenham,
inferiority boundary of HR=1·18 or less (HR=1·06, 90% CI 0·97–1·17). UK (S Shepherd MD); Princess
Royal Hospital, Hull, UK
(A Maraveyas PhD); New Cross
Interpretation Our data challenge the assumption that, in this non-curative setting, maximum tolerable treatment must Hospital, Wolverhampton, UK
necessarily be used first-line. The staged approach of initial single-agent treatment upgraded to combination when (Prof D R Ferry MD); and the
required is not worse than first-line combination, and is an alternative option for discussion with patients. Medical Research Council
Clinical Trials Unit, London, UK
(A M Meade PhD,
Introduction first-line fluorouracil followed, on progression, by L Thompson MSc,
Advanced colorectal cancer causes over half a million single-agent irinotecan. G O Griffiths MSc,
deaths every year worldwide.1 This death toll could fall with Four trials in 1999–2000 randomly assigned patients Prof M K B Parmar DPhil,
R J Stephens)
advances in prevention, screening, and curative treatment; with metastatic colorectal cancer to initial treatment with
Correspondence to:
however, there are—and will remain—many patients with fluorouracil alone or in combination with either irinotecan Prof Matt Seymour,
advanced disease for whom our realistic therapeutic goal is or oxaliplatin.8–11 In all these trials, combination treatment Gastrointestinal Cancer Research
not complete cure, but rather to control the cancer improved the objective response rate and time to Unit, Cookridge Hospital, Leeds
sufficiently to postpone death and reduce symptoms, with progression. Second-line treatment was not prespecified LS16 6QB, UK
matt.seymour@leedsth.nhs.uk
toxic effects and inconvenience for the patient kept to a and differed between groups, making interpretation of
minimum. overall survival difficult, but the two trials with irinotecan
Until 2005, colorectal cancer drug treatment largely showed improved overall survival with first-line
centred on only three active agents: 5-fluorouracil, combination chemotherapy8,9 whereas those with
oxaliplatin, and irinotecan. Several trials with fluorouracil oxaliplatin did not.10,11 Taken together, the four trials
showed that its effectiveness is improved when given as a provided good evidence that the use of at least one of
slow infusion,2 with the addition of leucovorin,3 or using these drugs in addition to fluorouracil improves survival
both of these methods.4 Irinotecan and oxaliplatin have in patients with metastatic colorectal cancer. There
mechanisms that differ from fluorouracil, and either can remained some doubt, however, whether first-line
show non-crossresistance or synergy with this agent in combination treatment was essential to obtain this
some preclinical models.5,6 Irinotecan was licensed in the benefit—might equally good results be achieved with less
UK in 1998 as single-agent treatment after fluorouracil toxic effects and cost with a staged treatment approach,
failure.7 By 2000, standard treatment for most patients starting with fluorouracil and adding or changing to other
treated within the UK National Health Service was drugs after failure?

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Fluorouracil Irinotecan Irinotecan/fluorouracil Oxaliplatin/fluorouracil

Regimen FU Ir IrFU OxFU
Intravenous Levofolinate 175 mg (2 h), then Irinotecan 350 mg/m² Irinotecan 180mg/m² (30 min), Oxaliplatin 85mg/m² plus
drug schedule FU 400 mg/m² (bolus) (30–90 min). (300 mg/m² if then levofolinate 175 mg (2 h), levofolinate 175 mg (concurrent,
FU 2800 mg/m² (46 hr) age >70 years or performance then FU 400 mg/m² (bolus) 2 h), then FU 400 mg/m² (bolus)
status 2) FU 2400 mg/m² (46 h) FU 2400 mg/m² (46 h)
Dexamethasone 8 mg intravenously bolus day 1. 8 mg intravenously bolus day 1. 8 mg intravenously bolus day 1. 8 mg intravenously bolus day 1.
Oral days 2–4, (decreasing course) Oral days 2–4, (decreasing course) Oral days 2–4, (decreasing course) Oral days 2–4, (decreasing course)
Cycle repeat 14 days 21 days 14 days 14 days

For full details of regimens used please see references as follows: FU,18 Ir,7 IrFU,19 and OxFU.18

