Stereotactic radiotherapy for large solitary brain metastases

PurposeTo assess effectiveness and toxicity levels of stereotactic radiation therapy without whole brain radiation therapy in patients with solitary brain metastases larger than 3 cm.Patients and methodsBetween June 2007 and March 2009, 12 patients received fractionated stereotactic radiation therapy and 24 patients underwent stereotactic radiosurgery. For the fractionated stereotactic radiation therapy group, 3 × 7.7 Gy were delivered to the planning target volume (PTV); median volume and diameter were 29.4 cm³ and 4.4 cm, respectively. For the stereotactic radiosurgery group, 14 Gy were delivered to the PTV; median volume and diameter were 15.6 cm³ and 3.7 cm, respectively.ResultsMedian follow-up was 218 days. For the fractionated stereotactic radiation therapy group, local control rates were 100% at 360 days and 64% at 720 days; for the stereotactic radiosurgery group, rates were 58% at 360 days and 48% at 720 days (P = 0.06). Median survival time was 504 days for the fractionated stereotactic radiation therapy group and 164 days for the stereotactic radiosurgery group (P = 0.049). Two cases of grade 2 toxicity were observed in the fractionated stereotactic radiation therapy group, and 6 cases of grade 1–2 toxicity, in the stereotactic radiosurgery group.ConclusionsThis study provides data to support that fractionated stereotactic radiation therapy without whole brain radiation therapy with a margin dose of 3 fractions of 7.7 Gy for treatment of solitary large brain metastases is efficient and well-tolerated. Because of the significant improvement in overall survival, this schedule should be assessed in a randomized trial.     

Hypofractionated stereotactic radiotherapy for large brain metastases: Optimizing the dosimetric parameters

PurposeStereotactic radiotherapy plays a major role in the treatment of brain metastases (BM). We aimed to compare the dosimetric results of four plans for hypofractionated stereotactic radiotherapy (HFSRT) for large brain metastases.Material and methodsTen patients treated with upfront NovalisTx® non-coplanar multiple dynamic conformal arcs (DCA) HFSRT for ≥ 25 mm diameter single BM were included. Three other volumetric modulated arc therapy (VMAT) treatment plans were evaluated: with coplanar arcs (Eclipse®, Varian, VMATc_Eclipse®), with coplanar and non-coplanar arcs (VMATnc_Eclipse®), and with non-coplanar arcs (Elements Cranial SRS®, Brainlab, VMATnc_Elements®). The marginal dose prescribed for the PTV was 23.1 Gy (isodose 70%) in three fractions. The mean GTV was 27 mm³.ResultsBetter conformity indices were found with all VMAT techniques compared to DCA (1.05 vs 1.28, P < 0.05). Better gradient indices were found with VMATnc_Elements® and DCA (2.43 vs 3.02, P < 0.001). High-dose delivery in healthy brain was lower with all VMAT techniques compared to DCA (5.6 to 6.3 cc vs 9.4 cc, P < 0.001). Low-dose delivery (V5 Gy) was lower with VMATnc_Eclipse® or VMATnc_Elements® than with DCA (81 or 94 cc vs 110 cc, P = 0.02).ConclusionsNovalisTx® VMAT HFSRT for ≥ 25 mm diameter brain metastases provides the best dosimetric compromise in terms of target coverage, sparing of healthy brain tissue and low-dose delivery compared to DCA.     

Long duration of immunotherapy before radiosurgery might improve intracranial control of melanoma brain metastases

