Exclusion from clinical trials for the elderly: protection or discrimination?

Last weekend I flew to Rome to attend the 1st European Expert Forum on Blood Cancer in the Elderly. The symposium, organized by ecancermedicalscience, brought together for the first time haematologists, oncologists and geriatricians from all Europe to discuss strategies to treat in the best possible ways haematological malignancies in elderly patients. While this kind of tumors, eg chronic myeloid leukemia, affects predominantly people over 65 years of age, elderly patients are not treated with the most innovative and targeted drugs as younger patients are.
Several are the misconceptions underlying the status quo for this category of patients, for which -as put with the words with one of the speakers, professor Lodovico Balducci from the Lee Moffett Cancer Centre, Florida- age represents a “risk factor for inadequate treatment” and, as a consequence, worse clinical outcome. For one, the anagraphical age of 65 yo is still used as a cut off to exclude patients from clinical trials. Such an exclusion is neither scientifically -as the biological, and not the anagraphical age is the relevant factor to take into account when deciding which therapy to administer- nor ethically justified, but represents an entrenched clinical routine.
A consensus emerged from the symposium that much needs to be done to eradicate it. Professor Antonio Cherubini (Institute of Gerontology and Geriatrics, Perugia University) and Dr Beatrice Lucaroni from the European Commission presented their data on PREDICT, a project of the 7th European Framework Programme focused on human development and ageing and aimed at increasing participation in clinical trials in the elderly. With the words of the European geriatricians that are members of the PREDICT consortium, they have all too frequently found themselves “in a situation where they are unable to prescribe the best course of treatment with the weight of scientific evidence behind them, due to insufficient evidence from clinical trials. […] In practice, clinicians are left to extrapolate from studies of younger, healthier subjects – a practice fraught with difficulty. An analogous problem has occurred in the paediatric context but research in this domain, is much better developed than for the frail older person“.
Two are the interwined issues to take into account when evaluating participation of the elderly in clinical trial: their ability to give informed consent and the risk of discrimination deriving from exclusion. The elderly patient is a very heterogeneous category, which needs propered tailored assessment and consequent stratigication to form the basis of personalized therapy. Indeed, the elderly patient can be fit and able to receive an aggressive treatment as the adult, or unfit for aggressive treatment and able to receive only a lower dose of treatment, or frail and therefore more vulnerable and in need of palliative care and of a complex and multidisciplinarity management by both the geriatricians and the (haemato) oncologist. On the one hand, the frail patient has often associated co-morbidities such as senile dementia, and is therefore unable to consent to informed consent models as the ones prepared for the unfrail patient. Therefore the frail elderly patient is in a vulnerable condition which deserves special protection. On the other hand, labelling elderly patients per se as vulnerable and excluding them from clinical trials represent a discrimination and an injustice, which can and indeed has negative consequences on prognosis and treatment. This was the message strongly put forward in the patient advocacy session by Giora Sharf, elderly CML survivor and head of the CML Advocates Network, and by Joerg Hasford, founding member of the German Drug Utilization Center. For the future, strategies to implement trial participation in the elderly, while taking care of their reduced autonomy and capacity to consent, need to be developed.

Further reading

Defining old: clinical challenges and changing ideas in haemato-oncology, Insider News, ecancermedicalscience, March 19, 2011.

Cherubini A, Del Signore S, Ouslander J, et al. Fighting against age discrimination in clinical trials. J Am Geriatr Soc. 2010 Sep;58(9):1791-6.

Kumar PS, Katheria K, et al. Evaluating the Older Patient with Cancer: Understanding Frailty and the Geriatric Assessment, CA Cancer J Clin 2010; 60:120-132.

Mallery LH, Moorhouse P. Respecting frailty. J Med Ethics 2011;37:126-128.

PREDICT project for Increasing the Participation of the ElDerly In Clinical Trials

A transatlantic health divide? England citizens score ‘healthier’ than their US cousins.