Table 1: Chemotherapy regimens

Strategy A Strategy B Strategy C how should our active drugs be sequenced to provide
Group A Group B-ir Group B-ox Group C-ir Group C-ox patients with the maximum duration of disease control
Total patients 710 356 356 356 357 and minimum of adverse effects?
Male 494 (70%) 244 (69%) 235 (66%) 240 (67%) 247 (69%) In May, 2000, the UK Medical Research Council launched
Age (years) 63 (56–69) 64 (57–70) 64 (56–69) 64 (57–69) 64 (56–69) FOCUS (Fluorouracil, Oxaliplatin, and CPT11 [irino-
Primary site* tecan]—Use and Sequencing). We aimed to establish the
Colon 487 (69%) 232 (65%) 240 (67%) 226 (63%) 234 (66%) best sequence of the first two cytotoxic drugs, fluorouracil
Rectum 222 (31%) 123 (35%) 114 (32%) 130 (37%) 123 (34%) and either irinotecan or oxaliplatin, when treating patients
Prior adjuvant chemotherapy 163 (23%) 96 (27%) 89 (25%) 94 (26%) 94 (26%) with poor prognosis advanced colorectal cancer.
WHO performance status
0 294 (41%) 147 (41%) 147 (41%) 147 (41%) 148 (41%) Methods
1 355 (50%) 181 (51%) 178 (50%) 179 (50%) 179 (50%) Patients
2 61 (9%) 28 (8%) 31 (9%) 30 (8%) 30 (8%) Patients were required to have histologically confirmed
Baseline white blood cell count colorectal adenocarcinoma, with inoperable metastatic or
<10x10⁹/L 519 (73%) 271 (76%) 253 (71%) 260 (73%) 266 (75%) locoregional disease. The trial targeted patients with poor
≥10x10⁹/L 183 (26%) 82 (23%) 99 (28%) 93 (26%) 91 (25%) prognosis—namely, those with inoperable disease for
Distant metastases whom the clinician judged that, even if there was a
Synchronous 398 (56%) 198 (56%) 187 (53%) 203 (57%) 210 (59%) response to chemotherapy, curative surgery would still not
Metachronous 297 (42%) 150 (42%) 161 (45%) 147 (41%) 138 (39%) be feasible. Eligibility criteria included: disease measurable
None (local disease) 15 (2%) 8 (2%) 8 (2%) 16 (4%) 9 (3%) by RECIST (response evaluation criteria in solid tumours);16
Number of disease sites WHO performance status 0–2;17 no previous chemotherapy
1 235 (33%) 126 (36%) 123 (35%) 111 (31%) 103 (29%) for metastatic disease; white blood count greater
2 295 (42%) 142 (40%) 143 (40%) 154 (43%) 169 (47%) than 4×10⁹/L, platelet count greater than 150×10⁹/L, serum
>2 180 (25%) 88 (25%) 90 (25%) 91 (26%) 85 (24%)
bilirubin concentration less than 1·25×upper limit of
Disease sites
normal, alkaline phosphatise concentration less than
Liver 527 (76%) 266 (76%) 266 (76%) 279 (80%) 275 (79%)
5×upper limit of normal, calculated glomerular filtration
Lymph nodes 296 (43%) 116 (33%) 130 (37%) 119 (34%) 118 (34%)
rate or EDTA (edetic acid) clearance greater than 50 mL
Lungs 237 (34%) 130 (37%) 118 (34%) 130 (37%) 135 (39%)
per min; and older than 18 years. Exclusion criteria
Peritoneum 94 (14%) 46 (13%) 51 (15%) 45 (13%) 52 (15%)
included uncontrolled medical comorbidity likely to
Primary unresected 176 (25%) 92 (26%) 90 (25%) 89 (25%) 87 (24%)
compromise treatment.
Local recurrence 27 ( 4%) 15 ( 4%) 14 (4%) 15 (4%) 16 (4%)
Other sites 91 (13%) 52 (15%) 49 (14%) 53 (15%) 50 (14%)
Study design and interventions
Measurable disease 688 (97%) 340 (96%) 346 (97%) 340 (96%) 349 (98%)
Patients were randomly assigned with a minimisation
Unmeasurable disease 22 (3%) 16 (4%) 10 (3%) 16 (4%) 8 (2%)
procedure to stratify for clinician, performance status,
Data are number (%) or median (IQR). *Data missing or uncertain for primary site in group A (one patient), primary tumour resected or in situ, and distant metastases
B-ir (one patient), and B-ox (two patients).
present or absent.
Table 2: Baseline patient characteristics Three treatment strategies were compared, each with a
different sequence of use for the first two cytotoxic drugs.
In subsequent years, evidence has emerged for use of all Strategy A was the control group. First-line treatment was
three cytotoxic drugs during the course of a patient’s with fluorouracil (using the FU regimen18 defined in
illness,12,13 and for adding targeted treatments against table 1) and continued until evidence of treatment failure.
vascular endothelial growth factor 14 and epidermal growth Thereafter, in patients fit enough for second-line treatment,
factor receptor.15 However, the underlying question single-agent irinotecan was given (with the Ir regimen,7 as
remains—in the context of non-curative cancer treatment, defined in table 1). Strategy B was deferred combination

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2135 patients randomly assigned

Strategy A Strategy B Strategy C

710 allocated to 356 allocated to 356 allocated to 356 allocated to 357 allocated to
group A group B-ir group B-ox group C-ir group C-ox

6 received alternative 5 received alternative 3 received alternative 8 received alternative 3 received alternative
first-line regimen first-line regimen first-line treatment fist-line regimen first-line regimen
6 died/progressed to 2 died/progressed to 2 missing data 5 died/progressed to 7 died/progressed to
terminal care terminal care terminal care terminal care
2 missing data 3 missing data 1 missing data 3 missing data

First-line
treatment 696 received 346 received 351 received 342 received 344 received
FU FU FU IrFU OxFU

30 not yet failed 7 not yet failed 8 not yet failed 20 not yet failed 17 not yet failed

666 failed 339 failed 343 failed 322 failed 327 failed
first-line first-line first-line first-line first-line
treatment treatment treatment treatment treatment

251 died/progressed to 110 died/progressed to 106 died/progressed to

terminal care terminal care terminal care
51 received alternative 44 received alternative 36 received alternative
2nd line regimen 2nd line regimen 2nd line regimen

Second-line
treatment 364 received 185 received 201 received
Ir IrFU OxMdG

18 not yet failed 8 not yet failed 5 not yet failed

346 failed 177 failed 196 failed

second-line second-line second-line
treatment treatment treatment

193 died without salvage 101 died without salvage 114 died without salvage 142 died without salvage 149 died without salvage
chemotherapy chemotherapy chemotherapy chemotherapy chemotherapy

153 received 76 received 82 received 180 received 178 received

salvage salvage salvage salvage salvage
chemotherapy chemotherapy chemotherapy chemotherapy chemotherapy

Figure 1: Trial profile

chemotherapy. Again, first-line treatment was with
fluorouracil, but patients fit enough for second-line
treatment were to receive combination chemotherapy.
Strategy B was further divided into two groups, B-ir and
B-ox, in a 1:1 ratio at the time of initial randomisation. For
patients in group B-ir, the planned second-line combination
was irinotecan and fluorouracil, whereas in group B-ox it
was oxaliplatin and fluorouracil (using the IrFU19 and
OxFU18 regimens, respectively; table 1). Strategy C was
first-line combination treatment. These patients received
combination chemotherapy from the outset, continued
until treatment failure. This strategy was also subdivided,
in a 1:1 ratio, into two groups, with patients in group C-ir
receiving irinotecan and fluorouracil, and those in group
C-ox receiving oxaliplatin and fluorouracil.
Treatment was started as soon as possible after
randomisation and continued until treatment failure.
Breaks (eg, for holidays) were not allowed during the first
3 months, and were restricted to 4 weeks during the
second 3 months. Thereafter, on the basis of evidence

