solution has been shown to not work repeatedly and over a long period of
time, would you keep using it? Probably not. That exact thing is happening
with chemotherapy in cancer treatment, however.
chemo drugs get approved based on comparably short studies that show they
can reduce tumors. But will they also increase survival? It takes much more
time to find out, and so it takes time until these life expectancy studies
come out and are published. They have two advantages:
they are usually independent studies, while the studies that get the drug
approved are paid by the pharmaceutical companies that want to get it approved.
they look at survival, rather than some intermediate treatment point (such
as tumor shrinking), and survival together with quality of life is the only
thing that really matters. And what chemo does to quality of life is commonly
what these survival studies show, and have invariably shown for the past
40 years since the "war on cancer" has started, is: chemo is largely
new article in the British Medical Journal (BMJ) called "Cancer Drugs,
Survival and Ethics" (article at end of this page) sheds some light
on the situation (www.bmj.com/content/355/bmj.i5792):
Among solid tumors, there are five for which there is a significant benefit
from chemo (though far from being a cure, with 5 year survival rates increasing
between 8.8% and 40%): testicular cancer (40%), Hodgkin’s disease
(37%), cancer of the cervix (12%), lymphoma (10.5%), and ovarian cancer
all other solid tumors, chemo is largely useless and contributes additional
survival of between 1 and 2 months -- on average. Some treatments may
even shorten the life expectancy.
statistics suggest that 5 year survival rates have increased over the
past 40 years. The biggest part of that, however, is that cancers are
diagnosed at earlier stages thanks to better diagnostics. Of course 5
year survival is better when the cancer is detected earlier in the process.
if chemo was effective, it is a fundamental ethical question whether $100,000
or $200,000 or more should be spent on a treatment when with the same money
in prevention or other places, many more lives could be saved. But when
for those giant sums of money that are being spent on chemo, the result
is close to non-existent, then it becomes frivolous.
is the upshot? -- When faced with the option of chemo, first and foremost
be aware that it is not working, no matter what your doctor might tell you.
Doctors usually do not understand statistics and if they do, they often
do not read the studies that would reveal that it is not working. Doctors
fall for the drug companies' PR and think that "while it is not a perfect
solution, at least there is something we can do". And they see the
tumors shrinking, thinking the treatment works, but they don't know what
that will do to life expectancy.
at the actual data that is available. Don't buy into the sweet talk. Look
at the numbers. Are there studies about survival and what do they say? If
your cancer is not one of the five mentioned above, then you can be pretty
certain that any chemo offered to you is not going to do anything for you.
argument that "there is nothing else we can do" is no logical
reason to do something you already know is ineffective. It is like in the
anecdote of Nasruddin looking for his car key under the street light. When
someone asked whether he was sure that he lost the key about there he, replied
"no, I lost it somewhere else, but it's easier to search here in the
light". Doing something known to be ineffective because no other solution
comes to mind is terrible logic.
selling point is that "maybe these older treatments didn't work, but
now there is a new drug that is much better", don't buy it unless survival
data is available. This promise has been made for 40 years and has never
borne out with the few exceptions mentioned above.
look into the options you do have. It won't surprise you that I am a proponent
of Dr. Clark's protocol, being that I have spent 20 years working with it,
but there are many options out there and your doctor will probably not know
any of them. As an example, vitamin C infusion therapy has been described
by Nobel Prize laureate Linus Pauling in the 70ies and shown to be extremely
effective, and that still holds true.
Cancer Requires New Kind Of Thinking read
Drugs, Survival, and Ethics
BMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i5792 (Published 09 November
Cite this as: BMJ 2016;355:i5792
Peter H Wise, former consultant physician and senior lecturer
Accepted 24 October 2016
considerable investment and innovation, chemotherapy drugs have had little
effect on survival in adults with metastatic cancer. Peter Wise explores
the ethical issues relating to research, regulation, and practice
survival has improved in recent decades. Trends in the US show that five
year relative survival in adults with solid cancer has increased from 49%
to 68% over 40 years.1 There have been important advances in chemotherapy
in recent years, including for melanoma, medullary thyroid cancer, and prostate
cancer. Immunotherapy, together with targeted and precision (personalised)
approaches guided by patient and tumour biomarkers, also produces benefit
in subgroups of the more common cancers.2 But how much of the improvement
in cancer survival can we attribute to drugs?
published in 2004 explored the contribution of cytotoxic chemotherapy to
five year survival in 250,000 adults with solid cancers from Australian
and US randomised trials.3 An important effect was shown on five year survival
only in testicular cancer (40%), Hodgkin’s disease (37%), cancer of
the cervix (12%), lymphoma (10.5%), and ovarian cancer (8.8%). Together,
these represented less than 10% of all cases. In the remaining 90% of patients—including
those with the commonest tumours of the lung, prostate, colorectum, and
breast—drug therapy increased five year survival by less than 2.5%—an
overall survival benefit of around three months.3 Similarly, 14 consecutive
new drug regimens for adult solid cancers approved by the European Medicines
Agency provided a median 1.2 months overall survival benefit against comparator
regimens.4 Newer drugs did no better: 48 new regimens approved by the US
Food and Drug Administration between 2002 and 2014 conferred a median 2.1
month overall survival benefit.5 Drug treatment can therefore only partly
explain the 20% improvement in five year survival mentioned above. Developments
in early diagnosis and treatment may have contributed much more.6
approval of drugs with such small survival benefits raises ethical questions,
including whether recipients are aware of the drugs’ limited benefits,
whether the high cost:benefit ratios are justified, and whether trials are
providing the right information.
