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Advances in Stereotactic Radiotherapy of Brain Metastases

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (15 April 2024) | Viewed by 14853

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Special Issue Editors

Prof. Dr. Florian Wur̈schmidt

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Guest Editor

Department of Radiotherapy, Radiology Allianz, Hamburg, Germany
Interests: brain metastases; neurosurgery; stereotactic treatment

Prof. Dr. Bodo Lippitz

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Guest Editor

Interdisciplinary Centre for Radiosurgery (ICERA), Radiology Allianz, Hamburg, Germany
Interests: neurosurgery; brain tumors; gamma knife treatment

Special Issue Information

Dear Colleagues,

Brain metastases occur in 10 to 30% of adult cancer patients. Without local treatment, overall survival was historically limited to a couple of weeks. Over the past several years, the treatment of brain metastases became increasingly individualized, and progress in systemic therapy now offers better treatment options and the possibility of disease control both extra- and intracranially. Patient quality of life has significantly moved into the focus when selecting oncological treatments, resulting in a more holistic and multidisciplinary approach to cancer. With increasing length of survival, more cancer patients appear to develop brain metastases, which, unless swiftly treated, cause neurological symptoms and become life-threatening. Brain metastases require fast and effective tumor control with the avoidance of functional deficits, while systemic treatment should not be compromised. Unfortunately, standard treatments do not always fulfill these requirements. Increasingly, focal therapies are prevailing.

So far, a rather stationary focus of research and publications has been on the ‘optimal’ treatment of brain metastases, while the ‘real-life’ perspective has moved on. With more effective systemic treatments, we are clinically dealing with a ‘new’ dimension of oncological therapy: time. Rather than considering the generally best treatment of a brain metastasis, we must accept that there are a variety of answers in a short-term perspective. The truly complicated question concerns the longer-term effects of our therapy and the strategies to deal with our treatment failures. Despite recent significant progress, neither cancer chemotherapy nor immunotherapy alone are sufficiently effective in the treatment of brain metastases.

Very little data are available on how to combine our treatments to cover a longer period of time. What are the realistic interferences, and do they have an impact on our choices? What are the quantitative limits in terms of numbers of tumors or volumes? We have learned that the occurrence of brain metastases is not a single event, as new brain metastases occur with a stochastic probability. It is a myth that successful systemic therapies prevent new brain metastases. We do not have sufficient data on either issue. In our dealing with brain metastases, we must enter a new level of complexity: the use of focal treatments over time, with the focus on the combination and repetition of treatments, on long-term management.

The aim of this Special Issue is to initiate a discussion around these novel developments, with the goal of providing clinical answers with a translational perspective. In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

What do we know about the importance of immune effects in stereotactic irradiation of brain metastases?
Single fraction vs. fractionated stereotactic radiotherapy of brain metastases—one fits all?
Staged radiosurgery of large brain metastases.
Preoperative stereotactic radiotherapy or postoperative radiotherapy of metastatic bed.
Can we safely retreat brain metastases after previous stereotactic radiotherapy?
Do we still need whole-brain irradiation for brain metastases? Pro/con discussion.
Treatment of brain metastases: single event or long-term management.
Treatment of oligometastatic brain metastases.

We are pleased to invite you to contribute to this Special Issue, and look forward to receiving your contributions.

Prof. Dr. Florian Wur̈schmidt
Prof. Dr. Bodo Lippitz
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

brain metastases
radiosurgery
multiple brain metastases
long-term management
combined modality treatment
immune modulation
immunotherapy
stereotactic radiotherapy
adverse radiation effect
reirradiation

Published Papers (8 papers)

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Research

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13 pages, 1299 KiB

Open AccessArticle

Stereotactic Radiation Therapy for Brain Metastases: Factors Affecting Outcomes and Radiation Necrosis

by Angela Barillaro, Mara Caroprese, Laura Cella, Anna Viggiano, Francesca Buccelli, Chiara Daponte, Chiara Feoli, Caterina Oliviero, Stefania Clemente, Antonio Farella, Manuel Conson and Roberto Pacelli