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committee. An independent data monitoring committee

First-line treatment Second-line treatment
met yearly with a remit including closure of the trial or
FU IrFU OxFU Ir IrFU OxFU
individual groups if, in their opinion, a difference had
Study groups A, B-ir, B-ox C-ir C-ox A B-ir B-ox emerged that would affect patient management.
Patients assessed 1305 337 339 349 180 199 Tumour assessment was done at baseline (≤4 weeks
Neutropenia 118 (9%) 65 (19%) 94 (28%) 43 (12%) 32 (18%) 50 (25%) before treatment), then every 12 weeks, with CT or MRI,
Nausea or vomiting 55 (4%) 32 (10%) 31 (9%) 31 (9%) 9 (5%) 14 (7%) scored by RECIST.16 However, responses were not routinely
Stomatitis 25 (2%) 6 (2%) 6 (2%) 3 (1%) 2 (1%) 6 (3%) confirmed by repeat scans, and external radiological review
Diarrhoea 74 (6%) 38 (12%) 34 (10%) 58 (17%) 14 (8%) 16 (8%) was not undertaken. Toxic effects were scored with National
Hand/foot syndrome 22 (2%) 4 (1%) 4 (1%) 2 (1%) 2 (1%) 6 (1%) Cancer Institute common terminology criteria (version 2.0).
Sensory neuropathy 11 (1%) 5 (2%) 34 (10%) 3 (1%) 2 (1%) 6 (3%) Quality of life was assessed at baseline, 6 and 12 weeks,
Alopecia 3 (<1%) 8 (2%) 3 (1%) 34 (10%) 5 (3%) 0 (0%) and every 12 weeks thereafter, with the European
Lethargy 174 (13%) 66 (20%) 73 (21%) 59 (17%) 37 (21%) 41 (20%) Organisation for Research and Treatment of Cancer core
Pain 176 (14%) 73 (22%) 60 (18%) 79 (23%) 26 (14%) 39 (20%) quality of life questionnaire (EORTC QLQ-C30).24 Overall
Treatment-related death 11 (1%) 3 (1%) 4 (1%) 3 (1%) 1 (1%) 2 (1%) survival was calculated from randomisation to death by
60-day all-cause mortality 52 (4%) 17 (5%) 14 (4%) 31 (9%) 13 (7%) 12 (6%) any cause. Progression-free survival was calculated from
randomisation to first evidence of progression or death
Data are the number (%) of patients who received at least one dose of each regimen who experienced an adverse event
from any cause.
of grade 3 or worse, scored using National Cancer Institute common terminology criteria (version 2.0). For details of
drug regimens please see table 1. For details of study groups please see text and figure 1.
Statistical methods
Table 3: Grade 3 or 4 adverse events reported For time-to-event outcomes, Kaplan-Meier curves were
produced, patients alive without the event having occurred
from our group’s previous trial,20 patients with responding were censored at the time last seen, and log-rank tests were
or stable disease were allowed to pause their treatment, used to compare curves. Hazard ratios and 95% CIs were
resuming the same treatment thereafter provided that calculated for all comparisons. Exploratory subgroup
progression did not take place within 12 weeks of the last analyses were done according to the baseline characteristics
treatment. In the sequenced strategies (A and B), the listed in table 2.
planned second-line treatment was started, provided that The planned sample size was 2100 patients: 700 in every
the patient met the fitness criteria of the regimen, at the treatment strategy (A, B, and C) and 350 in each subgroup
first evidence of progression during—or within 12 weeks of strategies B and C. An anticipated 2-year survival of
if pausing—first-line fluorouracil. 15% in the control group would detect an improvement
Detailed dose reduction and delay protocols were of 7·5% (to 22·5%) in any pair-wise comparison of control
provided, which, in general, required a 1 week delay for versus an individual novel group (1050 patients, one-sided
unresolved toxic effects of grade 2 or more, and a 20% dose log-rank, 80% power, 1% significance to correct for
reduction after toxic effects of grade 3 or more, or after two multiple comparisons). However, for consistency with
delays for grade 2 toxic effects. Patients receiving oxaliplatin other studies, a two-sided log-rank test is presented for
plus fluorouracil were carefully monitored for neurosensory these comparisons.
toxicity, and oxaliplatin was suspended from the schedule Since starting FOCUS, standard practice has changed
if symptoms of grade 2 or more persisted between cycles. internationally and in the UK, altering the emphasis of
When the full allocated treatment plan had failed, further the questions posed by the trial. First-line treatment with
options were considered, including purely symptomatic fluorouracil, although remaining standard in the UK
treatment or salvage chemotherapy. Before December, until 2005, was replaced by combination therapy from
2002, the recommended salvage in all groups was mid-2000 in many countries (and subsequently in some
infusional fluorouracil plus mitomycin-C,21 avoiding countries by combination treatment with bevacizumab),
crossover. Thereafter, with evidence emerging to support making strategy C more relevant to standard practice.
sequential use of both oxaliplatin and irinotecan,12,13 the Therefore, before completion of accrual, we decided to
protocol was modified. The new recommendation was for add a supplementary analysis to those specified in the
patients who had received irinotecan in our study to be original protocol, taking strategy C as the reference and
offered oxaliplatin in combination with either fluorouracil examining strategy B for non-inferiority. This analysis is
or capecitabine, and for those who had received oxaliplatin based on a CI approach, since the trial was not originally
to have irinotecan with fluorouracil or capecitabine, in designed to answer a non-inferiority question. It assumes
both cases with fortnightly schedules.22 no interaction between strategy and second drug
Multicentre and institutional research ethics committee (oxaliplatin or irinotecan). A reduction in 2-year survival
approval was obtained, and patients provided written of 5% (eg, from 20% to 15%), assuming proportional
informed consent. Trial management was by the MRC hazards, equates to a hazard ratio (HR) of about 1·18.
Clinical Trials Unit, with MRC good clinical research With the CI approach with a one-sided significance level
practice,23 overseen by an independent trial steering of 5% we formed a 90% CI for the HR; non-inferiority as

