Are chemotherapy drugs as successful as they seem?

Despite considerable investment and innovation, the conclusion of researcher Peter Wise is that chemotherapy drugs have had little effect on survival in adults with metastatic cancer.

A meta-analysis published in 2004 explored the contribution of cytotoxic chemotherapy to 5-year survival in 250,000 adults with solid cancers from Australian and United States randomized trials. [1] An important effect was shown on 5-year survival only in testicular cancer (40 percent), Hodgkin’s disease (37 percent), cancer of the cervix (12 percent), lymphoma (10.5 percent), and ovarian cancer (8.8 percent). Together, these represented less than 10 percent of all cases.

In the remaining 90 percent of patients — including those with common tumors of the lung, prostate, colorectum, and breast — drug therapy increased 5-year survival by less than 2.5 percent — an overall survival benefit of around three months.

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. [2]

Newer drugs did no better: 48 new regimens approved by the U.S. Food and Drug Administration between 2002 and 2014 conferred a median 2.1-month overall survival benefit. [3]

Drug treatment can therefore only partly explain the 20 percent improvement in 5-year survival rates. Developments in early diagnosis and treatment may have contributed much more. [4]

Wise has had a career-long involvement with medical ethics, including major responsibilities to research, ethical, and drug evaluation committees at the hospital, university, and government levels in Australia and the United Kingdom. He represented the Royal College of Physicians for many years on the clinical research ethics committee of the Royal College of General Practitioners, London, and served as its vice chairman.

As an endocrinologist and researcher, Wise has a particular interest in paraneoplastic endocrinopathies, which has brought him into contact with many patients with advanced cancer. He penned “Cancer drugs, survival, and ethics” for the November issue of The BMJ, a British weekly peer-reviewed medical journal.

Five key takeaways from Wise:

• 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 centers 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.

At most 3 percent of adult cancer patients participate in trials, and given the many new drugs and regimens, greater enrolment is a constant aim. [5] 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 $95 billion was spent on cancer drugs in 2015).

Trials also allow patients the opportunity of having otherwise unavailable or unaffordable treatment under the close supervision of a trial center, although most studies show that patients do not realize that participating in a trial will primarily benefit others. An unethical pressure to enroll is reflected by several studies showing that up to half of the patients in cancer drug trials were led to believe that such participation was their only option. [6]

Bypassing previous university-based trial procedures, pharma now outsources many trials to commercial contract research organizations (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.” [7]

Risks of premature approval

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, minimize 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 tumor 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.

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. Some of these drugs are logically withdrawn but others remain inexplicably on the market.

The FDA’s decision to introduce a “breakthrough” category in 2012 compounds the risks of premature approval on limited evidence. [8] 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 more momentum.

The quality of life assessments increasingly forms part of cancer drug trials. However, many evaluations are invalidated by selective use of questionnaire items and time points to demonstrate drug benefit, 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 tumor shrinkage.

Empowerment of cancer patients

Many irregularities and competing interests — in Big 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 percent of the Western population who will almost inevitably die from solid tumor 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 localized and regional disease, together with highly skilled, earlier, supportive care are the important yet under-financed priorities in cancer control.

The efficacy bar for approval needs to be raised for both new and existing cancer drugs — by using more meaningful statistical and disease-specific criteria of risk-benefit and cost-benefit. [9]

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.