A matched-pair analysis comparing stereotactic radiosurgery with whole-brain radiotherapy for patients with multiple brain metastases.

INTRODUCTION: Stereotactic radiosurgery (SRS) is an emerging treatment for patients with multiple brain metastases (BM). The present work compares the SRS of multiple brain metastases with whole-brain radiotherapy (WBRT). METHODS: We performed a matched-pair analysis for 128 patients with multiple BM treated with either SRS or WBRT over a 5-year period. Patients were matched pairwise for seven potential prognostic factors. A mixed Cox Proportional Hazards model with univariate and multivariate analysis was fitted for overall survival (OS). Distant intracranial progression-free survival (icPFS) and local control were assessed using a Fine and Gray subdistribution hazard model and considering death as competing event. RESULTS: Patients undergoing SRS had a median of 4 BM (range 3-16). 1-year local control of individual BM following SRS was 91.7%. Median OS in the SRS subgroup was 15.7 months (IQR 9.7-36.4) versus 8.0 months (interquartile range, IQR 3.8-18.0) in the WBRT subgroup (HR 2.25, 95% CI [1.5; 3.5], p < 0.001). Median icPFS was 8.6 (IQR 3.4-18.0) versus 22.4 (IQR 5.6-28.6) months, respectively (HR for WBRT 0.41, 95% CI [0.24; 0.71], p = 0.001). Following SRS, synchronous BM diagnosis (HR 2.51, 95% CI [1.30; 4.70], p = 0.004), higher initial number of BM (HR 1.21, 95% CI [1.10; 1.40], p = 0.002) and lung cancer histology (HR 2.05, 95% CI [1.10; 3.80], p = 0.024) negatively impacted survival. Excellent clinical performance (KPI 90%) was a positive prognosticator (HR 0.38, 95% CI [0.20; 0.72], p = 0.003), as was extracerebral tumor control (HR 0.48, 95% CI [0.24; 0.97], p = 0.040). Higher initial (HR 1.19, 95% CI [1.00; 1.40], p < 0.013) and total number of BM (HR 1.23, 95% CI [1.10; 1.40], p < 0.001) were prognostic for shorter icPFS. CONCLUSION: This is the first matched-pair analysis to compare SRS alone versus WBRT alone for multiple BM. OS was prolonged in the SRS subgroup and generally favorable in the entire cohort. Our results suggest SRS as a feasible and effective treatment for patients with multiple BM.

Radiation induced contrast enhancement after proton beam therapy in patients with low grade glioma - How safe are protons?

PURPOSE: The optimal treatment strategy for low-grade glioma (LGG) is still a matter of controversy. Considering that the prognosis is typically favorable, the prevention of late sequelae is of particular importance. Proton beam therapy (PRT) has the potential to further reduce the burden of treatment related side effects. We set out to evaluate the clinical outcome of proton irradiation with a particular focus on morphologic features on magnetic resonance imaging (MRI). METHODS: We assessed prospectively 110 patients who received radiotherapy with protons for histologically proven LGG. Clinical and radiological information were analyzed resulting in more than 1200 available MRI examinations with a median follow-up of 39 months. Newly diagnosed contrast-enhancing lesions on MRI were delineated and correlated with parameters of the corresponding treatment plan. A voxel-based dose-matched paired analysis of the linear energy transfer (LET) inside vs outside lesions was performed. RESULTS: Proton beam irradiation of patients with low-grade glioma results in overall survival (OS) of 90% after seven years. Median progression free survival had not yet been reached with surviving fraction of 54% after seven years. The incidence of temporary or clinically silent radiation induced contrast enhancement was significantly higher than previously assumed, however, symptomatic radiation necrosis was only detected in one patient. These radiation-induced contrast-enhancing lesions were almost exclusively seen at the distal beam end of the proton beam. In 22 out of 23 patients, the average LET of voxels inside contrast-enhancing lesions was significantly increased, compared to dose-matched voxels outside the lesions. CONCLUSION: Symptomatic radiation necrosis following PRT was as rare as conventional photon-based treatment series suggest. However, the increased incidence of asymptomatic radiation-induced brain injuries with an increased average LET observed in this cohort provides strong clinical evidence to support the hypothesis that the relative biological effectiveness of protons is variable and different to the fixed factor of 1.1 currently used worldwide.

Stereotactic body radiotherapy (SBRT) for adrenal metastases of oligometastatic or oligoprogressive tumor patients.