A recent paper just appeared on the American Journal of Epidemiology makes the case for England being “healthier”, or scoring better for many health parameters, than US.(Martinson et al, 2011) The study performed by researchers at the Office of Population Research, Princeton US, systematically compared health indicators in the United States and England from childhood through old age. Results showed that individuals in the United States have higher rates of most chronic diseases and markers of disease than their counterparts across the Atlantic. The study also shows that differences at young ages are as large as those at older ages for most conditions, including obesity, diabetes, asthma, heart attack or angina. Similar patterns were observed when the sample was restricted to whites, the insured, nonobese, nonsmoking nondrinkers, and specific income categories, and also when stratified by normal weight, overweight, and obese weight categories.
In another recent paper, Desai and coauthors apply the metaphor by George Bernard Shaw to the context of health care, when they define the UK and the US as “Two countries divided by a common language” (Desai et al, 2010). Cancer care costs money, and deciding how to allocate resources to treat cancer is inevitably a moral as well as a political act. As the rationing of oncologic care is necessary, it is important to reflect on the decision making process about the allocation of resources, ie to address the questions “Who decides? And on what basis?”. As outlined in the review by Desaid and coauthors, the US and British systems of healthcare both have strengths and weaknesses in relation to cancer care. While the USA achieves better outcomes than the UK among older people with cancer, outcomes among young people with chronic diseases are much worse in the USA than the UK, and the racial differences in outcome for cancer and other chronic diseases in the USA are very wide. Also, the USA spends three times as much per person on healthcare than does the UK, and even allowing for the higher transaction costs arising from multiple payers, the absence of pharmaceutical cost controls and the higher cost of malpractice insurance, the USA should be expected to achieve much better outcomes from treatable conditions than the UK, but it does not. The findings by Desai for cancer are in line with those by Martinson for other health parameters. The review by Desai and coauthors suggests two policy recommendations: a) for the UK: rather than seeking to preserve current levels of expenditure on the NHS, there is an argument for increasing them further; b) for the US: many commentators have condemned the healthcare reforms in the USA for creating something that might resemble the British NHS, but it is precisely those elements of the American health system that most resemble the NHS which seem to achieve the best results.
As reported by Michelle Roberts for BBC news, it is not clear from the study by Martinson why health status differs so dramatically between the US and England. According to the researchers, the difference is an “unresolved puzzle” for two countries which share much in terms of “history and culture”. But do they, really? I would not be so sure. What do you think? Please cast your views!

Further reading:
Desai M, Rachet B, Coleman MP, Two countries divided by a common language: health systems in the UK and USA. J R Soc Med. 2010 Jul;103(7):283-7

Martinson ML, Teitler JO, and Reichman NE. Health Across the Life Span in the United States and England Am. J. Epidemiol. 2011 doi:10.1093/aje/kwq325

Roberts, M. England ‘healthier than the US’, BBC news, March 9, 2011

Getting rid of entrenched but erroneous perceptions: cancer burden in the next decade.

While cancer is still broadly perceived as disease of high-income countries (HICs), nowadays low-middle income countries (LMICs) bear a majority share of the burden of cancer, and this trend will only be increasing over the next decade. Some figures are telling: over 70 % of all global cancer deaths occur LMICs, where cancer claims over 5,3 M lives each year. The rising proportion of cases in these countries is caused by population growth and ageing, combined with reduced mortality from infectious disease.
For many types of cancers, future changes in incidence, survival, and mortality rates will greatly depend on whether key risk factors can be controlled in LMICs, as in these countries major risk factors continue to rise and awareness of the importance of screening and early detection is low. Besides, in LMICs stigma associated with cancer and the financial barriers of poverty prevent many people from seeking preventive services or care at early stages.

While a widespread assumption is that cancer control and care is not feasible or effective in LMICs, the following evidence challenges it, and supports a global policy change:
1) much can be done without the latest and most expensive technologies to treat cancer. Indeed, for several cancers, life can be substantially extended with fairly low cost system drug treatment, mostly through prevention (tobacco for lung cancer, HPV per cervical, head and neck, anal cancer, hepatitis infection for hepatocellular cancer). Other cancers, as cervical, breast, colorectal, are potentially curable with early detection and treatment, including surgery.
2) pain control is typically low cost and easily delivered, and the barriers to delivery are mostly caused by substance controls. Better regulation for pain control could have a substantial impact at improving quality of life of oncological patients.
3) lessons from the past: think of HIV! A decade ago, vehement critics were asserting that complex care as that needed for AIDS could not be scaled up within weak health systems, such as sub-saharian Africa. However these predictions proved wrong, and represent now a fundamental precedent that we cannot ignore. The increasing burden of cancer in LMICs represents a problem of unacceptable inequality in the distribution of resources worldwide, and requires a transition from a policy focus on public health to a policy focus on global health. According to the definition proposed by Lee & Collins (2005), the transition from public health to global health issue occurs where “The determinants of health or health outcomes circumvent, undermine or are oblivious to the territorial boundaries of states and this beyond the capacity of individual countries alone to address through domestic institutions”.

The perception that cancer is a disease only of HICs is deeply entrenched in our society, but it has been proven erroneous, and needs getting rid of. Such a perception leads to an underestimation of the costs associated with premature death and disability in LMICs: according to current estimates, only around 5 % of global resources for cancer are spent in LMIC countries, while these countries get around 80 % of the disability-adjusted life years lost worldwide to cancer. This is the so-called 5/80 cancer disequilibrium and is no longer acceptable.

Further reading:

Farmer P, Frenk J, Kanul FM, et al. Expansion of cancer care and control in countries of low and middle income: a call to action, Lancet 2010, doi:10.1016/S0140-6736(08)61345-8.


Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries, 2010.

Lee K, Collin J, eds. Global change and health. Maidenhead, Berkshire UK; McgrawHill, Open University Press 2005.