Background
Although there is no proven standard therapy for leptomeningeal metastases (LM), treatment often includes intrathecal chemotherapy combined with whole brain radiation therapy (WBRT). ...Little is known about the toxicity of such combination therapies. We performed a retrospective safety analysis for the combination of intrathecal liposomal cytarabine with WBRT in patients with LM and validated the EANO-ESMO (European Association of Neuro-oncology—European Society for Medical Oncology) classification in this unique cohort.
Methods
Treatment toxicities in patients diagnosed with LM between 2004 and 2014 were retrospectively analyzed according to RTOG (Radiation Therapy Oncology Group) toxicity criteria and NCI CTCAE V5.0 (National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0). Diagnostic criteria and treatment response as assessed by EANO-ESMO classification were correlated with survival by Kaplan–Meier analysis and Breslow test.
Results
In all, 40 patients with LM who were treated with combined WBRT and intrathecal cytarabine, were identified. Ten patients (25%) experienced adverse events ≥grade 3 according to RTOG toxicity criteria; in 22 patients (55%) NCI CTCAE ≥grade 3 were detected. Median overall survival was 124 days. Median time to neurological progression was 52 days. Patients with positive cerebrospinal fluid (CSF) cytology (
n
= 26) showed worse prognosis compared to patients with negative CSF cytology (
n
= 14; mOS (median overall survival) 84 days versus 198 days,
p
= 0.006, respectively). The EANO-ESMO response assessment was significantly associated with survival: “stable” (
n
= 7) mOS 233 days, “response” (
n
= 10) mOS 206 days, “progression” (
n
= 17) mOS 45 days, “suspicion of progression” (
n
= 6) mOS 133 days; overall,
p
< 0.001.
Conclusions
In this retrospective analysis, combined treatment of WBRT and intrathecal liposomal cytarabine shows an acceptable safety profile and may indicate a trend towards improved efficacy. The EANO-ESMO classification for diagnosis and treatment response predicts survival.
To evaluate safety and efficacy of stereotactic body radiotherapy (SBRT) for stage I non–small-cell lung cancer (NSCLC) in a patterns-of-care and patterns-of-outcome analysis.
The working group ...“Extracranial Stereotactic Radiotherapy” of the German Society for Radiation Oncology performed a retrospective multicenter analysis of practice and outcome after SBRT for stage I NSCLC. Sixteen German and Austrian centers with experience in pulmonary SBRT were asked to participate.
Data of 582 patients treated at 13 institutions between 1998 and 2011 were collected; all institutions, except one, were academic hospitals. A time trend to more advanced radiotherapy technologies and escalated irradiation doses was observed, but patient characteristics (age, performance status, pulmonary function) remained stable over time. Interinstitutional variability was substantial in all treatment characteristics but not in patient characteristics. After an average follow-up of 21 months, 3-year freedom from local progression (FFLP) and overall survival (OS) were 79.6% and 47.1%, respectively. The biological effective dose was the most significant factor influencing FFLP and OS: after more than 106 Gy biological effective dose as planning target volume encompassing dose (N = 164), 3-year FFLP and OS were 92.5% and 62.2%, respectively. No evidence of a learning curve or improvement of results with larger SBRT experience and implementation of new radiotherapy technologies was observed.
SBRT for stage I NSCLC was safe and effective in this multi-institutional, academic environment, despite considerable interinstitutional variability and time trends in SBRT practice. Radiotherapy dose was identified as a major treatment factor influencing local tumor control and OS.
Abstract Background and purpose To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT ) for modeling local tumor control probability (TCP) ...in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). Materials and methods This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1–8) and median single fraction dose was 12.5 Gy (2.9–33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60–100%). Assuming an α / β -value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs). Results There was strong evidence for a dose–response relationship in the total patient cohort (BFs > 20), which was lacking in single-fraction SBRT (BFs < 3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose ( dT ) at 11 Gy (68% CI 8–14 Gy) or 22 Gy (14–42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter ( p = 0.07, BF = 2.1 and p = 0.86, BF = 0.8, respectively). Generally, isocentric doses resulted in much better dose–response relationships than PTV encompassing doses (BFs > 20). Conclusion Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism.
Abstract Background and purpose To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and ...between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. Materials and methods A retrospective multi-institutional ( n = 22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. Results After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose–response relationship was observed in the primary NSCLC and metastatic cohort but dose–response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151–223) and 160 Gy (123–237) (n.s.), respectively. The dose–response relationship was not influenced by the primary cancer site within the metastatic cohort. Conclusions Dose–response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases.
Several prognostic factors for local tumor control probability (TCP) after stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) have been described, but no ...attempts have been undertaken to explore whether a nonlinear combination of potential factors might synergistically improve the prediction of local control.