INTRODUCTION: Local ablative treatment strategies are frequently offered to patients diagnosed with oligometastatic disease. Stereotactic body radiotherapy (SBRT), as ablative treatment option, is well established for lung and liver metastases, whereas for isolated adrenal gland metastases the level of evidence is scarce. MATERIAL AND METHODS: This single-institution analysis of oligometastatic or oligoprogressive disease was limited to patients who received SBRT to adrenal metastasis between 2012 and 2019. Patient, tumor, treatment characteristics, and dosimetric parameters were analyzed for evaluation of their effect on survival outcomes. RESULTS: During the period of review 28 patients received ablative SBRT to their adrenal gland metastases. Most common primary tumors were non-small cell lung cancers (46%) with most patients diagnosed with a single adrenal gland metastasis (61%), which occurred after a median time of 14 months. SBRT was delivered to a median biological effective dose at α/ß of 10 (BED10) of 75 Gy (range: 58-151 Gy). Median gross tumor volume (GTV) and median planning target volume (PTV) were 42 and 111 mL, respectively. The homogeneity and conformity indices were 1.17 (range: 1.04-1.64) and 0.5 (range: 0.4.0.99), respectively, with the conformity index being affected by dose restrictions to organs at risk (OARs) in 50% of the patients. Overall response rate based on RECIST criteria was 86% (CR = 29%, PR = 57%) with 2-year local control (LC) of 84.8%, 2-year progression-free survival (PFS) of 26.3%, and 1-and 2-year overall survival (OS) of 46.6 and 32.0%, respectively. During follow up, only two local recurrences occurred. A trend for superior LC was seen if BED10 was ≥75Gy (p = 0.101) or if the PTV was < 100 ml (p = 0.072). SBRT was tolerated well with only mild toxicity. CONCLUSION: SBRT for adrenal metastases resulted in promising LC with low toxicity. Treatment response appeared to be superior, if SBRT was applied with higher BED. As the close proximity of OARs often limits the application of sufficiently high doses, further dose escalations strategies and techniques should be investigated in future.

Secondary Malignancy Risk Following Proton vs. X-ray Treatment of Mediastinal Malignant Lymphoma: A Comparative Modeling Study of Thoracic Organ-Specific Cancer Risk.

Purpose: Proton radiotherapy (PRT) is potentially associated with a lower risk for secondary malignancies due to a decreased integral dose to the surrounding organs at risk (OARs). Prospective trials confirming this are lacking due to the need for long-term follow-up and the ethical complexities of randomizing patients between modalities. The objective of the current study is to calculate the risk for secondary malignancies following PRT and photon-based intensity-modulated radiotherapy (IMRT). Materials and Methods: Twenty-three patients (16 female and seven male), previously treated with active scanning PRT for malignant mediastinal lymphoma at Heidelberg Ion Beam Therapy Center, were retrospectively re-planned using helical photon IMRT. The risk for radiation-induced secondary malignancies was estimated and evaluated using two distinct prediction models (1-4). Results: According to the Dasu model, the median absolute total risk for tumor induction following IMRT was 4.4% (range, 3.3-5.8%), 9.9% (range, 2.0-27.6%), and 1.0% (range, 0.5-1.5%) for lung, breast, and esophageal cancer, respectively. For PRT, it was significantly lower for the aforementioned organs at 1.6% (range, 0.7-2.1%), 4.5% (range, 0.0-15.5), and 0.8% (range, 0.0-1.6%), respectively (p ≤ 0.01). The mortality risk from secondary malignancies was also significantly reduced for PRT relative to IMRT at 1.1 vs. 3.1% (p ≤ 0.001), 0.9 vs. 1.9% (p ≤ 0.001), and 0.7 vs. 1.0% (p ≤ 0.001) for lung, breast, and esophageal tumors, respectively. Using the Schneider model, a significant risk reduction of 54.4% (range, 32.2-84.0%), 56.4% (range, 16.0-99.4%), and 24.4% (range, 0.0-99.0%) was seen for secondary lung, breast, and esophageal malignancies, favoring PRT vs. X-ray-based IMRT (p ≤ 0.01). Conclusion: Based on the two prediction models, PRT for malignant mediastinal lymphoma is expected to reduce the risk for radiation-induced secondary malignancies compared with the X-ray-based IMRT. The young age and the long natural history of patients diagnosed with mediastinal lymphoma predisposes them to a high risk of secondary malignancies following curative radiotherapy treatment and, as a consequence, potentially reducing this risk by utilizing advanced radiation therapy techniques such as PRT should be considered.

Stereotactic Cavity Irradiation or Whole-Brain Radiotherapy Following Brain Metastases Resection-Outcome, Prognostic Factors, and Recurrence Patterns.

