Patterns of distant brain recurrences after radiosurgery alone for newly diagnosed brain metastases: Implications for salvage therapy

doi:10.1016/j.radonc.2014.07.007

Radiotherapy and Oncology

Volume 112, Issue 2, August 2014, Pages 212-216

https://doi.org/10.1016/j.radonc.2014.07.007 Get rights and content

Abstract

Introduction

Single modality radiosurgery (RS) is an established treatment option for patients with brain metastases (BM) with the aim of achieving optimal local control while avoiding toxicity from whole brain radiotherapy (WBRT). Published studies generally lack detailed data on distant brain recurrence (DBR) rates and characteristics. This study describes the patterns of DBR and consequences for salvage treatment in a group of patients treated with RS alone for 1–3 BM.

Materials and methods

Between 2002 and 2012, 443 patients were treated with RS alone in doses ranging 15–24 Gy in 1–3 fractions. Patient selection for RS was performed using triple dose gadolinium-enhanced MRI scans, obtained with slice distance of 2 mm (until 2008), 1.5 mm (2008–2012), and of 1 mm (from 2012). During follow-up, a DBR was observed in 147 patients, but in 20 of these patients (14%) these “new lesions” could retrospectively be seen on the planning MRI scan. These missed metastases had a median size of 2 mm, and in order to study real DBR patterns, these patients were excluded from analysis.

Results

Actuarial DBR rates at 6, 12 and 24 months in the remaining 423 patients were 21%, 41% and 54%, respectively, with a median time to DBR of 5.6 months. In 42% of DBR, a single new lesion was seen, in 70% there were ⩽3 new lesions. Median diameter of the DBR was 6 mm; 97% of lesions were ⩽30 mm. Salvage therapy was delivered in 82% of DBR patients, consisting of WBRT (46%), repeated RS (27%), or systemic treatment (9%). A RPA classification system (DBR-RPA), based on WHO performance status and interval between initial RS and diagnosis of DBR, was developed to estimate life expectancy after the development of DBR, which can be used to guide salvage therapy.

Conclusions

In this study of patients treated with RS alone, only 25% of treated patients needed salvage treatment for DBR, and ultimately only 18% of all patients underwent WBRT at any time during follow-up. A three-monthly MRI follow-up scheme identifies DBR at an early stage with respect to size and number of lesions, and most patients were asymptomatic at radiological diagnosis.

Section snippets

Radiosurgery

In our institutional database, baseline characteristics, treatment details and follow-up data of newly diagnosed BM patients treated with Linac-based RS have been collected retrospectively [1]. According to our protocol, patients with 1–3 BM are eligible for RS as a single modality. Patient selection for RS alone was performed using triple dose gadolinium-enhanced MRI scans (1.5–2 Tesla), prior to 2008 obtained with 2 mm slice distance, from 2008 to 2011 with 1.5 mm slice distance, and from early

Results

Between 2002 and 2012, a total of 443 patients with 595 newly diagnosed BM were treated with RS as a single modality. A total of 147 patients with DBR were identified. However, in 20 patients these “DBR” could be seen in retrospect on the stereotactic planning MRI scan. These missed metastases had a median size of 2 mm, and in order to study real DBR patterns, these patients were excluded from analysis. The remaining 423 patients had a median age of 62 years (range 16 up to 89 years) with the

Discussion

As a result of several randomized studies, RS alone is the preferred treatment in patients with a limited number of BM in good performance status. Additional WBRT and its associated toxicity can be avoided without compromising survival [3], [9], [10], [11], [12]. RS alone provides high rates of local control with low toxicity, is a non-invasive outpatient treatment, however carries a substantial risk of the development of DBR. One of the first, although obvious, observations is the importance

Conflict of interest statement

•
Jaap D. Zindler has no personal conflicts of interest.
•
Ben J. Slotman has received payment for lectures (outside the scope of the manuscript) from Varian medical systems and BrainLAB AG.
•
Frank J. Lagerwaard has received payment for lectures (outside the scope of the manuscript) from Varian medical systems and BrainLAB AG.
•
Conflict of interest VUmc: Research agreements with Varian medical systems & BrainLAB AG.