most 3% of adult cancer patients participate in trials,7 and given the many
new drugs and regimens, greater enrolment is a constant aim. Since they
are mostly financed by the drug industry, trials can significantly reduce
national expenditure on cancer drugs at a time of escalating global costs
(around $110bn (£85bn; $95bn) was spent on cancer drugs in 2015).8
Trials also allow patients the opportunity of having otherwise unavailable
or unaffordable treatment under close supervision of a trial centre, although
most studies show that patients do not realise that participating in a trial
will primarily benefit others.9 An unethical pressure to enrol is reflected
by several studies showing that up to half of patients in cancer drug trials
were led to believe that such participation was their only option.9
we cannot infer that the benefits seen in the small number of trial participants
will be replicated in the 97% or more outside trial centres, where staffing,
procedure, and facilities might be different. Although there are a few reports
of similar outcomes in patients inside and outside trials, the uncontrolled
nature of those studies and non-homogeneous patient characteristics do not
allow a wider scale assumption of similarity.10
previous university based trial procedures, pharma now outsources many trials
to commercial contract research organisations (CROs), responsible only to
the company that hires them. A recent WHO supported Dutch study concluded
that many such trials “place patients at ethical risk.”11
agreed primary response marker of overall survival—the time from drug
assignment to death from any cause—is meaningful and, most importantly,
understandable by patients. However, to shorten trial duration, minimise
the number of trial participants, and enable rapid access of drugs to the
market, many trials use surrogate endpoints. These include overall response
rate, early tumour shrinkage, and, most commonly, progression-free survival
(time from assignment to progressive disease or death from any cause). These
endpoints are imaging based and more rapidly available but, with some exceptions,
have been shown to correlate poorly with overall survival.12
drugs approved on the basis of better progression-free survival have been
subsequently found not to produce better overall survival than the comparator
drug.14 Some of these drugs are logically withdrawn but others remain inexplicably
on the market.15
endpoints are also used by the FDA and EMA for accelerated and conditional
approval, respectively, of what are judged to be urgently needed new drugs.
A 2010 FDA review revealed that 45% of cancer drugs given accelerated approvals
were not granted full approval, either because subsequent trials failed
to confirm effectiveness or because the results of trials were not submitted.16
One reason may be the industry's reluctance to communicate negative results17
(heavy penalties for delayed or absent submission of confirmatory
trial results have only recently been introduced). Bearing in mind the usually
marginal survival benefits, any haste for approval is only occasionally
FDA’s decision to introduce a “breakthrough” category
in 2012 compounds the risks of premature approval on limited evidence.18
The pressure for early approval is enhanced by lobbying from patient
advocacy groups, prompted by industry and with often premature media announcements
of drugs that are “game changing,” “groundbreaking,”
“revolutionary,” “miracle,” or other unjustifiable
superlatives. The risky practice of approval before proof gains even more
of life assessments increasingly form part of cancer drug trials. However,
many evaluations are invalidated by selective use of questionnaire items
and time points to demonstrate drug benefit,19 together with frequent “drop
out” of patients, inability or refusal to answer questionnaires, and
other causes of missing data. Few studies show anything more than small
and transient improvements in quality of life from chemotherapy, mostly
reflecting temporary tumour shrinkage.
low threshold of approval (efficacy bar) for these expensive drugs ignores
the ethical principle of fairness and equity.20 By promoting treatment of
poorly responsive cancers it denies valuable resources to early diagnosis
approaches and other health needs. Generous approval may benefit some patients,
but it also helps pharma and government to profit. Corporate taxation of
30-35% on cancer industry’s average 22% profit margins on $50bn national
drug sales21 yielded the US government alone an estimated $3.8bn in 2015.
further doubtfully ethical practice of regulatory capture22 industry attracts
former staff from regulatory agencies to help perfect new applications and
so smooth their transit.23 Thus the regulator risks being regulated by the
industry that it has been appointed to regulate. This so called revolving
door phenomenon has proved difficult to eliminate, as is the case with other
the National Institute of Health and Care Excellence (NICE) has now taken
control of the Cancer Drugs Fund, which enables individual patients to receive
funding for drugs not routinely paid for by the NHS.24 The fund had been
criticised for poor monitoring of performance, spiralling annual costs (over
£300m), and inappropriate approvals. NICE is highly cost aware, and
it is to be hoped that a less permissive approval principle will evolve.