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A 1·0 B C
Events Total Events Total Events Total
0·8 Strategy A 617 710 Group A 617 710 Group A 617 710
Strategy B 616 712 Group B-ir 300 356 Group B-ox 316 356
Strategy C 606 713 Group C-ir 295 356 Group C-ox 311 357
0·6
Survival

0·4

0·2

0
0 6 12 18 24 30 36 0 6 12 18 24 30 36 0 6 12 18 24 30 36
Months
Patients at risk
Strategy A 710 562 397 247 139 73 40 Group A 710 562 397 247 139 73 40 Group A 710 562 397 247 139 73 40
Strategy B 712 594 425 270 153 72 38 Group B-ir 356 300 207 131 72 40 21 Group B-ox 356 294 218 139 81 32 17
Strategy C 713 598 448 294 174 84 42 Group C-ir 356 291 223 148 93 49 23 Group C-ox 357 307 225 146 81 35 19

Figure 2: Kaplan-Meier plots for overall survival by intention to treat

(A) Survival by treatment strategy. (B) Survival by treatment group (control vs B-ir vs C-ir). (C) Survival by treatment group (control vs B-ox vs C-ox). See table 4 for log-rank statistics.

defined above needs exclusion of an upper confidence Those in group B receiving irinotecan received a median
limit 1·18 or more. of six cycles (1–23) of irinotecan plus fluorouracil every
This study is registered as an International Standard 2 weeks. Those in group B allocated second-line oxaliplatin
Randomised Controlled Trial, number ISRCTN 79877428. plus fluorouracil, received a median of six cycles (1–24), of
which oxaliplatin was included for 1582/1688 (94%) cycles
Role of the funding source (median six [1–21] per patient).
The study design, data collection, data analysis, data Figure 1 also shows the usage of salvage chemotherapy.
interpretation, writing of the report, and the decision to To date, 49% of patients (669/1368) in whom the allocated
submit for publication involved employees of MRC Clinical treatment has failed have received salvage chemotherapy.
Trials Unit. The corresponding author had full access to all The proportion was higher for those in strategy C
the data in the study and had final responsibility for the (358/649 [55%]), for whom FOCUS treatment was a
decision to submit for publication. single line of treatment, than it was for those in strategy A
and B (311/719 [43%]), who had already received two lines
Results of therapy at the time of FOCUS failure (figure 1). After
From May 1, 2000 to Dec 31, 2003, 2135 patients were the change in salvage therapy recommendations in
randomly assigned at 59 centres in the UK and one in December, 2002, FOCUS patients could receive all three
Cyprus. Table 2 shows baseline characteristics. Figure 1
shows the trial profile. Patients in strategies A and B Log-rank test HR p-value Median Difference†
received a median of 11 cycles (range 1–51) of the allocated comparison (95% CI) (two-sided test) survival in (95% CI) between
reference reference group
first-line fluorouracil regimen; patients assigned to
group* and comparitor
irinotecan plus fluorouracil in strategy C received a median
Are any of the novel plans better than the control?
of 12 cycles (1–36). Patients in strategy C allocated to
A vs B 0·94 (0·84 – 1·05) 0·24 13·9 0·9 (–0·7 to 2·6)
oxaliplatin plus fluorouracil received a median of
12 cycles (1–58), of which oxaliplatin was included for 3506 A vs B-ir 0·91 (0·79–1·03) 0·16 13·9 1·4 (–0·4 to 3·7)

of 3740 (94%) cycles (median 11 [1–58] per patient); the A vs B-ox 0·97 (0·85–1·11) 0·65 13·9 0·4 (–1·4 to 2·5)
remainder were given as fluorouracil alone after A vs C 0·88 (0·79 – 0·98) 0·02 13·9 1·9 (+0·3 to 3·7)
development of persistent neuropathy. A vs C-ir 0·84 (0·73–0·96) 0·01 13·9 2·6 (+0·6 to 5·1)
Figure 1 shows the numbers of patients in the two-stage A vs C-ox 0·93 (0·81–1·06) 0·26 13·9 1·1 (–0·8 to 3·3)
strategies who proceeded to second-line chemotherapy. Of Does the choice of irinotecan or oxaliplatin affect survival?
the 1348 in whom fluorouracil had failed at the time of [B-ir + C-ir] vs 1·09 (0·97–1·21) 0·14 15·8 –1·3 (–2·7 to 0·5)
[B-ox + C-ox]
analysis, 750 (56%) had received the planned second-line
regimen, and a further 131 (10%) received an alternative B-ir vs B-ox 1·06 (0·91–1·24) 0·46 15·0 –0·8 (–2·9 to 1·5)

second-line regimen; however, 467 (35%) patients had C-ir vs C-ox 1·12 (0·95–1·31) 0·18 16·7 –1·8 (–4·0 to 0·9)

moved to terminal care or died without receiving further

chemotherapy after first-line fluorouracil. The median
amount of time spent on second-line combination therapy
was similar in all groups. Patients in group A received a
median of four cycles (1–24) of irinotecan every 3 weeks.
*Group A is the reference group for whether any of the novel plans are better than the control. Irinotecan group is the
reference group for whether the choice of irinotecan or oxaliplatin affect survival. †Difference calculated by application
of log-rank HR to median survival in control group.
Table 4: Overall survival log-rank comparisons

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610 patients (29%) had a serious adverse event caused or

