ESTRO 2024 Congress report

The combination of medication with radiotherapy has received increasing attention across healthcare research circles and at the ESTRO 2024 conference. In this report, we focus on new compounds or beam qualities that are under test for combination with radiotherapy. Other interesting presentations, which are directly related to clinical care, are not mentioned here.

One of the drug classes of interest is that of DNA repair pathway inhibitors, as they have radio- and immuno-sensitising properties.

Poly(adenosine-diphosphate-ribose) polymerase (PARP) is a key DNA repair protein that is over-expressed in glioblastoma (GBM) but is barely detectable in normal brain. The PARP inhibitor olaparib has been found in preclinical models to show radio- and chemosensitising effects and is known to penetrate GBM in patients at radiosensitising concentrations. With this background, Shad et al. (date) reported the results of the PARADIGM-2 phase-I study, in which patients with GBM unmethylated by methylguanine-DNA methyltransferase (MGMT) were treated with olaparib and radiotherapy. Patients with an MGMT-unmethylated tumour do not benefit from treatment with temozolamide. The median overall survival (OS) of the 42 eligible MGMT-unmethylated patients was 14.1 months, with 12- and 24-month OS estimates of 64.3% and 16.7% respectively. This compares favourably with historical controls.

In an overview, Professor K. Harrington looked more deeply at the modulation of innate immunity by DNA damage response inhibitors. Inhibition by ataxia telangiectasia and Rad3-related protein (ATR) radiosensitises cancer cells, as was shown in the study of an ATR inhibitor alone or with palliative radiotherapy (PATRIOT) trials. The immune micro-environment could be sculpted favourably by the concurrent administration of radiotherapy with DNA repair inhibitors or second mitochondria-derived activator of caspases (SMAC) mimetics, followed by immune checkpoint antagonists or stimulator of interferon gene (STING) agonists.

In preclinical studies, some new drugs as immunotherapies have shown perfect synergy with hypo-fractionated radiotherapy. Normal tissue toxicity is the primary factor that limits the efficient treatment of some tumours. Two novel strategies are spatially fractionated radiation therapy (SFRT) and FLASH radiotherapy (FLASH-RT). In SFRT, the dose is spatially modulated to create alternating regions of high dose, called peaks, and low dose, called valleys. FLASH-RT reconsiders temporal aspects of the dose delivery and employs ultra-high dose rates of more than 40Gy/s and very short delivery times of <200ms. These promising strategies could be used to decrease the toxicity of radiotherapy used with new medication.

The preclinical data obtained thus far illustrate how FLASH-RT and SFRT can modulate biological responses and improve the outcome for patients with non-conventional irradiation parameters. Although probably based on different mechanisms, both FLASH-RT and SFRT have been shown to elicit radiobiological effects that significantly differ from those induced by conventional radiotherapy. The combination of FLASH-RT and SFRT might represent a winning alliance. It has already been demonstrated that those techniques are safe in hypo-fractionation schemes, including in the treatment of bulky tumours in clinical and preclinical contexts. The first studies are running, but the plan is to employ FLASH-RT and SFRT together in the treatment in order to improve the efficacy and reduce the toxicity.

Dirk de Ruysscher

Member of the ESTRO focus group on Systemic Therapy

Maastricht University Medical Center, Department of Radiation Oncology (Maastro)/University of Maastricht (GROW)

Erasmus MC Cancer Institute, Department of Radiotherapy, University Medical Center Rotterdam

The Netherlands

Youlia M. Kirova

Member of the ESTRO focus group on Systemic Therapy

Radiation oncologist and associate professor

Department of Radiation Oncology

 Institut Curie, Paris, France