Cancers 2023, 15(7), 2094; https://doi.org/10.3390/cancers15072094 - 31 Mar 2023

Cited by 1 | Viewed by 1667

Abstract

Stereotactic radiation therapy (SRT) is a proven effective treatment for brain metastases (BM); however, symptomatic radiation necrosis (RN) is a late effect that may impact on patient’s quality of life. The aim of our study was to retrospectively evaluate survival outcomes and characterize the occurrence of RN in a cohort of BM patients treated with ablative SRT at Federico II University Hospital. Clinical and dosimetric factors of 87 patients bearing a total of 220 BMs treated with SRT from 2016 to 2022 were analyzed. Among them, 46 patients with 127 BMs having clinical and MRI follow-up (FUP) ≥ 6 months were selected for RN evaluation. Dosimetric parameters of the uninvolved brain (brain without GTV) were extracted. The crude local control was 91% with neither clinical factors nor prescription dose correlating with local failure (LF). At a median FUP of 9 (1–68) months, the estimated median overall survival (OS), progression-free survival (PFS), and brain progression-free survival (bPFS) were 16, 6, and 9 months, respectively. The estimated OS rates at 1 and 3 years were 59.8% and 18.3%, respectively; bPFS at 1 and 3 years was 29.9% and 13.5%, respectively; PFS at 1 and 3 years was 15.7% and 0%, respectively; and local failure-free survival (LFFS) at 1 and 3 years was 87.2% and 83.8%, respectively. Extracranial disease status was an independent factor related to OS. Fourteen (30%) patients manifested RN. At multivariate analysis, adenocarcinoma histology, left location, and absence of chemotherapy were confirmed as independent risk factors for any-grade RN. Nine (20%) patients developed symptomatic (G2) RN, which improved or stabilized after 1–16 months of steroid therapy. With prompt recognition and, when necessary, medical therapy, RN radiological and clinical amelioration can be obtained. Full article

(This article belongs to the Special Issue Advances in Stereotactic Radiotherapy of Brain Metastases)

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16 pages, 7552 KiB

Open AccessArticle

Dosimetric Impact of Lesion Number, Size, and Volume on Mean Brain Dose with Stereotactic Radiosurgery for Multiple Brain Metastases

by Alonso La Rosa, D Jay J. Wieczorek, Ranjini Tolakanahalli, Yongsook C. Lee, Tugce Kutuk, Martin C. Tom, Matthew D. Hall, Michael W. McDermott, Minesh P. Mehta, Alonso N. Gutierrez and Rupesh Kotecha

Cancers 2023, 15(3), 780; https://doi.org/10.3390/cancers15030780 - 27 Jan 2023

Viewed by 1923

Abstract

We evaluated the effect of lesion number and volume for brain metastasis treated with SRS using GammaKnife^® ICON™ (GK) and CyberKnife^® M6™ (CK). Four sets of lesion sizes (<5 mm, 5–10 mm, >10–15 mm, and >15 mm) were contoured and prescribed a dose of 20 Gy/1 fraction. The number of lesions was increased until a threshold mean brain dose of 8 Gy was reached; then individually optimized to achieve maximum conformity. Across GK plans, mean brain dose was linearly proportional to the number of lesions and total GTV for all sizes. The numbers of lesions needed to reach this threshold for GK were 177, 57, 29, and 10 for each size group, respectively; corresponding total GTVs were 3.62 cc, 20.37 cc, 30.25 cc, and 57.96 cc, respectively. For CK, the threshold numbers of lesions were 135, 35, 18, and 8, with corresponding total GTVs of 2.32 cc, 12.09 cc, 18.24 cc, and 41.52 cc respectively. Mean brain dose increased linearly with number of lesions and total GTV while V8 Gy, V10 Gy, and V12 Gy showed quadratic correlations to the number of lesions and total GTV. Modern dedicated intracranial SRS systems allow for treatment of numerous brain metastases especially for ≤10 mm; clinical evidence to support this practice is critical to expansion in the clinic. Full article

(This article belongs to the Special Issue Advances in Stereotactic Radiotherapy of Brain Metastases)