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Immune checkpoint inhibitors (ICIs) have shown growing promise in the treatment of brain metastases, especially combined with stereotactic radiosurgery (SRS). The combination of ICIs with SRS has been studied for efficacy as well as increasing radiation necrosis risks. In this review, we compare clinical outcomes of radiation necrosis, intracranial control, and overall survival between patients with brain metastases treated with either SRS alone or SRS-ICI combination therapy.
A literature search of PubMed, Scopus, Embase, Web of Science, and Cochrane was performed in May 2023 for articles comparing the safety and efficacy of SRS/ICI versus SRS-alone for treating brain metastases.
The search criteria identified 1961 articles, of which 48 met inclusion criteria. Combination therapy with SRS and ICI does not lead to significant increases in incidence of radiation necrosis either radiographically or symptomatically. Overall, no difference was found in intracranial control between SRS-alone and SRS-ICI combination therapy. Combination therapy is associated with increased median overall survival. Notably, some comparative studies observed decreased neurologic deaths, challenging presumptions that improved survival is due to greater systemic control. The literature supports SRS-ICI administration within 4 weeks of another for survival but remains inconclusive, requiring further study for other outcome measures.
Combination SRS-ICI therapy is associated with significant overall survival benefit for patients with brain metastases without significantly increasing radiation necrosis risks compared to SRS alone. Although intracranial control rates appear to be similar between the 2 groups, timing of treatment delivery may improve control rates and demands further study attention.
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Whole-brain radiation therapy (WBRT) has commonly been prescribed to palliate symptoms from brain metastases, to reduce the risk of local relapse after surgical resection, and to improve distant brain control after resection or radiosurgery. While targeting micrometastases throughout the brain can be considered advantageous, the simultaneous exposure of healthy brain tissue might cause adverse events. Attempts to mitigate the risk of neurocognitive decline after WBRT include the selective avoidance of the hippocampi, among others. Besides selective dose reduction, dose escalation to boost volumes, for example, simultaneous integrated boost, aiming at increased tumor control probability is technically feasible. While up-front radiotherapy for newly diagnosed brain metastases often employs radiosurgery or other techniques targeting visible lesions only, sequential (delayed) salvage treatment with WBRT might still become necessary. In addition, the presence of leptomeningeal tumors or very widespread parenchymatous brain metastases might prompt clinicians to prescribe early WBRT.
Repeated irradiation of brain metastases under stereotactic conditions: A review of the literature
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La radiothérapie en conditions stéréotaxiques est devenue un standard dans la prise en charge des patients atteints de métastases cérébrales ; son principal intérêt est de différer la radiothérapie de l’encéphale en totalité pourvoyeur de toxicité neurocognitive et d’augmenter le taux de contrôle local. La répétition de sessions de radiothérapie en conditions stéréotaxiques n’est quant à elle pas codifiée, ni sur le nombre de sessions techniquement et cliniquement possible, ni sur le nombre, ni le volume de métastase à traiter. L’objectif de cette revue est d’analyser les données de la littérature concernant les irradiations répétées en conditions stéréotaxiques. La seconde réirradiation en conditions stéréotaxiques montre des résultats satisfaisants en termes de survie globale, de contrôle local et de toxicité. Cependant, nous manquons de données pour les patients recevant plus de deux sessions de radiothérapie en conditions stéréotaxiques, ainsi que pour définir des contraintes de dose aux tissus sains réirradiés. Des essais prospectifs restent nécessaires pour valider la prise en charge des métastases cérébrales après radiothérapie en conditions stéréotaxiques initiale.
Stereotactic radiotherapy has become a standard in the management of patients with brain metastases; its main interest is to differ whole brain radiotherapy, provider of neurocognitive toxicity and to increase the rate of local control. The repetition of radiotherapy sessions under stereotactic conditions is not codified, neither on the number of technically and clinically possible sessions, nor on the maximum total number or volume of metastases to be treated. The purpose of this review is to analyse the data in the literature concerning repeated irradiations under stereotactic conditions. The second reirradiation in stereotactic condition shows satisfactory results in terms of overall survival, local control, and toxicity. However, we lack data for patients receiving more than two sessions of SRS as well as to define dose constraints to reirradiated healthy tissues. Prospective trials are still needed to validate the management of recurrent brain metastases after initial SRS.