Log-rank test HR Median survival Confidently excludes detriment with
comparison (90% CI) (months) strategy B larger than:*
Strategy C Strategy B
(reference)
C vs B 1·06 (0·97–1·17) 15·9 15·1 2·3 months
C-ir vs B-ir 1·08 (0·94–1·24) 16·7 15·0 3·2 months
C-ox vs B-ox 1·04 (0·92–1·19) 15·4 15·2 2·5 months
*Estimation of the largest detriment to the comparator group that cannot be reliably excluded. It is calculated by using
the upper end of the 90% CI in the following way: comparator median–([1/upper end of 90%CI]×comparator median).
Table 5: Is deferred combination (strategy B) non-inferior to first-line combination (strategy C)?
drugs (fluorouracil, irinotecan, and oxaliplatin) at some
point in their management. However, at the time of
analysis, only 482 (23%) patients had done so. The
proportion who had received all three drugs was higher
for patients allocated to strategy C (233/713 [33%]) than
to A (113/710 [16%]) or B (136/712 [19%]). The proportion
was much the same in patients allocated to irinotecan
groups in strategies B and C (175/712 [25%]) or oxaliplatin
groups in strategies B and C (194/713 [27%]).
All regimens were fairly well tolerated and safe. Treat-
ment delays or modifications were made in less than
40% of patients at any point for all treatment regimens
with one exception; first-line OxFU regimen was delayed
or modified in 50% of patients, usually for neurosensory
or haematological toxic effects after several cycles. Table 3
shows grade 3 or 4 toxic effects. Neutropenia and neuro-
pathy were the main toxicities of OxFU, although grade 3
neuropathy was uncommon in the second-line setting, in
which treatment duration was shorter. Diarrhoea and
alopecia were most common with single-agent irinotecan.
Diarrhoea was no more frequent with IrFU regimen than
with OxFU. Pain and lethargy were common with all regi-
mens, which might have been in part due to the under-
lying disease. However, their incidence was noticeably
lower with the FU regimen than with the other regimens.
probably caused by the trial drugs; a further
262 patients (12%) had serious adverse events related to
venous access. 24 deaths (1·1% of patients) were reported
as definitely or probably caused or precipitated by FOCUS
treatment, with no great difference between the regimens.
18 of these deaths were in the 2093 patients receiving
first-line treatment (0·9% of patients), and six were in the
755 receiving second-line therapy (0·8%). Death occurred
within 30 days of the final dose of the first-line
chemotherapy in a further 130 (6·2%) patients (124 because
of cancer; six from an unrelated medical illness), and
within 30 days of the last second-line chemotherapy in a
further 42 (5·6%) patients (39 because of cancer, three
from intercurrent illness). There was no imbalance in
all-cause mortality at day 60 (table 3).
Up until now, 1839 (86%) patients have died, and the
median follow-up of the survivors is 26·5 months. Figure 2
shows the Kaplan-Meier overall survival curves by intention
to treat for all patients randomly assigned. Strategies B and
C produced very similar survival, both slightly better than
strategy A. 2-year survival was 22% with strategy A, 25%
with strategy B, and 28% with strategy C. In pairwise log-
rank tests (table 4), overall comparison of strategy C with
control reached p=0·02, but did not satisfy the stringent
level of p<0·01 required to confirm superiority in the
context of multiple testing.
Figure 2 also shows overall survival by the individual
treatment groups. All four groups in strategies B and C
provided longer overall survival than did the control group,
but only irinotecan used in the first-line combination
treatment was significantly better (table 4). Comparison of
irinotecan versus oxaliplatin, whether used in the first-line
combination setting, second-line combination, or at any
time showed no significant difference (table 4).
In response to changes in standard practice after the
start of the trial, an additional non-inferiority analysis was

First-line treatment Second-line treatment

Fluorouracil Irinotecan+ oxaliplatin+ Irinotecan Irinotecan+ oxaliplatin+
fluorouracil fluorouracil fluorouracil fluorouracil
Study groups A, B-ir, B-ox C-ir C-ox A B-ir B-ox
Total number treated (receiving ≥1 dose) 1393 342 344 364 185 201
CR 57 19 29 8 1 3
PR 335 147 166 31 29 43
SD (≥12 weeks) 487 89 72 107 68 74
PD 249 40 40 149 52 50
Not assessed† 265 47 37 69 35 31
Response rate (CR+PR)‡ 28% 49% (p<0·001)§ 57% (p<0·001)§ 11% 16% (p=0·07)¶ 23% (p<0·001)¶
Disease control ≥12 weeks (CR+PR+SD)‡ 63% 75% (p<0·001)§ 78% (p<0·001)§ 40% 53% (p=0·004)¶ 60% (p<0·001)¶
Median PFS (months) 6·3 8·5 (p<0·001)§ 8·7 (p<0·001)§ 4·3 4·4 (p=0·75)¶ 4·8 (p=0·74)¶

RECIST=response evaluation criteria in solid tumours. PFS=progression free survival. CR=complete response. PR=partial response. SD=stable disease. PD=progressive disease.
*Responses did not need to be confirmed by a second scan. †Includes any reason for failure to reassess radiologically—eg, clinically obvious deterioration. ‡Denominator
includes all patients who received one or more dose, whether or not subsequently assessed. §Compared with fluorouracil (χ² test for response rate and disease control;
log-rank test for PFS.) ¶Compared with irinotecan (χ² test for response rate and disease control; log-rank test for PFS).

Table 6: RECIST* response and progression-free survival

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Number events/number entered O–E Variance HR (95% CI)

Strategy B Strategy C

Sex
Male 405/480 423/488 3·11 206·14 1·02 (0·89–1·16) p=0·828
Female 211/231 183/225 16·54 97·89 1·18 (0·97–1·44) p=0·095
Interaction p=0·21
Age (years)
<60 203/230 201/252 19·07 99·65 1·21 (1·00–1·47) p=0·056
60–69 258/304 257/290 –9·48 127·99 0·93 (0·78–1·10) p=0·402
70+ 155/178 148/171 8·64 74·94 1·12 (0·89–1·41) p=0·318
Interaction p=0·51
Primary site
Colon 412/467 392/452 3·27 200·09 1·02 (0·88–1·17) p=0·817
Rectum 200/237 206/253 14·21 100·00 1·15 (0·95–1·40) p=0·155
Interaction p=0·31
Prior adjuvant fluorouracil
Yes 155/185 159/189 –1·61 77·97 0·98 (0·78–1·22) p=0·855
No 460/523 447/523 20·51 225·33 1·10 (0·96–1·25) p=0·172
Interaction p=0·40
WHO performance status
0 243/293 240/295 7·34 120·30 1·06 (0·89–1·27) p=0·503
1 318/358 310/358 5·93 156·18 1·04 (0·89–1·22) p=0·635
2 55/59 56/60 9·52 26·13 1·44 (0·98–2·11) p=0·063
Interaction p=0·38
WBC
<10×10⁹/L 444/526 438/526 4·48 219·78 1·02 (0·89–1·16) p=0·763
≥ 10×10⁹/L 169/181 166/184 19·16 80·84 1·27 (1·02–1·58) p=0·033
Interaction p=0·10
Number of disease sites
1 195/242 157/205 5·84 86·91 1·07 (0·87–1·32) p=0·531
2 252/285 281/322 18·66 130·36 1·15 (0·97–1·37) p=0·102
>2 169/185 168/186 6·03 83·69 1·07 (0·87–1·33) p=0·510
Interaction p=0·97
Type of disease
Measurable 594/684 583/687 25·26 292·98 1·09 (0·97–1·22) p=0·140
Unmeasurable 21/25 20/22 –3·46 9·81 0·70 (0·38–1·31) p=0·270
Interaction p=0·18

