A radical new approach to de-escalation of treatment is needed in medical oncology, starting with a change in name to ‘de-intensification’, according to members of an ESMO working group.
Striking a balance between treatment efficacy and reducing negative impacts on the patient from toxicity, treatment burden and quality of life should be the aim of all clinicians interested in personalised medicine, but there are still many barriers to implementing this, oncologists told the ESMO 2022 meeting in Paris.
Professor Henrik Van Halteren, of the Adrz-Admiraal de Ruijter Hospital-Goes, Netherlands, said the traditional “more is better” paradigm in oncology was difficult to counter at an individual and institutional level but the way clinical trials were designed also inherently promoted overtreatment.
He said the principle of giving the lowest effective dose for the shortest possible time was in line with the guiding principle of ‘primum non nocere’, but it was difficult to achieve this in practice because of factors such as overcoming patient fears about cancer recurrence and also the difficulty in obtaining robust evidence for de-escalation from non-inferiority studies.
“De-escalation is primarily successful in cancers with a high cure rate such as breast and colorectal cancer, but there are ethical issues in withholding ‘maximal’ therapy in patients with cancers that have a poor prognosis such as mesothelioma,” he said.
According to Professor Van Halteren one place to start was with a change in nomenclature to emphasise the positive impact on the patient through ‘risk-adapted modulation to de-intensify therapy’ as recommended in a recent ESMO statement.
And he pointed to some notable early successes with de-intensifying treatment strategies in breast cancer, where there have been moves to reduce mastectomies and the use of genomic testing to identify patients who can safely avoid further chemotherapy.
But advocates of de-intensification faced the major barrier of designing and obtaining funding for non-inferiority trials to obtain evidence to support less intensive treatment. He cited the example of Herceptin in early Her-2-positive breast cancer. The original trials showed that 12 months of trastuzumab added to chemotherapy led to improvements in survival. However it took 20 years and five non-inferiority trials to show that this period could be cut by half without affecting efficacy.
The consequences of this were that many women had an unnecessary treatment burden and the cost to society was billions of dollars in funding for extended course of a drug that conferred no additional benefit.
According to Prof Van Halteren, this showed there should be more emphasis should on “cautious non-escalation” at an early stage in drug development and treatment rather than retrospective efforts to find evidence for de-escalation.
This would mean preclinical research and early clinical trials exploring alternative lower intensity treatment options by having three arm studies instead of the current 2-arm model, he suggested.
“The provocative point I would like to make is … there are too often doubts about overtreatment when we have passed phase 3. We sometimes manage to carry out de-escalation trials (but) results arrive much later and sometimes too late – at the expense of many more participating patients.”
The paradox of sustainable cancer care was that society pays for overtreatment but there are only limited funds available for de-escalation trials, he added.
Prof Van Halteren went as far as to suggest that if drug developers did not adopt such protocols, they should be made mandatory by regulators.
In the meantime, he pointed to the recent ESMO recommendations for the risk-guided intensity modulation of cancer treatments link here]. These provide a set of evidence-based criteria to categorise biomarkers deemed to inform de-intensification of cancer treatments, in risk-defined patients, he said.