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Cancer 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?
Survival
A meta-analysis 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
The 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. [It is worse than that
because industry-funded trials ALWAYS is distorted to favor industry. The methods
of cheating are shocking, and indicate a very broken system of journal reviews—See Prof. Ben Goldacre’s Bad Pharma]
Cancer trial concerns
At 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).8Trials 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
Furthermore, 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
[The norm is to select an ideal group of patients who show reduced side effects and better outcome—they
are not the real world population.] Bypassing 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 [Most of the CRO studies are done in underdeveloped
nations with language barriers, which permits more room for tobacco-science trials.]
The 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 13
Many 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
Surrogate 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 justified.
The 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 momentum.
Quality 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.
Drug approval
The 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.
In a 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 industry-government interactions.
In England, 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.
More 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 drugs.
In low 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
Inadequate consent
In 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.28Furthermore, consent is valid only if it relates
to the individual information discussed with that patient20—which is usually even less well documented.
There are few data on patients’ awareness of cancer drug [lack of] 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.32Unawareness of poor treatment outcomes leads patients
to only rarely question a physician’s proposal for chemotherapy.33
Patients 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
Informed 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
In search of ethics
Many 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.
Ethical 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.
Key messages
· Advances in chemotherapy have contributed little to population cancer survival
· Responses in clinical trials may not apply to patients treated in the community
· Evaluation outside trial centres is essential to ensure that scarce resources are not squandered
· Stricter approval criteria are needed to achieve ethical treatment and reduce cancer costs
· Ethical informed consent and empowerment of patients must be promoted
Footnotes
·
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.
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Afterword
It is worse than that, they are over overly optimistic: 1) doesn’t
consider long-term survival—past 5 years, 2) the reduced quality of life, 3) short-term
suffering associated with chemo, 4) and that industry funded studies always favors industry (positive bias). It starts with journal articles façade review: they don’t
receive the raw data, only the industry writes of the clinical trial or experiment. For
the common ways they cheat read Ben Goldacre’s “Bad Pharma” or click on my assessments at side effects and marketing science. Over to-thirds of patients do not have metastatic cancer, and thus excision
has assured their survival; thus the chemotherapy being of no benefit only harms these patients who had their cancer cut out. And those who have adjacent cancer remaining that is indolent, the chemo won’t
affect the course of events. Merely shrink a cancer (the commonly used surrogate
endpoint) entails the proliferation of the cancer cells that are resistant to the chemotherapy. Remember that a cancer tumor has a high rate of mutation, thus it consist of a diverse group of cells.
Making dormant or killing some of those cells assures that the worst of them survive and not competing with less aggressive
cells for nutrients and oxygen. This helps to explain why pharma normally compares
in phase III trial the new drug to an older treatment (often at less than optimal dose) rather than those who refuse treatment
to the treatment.
I would not confuse “survival”, which typically is measured in weeks of longer life with “cure. “Survival” is used by the oncologist to sell their in-office chemo
treatment does not mean “cure”. Those without metastatic cancer are cured by excision, and if the some cancer
is missed, the chemo does not have the ability to destroy the remaining cancer. The
norm is for the chemo to be given in the clinic, thus the clinic profits from the spread between what they bill insurance
and Medicare and the wholesale price of the chemo. This explains why oncologists will often require chemo prior excision—more
pressure upon the patient to submit. Business is profit driven.
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