The use of irinotecan, oxaliplatin and
raltitrexed for the treatment of
advanced colorectal cancer: systematic
review and economic evaluation
D Hind,*P Tappenden, I Tumur, S Eggington,
P Sutcliffe and A Ryan
School of Health and Related Research (ScHARR),
University of Sheffield, UK
* Corresponding author
Health Technology Assessment
NHS R&D HTA Programme
Health Technology Assessment 2008; Vol. 12: No. 15
The use of irinotecan, oxaliplatin and raltitrexed for the
treatment of advanced colorectal cancer
The objective of this study were to evaluate three
technologies for the management of advanced
colorectal cancer: (1) first-line irinotecan
combination [with 5-fluorouracil (5-FU)] or
second-line monotherapy; (2) first or second-line
oxaliplatin combination (again, with 5-FU); and
(3) raltitrexed, where 5-FU is inappropriate. The
study also examined the role of irinotecan and
oxaliplatin in reducing the extent of incurable
disease before curative surgery (downstaging).
Searches in ten electronic bibliographic databases
identified existing studies of the effectiveness and
economics of the technologies. Studies that
evaluated any of the indications outlined above
were included. Two reviewers independently
extracted data and assessed generic components
of methodological quality. Survival outcomes were
Seventeen trials were found, of varying
Caveat: over half of first-line trial participants
across all studies, except for two, were treated with
unplanned second-line therapies (a confounding
factor); estimates of overall survival (OS) should be
read with caution. Trial data are based on
atypically young populations, but available
evidence suggests no difference in the efficacy or
toxicity of combination therapy in older people.
Compared with 5-FU, first-line irinotecan
improved OS by 2–4 months (p = 0.0007),
progression-free survival (PFS) by 2–3 months
(p < 0.00001) and response rates (p < 0.001). It
offered a different toxicity profile and no quality
of life (QoL) advantage.
Compared with 5-FU, second-line irinotecan
improved OS by 2 months (p = 0.035) and PFS by
1 month (p = 0.03), and provided a better partial
response rate, but with more toxicities and no
Compared with second-line best supportive care,
irinotecan improved OS by 2 months (p = 0.0001),
had a different toxicity profile and maintained
baseline quality of life longer, but with no overall
The addition of oxaliplatin to first-line 5-FU was
associated with no difference in OS (see caveat),
improved PFS (p < 0.00001), higher response
rates (p < 0.0001), more gastrointestinal and
haematological toxicities, and no QoL advantage.
Schedules with treatment breaks may not reduce
clinical effectiveness but reduce toxicity.
The addition of oxaliplatin to second-line 5-FU is
associated with a borderline significant
improvement in overall survival (p < 0.07); a
significantly higher response rate (<0.0001); and
more serious toxicities. There is no evidence for a
significant difference in QoL.
There was no significant difference in OS or PFS
between first-line irinotecan and oxaliplatin
combinations except when 5-FU was delivered by
bolus injection, when oxaliplatin provided better
OS (p = 0.032) and response rates (p = 0.032),
but not PFS (p = 0.169). The regimens had
different toxicity profiles and neither conferred a
When compared to 5-FU, raltitrexed is associated
with no significant difference in overall or
progression-free survival; no significant difference
in response rates; more vomiting and nausea, but
less diarrhoea and mucositis; no significant
difference in, or worse QoL. Raltitrexed treatment
was cut short in two out of four included trials due
to excess toxic deaths.
5-FU followed by irinotecan was inferior to any
other sequence. First-line irinotecan/5-FU
combination improved OS and PFS, although
further unplanned therapy exaggerated the OS
effect size. Staged combination therapy
(combination oxaliplatin followed by combination
irinotecan or vice versa) provided the best OS and
PFS, although there was no head-to-head
Executive summary: The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer
comparison against other treatment plans. In the
only trial to use three active chemotherapies in
any staged combination, median OS was over
20 months. In another study, the longest median
OS from a treatment plan using two active agents
was 16.2 months.
Where irinotecan or oxaliplatin were used with
5-FU to downstage people with unresectable liver
metastases, studies consistently showed response
rates of around 50%. Resection rates ranged from
9 to 35% with irinotecan and from 7 to 51% with
oxaliplatin. In the one study that compared the
regimens, oxaliplatin enabled more resections
(p = 0.02). Five-year OS rates of 5–26% and
disease-free survival rates of 3–11% were reported
in studies using oxaliplatin.
Alone or in combination, 5-FU was more effective
and less toxic when delivered by continuous
Existing economic models were weak because of
the use of unplanned second-line therapies in
their trial data: the survival benefits in patients on
such trials cannot be uniquely attributed to the
allocated therapy. Consequently, the economic
analyses are either limited to the use of PES
(at best, a surrogate outcome) or are subject to
confounding. Weaknesses in cost components, the
absence of direct in-trial utility estimates and the
limited use of sensitivity analysis were identified.
