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AUSTRALIAN ONCOLOGISTS CRITICIZE CHEMOTHERAPY
An important paper has been published in the journal
Clinical Oncology. This meta-analysis, entitled "The
Contribution of Cytotoxic Chemotherapy to 5-year
Survival in Adult Malignancies" set out to
accurately quantify and assess the actual benefit
conferred by chemotherapy in the treatment of adults
with the commonest types of cancer. Although the
paper has attracted some attention in Australia, the
native country of the paper's authors, it has been
greeted with complete silence on this side of the
world.
All three of the paper's authors are oncologists.
Lead author Associate Professor Graeme Morgan is a
radiation oncologist at Royal North Shore Hospital
in Sydney; Professor Robyn Ward is a medical
oncologist at University of New South Wales/St.
Vincent's Hospital. The third author,
Dr. Michael
Barton, is a radiation oncologist and a member of
the Collaboration for Cancer Outcomes Research and
Evaluation, Liverpool Health Service, Sydney. Prof.
Ward is also a member of the Therapeutic Goods
Authority of the Australian Federal Department of
Health and Aging, the official body that advises the
Australian government on the suitability and
efficacy of drugs to be listed on the national
Pharmaceutical Benefits Schedule (PBS) – roughly the
equivalent of the US Food and Drug Administration.
Their meticulous study was based on an analysis of
the results of all the randomized, controlled
clinical trials (RCTs) performed in Australia and
the US that reported a statistically significant
increase in 5-year survival due to the use of
chemotherapy in adult malignancies. Survival data
were drawn from the Australian cancer registries and
the US National Cancer Institute's Surveillance
Epidemiology and End Results (SEER) registry
spanning the period January 1990 until January 2004.
Wherever data were uncertain, the authors
deliberately erred on the side of over-estimating
the benefit of chemotherapy. Even so, the study
concluded that overall, chemotherapy contributes
just over 2 percent to improved survival in cancer
patients.
Yet despite the mounting evidence of chemotherapy's
lack of effectiveness in prolonging survival,
oncologists continue to present chemotherapy as a
rational and promising approach to cancer treatment.
"Some practitioners still remain optimistic that
cytotoxic chemotherapy will significantly improve
cancer survival," the authors wrote in their
introduction. "However, despite the use of new and
expensive single and combination drugs to improve
response rates...there has been little impact from
the use of newer regimens" (Morgan 2005).
The Australian authors continued: "...in lung
cancer, the median survival has increased by only 2
months [during the past 20 years, ed.] and an
overall survivalbenefit of less than 5 percent has been achieved in
the adjuvant treatment of breast, colon and head and
neck cancers."
The results of the study are summarized in two
tables.
Table 1 shows the results
for Australian patients;
Table 2 shows the results
for US patients.
The authors point out that the
similarity of the figures for Australia and the US
make it very likely that the recorded benefit of 2.5
percent or less would be mirrored in other developed
countries also.
Basically, the authors found that the contribution
of chemotherapy to 5-year survival in adults was 2.3
percent in Australia, and 2.1 percent in the USA.
They emphasize that, for reasons explained in detail
in the study, these figures "should be regarded as
the upper limit of effectiveness" (i.e., they are an
optimistic rather than a pessimistic estimate).
Understanding Relative Risk
How is it possible that patients are routinely
offered chemotherapy when the benefits to be gained
by such an approach are generally so small? In their
discussion, the authors address this crucial
question and cite the tendency on the part of the
medical profession to present the benefits of
chemotherapy in statistical terms that, while
technically accurate, are seldom clearly understood
by patients.
For example, oncologists frequently express the
benefits of chemotherapy in terms of what is called
"relative risk" rather than giving a straight
assessment of the likely impact on overall survival.
Relative risk is a statistical means of expressing
the benefit of receiving a medical intervention in a
way that, while technically accurate, has the
effect of making the intervention look considerably
more beneficial than it truly is. If receiving a
treatment causes a patient's risk to drop from 4
percent to 2 percent, this can be expressed as a
decrease in relative risk of 50 percent. On face
value that sounds good. But another, equally valid
way of expressing this is to say that it offers a 2
percent reduction in absolute risk, which is less
likely to convince patients to take the treatment.
It is not only patients who are misled by the
overuse of relative risk in reporting the results of
medical interventions. Several studies have shown
that physicians are also frequently beguiled by this
kind of statistical sleight of hand. According to
one such study, published in the British Medical
Journal, physicians' views of the effectiveness of
drugs, and their decision to prescribe such drugs,
was significantly influenced by the way in which
clinical trials of these drugs were reported. When
results were expressed as a relative risk reduction,
physicians believed the drugs were more effective
and were strongly more inclined to prescribe than
they were when the identical results were expressed
as an absolute risk reduction (Bucher 1994).
