ESMO Makes New Guidelines for Classifying Research Into De-Intensification of Cancer Treatments

The European Society of Medical Oncology (ESMO) has announced the development of a new evidence-based classification framework to guide research and interpretation of data on the de-intensification of cancer treatments. The framework establishes common definitions and criteria when looking at de-intensification of treatment in the clinic, according to research published in the Annals of Oncology.¹

A subgroup of the ESMO Precision Medicine Working Group created an international collaborative project to develop the tiered approach classification system for biomarkers used in the cancer treatment de-intensification. Then, a group of disease-oriented clinical, translational, methodology and public health experts, and patients’ representatives provided an analysis of the status quo, and ongoing clinical trials.

Through multiple rounds of revisions and debate, the group agreed on several definitions on treatment de-intensification depending on the context is for each patient. For example, a common way to de-intensify treatment is to forgo, or delete, a segment of treatment such as when a patient is on sequential chemotherapy and clinicians decide to only provide a portion of the treatment.

Other methods of de-intensification identified by the group were shortened duration of treatment, encouraging clinicians to look at if patients can receive less treatment where possible, and combining treatment by entirely getting rid of one portion of treatment. The group highlighted how select patients being treated with chemotherapy and radiotherapy researchers may exclude 1 and still see non-inferior survival outcomes.

According to the group, there is evidence for this approach that shows it can shorten treatment and reduce the risk of long term adverse events (AEs).

The working group criteria for the designation of a modulation of cancer treatment through de-intensification required that 2 conditions are met. First, clear evidence of treatment de-escalation, and second, tangible evidence of improved patient outcomes. This would require that further research is needed to highlight the use of treatment de-intensification and its impact on patients with cancer.

“Clear evidence of treatment de-escalation requires evidence of reduction in the dose-density, intensity, or cumulative dose, including intermittent schedules or shorter treatment duration or omission of one or more segments of the standard regimens or one or more compounds or treatment modality,” the group explained in their guidelines.

The group also advocated for clinicians to rigorously assess the reduction of toxicity and improvement of quality of life when considering de-intensification of cancer treatments. When classifying toxicity, clinicians should consider chronic, persistent, or disabling AEs, and the burden of low-grade toxicities affecting the daily well-being of patients. Moreover, they argued for considering the contextuality of single arm studies that may just look at safety and how it will relate to the overall population.

“Randomized controlled non-inferiority trials are the gold standard when it comes to testing de-escalated treatments, but they take many years, very large sample sizes and heavy financial investments to run,” said senior author Professor Fabrice André, Gustave Roussy Cancer Campus, France, when explaining the rationale behind this approach in an ESMO press release.2 “To drive progress in this field of research, led more often by academic groups than by the pharma industry, we need to be able to design high-quality studies with fewer patients and shorter running times, which may be used to assess de-intensification in very low-risk populations.”

In the press release, ESMO also called for using this approach to explain to patients why de-intensification of their treatment is okay and can be beneficial without losing out on outcomes of the therapies. Moreover, a recommendation in their guidelines is to explain any potential tradeoffs to patients and how outcomes would not be impacted, and more research is being done to show this.

Ultimately, the ESMO group decided on 3 tiers to look at non-inferiority trials for their recommended approach. In tier A, they agreed that intensity-modulated regimens should be compared to standard of care treatments to demonstrate a non-inferior overall survival to acceptable outcomes alongside improved safety, tolerability, and/or quality of life. These differences must be statistically significant as well. Tier B was used for biomarkers in single-arm investigations, contextual or not to larger trials with a historical control agreed upon outside of the trial. Finally, tier C classified biomarkers from retrospective re-analyses that must be robust and look at the majority of the population from the previous study.

“This expert group advocates a stepwise clinical research approach: (1) harm-minimization regimens could be initially assessed using stand-alone randomized phase II studies that recruit and report before proceeding to phase 3 studies; (2) if no detriment in clinical outcome is identified, then a phase 3 trial could follow,” the experts concluded.

References

1. Trapani D, Franzoi MA, Burstein HJ, et al. Risk-adapted modulation through de-intensification of cancer treatments: an ESMO classification. Ann Oncol. 2022 May 3:S0923-7534(22)00669-X. doi: 10.1016/j.annonc.2022.03.2732.

2.New ESMO Framework To Resolve Uncertainties About The De-Intensification of Cancer Treatments. ESMO. May 10, 2022. Accessed: May 20, 2022. https://bit.ly/3MyoRqI