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12 pages, 279 KiB

Open AccessArticle

Dosimetric Parameters in Hypofractionated Stereotactic Radiotherapy for Brain Metastases: Do Flattening Filter-Free Beams Bring Benefits? A Preliminary Study

by Diana M. Ghemiș and Loredana G. Marcu

Cancers 2023, 15(3), 678; https://doi.org/10.3390/cancers15030678 - 21 Jan 2023

Viewed by 1318

Abstract

Purpose: This study aimed to compare the dosimetric results of flattening filter-free (FFF) vs. flattened (FF) treatment plans for fractionated stereotactic radiotherapy (fSRT), with the goal to highlight potential advantages of FFF beams. Methods: A group of 18 patients with brain metastases treated with fSRT (30 Gy delivered in 5 fractions) were included. The dosimetric parameters evaluated were: (1) physical dosimetric parameters (number of monitor units (MUs), conformity index (CI), dose gradient index (DGI), beam on time (BOT)); (2) clinical dosimetric parameters pertaining to target volume (PTV) and organs at risk (OARs). Two treatment plans were performed for all patients: one used 6 MV FFF beams and the other used 6 MV flattened beams. Results: A slight increase in MUs was observed for the FFF mode (+23.3 MUs). The CI showed a difference of −2.7% for the FF plans (p = 0.28), correlated with a poorer coverage of the PTV. DGI values reported in terms of PTV are in line with international recommendations and showed a +1.9% difference for FFF plans. An average BOT of 90.3 s was reported for FFF plans, which was 2.3 times shorter than that required for FF plans delivery (p ≤ 0.001). A slight decrease of PTV coverage (−1.26%, p = 0.036) for FF plans can be considered relevant, but no other significant differences were observed between the two optimizations. No statistically significant benefit of using FFF beams to reduce V₂₀ for normal brain could be demonstrated. Conclusion: These dosimetric results encourage the implementation of fSRT with standard flattened beams in centers where FFF linacs are not available. Full article

(This article belongs to the Special Issue Advances in Stereotactic Radiotherapy of Brain Metastases)

11 pages, 897 KiB

Open AccessArticle

Associated Factors of Spontaneous Hemorrhage in Brain Metastases in Patients with Lung Adenocarcinoma

by Song Soo Kim, Seoyoung Lee, Mina Park, Bio Joo, Sang Hyun Suh and Sung Jun Ahn

Cancers 2023, 15(3), 619; https://doi.org/10.3390/cancers15030619 - 19 Jan 2023

Cited by 2 | Viewed by 2043

Abstract

Background: Hemorrhage in brain metastases (BMs) from lung cancer is common and associated with a poor prognosis. Research on associated factors of spontaneous hemorrhage in patients with BMs is limited. This study aimed to investigate the predictive risk factors for BM hemorrhage and assess whether hemorrhage affects patient survival. Methods: We retrospectively evaluated 159 BMs from 80 patients with lung adenocarcinoma from January 2017 to May 2022. Patients were classified into hemorrhagic and non-hemorrhagic groups. Patient demographics, lung cancer molecular subtype, treatment type, and tumor–node–metastasis stage were compared between the groups. Multivariate generalized estimating equation (GEE) analysis and gradient boosting were performed. To determine whether BM hemorrhage can stratify overall survival after BM (OSBM), univariate survival analysis was performed. Results: In the univariate analysis, hemorrhagic BMs were significantly larger and had a history of receiving combination therapy with tyrosine kinase inhibitor (TKI) and intracranial radiation (p < 0.05). Multivariate GEE showed that tumor size and combination therapy were independent risk factors for BM hemorrhage (p < 0.05). Gradient boosting demonstrated that the strongest predictor of BM hemorrhage was tumor size (variable importance: 49.83), followed by age (16.65) and TKI combined with intracranial radiation (13.81). There was no significant difference in OSBM between the two groups (p = 0.33). Conclusions: Hemorrhage in BMs from lung adenocarcinomas may be associated with BM tumor size and a combination of TKI and intracranial radiotherapy. BM hemorrhage did not affect OSBM. Full article

(This article belongs to the Special Issue Advances in Stereotactic Radiotherapy of Brain Metastases)

