Whole brain radiotherapy (WBRT) is considered standard of care for patients with multiple brain metastases or unfit for radical treatment modalities. Recent studies raised discussion about the expected survival after WBRT. Therefore, we analysed survival after WBRT for brain metastases 'in daily practice' in a large nationwide multicentre retrospective cohort. Between 2000 and 2014, 6325 patients had WBRT (20 Gy in 4 Gy fractions) for brain metastases from non-small cell lung cancer (NSCLC; 4363 patients) or breast cancer (BC; 1962 patients); patients were treated in 15 out of 21 Dutch radiotherapy centres. Survival was calculated by the Kaplan-Meier method from the first day of WBRT until death as recorded in local hospital data registration or the Dutch Municipal Personal Records Database. The median survival was 2.7 months for NSCLC and 3.7 months for BC patients (p < .001). For NSCLC patients aged 70 years, survival was 4.0, 3.0, 2.8 and 2.1 months, respectively (p < .001). For BC patients, survival was 4.5, 3.8, 3.2 and 2.9 months, respectively (p = .047). In multivariable analyses, higher age was related to poorer survival with hazard ratios (HR) for patients aged 50-60, 60-70 and >70 years being 1.05, 1.19 and 1.34, respectively. Primary BC (HR: 0.83) and female sex (HR: 0.85) were related to better survival (p < .001). The survival of patients after WBRT for brain metastases from NSCLC treated in Dutch 'common radiotherapy practice' is poor, in breast cancer and younger patients it is disappointingly little better. These results are in line with the results presented in the QUARTZ trial and we advocate a much more restrictive use of WBRT. In patients with a more favourable prognosis the optimal treatment strategy remains to be determined. Prospective randomized trials and individualized prognostic models are needed to identify these patients and to tailor treatment.

The clinical value of whole brain radiotherapy (WBRT) for brain metastases (BM) is a matter of debate due to the significant side effects involved. Stereotactic radiosurgery (SRS) is an attractive alternative treatment option that may avoid these side effects and improve local tumor control. We initiated a randomized trial (NCT02353000) to investigate whether quality of life is better preserved after SRS compared with WBRT in patients with multiple brain metastases. Patients with 4–10 BM were randomized between the standard arm WBRT (total dose 20 Gy in 5 fractions) or SRS (single fraction or 3 fractions). The primary endpoint was the difference in quality of life (QOL) at 3 months post-treatment. The study was prematurely closed due to poor accrual. A total of 29 patients (13%) were randomized, of which 15 patients have been treated with SRS and 14 patients with WBRT. The median number of lesions were 6 (range: 4–9) and the median total treatment volume was 13.0 cc³ (range: 1.8–25.9 cc³). QOL at 3 months decreased in the SRS group by 0.1 (SD = 0.2), compared to 0.2 (SD = 0.2) in the WBRT group (P = .23). The actuarial 1-year survival rates were 57% (SRS) and 31% (WBRT) (P = .52). The actuarial 1-year brain salvage-free survival rates were 50% (SRS) and 78% (WBRT) (P = .22). In patients with 4–10 BM, SRS alone resulted in 1-year survival for 57% of patients while maintaining quality of life. Due to the premature closure of the trial, no statistically significant differences could be determined.

