Klaus-Henning Kahl

Brain metastases (BMs) are common in advanced cancers such as lung, breast, and melanoma, and carry a poor prognosis with high morbidity and local recurrence rates after surgery alone. Intraoperative radiotherapy (IORT) has emerged as a promising adjuvant treatment, delivering radiation directly to the resection cavity to reduce recurrence and minimize delays to systemic therapy. IORT also demonstrated more favorable dose homogeneity than single-fraction stereotactic radiosurgery, with fractionated IMRT achieving the highest uniformity. However, evidence regarding its efficacy and safety compared to non-IORT approaches remains limited. This meta-analysis synthesized data from 16 studies (2006–2023) involving 966 patients undergoing surgical resection of brain metastases, comparing outcomes between IORT (n = 616) and non-IORT (n = 350) groups. Key outcomes assessed included local control, overall survival (OS), distant brain control (DBC), postoperative complications, and adverse events. Meta-regression was used to explore associations between clinical factors and outcomes. IORT patients had significantly lower postoperative complication rates than non-IORT patients (risk ratio 0.52, 95% CI 0.43–0.62, p < 0.00001). Pooled local necrosis and postoperative mortality rates after IORT were low at 4.6% and 5.0%, respectively, with no significant variation by radiation dose or duration. The pooled local control rate (LCR) across eight studies was 92.5% (95% CI: 88.1–96.8%), despite moderate heterogeneity (I² = 65.4%, p = 0.005), highlighting IORT’s effectiveness in local tumor control. IORT was also linked to shorter hospital stays (mean 8.8 vs. 19 days) and comparable or improved local recurrence rates. Meta-regression showed a positive correlation between lesion size and mortality (p < 0.05). Distant brain control averaged 52.4%, with moderate-to-low risk of bias across studies. IORT following surgical resection of brain metastases is a safe and effective modality, offering reduced postoperative complications and promising local control while enabling faster initiation of systemic therapy. Delivering adequate radiation doses tailored to tumor biology and size is critical to minimize local recurrence. Future clinical trials should focus on optimizing IORT parameters and establishing standardized guidelines to improve patient outcomes.

Background: Malignant brain tumors, including gliomas and brain metastases, present therapeutic challenges due to their aggressive nature and high recurrence rates. Intraoperative radiotherapy (IORT) is a promising novel therapeutic approach that delivers immediate irradiation to the resection cavity. This may trigger a local and systemic immune response. However, the immunological effects of IORT remain poorly understood. Objectives: To investigate the immunomodulatory effects of IORT by analyzing perioperative profiles of inflammatory mediators (IMs) in patients undergoing surgical resection of malignant brain tumors. Design: A prospective observational cohort study comparing IM responses in patients undergoing brain tumor resection with and without IORT. Methods: In total, 44 patients undergoing surgical resection of brain tumors were included, with 20 receiving IORT and 24 serving as controls without IORT. In both groups, cerebrospinal fluid/wound fluid samples were collected from the resection cavity at several predefined intraoperative and postoperative time points. A multiplex proteomic assay was used to measure 19 IM involved in inflammation and immune activation. Results: IORT significantly increased the levels of seven IM (interleukin (IL)-1β, IL-6, IL-8, IP-10, MCP-1, MIP-1β, and VEGF) within the IORT group compared to baseline levels. When comparing to the non-IORT group, the increase in IL-1β was significantly greater for patients with metastases, while IL-10 also showed a trend toward significance. Conclusion: IORT induces distinct changes in levels of IM, which may contribute to improved tumor control. These findings provide novel insights into the immunomodulatory effects of IORT and may have implications for optimizing multimodal treatment strategies for malignant brain tumors. As an exploratory study with a limited sample size, the findings should be interpreted as hypothesis-generating.

