Herceptin and early breast cancer: a moment for caution
Published online November 9, 2005 DOI:10.1016/S0140-6736(05)67670-2
It is no surprise that patients with cancer, together with
leading cancer charities, are calling for the faster
approval of drugs they see as life saving. One UK
charity, Cancer Bacup, has identified a “dossier of delay”
in current procedures. The chief culprit in Britain is said
to be the National Institute for Health and Clinical
Excellence (NICE). The story is not so simple.
Under considerable political and media pressure, NICE
and the Department of Health last week announced the
launch of a rapid process for assessing new and
potentially life-saving medicines. Five drugs have been
targeted for fast-track: trastuzumab (Herceptin), docetaxel,
and paclitaxel for breast cancer; rituximab for
non-Hodgkin’s lymphoma; and bortezomib for
multiple myeloma. While these developments show
commendable responsiveness to public concern, they
must not be allowed to undermine NICE’s hard-won
and well-deserved reputation for independence and
scientific rigour. Herceptin is a case in point.
In March, 2002, NICE recommended Herceptin for
use in women with HER2-positive advanced breast
cancer, either alone or in combination with paclitaxel.
The process leading to this decision was criticised for
taking too long. NICE justified its timing by pointing
out the need for careful and thoughtful scrutiny of the
available data by an independent advisory committee.
NICE’s principal concern was to provide reliable advice.
Their spokeswoman noted that, “we felt it right that we
allow the independent committee that advises NICE
the time it needed to analyse and consider this evidence
before they gave us their final advice”. This view is
surely correct. Whatever the sense of urgency, it is
crucial that NICE resists pressure to make expedient
Three years on, a similar but even more intense
debate surrounds the use of Herceptin for early breast
cancer. Promising results were initially presented at this
year’s American Society of Clinical Oncology annual
meeting. An immediate wave of demand for Herceptin
grew, despite the fact that the drug was not only
unlicensed for this indication but also that its
manufacturer, Roche, had not even submitted data for
the drug’s approval. Some countries, such as France,
bypassed their official approvals procedure to make
Herceptin available. In October, these studies were
finally reported in the New England Journal of Medicine.
In an accompanying editorial, Dr Gabriel Hortobagyi
described the results as “simply stunning” and
“revolutionary”. He even went so far as to say that
Herceptin was “maybe even a cure” for breast cancer.
Naturally this comment was picked up and repeated
across the world, fuelling demand for rapid access to
Herceptin. The excitement is premature.
The studies so far reported represent interim efficacy
analyses. As Victor Montori and colleagues advised in
last week’s JAMA, such analyses may “show implausibly
large treatment effects”. They recommend that
“clinicians should view the results of such trials with
scepticism”. The two NEJM reports use different dosing
regimens, making comparisons and conclusions
additionally more difficult. It is especially hard to tease
apart the results because one of the papers combines
results from two trials sponsored by Genentech.
Although the “joint analysis was developed and
analysed” by both trial teams, it is not made clear
whether this synthesis was planned in advance of the
start of both trials. The report merely notes that the US
FDA and National Cancer Institute approved the joint
analysis plan, which may reflect the expectation that
neither trial alone would demonstrate a positive result.
Comparisons are further hampered by the omission of
crucial overall and disease-free survival data, as well as
information on cardiotoxicity. However, it is clear that
Herceptin can precipitate severe heart failure in some
patients. The best that can be said about Herceptin’s
efficacy and safety for the treatment of early breast
cancer is that the available evidence is insufficient to
make reliable judgments. It is profoundly misleading to
suggest, even rhetorically, that the published data may
be indicative of a cure for breast cancer.
Drug regulatory agencies and bodies such as NICE
play an important part in translating research evidence
into clinical guidance. It is vital that their decisions are
made carefully after considering the totality of available
evidence. They must be free from political, special
interest, or media influence, no matter how well
meaning. The debate about the availability of Herceptin
to women with early breast cancer demands cooler
heads than have so far prevailed, in politics, in public,
and even in medical journals. The Lancet