Introduction: Following the resection of brain metastases (BM), whole-brain radiotherapy (WBRT) is a long-established standard of care. Its position was recently challenged by the less toxic single-session radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) of the resection cavity, reducing dose exposure of the healthy brain. Patients and Methods: We analyzed 101 patients treated with either SRS/FSRT (n = 50) or WBRT (n = 51) following BM resection over a 5-year period. Propensity score adjustment was done for age, total number of BM, timepoint of BM diagnosis, controlled primary and extracranial metastases. A Cox Proportional Hazards model with univariate and multivariate analysis was fitted for overall survival (OS), local control (LC) and distant brain control (DBC). Results: Median patient age was 61 (interquartile range, IQR: 56-67) years and the most common histology was non-small cell lung cancer, followed by breast cancer. 38% of the patients had additional unresected BM. Twenty-four patients received SRS, 26 patients received FSRT and 51 patients received WBRT. Median OS in the SRS/FSRT subgroup was not reached (IQR NA-16.7 months) vs. 12.6 months (IQR 21.3-4.4) in the WBRT subgroup (hazard ratio, HR 3.3, 95%-CI: [1.5; 7.2] p < 0.002). Twelve-months LC-probability was 94.9% (95%-CI: [88.3; 100.0]) in the SRS subgroup vs. 81.7% (95%-CI: [66.6; 100.0]) in the WBRT subgroup (HR 0.2, 95%-CI: [0.01; 0.9] p = 0.037). Twelve-months DBC-probabilities were 65.0% (95%-CI: [50.8; 83.0]) and 58.8% (95%-CI: [42.9; 80.7]), respectively (HR 1.4, 95%-CI: [0.7; 2.7] p = 0.401). In propensity score-adjusted multivariate analysis, incomplete resection negatively impacted OS (HR 3.9, 95%-CI: [2.0;7.4], p < 0.001) and LC (HR 5.4, 95%-CI: [1.3; 21.9], p = 0.018). Excellent clinical performance (HR 0.4, 95%-CI: [0.2; 0.9], p = 0.030) and better graded prognostic assessment (GPA) score (HR 0.4, 95%-CI: [0.2; 1.0], p = 0.040) were prognostic of superior OS. A higher number of BM was associated with a greater risk of developing new distant BM (HR 5.6, 95%-CI: [1.0; 30.4], p = 0.048). In subgroup analysis, larger cavity volume (HR 1.1, 95%-CI: [1.0; 1.3], p = 0.033) and incomplete resection (HR 12.0, 95%-CI: [1.2; 118.3], p = 0.033) were associated with inferior LC following SRS/FSRT. Conclusion: This is the first propensity score-adjusted direct comparison of SRS/FSRT and WBRT following the resection of BM. Patients receiving SRS/FSRT showed longer OS and LC compared to WBRT. Future analyses will address the optimal choice of safety margin, dose and fractionation for postoperative stereotactic RT of the resection cavity.

Single-Isocenter Volumetric Modulated Arc Therapy vs. CyberKnife M6 for the Stereotactic Radiosurgery of Multiple Brain Metastases.

Introduction: Stereotactic radiosurgery (SRS) is becoming more frequently used for patients with multiple brain metastases (BMs). Single-isocenter volumetric modulated arc therapy (SI-VMAT) is an emerging alternative to dedicated systems such as CyberKnife (CK). We present a dosimetric comparison between CyberKnife M6 and SI-VMAT, planned at RayStation V8B, for the simultaneous SRS of five or more BM. Patients and Methods: Twenty treatment plans of CK-based single-session SRS to ≥5 brain metastases were replanned using SI-VMAT for delivery at an Elekta VersaHD linear accelerator. Prescription dose was 20 or 18 Gy, conformally enclosing at least 98% of the total planning target volume (PTV), with PTV margin-width adapted to the respective SRS technique. Comparatively analyzed quality metrics included dose distribution to the healthy brain (HB), including different isodose volumes, conformity, and gradient indices. Estimated treatment time was also compared. Results: Median HB isodose volumes for 3, 5, 8, 10, and 12 Gy were consistently smaller for CK-SRS compared to SI-VMAT (p < 0.001). Dose falloff outside the target volume, as expressed by the gradient indices GI_high and GI_low, was consistently steeper for CK-SRS compared to SI-VMAT (p < 0.001). CK-SRS achieved a median GI_high of 3.1 [interquartile range (IQR), 2.9-1.3] vs. 5.0 (IQR 4.3-5.5) for SI-VMAT (p < 0.001). For GI_low, the results were 3.0 (IQR, 2.9-3.1) for CK-SRS vs. 5.6 (IQR, 4.3-5.5) for SI-VMAT (p < 0.001). The median conformity index (CI) was 1.2 (IQR, 1.1-1.2) for CK-SRS vs. 1.5 (IQR, 1.4-1.7) for SI-VMAT (p < 0.001). Estimated treatment time was shorter for SI-VMAT, yielding a median of 13.7 min (IQR, 13.5-14.0) compared to 130 min (IQR, 114.5-154.5) for CK-SRS (p < 0.001). Conclusion: SI-VMAT offers enhanced treatment efficiency in cases with multiple BM, as compared to CyberKnife, but requires compromise regarding conformity and integral dose to the healthy brain. Additionally, delivery at a conventional linear accelerator (linac) may require a larger PTV margin to account for delivery and setup errors. Further evaluations are warranted to determine whether the detected dosimetric differences are clinically relevant. SI-VMAT could be a reasonable alternative to a dedicated radiosurgery system for selected patients with multiple BM.