PurposeDespite significant advances that have been made in management of metastatic melanoma with immune checkpoint therapy, optimal timing of combination immune checkpoint therapy and stereotactic radiosurgery is unknown. We have reported toxicity and efficiency outcomes of patients treated with concurrent immune checkpoint therapy and stereotactic radiosurgery.Patients and methodsFrom January 2014 to December 2016, we analyzed 62 consecutive patients presenting 296 melanoma brain metastases, treated with gamma-knife and receiving concurrent immune checkpoint therapy with anti-CTLA4 or anti-PD1 within the 12 weeks of SRS procedure. Median follow-up time was 18 months (mo) (13–22). Minimal median dose delivered was 18 gray (Gy), with a median volume per lesion of 0.219 cm³.ResultsThe 1-year control rate per irradiated lesion was 89% (CI 95%: 80.41–98.97). Twenty-seven patients (43.5%) developed distant brain metastases after a median time of 7.6 months (CI 95% 1.8–13.3) after gamma-knife. In multivariate analysis, positive predictive factors for intracranial tumor control were: delay since the initiation of immunotherapy exceeding 2 months before gamma-knife procedure (P = 0.003) and use of anti-PD1 (P = 0.006). Median overall survival (OS) was 14 months (CI 95%: 11–NR). Total irradiated tumor volume < 2.1 cm³ was a positive predictive factor for overall survival (P = 0.003). Ten patients (16.13%) had adverse events following irradiation, with four grade ≥ 3. Predictive factors of all grade toxicity were: female gender (P = 0.001) and previous treatment with MAPK (P = 0.05).ConclusionA long duration of immune checkpoint therapy before stereotactic radiosurgery might improve intracranial tumor control, but this relationship and its ideal timing need to be assessed in prospective trials.     

Place de l’irradiation stéréotaxique hypofractionnée dans le traitement des métastases cérébrales

PurposeA survey of the literature has been performed to find arguments in order to help the choice between radiosurgery and hypofractionnated stereotactic radiotherapy in the treatment of brain metastases.Patients and methodsA comparison of two groups of brain metastases treated with hypofractionnated stereotactic radiotherapy or radiosurgery, with or without WBRT was performed. Hypofractionnated stereotactic radiotherapy: there were eight series including 448 patients published from 2000 to 2009; treated with 5–6 MV X-Rays, non invasive head immobilization, a margin 2 to 10 mm; 24 to 40 Gy in three to five fractions; a 5 to 8 days duration in six series and 15–16 days in two other series. WBRT (30%) ; radiosurgery: there were 12 series (1994 to 2005) including 2157 patients; an invasive head immobilization, no margin; doses from 10 to 25 Gy; six series over 12 had Gamma Knife radiosurgery and six had Linacs X-Rays. WBRT (30 Gy/10 F/12 days) associated to radiosurgery in several series. The following parameters were compared: median GTV, median survival, 1-year survival rate, local control rate, necrosis and WBRT rates.ResultsHypofractionnated stereotactic radiotherapy series: the parameters were respectively: 0,52–4,47 cm³ (median 2,8 cm³); 5–16 months (median 8,7 months); 68,2–93% (median 82,5%); necrosis rate 3,1%; associated WBRT 30%. Radiosurgery series: the parameters were respectively: 1,3 to 5,5 cm³ (median 2 cm³); 5,5 to 22 months (median 11 months); 71 to 95% (median 85%); 0,5 to 6% (median 2,4%); associated WBRT 58%. Results seem similar in the two groups: Hypofractionnated stereotactic radiotherapy with non invasive immobilization could theoretically treat all brain metastases sizes except lesions < 10 mm (500 mm³). In large volumes, > 4200 mm³ GTV, the toxicity of hypofractionnated stereotactic radiotherapy was not reported, thus it was difficult to compare its results with the published reports of radiosurgery toxicity. WBRT was a confusing parameter. Obviously, this initial survey has important limitations, specifically its methodology.ConclusionRadiosurgery and hypofractionnated stereotactic radiotherapy could be used to treat brain metastases with GTV > 500 mm³ and ≤ 4200 mm³ (Ø 20 mm); for GTV < 500 mm³ (Ø 10 mm) an invasive procedure with radiosurgery is necessary. For GTV > 4200 mm³ (Ø 20 mm), hypofractionnated stereotactic radiotherapy could be proposed, provided further studies, using 4 to 6 Gy fractions, a duration less or equal to 10–12 days and a margin of 2 mm will be performed.     

Radiothérapie stéréotaxique hypofractionnée des métastases cérébrales : bénéfice de l’irradiation encéphalique totale ?