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Review

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33 pages, 2819 KiB

Open AccessReview

Modern Stereotactic Radiotherapy for Brain Metastases from Lung Cancer: Current Trends and Future Perspectives Based on Integrated Translational Approaches

by Mario Levis, Alessio Gastino, Greta De Giorgi, Cristina Mantovani, Paolo Bironzo, Luca Mangherini, Alessia Andrea Ricci, Umberto Ricardi, Paola Cassoni and Luca Bertero

Cancers 2023, 15(18), 4622; https://doi.org/10.3390/cancers15184622 - 18 Sep 2023

Cited by 2 | Viewed by 1591

Abstract

Brain metastases (BMs) represent the most frequent metastatic event in the course of lung cancer patients, occurring in approximately 50% of patients with non-small-cell lung cancer (NSCLC) and in up to 70% in patients with small-cell lung cancer (SCLC). Thus far, many advances have been made in the diagnostic and therapeutic procedures, allowing improvements in the prognosis of these patients. The modern approach relies on the integration of several factors, such as accurate histological and molecular profiling, comprehensive assessment of clinical parameters and precise definition of the extent of intracranial and extracranial disease involvement. The combination of these factors is pivotal to guide the multidisciplinary discussion and to offer the most appropriate treatment to these patients based on a personalized approach. Focal radiotherapy (RT), in all its modalities (radiosurgery (SRS), fractionated stereotactic radiotherapy (SRT), adjuvant stereotactic radiotherapy (aSRT)), is the cornerstone of BM management, either alone or in combination with surgery and systemic therapies. We review the modern therapeutic strategies available to treat lung cancer patients with brain involvement. This includes an accurate review of the different technical solutions which can be exploited to provide a “state-of-art” focal RT and also a detailed description of the systemic agents available as effective alternatives to SRS/SRT when a targetable molecular driver is present. In addition to the validated treatment options, we also discuss the future perspective for focal RT, based on emerging clinical reports (e.g., SRS for patients with many BMs from NSCLC or SRS for BMs from SCLC), together with a presentation of innovative and promising findings in translational research and the combination of novel targeted agents with SRS/SRT. Full article

(This article belongs to the Special Issue Advances in Stereotactic Radiotherapy of Brain Metastases)

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13 pages, 1725 KiB

Open AccessReview

PRO: Do We Still Need Whole-Brain Irradiation for Brain Metastases?

by Ilinca Popp, Nanna E. Hartong, Carsten Nieder and Anca-L. Grosu

Cancers 2023, 15(12), 3193; https://doi.org/10.3390/cancers15123193 - 15 Jun 2023

Viewed by 1641

Abstract

(1) Background: In recent decades, the use of whole-brain radiation therapy (WBRT) in the treatment of brain metastases has significantly decreased, with clinicians fearing adverse neurocognitive events and data showing limited efficacy regarding local tumor control and overall survival. The present study thus aimed to reassess the role that WBRT holds in the treatment of brain metastases. (2) Methods: This review summarizes the available evidence from 1990 until today supporting the use of WBRT, as well as new developments in WBRT and their clinical implications. (3) Results: While one to four brain metastases should be exclusively treated with radiosurgery, WBRT does remain an option for patients with multiple metastases. In particular, hippocampus-avoidance WBRT, WBRT with dose escalation to the metastases, and their combination have shown promising results and offer valid alternatives to local stereotactic radiotherapy. Ongoing and published prospective trials on the efficacy and toxicity of these new methods are presented. (4) Conclusions: Unlike conventional WBRT, which has limited indications, modern WBRT techniques continue to have a significant role to play in the treatment of multiple brain metastases. In which situations radiosurgery or WBRT should be the first option should be investigated in further studies. Until then, the therapeutic decision must be made individually depending on the oncological context. Full article

(This article belongs to the Special Issue Advances in Stereotactic Radiotherapy of Brain Metastases)

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15 pages, 942 KiB

Open AccessSystematic Review

Stereotactic Radiation Therapy of Single Brain Metastases: A Literature Review of Dosimetric Studies

by Isabelle Chambrelant, Delphine Jarnet, Jolie Bou-Gharios, Clara Le Fèvre, Laure Kuntz, Delphine Antoni, Catherine Jenny and Georges Noël

Cancers 2023, 15(15), 3937; https://doi.org/10.3390/cancers15153937 - 02 Aug 2023