Total 616/709 606/711 19·68 304·32 1·07 (0·95–1·19) p=0·259

0 0·5 1 1·5 2
Strategy B better Strategy C better

Figure 3: Forest plot of overall survival with strategy B or strategy C (according to subgroups)
Horizontal tails indicate 99% and 95% CIs. O-E=observed minus expected results. WBC=white blood cell count.

added, to compare deferred combination treatment
(strategy B) with the new international standard of first-
line combination (strategy C). When analysed for non-
inferiority with reference to strategy C, strategy B gave a
HR of 1·06 (90% CI 0·97–1·17). These data exclude an
inferiority margin of HR 1·18 or more, corresponding to a
reduction of more than 5% in 2-year survival or a difference
in median survival of more than 2·3 months. The results
for the two individual drugs irinotecan and oxaliplatin are
similar (table 4), but with fewer patients the CIs are wider
than for the grouped comparison, so these individual
comparisons do not have adequate power to conclude
non-inferiority (table 5).
Table 6 shows RECIST responses and median
progression-free survival for all treatment phases, and
should be interpreted in the context that scans were not
reviewed externally. As anticipated from previous trials,
the response rates and progression-free survival for
first-line IrFU and OxFU regimens were significantly
better than for fluorouracil alone. For patients in strategy A
or B who went on to receive their allocated second-line
treatment, the combination therapies IrFU and OxFU both
gave higher response rates than did irinotecan alone,
significantly so in the case of OxFU, although the rates of
progression-free survival were not significantly improved.
During the first 18 months from randomisation, the
mean WHO performance status fell from 0·7 to about 1·1
but no differences were seen between the five treatment
groups. Detailed quality of life data were obtained and will
be reported elsewhere. However, the mean overall quality

www.thelancet.com Vol 370 July 14, 2007 149

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of life score (combining questions 29 and 30 from the
EORTC QLQ-C30) varied very little over time or between
regimens; in particular we were not able to detect any
advantage or disadvantage at 3 and 6 months associated
with first-line combination chemotherapy (strategy C).
There was no definite evidence that the effect of treatment
on survival was different in any of the subgroups of patients
defined by the baseline characteristics. Figure 3 shows the
HRs for strategy B versus strategy C according to the
baseline characteristics in table 2. No clear evidence of a
differential benefit of strategy C over strategy B was noted
in these categories; however, a non-significant trend was
seen favouring strategy C over B in patients with WHO
performance status 2.
Discussion
This large randomised trial has produced a surprising
result which challenges accepted standard treatment
approaches in advanced colorectal cancer therapy. It shows
that, in the context of non-curative treatment, the strategy
of initial fluorouracil alone, reserving combination therapy
for second-line treatment, does not compromise patients’
survival or quality of life compared with first-line combin-
ation chemotherapy. Several previous trials have compared
first-line fluorouracil or combination therapy, but our trial
prospectively compares the same drugs used in different
sequence strategies. Two subsequent trials have used
similar designs. CAIRO-1 (Dutch Colorectal Cancer
Group),25 reported in this issue, compares sequenced
single-agent capecitabine then irinotecan or first-line
irinotecan plus capecitabine (similar to groups A and C-ir
in this trial), in both cases with planned oxaliplatin-based
salvage therapy. FFCD 2000-05 (Federation Francophone
de la Cancerologie) also compares sequence strategies and
may add further supportive data to our findings.
Improved treatment of metastatic colorectal cancer over
the past decade has produced two linked but distinct
benefits for patients. First, a small but increasing number
of patients can now be treated with a possibility of complete
cure, usually through a combination of surgery and drug
treatment.26 Second, for patients who are not cured, new
therapies offer the probability of increased survival,
including a longer period with good quality of life.
These distinct goals—curative and non-curative—might
be served by the same drug treatment strategy, but this is
not necessarily so. Curative intent demands the maximum
possible short-term anticancer effect; active agents need
not be kept in reserve, and high toxic effects could be a
worthwhile price for a major potential gain. By contrast,
with non-curative treatment, longer-term scheduling to
make best use of active agents throughout the illness is
highly relevant and, with more modest potential gains, the
negative effects of treatment are more important.
We addressed the clinical setting of non-curative
treatment. From the outset, patients with operable
metastases were excluded and clinicians were also
encouraged not to enter patients into the study who might
150
become operable should they respond well. Subsequently,
guidance from the UK National Institute of Clinical
Excellence in 2002 mandated NHS-funded combination
chemotherapy for any patient with liver metastases “that
may become resectable following treatment”.27
Consequently, patients accruing to FOCUS were
increasingly selected as a poor-prognosis group who were
definitely incurable. This approach might explain why,
despite excellent response and progression free survival
data, the overall survival is lower in FOCUS than in
contemporaneous trials that included all patients with
metastatic disease.28,29 Our findings should therefore be
interpreted with careful reference to the trial’s population.
Clinicians and patients considering the staged treatment
approach may be attracted by the prospect of a low risk of
toxic effects during first-line therapy; indeed, the
fluorouracil regimen that we used produced an extremely
favourable profile (table 3). However, staged therapy also
brings two concerns. At the time of progressing on first-
line treatment, will the patient be unfit for the planned
second-line schedule, compromising their survival? And
will the lower initial response rate—and a disease
progression episode before introduction of the second
drug—compromise their quality of life? In FOCUS, a third
of patients allocated to staged strategies never received
second-line therapy. This proportion could possibly have
been reduced by more frequent CT scan surveillance.
However, despite this factor, which might have
disadvantaged patients in staged treatment plans, we
found that overall survival with strategy B was no worse
than strategy C. Similarly, we detected no differences in
quality of life scores or performance status between the
first-line combination and staged treatment approaches.
These findings are hard to explain. Perhaps patients whose
condition deteriorates most rapidly on fluorouracil alone
are also least likely to benefit from combination therapy.
Or perhaps the staged treatment approach actually
improves the survival of patients with fluorouracil-sensitive
disease, off-setting and so masking a detriment in patients
who are fluorouracil-resistant.
A molecular marker sub-study of FOCUS has reported
that low tumour protein expression of topoisomerase-1 is
associated with low expression of thymidylate synthase,
and that patients with this molecular profile have good
outcomes when given fluorouracil alone but gain little
additional benefit from irinotecan or oxaliplatin.
Conversely, patients with high expression of these proteins
have poor outcomes with fluorouracil alone but major
benefit from receiving irinotecan or oxaliplatin first-line.30
These data need to be validated in other trial populations,
but hold promise for molecular selection of the best
therapeutic strategy for individual patients.
Compared with the control strategy of sequential single-
agent fluorouracil then irinotecan, median survival times
were longer with each of the novel groups. However, most
of the differences were minor, and in only one group—
first-line irinotecan plus fluorouracil—was the statistical
www.thelancet.com Vol 370 July 14, 2007