Purpose

To study overall survival, risk of neurological death, local recurrence and development of new brain metastasis in patients treated for brain oligometastases with hypofractionated stereotactic radiotherapy with CyberKnife^®, according to the association or not with an additional whole brain irradiation.

Risque de radionécrose après radiothérapie hypofractionnée en conditions stéréotaxiques du lit opératoire de métastases cérébrales

Purpose

To investigate the factors that potentially lead to brain radionecrosis after hypofractionated stereotactic radiotherapy targeting the postoperative resection cavity of brain metastases.

Stereotactic radiotherapy following surgery for brain metastasis: Predictive factors for local control and radionecrosis

Purpose

To evaluate local control and adverse effects after postoperative hypofractionated stereotactic radiosurgery in patients with brain metastasis.

Radiation-induced lung toxicity predictors: Retrospective analysis of 90 patients treated with stereotactic body radiation therapy for stage I non-small-cell lung carcinoma

BackgroundThe main complication after hypofractionated radiotherapy for lung carcinoma is radiation-induced lung toxicity, which can be divided into radiation pneumonitis (acute toxicity, occurring within 6 months) and lung fibrosis (late toxicity, occurring after 6 months). The literature describes several predictive factors related to the patient, to the tumor (volume, central location), to the dosimetry and to biological factors.Materials and methodsThis study is a retrospective analysis of 90 patients treated with stereotactic body irradiation for stage I non-small-cell lung carcinoma between December 2010 and May 2015.ResultsRadiation pneumonitis was observed in 61.5% of the patients who were mainly asymptomatic (34%). Chronic obstructive pulmonary disease was not predictive of radiation pneumonitis, whereas active smoking was protective. Centrally located tumors were not more likely to result in this complication if the radiation schedule utilized adapted fractionation. In our study, no predictive factor was identified. Whereas the mean lung dose was a predictive factor in 3D radiotherapy, the lung volume irradiated at high doses seemed to be involved in the pathogenesis after hypofractionated radiotherapy.ConclusionThe discovery of predictive factors for radiation pneumonitis is difficult due to the rarity of this complication, especially with an 8 × 7.5 Gy schedule. Radiation pneumonitis seems to be correlated with the volume irradiated at high doses, which is in contrast to the known knowledge about the organs in parallel. This finding leads us to raise the hypothesis that vessel damage, organs in series, occurring during hypofractionated radiotherapy could be responsible for this toxicity.     

Application of a multi-institutional nomogram predicting salvage whole brain radiation-free survival to patients treated with postoperative stereotactic radiotherapy for brain metastases

PurposeThe ultimate goal of stereotactic radiotherapy (SRT) of brain metastases (BM) is to avoid or postpone whole brain radiotherapy (WBRT). A nomogram based on multi-institutional data was developed by Gorovets, et al. to estimate the 6 and 12-months WBRT-free survival (WFS). The aim of the current retrospective study was to validate the nomogram in a cohort of postoperative BM patients treated with adjuvant SRT.Material and methodsWe reviewed the data of 68 patients treated between 2008–2017 with postoperative SRT for BM. The primary endpoint was the WFS. The receiver operating characteristic curve and area under the curve (AUC) were calculated for both 6- and 12-months time points.ResultsAfter a median follow-up of 64 months, the 1-year cumulative incidence of local and distant brain relapse rates were 15% [95% CI = 8–26%] and 34% [95% CI = 24–48%], respectively. At recurrence, repeated SRT or salvage WBRT were applied in 33% and 57% cases, respectively. The WFS rates at 6 and 12 months were 88% [95% CI = 81–97%] and 67% [95% CI = 56–81%], respectively. Using the Gorovets nomogram, the 6 months rates were overestimated while they were accurate at 12 months. AUC values were 0.47 and 0.62 for the 6- and 12-months respectively. Overall, Harrell's concordance index was 0.54.ConclusionThis nomogram-predicted well the 12 months WFS but its discriminative power was quite low. This underlines the limits of this kind of predictive tool and leads us to consider the use of big data analysis in the future.     