Another study, published in the Journal of Clinical
Oncology, demonstrated that the way in which
survival benefits are presented specifically
influenced the decision of medical professionals to
recommend chemotherapy. Since 80 percent of patients
chose what their oncologist recommends, the way in
which the oncologist perceives and conveys the
benefits of treatment is of vital importance. This
study showed that when physicians are given relative
risk reduction figures for a chemotherapy regimen,
they are more likely to recommend it to their
patients than when they are given the mathematically
identical information expressed as an absolute risk
reduction (Chao 2003).
The way that medical information is reported in the
professional literature therefore clearly has an
important influence on the treatment recommendations
oncologists make. A drug that can be said, for
example, to reduce cancer recurrence by 50 percent,
is likely to get the attention and respect of
oncologists and patients alike, even though the
absolute risk may only be a small one - perhaps only
2 or 3 percent - and the reduction in absolute risk
commensurately small.
To their credit, the Australian authors of the study
on the effectiveness of chemotherapy address the
issue of relative versus absolute risk. They suggest
that the apparent gulf between the public perception
of chemotherapy's effectiveness and its actual
mediocre track record can largely be attributed to
the tendency of both the media and the medical
profession to express efficacy in terms of relative
rather than absolute risk.
"The minimal impact on survival in the more common
cancers conflicts with the perceptions of many
patients who feel they are receiving a treatment
that will significantly enhance their chances of
cure," the authors wrote. "In part this represents
the presentation of data as a reduction in risk
rather than as an absolute survival benefit and by
exaggerating the response rates by including 'stable
disease.'"
As an example of how chemotherapy is oversold, they
cite the treatment of breast cancer. In 1998 in
Australia, out of the total of 10,661 women who were
newly diagnosed with breast cancer, 4,638 women were
considered eligible for
chemotherapy. Of these 4,638 women, only 164 (3.5
percent) actually gained some survival benefit from
chemotherapy. As the authors point out, the use of
newer chemotherapy regimens including the taxanes
and anthracyclines for breast cancer may raise
survival by an estimated additional one percent –
but this is achieved at the expense of an increased
risk of cardiac toxicity and nerve damage.
"There is also no convincing evidence," they write,
"that using regimens with newer and more expensive
drugs is any more beneficial than the regimens used
in the 1970s." They add that two systematic reviews
of the evidence been not been able to demonstrate
any survival benefit for chemotherapy in recurrent
or metastatic breast cancer.
Another factor clouding the issue is the growing
trend for clinical trials to use what are called
'surrogate end points,' as a yardstick by which to
measure a chemotherapy regimen's effectiveness. This
is instead of using the only real measures that
matters to patients – prolongation of life as
measured by overall survival and improved quality of
life. Surrogate end points such as 'progression-free
survival,' 'disease-free survival' or
'recurrence-free survival' may only reflect
temporary lulls in the progression of the disease.
Such temporary stabilization of disease, if it
occurs at all, seldom lasts for more than a few
months at best. The cancer typically returns,
sometimes with renewed vigour, and survival is not
generally extended by such interventions. However,
trials reported in terms of surrogate end points can
create the illusion that the lives of desperately
ill patients are being significantly extended or
made more bearable by chemotherapy, when in reality
this is not the case.
In summary, the authors state:
"The introduction of cytotoxic chemotherapy for
solid tumours and the establishment of the
sub-specialty of medical oncology have been accepted
as an advance in cancer management. However, despite
the early claims of chemotherapy as the panacea for
curing all cancers, the impact of cytotoxic
chemotherapy is limited to small subgroups of
patients and mostly occurs in the less common
malignancies."
Splitting Hairs
In view of the highly controversial nature of the
study's findings, one might have expected it to
receive enormous international attention. Instead,
media reaction has been largely limited to the
authors' native land of Australia; the study
received almost no coverage whatsoever in the US. In
fact, although the paper appeared in December 2004,
there was limited coverage even Down Under. The
authors were interviewed for the Australian
Broadcasting Corporation (ABC) program The Health
Report in April 2005. But their landmark paper did
not come to most doctors' attention until a widely
distributed medical practice periodical, the
Australian Prescriber, ran an editorial on the study
early in 2006.
On ABC's The Health Report, Prof. Morgan, the
paper's principal author, reiterated the study's
conclusions that chemotherapy had been oversold, and
pointed to the fact that relative risk reduction is
being used as the yardstick of efficacy, with its
deceptively large percentage differences.
For balance, the show host, Norman Swan, interviewed
Prof. Michael Boyer, chief of medical oncology at
Australia's Royal Prince Albert Hospital, Sydney.