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Citation Excerpt :
High dose radiation in the form of stereotactic radiosurgery or fractionated regional radiation has become conventional therapy for patients with brain metastases and malignant gliomas respectively, as well as for patients with either that are not amenable to surgery [2,3]. Initial local control rates of tumor growth with radiation therapy are excellent but complications such as tumor recurrence and radiation necrosis can develop in these patients [4,5]. Specifically in these patients, differentiating between radiation necrosis and local tumor recurrence, which usually exhibit similar imaging findings, is a long-standing area of difficulty [6,7].
Given increasing interest in laser interstitial thermotherapy (LITT) to treat brain tumor patients, we explored if examining multiple MRI contrasts per brain tumor patient undergoing surgery can impact predictive accuracy of survival post-LITT.
MRI contrasts included fluid-attenuated inversion recovery (FLAIR), T1 pre-gadolinium (T1pre), T1 post-gadolinium (T1Gd), T2, diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC), susceptibility weighted images (SWI), and magnetization-prepared rapid gradient-echo (MPRAGE). The latter was used for MRI data registration across preoperative to postoperative scans. Two ROIs were identified by thresholding preoperative FLAIR (large ROI) and T1Gd (small ROI) images. For each MRI contrast, a numerical score was assigned based on changing image intensity of both ROIs (vs. a normal ROI) from preoperative to postoperative stages. The fully-quantitative method was based on changing image intensity across scans at different stages without any human intervention, whereas the semi-quantitative method was based on subjective criteria of cumulative trends across scans at different stages. A fully-quantitative/semi-quantitative score per patient was obtained by averaging scores for each MRI contrast. A standard neuroradiological reading score per patient was obtained from radiological interpretation of MRI data. Scores from all 3 methods per patient were compared against patient survival, and re-examined for comorbidity and pathology effects.
Patient survival correlated best with semi-quantitative scores obtained from T1Gd, ADC, and T2 data, and these correlations improved when biopsy and comorbidity were included.
These results suggest interfacing neuroradiological readings with semi-quantitative image analysis can improve predictive accuracy of patient survival.
Epidermal growth factor receptor mutation predicts favorable outcomes in non-small cell lung cancer patients with brain metastases treated with stereotactic radiosurgery
2018, Radiotherapy and Oncology
The impact of epidermal growth factor receptor (EGFR) mutations on radiotherapy for brain metastases (BM) is undetermined. We evaluated the effects of EGFR mutation status on responses and outcomes in non-small cell lung cancer (NSCLC) patients with BM, treated with upfront or salvage stereotactic radiosurgery (SRS).
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Stereotactic radiotherapy of the tumor bed compared to whole brain radiotherapy after surgery of single brain metastasis: Results from a randomized trial
2016, Radiotherapy and Oncology
To evaluate if neurological/cognitive function outcomes in patients with resected single brain metastasis (BM) after stereotactic radiotherapy of the tumor bed (SRT-TB) are not inferior compared to those achieved with whole-brain radiotherapy (WBRT).
Patients with total/subtotal resection of single BM were randomly assigned either to SRT-TB (n = 29) or WBRT (n = 30). SRT-TB arm consisted of 15 Gy/1 fraction, or 5 × 5 Gy. WBRT consisted of 30 Gy/10 fractions. Neurological/cognitive failure was defined as a decrease of neurological score by one point or more, or a worsening of the MiniMental test by at least 3 points, or neurological death. Cumulative incidence of neurological/cognitive failure (CINCF), neurological death (CIND), and overall survival (OS) were compared.
Median follow-up was 29 months (range: 8–45) for 15 patients still alive. The difference in the probability of CINCF at 6 months (primary endpoint) was −8% in favor of WBRT (95% confidence interval: +17% −35%; non-inferiority margin: −20%). In the intention-to-treat analysis, two-year CIND rates were 66% vs. 31%, for SRT-TB and WBRT arm, respectively, p = .015. The corresponding figures for OS were 10% vs. 37%, p = .046.
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¹: Current working address: Department of Radiation Oncology, Maastro Clinic, Maastricht, The Netherlands.

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CNS RadiosurgeryPatterns of distant brain recurrences after radiosurgery alone for newly diagnosed brain metastases: Implications for salvage therapy

Abstract

Introduction

Materials and methods

Results

Conclusions

Section snippets

Radiosurgery

Results

Discussion

Conflict of interest statement

Radiother Oncol

Radiother Oncol

Contr Clin Trials

Lancet Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases – a randomized controlled trial

JAMA

CNS Radiosurgery
Patterns of distant brain recurrences after radiosurgery alone for newly diagnosed brain metastases: Implications for salvage therapy