Fractionated Stereotactic Radiation Therapy for Pituitary Adenomas: An alternative escalating protocol of hypofractionated stereotactic radiotherapy delivering 35 Gy in 5 fractions

PurposeEvaluate efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) for patients treated for pituitary adenoma (PA) with an alternative HSRT escalating protocol delivering 35 Gy in 5 fractions.Material and methodsFrom June 2007 to March 2017, 29 patients with pituitary adenoma were treated in Antoine Lacassagne Cancer Centre with an alternative HSRT protocol. Prescribed dose was 35 Gy in 5 fractions of 7 Gy. Radiographic responses were assessed by annual MRI. Hormone blood samples were evaluated each year after HSRT.ResultsA total of 29 patients aged between 23 and 86 years (median 54 years) were included. Twelve patients received HSRT for recurrent cases and 12 received postoperative adjuvant HSRT, 5 patients did not have surgery. After a median follow-up period of 47 months local control rate was 96%. One patient presented an out-field tumor regrowth 73 months after HSRT. The majority of PA were endocrine-active (18 patients, 62%). After HSRT, 8 patients (44%) presented complete response on initial secretion, 4 patients (23%) presented partial response on initial secretion. Four patients (14%) presented grade 2 or more acute radiation toxicities. One grade 4 visual disorder was observed for one patient.ConclusionsHSRT delivering 35 Gy in 5 fractions represents a feasible treatment and shows promising results to reduce hormonal overproduction and to improve local control in PA.     

Intrafraction variations in linac-based image-guided radiosurgery of intracranial lesions

PurposeThis study investigated image-guided patient positioning during frameless, mask-based, single-fraction stereotactic radiosurgery of intracranial lesions and intrafractional translational and rotational variations in patient positions.Patients and methodsA non-invasive head and neck thermoplastic mask was used for immobilization. The Exactrac/Novalis Body system (BrainLAB AG, Germany) was used for kV X-ray imaging guided positioning. Intrafraction displacement data, obtained by imaging after each new table position, were evaluated.ResultsThere were 269 radiosurgery treatments performed on 190 patients and a total of 967 setups within different angles. The first measured error after each table rotation (mean 2.6) was evaluated (698 measurements). Intrafraction translational errors were (1 standard deviation [SD]) on average 0.8, 0.8, and 0.7 mm for the left–right, superior–inferior, and anterior–posterior directions, respectively, with a mean 3D-vector of 1.0 mm (SD 0.9 mm) and a range from –5 mm to +5 mm. On average, 12%, 3%, and 1% of the translational deviations exceeded 1, 2, and 3 mm, respectively, in the three directions.ConclusionThe range of intrafraction patient motion in frameless image-guided stereotactic radiosurgery is often not fully mapped by pre- and post-treatment imaging. In the current study, intrafraction motion was assessed by performing measurements at several time points during the course of stereotactic radiosurgery. It was determined that 12% of the intrafraction values in the three dimensions are above 1 mm, the usual safety margin applied in stereotactic radiosurgery.     

Contraintes de dose en radiothérapie conformationnelle fractionnée et en radiothérapie stéréotaxique dans les hippocampes,le tronc cérébral et l’encéphale : limites et perspectives

Cerebral radiation-induced toxicities after radiotherapy (RT) of brain tumors are frequent. The protection of organs at risk (OAR) is crucial, especially for brain tumors, to preserve cognition in cancer survivors. Dose constraints of cerebral OAR used in conventional RT, radiosurgery (SRS) and stereotactic radiotherapy (SRT) are debated. In fact, they are based on historical cohorts or calculated with old mathematical models. Values of α/β ratio of cerebral OAR are also controversial leading to misestimate the equivalent dose in 2 Gy fractions or the biological equivalent dose, especially during hypofractionated RT. Although recent progresses in medical imaging, the diagnosis of radionecrosis remains difficult. In this article, we propose a large review of dose constraints used for three major cerebral OAR: the brain stem, the hippocampus and the brain.     

Radionécrose après radiothérapie stéréotaxique d’une métastase cérébrale de 3 cm : la technique peut-elle améliorer les résultats dosimétriques ?