Evaluations using the European Society of Medical Oncology's clinical benefit
scale should also help to clarify ethically important cost-benefit relations25
in order to achieve the same aim.
post-approval “real world” evaluation of cancer drugs would
be an important step forward. Together with industry, the integration of
the Cancer Drugs Fund into NICE could facilitate a systematic and highly
relevant national assessment of the community’s benefit from cancer
and middle income countries, funding drugs for a rapidly increasing incidence
of cancer is even more difficult. With cost:benefit ratios probably even
higher, it remains to be seen how valuable the cancer drugs from the World
Health Organization’s recently published essential medicines list
prove to be.26
the US, cancer treatment now represents a major cause of personal bankruptcy.27
Cancer drugs have a greater imbalance of risks and benefits than many surgical
procedures and therefore warrant a consent document. However, this is often
not issued or signed.28 Furthermore, consent is valid only if it relates
to the individual information discussed with that patient20—which
is usually even less well documented.
are few data on patients’ awareness of cancer drug effectiveness or
the incidence and potential severity of their side effects. Many are likely
to be unaware of the 80% risk of diverse side effects, of which up to 64%
are serious (grades 3-4).29 There is also a drug and disease dependent risk
of death from treatment itself, especially in the first month of therapy.30
Nor are patients likely to be informed of the increased risk of dying in
hospital compared with patients receiving only supportive care.31 This is
important, since studies show that most patients prefer to end their lives
in their own homes or hospices rather than in hospital.32 Unawareness of
poor treatment outcomes leads patients to only rarely question a physician’s
proposal for chemotherapy.33
overestimate potential drug benefits. In an important multicentre study,
almost 75% of 1200 patients with metastatic colorectal and lung cancers
considered it likely that their cancers would be cured by chemotherapy.34
Yet a cure in these situations is virtually unknown. In another study of
decision making discussions about chemotherapy between doctors and patients,
survival issues were considered to have been properly covered in only 30%.35
Dutch and Australian studies have found that the option of supportive care
is raised in only one quarter of oncologist consultations,33 36 probably
because of patient and family expectations of active treatment. Physicians
also have competing interests; known to influence the choice of drug and
even a decision on whether to treat.37 Yet supportive care can extend life
and enhance its quality, especially if introduced early.38
consent is clearly a complex process extending far beyond the signed consent
form.39 It should follow discussions based on balanced and fully documented
verbal and written information, which perhaps would be more ethically provided
by independent trained counsellors less exposed to competing interests.20
Patients should be fully empowered by discussion and subsequent triage to
receive cancer drugs, to enrol in a clinical trial, or to accept best supportive
care—realising that a decision not to have drug treatment (often referred
to pejoratively as refusal) is ethically and morally appropriate.20 In one
study of 128 people with lung cancer, around a third of patients wished
to share decision making, yet were poorly catered for.40
search of ethics
irregularities and competing interests—in pharma, in trials, in government
approval, and in the clinical use of cancer drugs—impact ethically
on the care and costs of patients with cancer. Non-representative clinical
trials with imprecise endpoints and misinformed patients with unrealistic
expectations compel interventions that are mostly not in their best interests.
Spending a six figure sum to prolong life by a few weeks or months is already
unaffordable, and inappropriate for many of the 20% of the (Western) population
who will almost inevitably die from solid tumour metastases.
cancer care demands empowerment of patients with accurate, impartial information
followed by genuinely informed consent in both the clinical trial and therapeutic
settings. Intensified prevention, earlier detection, more prompt and radical
treatment of localised and regional disease, together with highly skilled,
earlier, supportive care are the important yet underfinanced priorities
in cancer control. Ethical impediments to sound practice need to be addressed
and corrected. Above all, the efficacy bar for approval needs to be raised
for both new and existing cancer drugs41 —by using more meaningful
statistical and disease specific criteria of risk-benefit and cost-benefit.25
Finally, aggressively targeting the less than ethical actions of stakeholders
in the heavily veiled medical-industrial complex may be the only way forward:
current market driven rather than health driven priorities and practices
do not benefit cancer patients.
in chemotherapy have contributed little to population cancer survival
in clinical trials may not apply to patients treated in the community
outside trial centres is essential to ensure that scarce resources are
approval criteria are needed to achieve ethical treatment and reduce cancer
informed consent and empowerment of patients must be promoted
Contributors and sources: PHW has had a career long involvement with medical
ethics, including major responsibilities to research, ethical, and drug
evaluation committees at hospital, university and government levels in Australia
and the UK. He represented the Royal College of Physicians for many years
on the clinical research ethics committee of the Royal College of General
Practitioners, London, latterly as its vice chairman. As an endocrinologist
and researcher, he has a particular interest in paraneoplastic endocrinopathies,
which has brought him into contact with many patients with advanced cancer.
interests: I have read and understood BMJ policy on declaration of interests
and declare that I have no competing interests.
and peer review: Not commissioned; externally peer reviewed.
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