Stereotactic Radiotherapy Management of Brain Metastases: the Value of a Longitudinal Multimodal Approach (POSTPONE)

The management of brain metastases has evolved́ rapidly in recent years. It is estimated that 20% to 40% of cancer patients will develop brain metastases (BM) during the course of their disease. Whole-brain radiotherapy has long been the first-line treatment for brain metastases. However, large-scale international clinical trials conducted over the past decade have established stereotactic radiotherapy (SRT) as the treatment of choice for the management of brain metastases (BM). However, even though the method of radiation delivery has evolved considerably, the problem of monitoring and managing brain metastases remains unresolved. Indeed, BM patients constitute a growing population due to the increased efficacy of systemic treatments, making the occurrence of BM higher. Management of the disease is not only aimed at alleviating symptoms and, initially, improving survival, but must also take into account patients' quality of life. Patients with a poor prognosis should not be over-treated, while those with a more favorable prognosis should not be under-treated.

With this in mind, a number of tools were rapidly developed to grade the prognosis of patients with BM. Recursive partitioning analysis (RPA) and Graded Prognostic Assessment (GPA) are the main ones. They are based on prognostic factors that include age, Karnofsky index, primary tumor control, presence of extracerebral localization, histological type and presence of genetic mutations for each primary. Finally, we must also take into account the growing involvement of systemic treatments in the control of brain disease when the blood-brain barrier (BBB) is crossed.

Several studies have shown that patients with symptomatic cerebral recurrences have poorer survival and generate higher costs for the healthcare system than asymptomatic patients whose recurrences have been detected by routine surveillance imaging. The importance of frequent surveillance imaging is therefore essential. National Comprehensive Cancer Network (NCCN) recommendations include MRI every 2-3 months for the first year, then every 4-6 months indefinitely. The recommendations of the Association des Neuro-Oncologues d'Expression Française (ANOCEF) recommend brain MRI at least every 3 months for the first year (9), RECORAD recommends MRI surveillance every 3 months for the first 2 years, then every 6 months (10), and Cancer Care Ontario Organization (CCO) recommends a 1st follow-up MRI 2 to 3 months after the end of treatment, followed by MRI surveillance every 2 to 3 months for 1 year, and MRI surveillance every 3 to 4 months for 2 to 3 years. Given the heterogeneity of follow-up modalities, and the absence of any recommendation for surveillance MRI imaging earlier than 3 months after treatment, the Brest University Hospital decided to carry out an early remnographic reassessment of patients treated with intracerebral stereotactic radiotherapy 6 weeks after the end of treatment, and then every 3 months for a minimum of 2 years.

After SRT for brain metastases, the median time to development of a radiation-induced adverse event or radionecrosis is 7 to 11 months. Similarly, the risk of local tumor recurrence after SR is < 5% after 18 months. In terms of complications, improvements in systemic therapy mean that patients are living longer and are at greater risk of tumour recurrence later than previously (defined as > 18 months after SRT). Radionecrosis may therefore occur in up to 50% of patients several months to several years after irradiation, depending on several factors, including dose fractionation patterns and the volume of normal brain receiving high-dose irradiation.

Radionecrosis can produce symptoms difficult to distinguish from those of local progression and, if left untreated, can lead to significant morbidity and mortality. Correct differential diagnosis between radionecrosis and local progression is extremely important, as the two situations must be managed differently. Surgery or re-irradiation is generally proposed as salvage therapy in patients with local progression, whereas radionecrosis is most often treated with corticosteroids.

Differential diagnosis between radiation-induced changes and brain tumor recurrence is a challenge in the treatment of brain metastases. The RANO (Response Assessment in Neuro-Oncology) group has recognized that an approach based on a single imaging modality is insufficient to establish a correct diagnosis. It recommends the use of advanced imaging techniques, such as MRI with diffusion sequence and perfusion map, spectroscopy and PET.

Several radiopharmaceuticals, including the amino acid tracers O-(2-[18F]fluoroethyl)-L-tyrosine (FET) and 3,4-dihydroxy-6-[18F]-fluoro- l-phenylalanine (F-DOPA), have proved useful in distinguishing radionecrosis from local progression in patients with brain metastases.

Several observations can therefore be made:

• Heterogeneity of practices concerning remnographic surveillance, particularly at an early stage.
• Heterogeneity in practices concerning suspicion of radionecrosis

This study therefore has several focuses:

1. Evaluation of the benefit of early remnographic assessment (6 weeks): impact on recurrence-free survival and overall survival.
2. Evaluation of a diagnostic approach to radionecrosis: complementarity of DOPA PET and multimodal MRI.
3. The benefits of longitudinal remnographic monitoring with the development of segmentation and automated follow-up tools