Stereotactic radiotherapy is a major issue in the management of brain metastases. Radionecrosis is a major concern, especially for large lesions. Optimizing dosimetric parameters is essential to allow optimal local control rate while minimizing potential toxicity. We report the case of a 30-mm brain metastases treated with stereotactic radiotherapy after initial whole brain radiotherapy, complicated with symptomatic radionecrosis. A dose of 24 Gy in three fractions on the 80% isodose were delivered using a dynamic conformal arc technique (Novalis TX^®). We realized a dosimetric comparison with: (i) optimization of initial conformal arc plan, (ii) volumetric modulated arctherapy with coplanar arcs and (iii) volumetric modulated arctherapy with coplanar and non-coplanar arcs. The optimal dose planning in terms of planning target volume coverage (99.2%) and normal brain sparing (V24 Gy = 0.4 cm³, V18 Gy = 6.5cm³, V10 Gy = 25.4 cm³, V5 = 83.9 cm³) was obtained with volumetric modulated arctherapy with coplanar and non-coplanar arcs. Volumetric modulated arctherapy-based stereotactic irradiation with coplanar and non-coplonar arcs seems an interesting option for the treatment of large brain metastases to optimize dosimetric parameters.     

Fiduciels intraprostatiques dans le cadre de la radiothérapie stéréotaxique du cancer de la prostate

PurposeImage-guided radiotherapy for prostate cancer is widely used in radiotherapy departments. Intraprostatic gold fiducial markers are used to visualize prostate position and motion before and during treatment. The aim of this report is to describe our experience of implanting intraprostatic fiducial markers under local anesthesia before hypofractionated stereotactic radiotherapy for prostate cancer and to assess its tolerance and reproducibility.Patients and methodsOver a 6 and a half year period, 226 patients with prostate cancer received a stereotactic radiotherapy using the CyberKnife^® system (Accuray) in our institution. Eighteen patients were treated for recurrence after prostatectomy; these patients were excluded from the study. Among the 208 remaining patients, 94 patients (45.2%) received stereotactic radiotherapy as a boost after external beam radiotherapy (three fractions of 6 Gy); 36 patients (17.3%) were had a re-irradiation (six fractions of 6 Gy) and 78 patients (37.5%) had a exclusive stereotactic radiotherapy (68 patients received five fractions of 7.25 Gy and 11 patients five fractions of 6.25 Gy). Four markers were implanted in all patients using transrectal ultrasound; the procedure was performed under local anesthesia, using transperineal access. The four fiducial markers were implanted in two strands with two fiducial each one, 1 cm apart. In order to follow the recommendations of the image-guided radiotherapy system, the two strands of the two markers were located on the same plane in the middle of the prostate, at least 2 cm apart from the midline. After insertion, correct positioning of fiducials markers was verified by X-ray. Dosimetry scanning was performed after the implantation procedure; prostate position tracking was possible before and during treatment through the kilovoltage incorporated system of the robotic accelerator. Clinical data, X-ray verification and dosimetry scanner have been retrospectively reviewed for all patients.ResultsThe tolerance to procedure was excellent; only four patients (1.8%) described pain related to implant. No urinary side effects were reported. Median time from fiducial implantation to dosimetry scanner was 16 days (4–113 days). Four fiducials were found within the prostate at dosimetry scanner in 181 patients and three in 27 remaining patients. All intraprostatic fiducials were used to track the prostate gland before and during treatment.ConclusionsIntraprostatic fiducial markers implantation is a safe and reproducible procedure that allows us to have reliable prostate information before and during stereotactic radiotherapy.     