Unable to deny the validity of the study's essential
findings, Prof. Boyer instead attempted to nitpick
the authors' methodology. He suggested that the
figure for chemotherapy's efficacy was actually
somewhat higher than the study had concluded. Yet
even so, when pushed, the most favourable figure he
could come up with was that chemotherapy might
actually be effective in 5 or 6 percent of cases
(instead of around 2 percent).
Interviewed by Australian Prescriber, Prof. Boyer
similarly commented: "If you start...saying how much
does chemotherapy add in the people that you might
actually use it [in], the numbers start creeping
up...to 5 percent or 6 percent" (Segelov 2006).
In my opinion, this sort of hair-splitting damns
chemotherapy with faint praise. It actually confirms
the central message of the three critics' study. If
the best defence of chemotherapy that orthodox
oncology can come up with is that it may actually be
effective for 5 or 6 percent of cancer patients,
rather than merely 2 percent, then surely it is high
time for a radical reassessment of the widespread
use of this toxic modality in cancer treatment.
Either figure - 2 percent or 6 percent - will come
as a shock to most patients offered this type of
treatment, and ought to generate serious doubt in
the minds of oncologists as to the ethics of
offering chemotherapy without explicitly warning
patients of its unlikely prospects for success.
It was also astonishing that the orthodox Prof.
Boyer complained that one of the major shortcomings
of the study was that it insisted on measuring
absolute instead of relative benefits. Asked by the
interviewer whether there weren't violations of
informed consent implicit in the way that benefits
of treatment were usually presented, Prof. Boyer
defended the use of the more impressive-sounding
relative risk reduction:
"One of the problems of this [Morgan, ed.] paper is
it uses absolute benefits rather than relative
benefits," he protested: "...the relative benefit is
about a one third reduction in your risk of death."
This, of course, is precisely the reverse of the
argument made by the study's authors, who clearly
demonstrated the misleading nature of relative risk
reduction as a means of describing the efficacy of
chemotherapy.
Other Critics Emerge
Prof. Morgan and his Australian colleagues are not
alone in criticizing the pervasive use of relative
risk as a means of inflating treatment efficacy.
There have been others in recent years who have also
voiced concern about this trend. For example, in a
letter to the editor of the medical practice journal
American Family Physician, James McCormack, PharmD,
a member of the faculty of Pharmaceutical Sciences,
University of British Columbia, made this same point
about relative vs. absolute risk with great clarity.
Dr. McCormack took as an example the prescription of
the bisphosphonate drugs in the treatment and
prevention of osteoporosis...but identical issues
apply to the use of anticancer drugs. The journal in
question had written that one of those drugs
produced
almost "a 50 percent decrease" in the risk of new
fractures. Addressing himself to a hypothetical
patient, Dr. McCormack reinterpreted this statement
in terms of absolute risk: "Mrs. Jones, your risk of
developing a...fracture over the next three years is
approximately 8 percent. If you take a drug daily
for the next three years, that risk can be reduced
from 8 percent to around 5 percent, or a difference
of just over 3 percent." Of course that sounds far
less impressive than saying that taking the drug
will decrease the risk of fracture by almost half,
even though technically both are mathematically
accurate ways of expressing the benefit to be gained
by the therapy.
The Good News and the Bad
News concerning conventional cancer treatments seems
to come in two varieties: good and bad. Good news,
meaning that conventional treatments work well,
often generates widespread press coverage and
enthusiastic statements from health officials. On
the other hand, bad news, such as the fact that
conventional treatments have generally been
oversold, usually comes and goes unseen, attracting
no media attention whatsoever.
An example of the first kind is the recent
announcement that for the first time in 70 years,
the absolute number of US cancer deaths had fallen.
Andrew C. von Eschenbach, MD, director of the US
National Cancer Institute (NCI), called this
"momentous news." Similarly, Dr. Michael Thun, head
of epidemiological research for the American Cancer
Society, said it was "a notable milestone." How big
was the celebrated decline? As we reported in a
recent newsletter, deaths actually fell by a total
of 370, from 557,272 in 2003 to 556,902 in 2004.
Expressed as a percentage of the total, it
represents a drop of seven hundredths of one percent
(0.066 percent).
Contrast the wildly enthusiastic coverage given to
this tiny improvement in the annual cancer death
rate with the almost total media blackout (at least
in North America) on this critical paper from
Australia. Yet nothing can obscure the fact that
chemotherapy, for most indications, has far less
effectiveness than the public is being led to
believe. Dr. Morgan and his colleagues deserve every
reader's gratitude for having pointed this out to
their colleagues around the world.
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