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My last blog discussed the commendable trend to develop cancer chemotherapy drugs that can be administered orally. No doubt, the fact that patients can receive chemotherapy without the need for needles or hospitalisations is a big factor in improving patients’ quality of life.
Incentives for this approach include safety, flexibility, reduced financial cost, improved quality of life, and the potential for improved efficacy. The ability to deliver chemotherapy at home and apply schedules of administration that increase the agent’s efficacy because patients do not require hospitalisation or visits to the clinic renders oral chemotherapy particularly attractive. With effective safeguards in place to ensure compliance with therapeutic regimens and prevent toxicity, this has to be the way forward.
Despite obstacles to oral chemotherapy in paediatric patients such as restrictions in dose size and schedule, uncertain or low bioavailability, adverse effects of malabsorption, and adherence, future developments in oral chemotherapy should not be limited to adult patient applications.
Oral cytotoxic preparations rarely provide suitable denominations of dose, or appropriate formulations – such as mixtures, melts or soluble tablets – for paediatric use. This leaves paediatric oncologists and pharmacists with the predicament of having to cut or crush tablets, or opening capsules and dispersing the resulting powder in water. This in turn exposes the environment to cytotoxic contamination with all the dangers that this entails.
One alternative is the use of pharmaceutical ‘specials’. ‘Specials’ have only limited quality control validation and have not had the benefit of the rigorous testing in a clinical setting that manufactured drugs undergo in order to satisfy licensing criteria.
Use of ‘specials’ can invalidate clinical trials (especially multicentre trials) given the difficulty of ensuring uniformity between various batches, from differing hospitals or situations. The ideal solution would be to develop, together with the pharmaceutical industry, paediatric oral chemotherapy preparations.
Health and safety legislation results in very high production costs for such hazardous substances suggesting that they are unlikely to be economically viable. It is improbable that they will appear on the market without some direct government intervention.
Compliance in children is a major problem. In childhood, acute lymphoblastic leukaemia (ALL) complete remission is usually followed by relapse unless patients receive prolonged outpatient ‘maintenance’ treatment based on daily oral 6-mercaptopurine and weekly methotrexate. Oral out-patient chemotherapy medications compromise the majority of therapy for children with ALL and are administered at the patient’s home, usually by parents with limited medical training. One study found nearly 10% of medications were given incorrectly.
About 20-30% of patients in Britain alone relapse unexpectedly some months or years after completing their planned schedule of treatment, indicating that the maintenance component of treatment has failed for some reason. It is now becoming increasingly apparent that some children simply do not take the drugs they are prescribed. Based on experience with asthma, tuberculosis, cystic fibrosis, diabetes, and penicillin prophylaxis for sickle cell disease, we know that children often fail to follow important diets or treatment schedules. It is therefore illogical to assume that, just because they have a life threatening disease, young patients with leukaemia will reliably take pills every day without fail for two years, especially when, for the most part, they feel well and healthy.
But despite warnings that is precisely what has been happening.
Reports suggest that 10-30% children fail to take a substantial amount of their prescribed chemotherapy. This can range from the occasional lapse to total refusal. The exact extent of non-compliance with maintenance treatment is unknown and varies in different communities. It probably contributes to a substantial proportion of unexplained late relapses of ‘standard-risk’ childhood ALL even in developed countries. Educational, cultural, and socioeconomic factors are important risk factors even allowing for variability between individuals in accumulation of intracellular metabolites of both mercaptopurine and methotrexate. Patients most likely to fail are adolescents. If it could be circumvented, long-term, disease-free survival might increase by 10%, even in countries where rates of 75% are already being achieved. On this basis, late relapse might be avoided in around 30-40 children per year in Britain alone, with the figure much higher in other countries.
Obviously, avoiding oral treatment completely and giving all drugs parenterally under medical supervision would eliminate non-compliance. Apart from this being impossible, practically speaking, it is exactly what we are trying to avoid.
Even delegating parenteral treatment to the patient or the parents does not necessarily overcome the potential for poor compliance. The only way is to educate and inform parents and children about the importance of oral treatment and carefully monitor progress, by regular and conspicuous measurement of drug metabolite concentrations.
Though it is a desirable goal at any price, such an achievement would be economically attractive. Outpatient antimetabolite treatment is inexpensive whereas salvage treatment for relapsed ALL, still unsuccessful in most patients, is extremely costly. The inexorable trend to more intensive, toxic and expensive first line treatment protocols might also be slowed down. On a worldwide scale, anything that simplifies, and reduces the cost of, paediatric cancer treatment will eventually lead to more children receiving potentially curative medications.
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