test for superiority significant. This finding is consistent
with the survival benefit seen in previous trials of
fluorouracil versus fluorouracil plus irinotecan in which
second-line treatment, although not controlled, consisted
of single-agent irinotecan for many patients assigned to
the control group.8,9 The results for irinotecan and
oxaliplatin were not identical. The response rate with
oxaliplatin plus fluorouracil—both first and second line—
was higher than it was with irinotecan plus fluorouracil;
however, overall survival tended to favour the strategies
that included the irinotecan combination. There was no
imbalance of third-drug salvage treatment to account for
this observation, and early omission of oxaliplatin for
neurotoxicity seems not to have been a major factor, since
it was omitted from only 6% of cycles. Our findings are not
inconsistent with previous trials in which, despite its high
response rate, first-line oxaliplatin combinations have not
shown definite survival benefits.10,11,31
What is the relevance of FOCUS in 2007, after the arrival
of targeted treatments against vascular endothelial growth
factor and epidermal growth factor receptor. Oncologists
in many countries are now not asking whether they should
give one drug or two, but rather whether they should use
three, four, or more in combination. The march of progress
in oncology has generally assumed that the greatest
anticancer activity today will automatically lead to the
greatest benefit tomorrow; keeping active treatment in
reserve is for the fainthearted. This assumption is rarely
challenged—few trials have methodically compared
strategies of using drugs immediately or reserving them
for later, and drug companies understandably prefer to
support trials which bring their drug earlier in the
treatment pathway. The result has been a progressive
escalation of the complexity, toxicity, and cost of first-line
treatment. For patients with limited metastatic disease,
this approach has certainly given an improved possibility
of cure. But, for the larger number of patients with more
extensive metastases who will not be cured, FOCUS offers
an important choice, informed by the knowledge that a
decision to opt for a staged treatment approach, starting
with less toxic therapy and keeping active agents in reserve,
entails minimal, if any, compromise in survival. The
addition of bevacizumab to single-agent fluoropyrimidine
treatment is safe and effective in first-line therapy,32 but is
usually reserved for patients thought to be unfit for
combination treatment; the FOCUS data support extending
this approach to a wider range of patients. Furthermore,
our study shows that it is ethical and reasonable, in this
defined patient population, to design first-line studies in
which novel agents are added to optimum fluoropyrimidine
treatment instead of combination chemotherapy, thus
reducing the burden of toxic effects for trial participants.
Contributors
MTS was chief investigator of the trial and chaired the trial management
group. MTS, TSM, MKBP, and RJS designed the trial, wrote the protocol,
and prepared the manuscript with input from all members of the trial
management group. TSM, JAL, CT, and RJ were members of the trial
management group and contributed patients to the trial. SJG was a
www.thelancet.com Vol 370 July 14, 2007
Articles
member of the trial management group and led in radiology aspects of the
trial. DBS, SS, AM, and DRF contributed patients to the trial and
commented on the manuscript. MKBP, AMM, LT, GOG, and RJS were
responsible for the data management, analysis, statistical analysis. and
interpretation.
Trial management group
MT Seymour (chair), TS Maughan, JA Ledermann, C Topham, R James,
SJ Gwyther, C Button, D Blake, J Smith, M Sculpher, G Griffiths, A Meade,
RJ Stephens, L Thompson.
MRC clinical trials unit
S Beall, C Chung, S Clawson, T Cullum, S Hassan, C Johnson, B May,
C Murphy, J Nuttall, J Pickering, L van Dyck.
Data monitoring committee
J Northover (chair), J Brown, JL Mansi, M Aapro, R Stout.
Trial steering committee
M Mason (chair), R Rudd, PWM Johnson.
Clinical investigators (institution [number of patients contributed])
D B Smith, P Clark, E Marshall, S Myint, S M O’Reilly, M Iqbal
(Clatterbridge Centre for Oncology, UK [180]); T S Maughan, A Brewster,
T D L Crosby, D Mort, N Iqbal (Velindre Hospital Cardiff, UK [138]);
S Shepherd, D Farrugia, K Benstead, S Elyan, R Owen, R Counsell
(Cheltenham General Hospital, UK [108]); C Topham, G Middleton
(St Luke’s Cancer Centre, Guildford, UK [104]); M Seymour, A Anthoney,
D Sebag-Montefiore (Cookridge Hospital, Leeds, UK [89]); M Saunders,
E Levine, J Valle, H Anderson, M Wilson, R E Hawkins (Christie Hospital,
Manchester, UK [88]); J Summers, M Hill, R James, S Beesley,