Viewed by 924

Abstract

Stereotactic radiotherapy (SRT) plays a major role in treating brain metastases (BMs) and can be delivered using various equipment and techniques. This review aims to identify the dosimetric factors of each technique to determine whether one should be preferred over another for single BMs treatment. A systematic literature review on articles published between January 2015 and January 2022 was conducted using the MEDLINE and ScienceDirect databases, following the PRISMA methodology, using the keywords “dosimetric comparison” and “brain metastases”. The included articles compared two or more SRT techniques for treating single BM and considered at least two parameters among: conformity (CI), homogeneity (HI) and gradient (GI) indexes, delivery treatment time, and dose-volume of normal brain tissue. Eleven studies were analyzed. The heterogeneous lesions along with the different definitions of dosimetric indexes rendered the studied comparison almost unattainable. Gamma Knife (GK) and volumetric modulated arc therapy (VMAT) provide better CI and GI and ensure the sparing of healthy tissue. To conclude, it is crucial to optimize dosimetric indexes to minimize radiation exposure to healthy tissue, particularly in cases of reirradiation. Consequently, there is a need for future well-designed studies to establish guidelines for selecting the appropriate SRT technique based on the treated BMs’ characteristics. Full article

(This article belongs to the Special Issue Advances in Stereotactic Radiotherapy of Brain Metastases)

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15 pages, 1003 KiB

Open AccessSystematic Review

Neoadjuvant Stereotactic Radiotherapy for Brain Metastases: Systematic Review and Meta-Analysis of the Literature and Ongoing Clinical Trials

by Paolo Palmisciano, Gianluca Ferini, Ramlah Khan, Othman Bin-Alamer, Giuseppe E. Umana, Kenny Yu, Aaron A. Cohen-Gadol, Tarek Y. El Ahmadieh and Ali S. Haider

Cancers 2022, 14(17), 4328; https://doi.org/10.3390/cancers14174328 - 04 Sep 2022

Cited by 8 | Viewed by 2489

Abstract

Background: Brain metastases (BMs) carry a high morbidity and mortality burden. Neoadjuvant stereotactic radiotherapy (NaSRT) has shown promising results. We systematically reviewed the literature on NaSRT for BMs. Methods: PubMed, EMBASE, Scopus, Web-of-Science, Cochrane, and ClinicalTrial.gov were searched following the PRISMA guidelines to include studies and ongoing trials reporting NaSRT for BMs. Indications, protocols, and outcomes were analyzed using indirect random-effect meta-analyses. Results: We included 7 studies comprising 460 patients with 483 BMs, and 13 ongoing trials. Most BMs originated from non-small lung cell carcinoma (41.4%), breast cancer (18.7%) and melanoma (43.6%). Most patients had single-BM (69.8%) located supratentorial (77.8%). Patients were eligible if they had histologically-proven primary tumors and ≤4 synchronous BMs candidate for non-urgent surgery and radiation. Patients with primary tumors clinically responsive to radiotherapy, prior brain radiation, and leptomeningeal metastases were deemed non-eligible. Median planning target volume was 9.9 cm³ (range, 2.9–57.1), and NaSRT was delivered in 1-fraction (90.9%), 5-fraction (4.8%), or 3-fraction (4.3%), with a median biological effective dose of 39.6 Gy10 (range, 35.7–60). Most patients received piecemeal (76.3%) and gross-total (94%) resection after a median of 1-day (range, 1–10) post-NaSRT. Median follow-up was 19.2-months (range, 1–41.3). Actuarial post-treatment rates were 4% (95%CI: 2–6%) for symptomatic radiation necrosis, 15% (95%CI: 12–18%) and 47% (95%CI: 42–52%) for local and distant recurrences, 6% (95%CI: 3–8%) for leptomeningeal metastases, 81% (95%CI: 75–87%) and 59% (95%CI: 54–63%) for 1-year local tumor control and overall survival. Conclusion: NaSRT is effective and safe for BMs. Ongoing trials will provide high-level evidence on long-term post-treatment outcomes, further compared to adjuvant stereotactic radiotherapy. Full article

(This article belongs to the Special Issue Advances in Stereotactic Radiotherapy of Brain Metastases)

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