Purpose: Due to significantly lower neurocognitive toxicity, whole-brain irradiation (WBI) has largely been replaced by focal irradiation of the resection cavity following brain metastasis surgery. However, the optimal treatment modality and fractionation scheme remain controversial. This study conducts a comparative analysis of hypofractionated stereotactic radiotherapy (HSRT) and intraoperative radiotherapy (IORT), focusing on clinical outcomes and toxicity profiles. Methods: A retrospective cohort study was conducted, analyzing 129 patients (HSRT: 72, IORT: 57) with 137 treated cavities (HSRT: 75, IORT: 62) at the University Hospital of Augsburg (UKA) between 2013 and 2021. Baseline characteristics, oncological outcomes, incidence of radionecrosis (RN), and time to further treatment were compared. Results: Radionecrosis occurred significantly less frequently in the IORT group compared to HSRT, with 1-year RN rates of 3.7% (95% CI: 0.5–23.5%) and 21.8% (95% CI: 11.7–39.2%), respectively (p = 0.00025). At two years, the RN rate remained substantially lower after IORT (8.5% vs. 53.2%). Notably, in patients without prior cerebral irradiation, no symptomatic RN (sRN) occurred following IORT, whereas the 2-year sRN rate in the HSRT group reached 35.5% (p = 0.0036). Oncological outcomes, including overall survival (OS), local control (LC), intracranial disease control, leptomeningeal dissemination (LMD), and WBI avoidance, were comparable between the two groups. However, distant brain control (DBC) at one year was higher in the HSRT group. While HSRT was initiated after a median delay of 29 days (range: 14–71), IORT was delivered intraoperatively, enabling immediate continuation of systemic therapy. Conclusion: In this retrospective single-center analysis, IORT demonstrated comparable oncological efficacy to HSRT while significantly reducing the risk of RN. Given its intraoperative delivery and the ability to promptly resume systemic therapy, and the precise application directly at the resection cavity, IORT may represent a practical and effective alternative in selected patients.

Purpose: With increasing use of human epithelial growth factor receptor two (HER2)-targeted therapies, outcomes for numerous breast cancer patients have improved. Nevertheless, patients with HER2-positive tumours face a comparatively heightened risk for developing brain metastases (BM), which are often treated with stereotactic radiosurgery (SRS). Radionecrosis represents one of the clinically most significant adverse events of SRS. However, a knowledge gap remains regarding the effects of concurrent use of HER2-targeted therapies with SRS on development of radionecrosis, given conflicting findings in existing studies. Methods: This systematic review was conducted in May 2024 through a search across electronic databases PubMed/MEDLINE and Cochrane library and was supplemented by citation searching and an artificial intelligence (AI) search. Results: The literature search yielded 194 articles. After applying eligibility criteria, a total of 13 studies with 3219 patients total were included, with approximately 270 patients in the topic-relevant subgroup. Investigated substances vary in different publications and include HER2 antibodies, antibody–drug conjugates (ADCs), such as trastuzumab emtansine (T-DM1), and kinase inhibitors. Four of six studies on ADCs demonstrated a higher risk for radionecrosis with concurrent administration. Two studies on lapatinib found no significant effects, as did as most studies investigating mainly HER2 antibodies. One publication reported an even lower risk for radionecrosis (RN) with concurrent use of HER2/EGFR tyrosine kinase inhibitors (TKIs). Conclusion: While concurrent use of T‑DM1/ADCs seems associated to elevated radionecrosis risk, an ambiguous situation for other substances persists. Heterogenous study designs with varying substances, definitions of concurrent use, and radionecrosis parameters must be considered. Included studies are partly limited by sample size and retrospective study design. Therefore, clinical implications remain difficult to claim; further research on this topic is needed.

Objectives: To analyze the results of interstitial (IRT) high-dose-rate (HDR) brachytherapy (BT) in the primary treatment of patients with unresectable superior sulcus tumors (SST) combined with external beam radiotherapy (EBRT). Methods: Between 2013 and 2023, seven patients with unresectable SST were treated with combined BT and EBRT with or without concomitant chemotherapy. The patients’ median age was 64 years (range, 49–79 years) and median tumor volume was 146.8 cm³ (range, 29.3–242.3 cm³). A median BT dose of 8 Gray (Gy) (range, 5–10 Gy) was prescribed and delivered in a single fraction. A median EBRT dose of 54 Gy (range, 30–59 Gy) was prescribed and administered normofractionated (single dose: 1.8 Gy). Results: We report the results of seven patients with SST treated with combined BT and EBRT and followed for a median of 38 months. The overall clinical response rate was 83.33% with five out of six patients achieving local control, while one out of six (16.66%) showed local and general progression. No deaths were attributed to the treatment itself; rather, one patient died during the course of therapy as a result of systemic progression. The most common radiation-related adverse events were grade I–II fatigue and mild paresthesia. No severe toxicity (CTCAE ≥ III°) was observed with interstitial high-dose-rate (HDR) BT combined with EBRT. Conclusions: For patients with unresectable superior sulcus tumors, interstitial HDR BT in combination with EBRT is a feasible treatment option that offers the potential for local control and long-term survival. The findings of this study should be validated in a larger patient cohort.