The immunocytokine L19-IL2 delivers interleukin-2 to the tumor by exploiting the selective L19-dependent binding of extradomain B of fibronectin on tumor blood vessels. In preclinical models, L19-IL2 has been shown to enhance the local and abscopal effects of radiation therapy. The clinical safety of L19-IL2 monotherapy has been established previously. In this study, the safety and tolerability of L19-IL2 after stereotactic body radiation therapy (SBRT) was assessed. Patients with oligometastatic solid tumors received radical SBRT to all visible metastases. Within 1 week after SBRT, intravenous L19-IL2 using a 3 + 3 dose escalation design was administered. Safety and tolerability were analyzed as the primary endpoint using the Common Terminology Criteria for Adverse Events 4.03 scoring system, with progression-free and overall survival as secondary endpoints. A total of 6 patients in 2 L19-IL2 dose levels were included. The 15 million International Units (Mio IU) dose level was well tolerated with no dose-limiting toxicity. The most frequently reported adverse events were chills, noninfectious fever, fatigue, edema, erythema, pruritus, nausea/vomiting, and cough and dyspnea. Blood analysis revealed abnormalities in liver function tests, anemia, hypoalbuminemia, and hypokalemia. At the second dose level (ie, 22.5 Mio IU), which is the recommended dose for L19-IL2 monotherapy, all 3 included patients experienced dose-limiting toxicity but recovered without sequelae. We documented 2 long-term progression-free responders, both having non-small cell lung cancer as primary tumor. Based on the results of this phase 1 clinical trial, the recommended phase 2 dose for SBRT combined with L19-IL2 is 15 Mio IU. The therapeutic efficacy of this combination is currently being evaluated in the multicentric EU-funded phase 2 clinical trial, ImmunoSABR.

In the era of personalized medicine, individualized prognostic models with tumor characteristics are needed to inform patients about survival. Before clinical use, external validation of such models by an independent group is needed. An updated version of the graded prognostic assessment (GPA) estimates survival in patients with brain metastases (BMs) of non-small cell lung cancer (NSCLC). This is the first external validation of the updated Lung-molGPA in patients treated with stereotactic radiotherapy (SRT) for one or more BMs. Patients treated with SRT for BMs from NSCLC adenocarcinoma were retrospectively included. GPA score was calculated for each patient based on six prognostic factors including age, Karnofsky Performance Status, number of BMs, extracranial metastases, EGFR/ALK status and PD-L1 expression. Kaplan-Meier analysis evaluated survival probability. Impact of individual prognostic factors on survival was assessed by univariate and multivariate analyses using the Cox proportional hazard model. Predictive performance was evaluated using discrimination (C-statistic) and calibration (Brier test). The cohort (n = 241) was divided into four prognostic groups. Overall median survival was 15 months. Predicted and observed median survival were similar between the original and validation cohorts, apart from the most favorable prognostic group. With adequate C-statistics and Brier scores, the Lung-molGPA provided accurate survival predictions. The Lung-molGPA accurately predicted survival in our European population, except for an overestimation of survival in the small most favorable prognostic group. This prognostic model was externally validated and is therefore useful for counseling of patients with BMs of NSCLC adenocarcinoma.

Background: Stereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases. Methods: Patients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15–24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life. Discussion: Currently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure. Trial registration: ClincalTrials.gov, trial registration number: NCT05346367, trial registration date: 26 April 2022.

To assess whether there are differences in the effects of time to treatment interval (TTI) on patient survival for head and neck cancer (HNC) sites in order to provide evidence that can support decision-making regarding prioritizing treatment. Patients in the Netherlands with a first primary HNC without distant metastasis between 2010 and 2014 were included for analysis (N = 10,486). TTI was defined as the time from pathologic diagnosis to the start of initial treatment. Overall survival (OS), cox regression analyses and cubic spline hazard models were calculated and visualized. Overall, the hazard of dying was higher (HR = 1.003; 95 % CI 1.001-1.005) with each additional day until treatment initiation. The pattern, as visualized in cubic spline graphs, differed by site the hazard increased more steeply with increasing TTI for oral cavity cancer. For oropharyngeal and laryngeal cancer, a slight increase commenced after a longer TTI than for oral cavity cancer, while there was hardly an increase in hazard with increasing TTI for hypopharyngeal cancer. The relationship between longer TTI and decreased survival was confirmed, but slight variations in the pattern of the hazard of dying by TTI by tumour site were observed. These findings could support decisions on prioritizing treatment. However, other aspects such as extent of treatment and quality of life should be investigated further so this can also be included.