D G L Pickering, (Mid-Kent Oncology Centre, Maidstone, UK [83]);
D J Radstone, B Orr, P Kirkbride, M Marples, D Levy, K Dunn
(Weston Park Hospital, Sheffield, UK [71]); R H Phillips, C Lowdell,
P Riddle (Charing Cross Hospital, London, UK [66]); H Wasan, C Vernon,
V Khoo (Hammersmith Hospital, London, UK [56]); A Maraveyas, M Lind
(Princess Royal Hospital, Hull, UK [55]); J C van der Voet, N Wadd,
N Storey (James Cook University Hospital, Middlesbrough, UK [52]);
J Stewart, C Macmillan (Northamptonshire Centre for Oncology, UK [51]);
M J Churn, R Mehra, R Allerton, D R Ferry (New Cross Hospital,
Wolverhampton, UK [51]); S Falk, K Hopkins (Bristol Oncology Centre, UK
[47]); D R Ferry (Russells Hall Hospital, UK [46]); A Robinson, P Leonard
(Southend Hospital, UK [45]); N J Hodson, M Wilkins, A Webb,
G Newman, G P Deutsch (Royal Sussex County Hospital, Brighton, UK
[45]); A O’Callaghan, G Khoury (Portsmouth Oncology Centre, UK [40]);
J Bridgewater, S Karp (North Middlesex Hospital, UK [38]); S Gollins,
N Stuart (Glan Clwyd Hospital, UK [38]); M Napier, C G Rowland,
D Sheehan, P Bliss, A Hong (Royal Devon and Exeter Hospital, Exeter, UK
[35]); P Mack (Diana Princess of Wales Hospital, Grimsby, UK [35]);
J Ledermann (UCL Hospitals, London, UK [34]); J K Joffe (Huddersfield
Hospital, UK [33); F N Daniel (Derriford Hospital, Plymouth, UK [33]);
P Chakraborti (Derbyshire Royal Infirmary, UK [33]); S M Crawford
(Airedale General Hospital, Keighley, UK [32]); C Wilson, P Corrie
(Addenbrooke’s Hospital, Cambridge, UK [32]); C Bradley (Bradford Royal
Infirmary, UK [30]); D Papamichael (Bank of Cyprus Oncology Centre,
Cyprus [30]); F A Adab (North Staffordshire Royal Infirmary, UK [24]);
A Weaver, A Jones (Churchill Hospital, Oxford, UK [23]); K McAdam,
K Fife (Peterborough District Hospital, UK [22]); I Geh (Birmingham
Heartlands Hospital, UK [22]); B Sizer (Essex County Hospital [20]);
N Bailey (Torbay Hospital, Torquay, UK [19]); T J Iveson (Royal South
Hants Hospital, Southampton, UK [18]); M Soukop, G Wilson, M Gray,
D Dunlop (Glasgow Royal Infirmary, UK [18]); F Lofts (St George’s
Hospital, London, UK [13]); H Yosef (Hairmyres Hospital, East Kilbride,
UK [13]); R Begent, T Meyer, D Hochauser (Royal Free Hospital, London,
UK [11]); S Beesley (Conquest Hospital, St Leonards on Sea, UK [11]);
M J Churn (Kidderminster Hospital, UK [9]); J Glaholm (Good Hope
Hospital, Sutton Coldfield, UK [9]); A T Axford (Bronglais General
Hospital, Aberystwyth, UK [9]); N Stuart (Ysbyty Gwynedd, Bangor, UK [8]);
S Falk (Yeovil Hospital, UK [8]); J Ledermann (Whittington Hospital,
London, UK [8]); D Landau, B Bryant (Queen Elizabeth Hospital,
Woolwich, UK [8]); J M Bozzino (South Tyneside District Hospital, South
Shields, UK [7]); S Tahir (Broomfield Hospital, Chelmsford, UK [6]);
T J Iveson (Salisbury District Hospital, UK [5]); F A Adab (Staffordshire
General Hospital, UK [4]); C S Askill (Singleton Hospital, Swansea, UK
151
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[4]); T Sreenivasan (Scunthorpe General Hospital, UK [4]); R Glynne-Jones
(Mount Vernon Cancer Centre, UK [4]); A Hartley (Manor Hospital,
Walsall, UK [4]); A Gershuny (Oldchurch Hospital, Romford, UK [3]);
R Ellis (Royal Cornwall Hospital, Truro, UK [2]); T Podd, E Sherwin
(Ipswich Hospital, UK [2]); F McKinna (Eastbourne District Hospital, UK
[2]); C Baughan (St Mary’s Hospital, Isle of Wight, UK [1]); N Mithal (Kent
& Canterbury Hospital, UK [1]).
Conflict of interest statement
We declare that we have no conflict of interest. During and subsequent
to the conduct of the trial, MTS, TSM, JAL, CT, RJ, DBS, SS, AM, and
DRF participated in other trials funded or part-funded by the
manufacturers of irinotecan and oxaliplatin, and receive educational
support in the form of travel bursaries or departmental research support.
Acknowledgments
We thank the 2135 patients who participated in FOCUS and the large
number of clinicians, research nurses, data managers, and other clinical
and support staff at the participating centres who contributed. This
research was funded by the UK Medical Research Council. MTS and TSM
are supported by Cancer Research UK. Cancerbackup provided advice and
support with patient information, and a specific booklet about the FOCUS
trial. Principal trial funding was from the UK Medical Research Council
(grant number E164/3). Additional support in the form of discounted
products was provided by Sanofi-Synthelabo, Rhone-Poulenc-Rorer (later
Aventis), Wyeth-Lederle, and Baxter. These companies did not have access
to data, and were not involved in trial design, data collection, the decision
to publish, or the writing of the manuscript.
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