Purpose: Stereotactic radiotherapy (SRT) is the predominant method for the irradiation of resection cavities after resection of brain metastases (BM). Intraoperative radiotherapy (IORT) with 50 kV x-rays is an alternative way to irradiate the resection cavity focally. We have already reported the outcome of our first 40 IORT patients treated until 2020. Since then, IORT has become the predominant cavity treatment in our center due to patients´ choice. Methods: We retrospectively analyzed the outcomes of all patients who underwent resection of BM and IORT between 2013 and August 2023 at Augsburg University Medical Center (UKA). Results: We identified 105 patients with 117 resected BM treated with 50 kV x-ray IORT. Median diameter of the resected metastases was 3.1 cm (range 1.3 – 7.0 cm). Median applied dose was 20 Gy. All patients received standardized follow-up (FU) including three-monthly MRI of the brain. Mean FU was 14 months, with a median MRI FU for patients alive of nine months. Median overall survival (OS) of all treated patients was 18.2 months (estimated 1-year OS 57.7%). The observed local control (LC) rate of the resection cavity was 90.5% (estimated 1-year LC 84.2%). Distant brain control (DC) was 61.9% (estimated 1-year DC 47.9%). Only 16.2% of all patients needed WBI in the further course of disease. The observed radio necrosis rate was 2.6%. Conclusion: After 117 procedures IORT still appears to be a safe and appealing way to perform cavity RT after neurosurgical resection of BM with low toxicity and excellent LC.

Postsurgical radiotherapy (RT) has been early proven to prevent local tumor recurrence, initially performed with whole brain RT (WBRT). Subsequent to disadvantageous cognitive sequalae for the patient and the broad distribution of modern linear accelerators, focal irradiation of the tumor has omitted WBRT in most cases. In many studies, the effectiveness of local RT of the resection cavity, either as single-fraction stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic RT (hFSRT), has been demonstrated to be effective and safe. However, whereas prospective high-level incidence is still lacking on which dose and fractionation scheme is the best choice for the patient, further ablative techniques have come into play. Neoadjuvant SRS (N-SRS) prior to resection combines straightforward target delineation with an accelerated post-surgical phase, allowing an earlier start of systemic treatment or rehabilitation as indicated. In addition, low-energy intraoperative RT (IORT) on the surgical bed has been introduced as another alternative to external beam RT, offering sterilization of the cavity surface with steep dose gradients towards the healthy brain. This consensus paper summarizes current local treatment strategies for resectable brain metastases regarding available data and patient-centered decision-making.

Purpose: Does focal cavity radiotherapy after resection of brain metastasis “spare” whole-brain radiotherapy, which is associated with toxicity for patients, through the complete course of their disease without compromising long-term local control of the brain? Methods: We retrospectively analyzed outcomes of patients who underwent adjuvant focal cavity radiotherapy between 2014 and 2021 at our center. Results: A total of 83 patients with 86 resected brain metastases were analyzed. 64% had singular, 36% two to four brain metastases. In cases with multiple metastases, omitted lesions were treated with radiosurgery. Median follow-up was 7.3 months (range 0–71.2 months), 1‑year overall survival rate was 57.8% (95% CI 44.9–68.8%). Radiotherapy was administered with a median biologically effective dose (α/β 10) surrounding the planning target volume of 48 Gy (range 23.4–60 Gy). Estimated 1‑year local control rate was 82.7% (95% CI 67.7–91.2%), estimated 1‑year distant brain control rate was 55.7% (95% CI 40.5–68.4%), estimated 1‑year leptomeningeal disease rate was 16.0% (95% CI 7.3–32.9%). Eleven distant brain recurrences could be salvaged with radiosurgery. In the further course of disease, 14 patients (17%) developed disseminated metastatic disease in the brain. Estimated 1‑year free of whole-brain radiotherapy rate was 72.3% (95% CI 57.1–82.9%). All applied treatments led to an estimated 1‑year neuro-control rate of 79.1% (95% CI 65.0–88.0%), estimated 1‑year radionecrosis rate was 23% (95% CI 12.4–40.5%). Conclusion: In our single-center study, focal cavity radiotherapy was associated with high local control. In three out of four patients, whole-brain radiotherapy could be avoided in the complete course of disease, using radiosurgery as salvage approach without compromising neuro-control.