Minimalism in oncology

Abstract

Expenses related to cancer treatment can diminish patients' quality of life and impede delivery of high-quality care. Thus, it is worrying that, in 2017, a study showed the price of some common cancer drugs in the USA rose at a rate higher than inflation. The US senate has recently started investigating why a 40-year-old cancer drug—lomustine, which has no generic competition—has increased in price by 1400% since 2013. At the 23rd Annual Conference of the National Comprehensive Cancer Network (Orlando, FL, USA, March 22–24, 2018), oncologists had a heated debate about the congressional mandate that prohibits the Centers for Medicaid and Medicare Services from negotiating drug prices with pharmaceutical companies in the USA. Although governmental action is needed to regulate the unit price at which cancer drugs are marketed, could the medical oncology community further help alleviate the financial burden placed on patients by rethinking the way oncology is practiced? Optimising treatment dose could be central to the financial toxicity debate. For example, a recent trial of abiraterone showed the concentration of drug that enters the bloodstream can be increased by four times if the drug is swallowed with a low-fat meal rather than on an empty stomach. Such a simple change in drug administration can reduce the current standard dose of abiraterone by three-quarters without compromising efficacy. This study supports anecdotal evidence that many oncology drugs could be taken at lower doses or for shorter periods without reducing effectiveness, alleviating both physical and financial toxicity to patients. Another example of successful dose reduction is immunisation against the HPV serotypes 16 and 18, for which two vaccine doses provide similar protection to the initially recommended three-dose schedule. The life-threatening condition of cancer has traditionally meant that high drug doses, and thereby high toxicity, have generally been considered acceptable if a treatment is effective. The presumed understanding that high dose translates into higher anti-tumour activity still drives clinical trial design, with maximum-tolerated doses (MTD; the highest dose of a treatment that does not cause unacceptable side effects) being established as the recommended dose for most new oncology drugs. Although fine-tuning a personalised dose for each patient is neither feasible nor plausible—the optimal dose is just an estimation for a particular patient, and optimisation strategies could substantially delay the market entry of new drugs—rethinking drug development to aim for a minimum-effective dose (MED; lowest dose of treatment that provides a clinically meaningful response) could be a sensible approach to find the balance between oncological effectiveness, and physical and financial toxicity. Furthermore, in the era of targeted therapies, which differ from cytotoxic chemotherapies in that they follow a non-linear dose-response saturation curve whereby the addition of more drug does not always improve outcomes, should the way that safety is assessed move away from the traditional pharmacology-driven study designs? A 2010 pooled analysis of trials of targeted therapy showed that patients treated with low doses (≤25% MTD) had similar outcomes to those treated with intermediate (25–75% MTD) and high doses (≥75% MTD) in terms of survival, objective responses, and toxicity. These findings suggest that receiving the maximum-tolerated dose for many targeted agents could imply overtreatment, and advise departure from the conventional use of maximum dose protocols. Additionally, adaptive studies in oncology, such as the KEYNOTE-001 trial (which led to the accelerated approval of pembrolizumab, following a customised trial design in which no MTD was reached and the recommended phase 2 dose was based on early safety and response assessments that led to the recruitment of several expansion cohorts), could serve as a precedent for future oncology trials. Adopting the minimum-effective dose as a recommended standard and customising trial design, aided by mathematical modelling and simulations for optimal dosage, suggest a new path towards practising minimalism in oncology that could avoid unnecessary financial and physical toxicity and improve patients' quality of life. The Value in Cancer Care Consortium—which plans to initiate trials that explore whether the dose, duration, or type of drug can be optimised—is a first, promising step to tackle financial toxicity. However, a more drastic transformation of the way oncology is practiced could start by simply redefining what the effective dose of a new regimen truly is. For more on the US senators investigation see http://thehill.com/policy/healthcare/381287-senators-launch-probe-into-why-price-of-cancer-drug-increased-1400-percent For more on the US senators investigation see http://thehill.com/policy/healthcare/381287-senators-launch-probe-into-why-price-of-cancer-drug-increased-1400-percent