We investigated a support vector machine (SVM) for predicting TCP in a cohort of 399 patients treated at 13 German and Austrian institutions. Among 7 potential input features for the SVM we selected those most important on the basis of forward feature selection, thereby evaluating classifier performance by using 10-fold cross-validation and computing the area under the ROC curve (AUC). The final SVM classifier was built by repeating the feature selection 10 times with different splitting of the data for cross-validation and finally choosing only those features that were selected at least 5 out of 10 times. It was compared with a multivariate logistic model that was built by forward feature selection.
Local failure occurred in 12% of patients. Biologically effective dose (BED) at the isocenter (BED(ISO)) was the strongest predictor of TCP in the logistic model and also the most frequently selected input feature for the SVM. A bivariate logistic function of BED(ISO) and the pulmonary function indicator forced expiratory volume in 1 second (FEV1) yielded the best description of the data but resulted in a significantly smaller AUC than the final SVM classifier with the input features BED(ISO), age, baseline Karnofsky index, and FEV1 (0.696 ± 0.040 vs 0.789 ± 0.001, P<.03). The final SVM resulted in sensitivity and specificity of 67.0% ± 0.5% and 78.7% ± 0.3%, respectively.
These results confirm that machine learning techniques like SVMs can be successfully applied to predict treatment outcome after SBRT. Improvements over traditional TCP modeling are expected through a nonlinear combination of multiple features, eventually helping in the task of personalized treatment planning.
Purpose: single-staged stereotactic radiosurgery (SRS) is an established part of the multimodal treatment in neuro-oncology. Radiation necrosis after high-dose irradiation is a known complication, ...but there is a lack of evidence about the risk factors. The aim of this study was to evaluate possible risk factors for radiation necrosis in patients undergoing radiosurgery. Methods: patients treated with radiosurgery between January 2004 and November 2020 were retrospectively analyzed. The clinical data, imaging and medication were gathered from electronic patient records. The largest diameter of the tumors was measured using MRI scans in T1 weighted imaging with gadolinium and the edema in T2 weighted sequences. The diagnosis of a radiation necrosis was established analyzing imaging criteria combined with clinical course or pathologically confirmed by subsequent surgical intervention. Patients developing radiation necrosis detected after SRS were compared to patients without evidence of an overshooting irradiation reaction. Results: 388 patients were included retrospectively, 61 (15.7%) of whom developed a radiation necrosis. Median follow-up was 24 (6–62) months with a radiation necrosis after 8 (6–12) months. The most frequent tumors were metastases in 47.2% of the cases, followed by acoustic neuromas in 32.2% and meningiomas in 13.4%. Seventy-three (18.9%) patients already underwent one or more previous radiosurgical procedures for different lesions. The mean largest diameter of the tumors amounted to 16.3 mm (±6.1 mm). The median—80%—isodose administered was 16 (14–25) Gy. Of the radiation necroses, 25 (43.1%) required treatment, in 23 (39.7%) thereof, medical treatment was applied and in 2 (3.4%) cases, debulking surgery was performed. In this study, significantly more radiation necroses arose in patients with higher doses (HR 1.3 CI 1.2; 1.5, p < 0.001) leading to a risk increment of over 180% between a radiation isodose of 14 and 20 Gy. The maximum diameter was a second significant risk factor (p = 0.028) with an HR of 1065 for every 1 mm increase in multivariate analysis. Conclusion: large diameter and high doses were reliable independent risk factors leading to more frequent radiation necroses, regardless of tumor type in patients undergoing radiosurgery. Alternative therapeutic procedures may be considered in lesions with large volume and an expected high radiation doses due to the increased risk of developing radiation necrosis.
The present study investigates the intrafractional accuracy of a frameless thermoplastic mask used for head immobilization during stereotactic radiotherapy. Non-invasive masks cannot completely ...prohibit head movements. Previous studies attempted to estimate the magnitude of intrafractional inaccuracy by means of pre- and postfractional measurements only. However, this might not be sufficient to accurately map also intrafractional head movements.
Intrafractional deviation of mask-fixed head positions was measured in five patients during a total of 94 fractions by means of close-meshed repeated ExacTrac measurements (every 1.4 min) conducted during the entire treatment session. A median of six (range: 4 to 11) measurements were recorded per fraction, delivering a dataset of 453 measurements.
Random errors (SD) for the x, y and z axes were 0.27 mm, 0.29 mm and 0.29 mm, respectively. Median 3D deviation was 0.29 mm. Of all 3D intrafractional motions, 5.5 and 0.4% exceeded 1 mm and 2 mm, respectively. A moderate correlation between treatment duration and mean 3D displacement was determined (r
= 0.45). Mean 3D deviation increased from 0.21 mm (SD = 0.26 mm) in the first 2 min to a maximum of 0.53 mm (SD = 0.31 mm) after 10 min of treatment time.
Pre- and post-treatment measurement is not sufficient to adequately determine the range of intrafractional head motion. Thermoplastic masks provide both reliable interfractional and intrafractional immobilization for image-guided stereotactic hypofractionated radiotherapy. Greater positioning accuracy may be obtained by reducing treatment duration (< 6 min) and applying intrafractional correction.