Improvements to the methodologies used in
existing economic studies are presented. Using
data from two trials that planned treatment
sequences, an independent economic evaluation of
six plans compared with first-line 5-FU followed
on progression by second-line irinotecan
monotherapy (NHS standard treatment) is
5-FU followed on progression by irinotecan
combination cost £13,174 per life-year gained
(LYG) and £10,338 per quality-adjusted life-year
(QALY) gained. Irinotecan combination followed
on progression by additional second-line therapies
was estimated to cost £12,418 per LYG and
£13,630 per QALY gained. 5-FU followed on
progression by oxaliplatin combination was
estimated to cost £23,786 per LYG and £31,556
per QALY gained. Oxaliplatin combination
followed on progression by additional second-line
therapies was estimated to cost £43,531 per LYG
and £67,662 per QALY gained. Evaluations
presented in this paragraph should be interpreted
with caution owing to missing information on the
costs of salvage therapies in the trial from which
data were drawn.
Irinotecan combination followed on progression
by oxaliplatin combination cost £12,761 per LYG
and £16,663 per QALY gained. Oxaliplatin
combination followed on progression by irinotecan
combination cost £16,776 per LYG and £21,845
per QALY gained. The evaluation suggests that
these two sequences have a cost-effectiveness
profile that is favourable in comparison to other
therapies currently funded by the NHS. However,
the differences in OS observed between the two
trials from which data were taken may be a result
of heterogeneous patient populations, unbalanced
protocol-driven intensity biases or other
differences between underlying health service
Treatment with three active therapies appears
most clinically effective and cost-effective.
Recommendations for research
The collection of routine data from within the
NHS would help to validate the downstaging of
people with liver metastasis. A meta-analysis using
individual patient-level data is also suggested to
validate the optimal treatment sequence and to
provide a baseline against which future treatment
sequences could be compared.
Hind D, Tappenden P, Tumur I, Eggington E,
Sutcliffe P, Ryan A. The use of irinotecan,
oxaliplatin and raltitrexed for the treatment of
advanced colorectal cancer: systematic review and
economic evaluation. Health Technol Assess
Health Technology Assessment 2008; Vol. 12: No. 15 (Executive summary)
NIHR Health Technology Assessment Programme Download full-text
effectiveness, costs and broader impact of health technologies for those who use, manage and provide
care in the NHS. ‘Health technologies’ are broadly defined as all interventions used to promote health,
prevent and treat disease, and improve rehabilitation and long-term care.
The research findings from the HTA Programme directly influence decision-making bodies such as the
National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee
(NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in that
they form a key component of the ‘National Knowledge Service’.
The HTA Programme is needs-led in that it fills gaps in the evidence needed by the NHS. There are
three routes to the start of projects.
First is the commissioned route. Suggestions for research are actively sought from people working in the
NHS, the public and consumer groups and professional bodies such as royal colleges and NHS trusts.
These suggestions are carefully prioritised by panels of independent experts (including NHS service
users). The HTA Programme then commissions the research by competitive tender.
Secondly, the HTA Programme provides grants for clinical trials for researchers who identify research
questions. These are assessed for importance to patients and the NHS, and scientific rigour.
Thirdly, through its Technology Assessment Report (TAR) call-off contract, the HTA Programme
commissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring
together evidence on the value of specific technologies.
Some HTA research projects, including TARs, may take only months, others need several years. They can
cost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence,
undertaking a trial, or other research collecting new data to answer a research problem.
The final reports from HTA projects are peer-reviewed by a number of independent expert referees
before publication in the widely read journal series Health Technology Assessment.
he Health Technology Assessment (HTA) Programme, part of the National Institute for Health
Research (NIHR), was set up in 1993. It produces high-quality research information on the
Criteria for inclusion in the HTA journal series
Reports are published in the HTA journal series if (1) they have resulted from work for the HTA
Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.
Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search,
appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the
replication of the review by others.
The research reported in this issue of the journal was commissioned and funded by the HTA Programme
on behalf of NICE as project number 04/12/01. The protocol was agreed in August 2004. The assessment
report began editorial review in May 2005 and was accepted for publication in October 2005. The
authors have been wholly responsible for all data collection, analysis and interpretation, and for writing
up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report
and would like to thank the referees for their constructive comments on the draft document. However,
they do not accept liability for damages or losses arising from material published in this report.
The views expressed in this publication are those of the authors and not necessarily those of the
HTA Programme or the Department of Health.
Editor-in-Chief: Professor Tom Walley
Series Editors:Dr Aileen Clarke, Dr Peter Davidson, Dr Chris Hyde,
Dr John Powell, Dr Rob Riemsma and Professor Ken Stein
Programme Managers: Sarah Llewellyn Lloyd, Stephen Lemon, Kate Rodger,
Stephanie Russell and Pauline Swinburne
© Queen’s Printer and Controller of HMSO 2008
This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided
that suitable acknowledgement is made and the reproduction is not associated with any form of advertising.
Applications for commercial reproduction should be addressed to: NCCHTA, Alpha House, Enterprise Road, Southampton Science Park,
Chilworth, Southampton SO16 7NS, UK.
Published by Gray Publishing, Tunbridge Wells, Kent, on behalf of NCCHTA.
Printed on acid-free paper in the UK by St Edmundsbury Press Ltd, Bury St Edmunds, Suffolk.