Clinicaltrials.gov, NCT03896555, Registered 01 April 2019 - retrospectively registered.
Background: Radiation necrosis (RN) is a possible late complication of stereotactic radiosurgery (SRS), but only a few risk factors are known. The aim of this study was to assess tumor location in ...correlation to the development of radiation necrosis for skull base (SB) and non-skull base tumors. Methods: All patients treated with radiosurgery for benign neoplasms (2004–2020) were retrospectively evaluated. The clinical, imaging and medication data were obtained and the largest axial tumor diameter was determined using MRI scans in T1-weighted imaging with gadolinium. The diagnosis of RN was established using imaging parameters. Patients with tumors located at the skull base were compared to patients with tumors in non-skull base locations. Results: 205 patients could be included. Overall, 157 tumors (76.6%) were located at the SB and compared to 48 (23.4%) non-SB tumors. Among SB tumors, the most common were vestibular schwannomas (125 cases) and meningiomas (21 cases). In total, 32 (15.6%) patients developed RN after a median of 10 (IqR 5–12) months. Moreover, 62 patients (30.2%) had already undergone at least one surgical resection. In multivariate Cox regression, SB tumors showed a significantly lower risk of radiation necrosis with a Hazard Ratio (HR) of 0.252, p < 0.001, independently of the applied radiation dose. Furthermore, higher radiation doses had a significant impact on the occurrence of RN (HR 1.372, p = 0.002). Conclusions: The risk for the development of RN for SB tumors appears to be low but should not be underestimated. No difference was found between recurrent tumors and newly diagnosed tumors, which may support the value of radiosurgical treatment for patients with recurrent SB tumors.
This study aims to evaluate the clinical outcome of stereotactic radiosurgery as the sole treatment for brain metastases and to assess prognostic factors influencing survival. A total of 108 ...consecutive patients with 213 metastases were retrospectively analyzed. Treatment was determined with close-meshed MRI follow-up. Various prognostic factors were assessed, and several prognostic indices were compared regarding their reliability to estimate overall survival. Median overall survival was 15 months; one-year overall survival was 50.5%. Both one- and two-year local controls were 90.9%. The rate of new metastases after SRS was 49.1%. Multivariate analysis of prognostic factors revealed that the presence of extracranial metastases, male sex, lower KPI, and progressive extracranial disease were significant risk factors for decreased survival. Of all evaluated prognostic indices, the Basic Score for Brain Metastases (BSBMs) showed the best correlation with overall survival. A substantial survival advantage was found for female patients after SRS when compared to male patients (18 versus 9 months,
= 0.003). SRS of brain metastasis is a safe and effective treatment option when frequent monitoring for new metastases with MRI is performed. Common prognostic scores lack reliable estimation of survival times. Female sex should be considered as an additional independent positive prognostic factor influencing survival.
Current literature regarding survival and treatment outcome of SBRT in patients with pulmonary oligometastatic head and neck squamous cell carcinoma (HNSCC) is limited. Additionally, most of the ...published studies include metastatic lesions deriving also from primaries with histologies other than SCC when investigating the outcome of SBRT. The aim of the present retrospective study is to explore local control (LC) of treated metastases, progression-free survival (PFS), and overall survival (OS) of exclusively pulmonary oligometastatic HNSCC-patients treated with SBRT. Between 2006 and 2021, a total of 46 patients were treated with SBRT for a maximum of four pulmonary oligometastases (PM) concurrently (mean PM per patient = 2.0; range 1 to 6 PM, total of 92). Of these, 17 patients (37.0%) developed new pulmonary metastases after their first SBRT. Repeated courses of SBRT were required once in 15 patients (88.2%) and twice in 2 patients (11.8%). Median follow-up was 17 months (range, 0–109 months). One year after completion of SBRT, LC rate, PFS, and OS were 98.7%, 37.9%, and 79.5%, respectively. After two years, LC rate, PFS, and OS were 98.7%, 28.7%, and 54.9%; as well as 98.7%, 16.7%, and 31.0% after five years. Radiochemotherapy (HR 2.72, p < 0.001) or radiotherapy as primary treatment (HR 8.60; p = 0.003), as well as reduced patient performance status (HR 48.30, p = 0.002), were associated with lower PFS. Inferior OS correlated with poor performance status (HR 198.51, p < 0.001) and surgery followed by radiochemotherapy (HR 4.18, p = 0.032) as primary treatment, as well as radiotherapy alone (HR 7.11, p = 0.020). Treatment of more than one PM is an independent predictor of impaired OS (HR 3.30, p = 0.016). SBRT of HNSCC-derived PMs results in excellent LC rates and encouraging OS rates of 54.9% at two years along with good tolerability (no more than grade 2 toxicities). Favourable outcome and low toxicity also apply to repeated courses of SBRT of newly emerging PMs.
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