Clinical outcome after CyberKnife® radiosurgery re-irradiation for recurrent brain metastases

PurposeThe objective of this study was to elucidate the impact on clinical outcomes resulting from re-irradiation for locally recurrent (LR) brain metastases (BM) using CyberKnife® stereotactic radiosurgery (SRS).Materials and methodsSeventy-seven patients with 254 LR BM lesions treated using SRS re-irradiation between January 2014 and December 2018 were analysed in this retrospective study. The local control (LC), overall survival (OS) rates, and adverse events were assessed. The adverse events were classified according to the Common terminology for adverse event (CTCAE) v5.0.ResultsThe median follow-up duration was 8.9 months. The median age of the patients was 55 years (IQR: 47–62). The 3, 6, and 9-month LC and OS rates were 92.2%, 73.4%, and 73.4% and 79.2%, 61.0%, and 48.1%, respectively. On multivariate analysis the gender (male vs. female; HR, 1.79; 95% CI, 1.06–3.01; P = 0.028), type of first brain radiation (WBI vs. SRS) followed by re-irradiation using SRS (HR, 9.32; 95% CI, 2.77–15.27; P < 0.001) tumour volume (> 12cc vs. ≤ 12cc; HR, 1.84; 95% CI, 1.10–3.11; P = 0.02), and recursive partitioning analysis (RPA) (I vs. II & III; HR, 0.38; 95% CI, 0.19–0.70; P = 0.001) were independent predictive factor for OS. Radionecrosis was reported in 3 patients.ConclusionWith acceptable toxicity, SRS re-irradiation for LR BM showed a favourable rate for LC and OS and reported better OS for the female gender, a patient undergoing first brain radiation with SRS, tumour volume ≤ 12cc, and RPA-I. This result needs to be further evaluated in future clinical studies.     

Comparison between the HyperArc™ technique and the CyberKnife® technique for stereotactic treatment of brain metastases

PurposeThe purpose of this study was to compare the planimetric capacities between HyperArc™-based stereotactic radiosurgery and robotic radiosurgery system-based planning using CyberKnife® M6 for single and multiple cranial metastases.Materials and methodsWe evaluated 51 treatment plans for cranial metastases, including 30 patients with a single lesion and 21 patients with multiple lesions, treated with the CyberKnife® M6. These treatment plans were optimized using the HyperArc™ (HA) system with the TrueBeam. The comparison of the quality of the treatment plans between the two treatment techniques (CyberKnife and HyperArc) was performed using the Eclipse treatment planning system. Dosimetric parameters were compared for target volumes and organs at risk.ResultsCoverage of the target volumes was equivalent between the two techniques, whereas median Paddick conformity index and median gradient index for all target volumes were 0.9 and 3.4, respectively for HyperArc plans, and 0.8 and 4.5 for CyberKnife plans (P < 0.001). The median dose of gross tumor volume (GTV) for HyperArc and CyberKnife plans were 28.4 and 28.8, respectively. Total brain V18 Gy and V12Gy-GTVs were 11 cm³ and 20.2cm³ for HyperArc plans versus 18 cm³ and 34.1 cm³ for CyberKnife plans (P < 0.001).ConclusionThe HyperArc provided better brain sparing, with a significant reduction in V12 Gy and V18 Gy, associated with a lower gradient index, whereas the CyberKnife gave a higher median GTV dose. The HyperArc technique seems to be more appropriate for multiple cranial metastases and for large single metastatic lesions.     

Meningioma of the skull base: Long-term outcome after image-guided stereotactic radiotherapy

PurposeThe purpose of this study was to analyse the feasibility, safety, and long-term efficacy of linear accelerator-based fractionated stereotactic radiotherapy for meningiomas of the skull base. We evaluated the long-term clinical outcome of patients and identified prognostic factors after fractionated stereotactic radiotherapy.Patients and methodsBetween 10/1995 and 03/2009, 136 patients with a median age of 57 years with skull base meningioma received fractionated stereotactic radiotherapy. A total of 34 patients had a grade I meningioma, in 102 cases no histology was obtained (grade 0). Fractionated stereotactic radiotherapy was delivered as primary treatment for 57 patients and postoperatively for 79. The patients received a mean total dose of 56.95 (min/max 32.4/63) Gy.ResultsMedian follow-up was 44.9 months. Overall progression-free survival was 96.9% after 3 years, 93.8% after 5 years, and 91.5% after 10 years. Patients with unknown histology showed progression-free survival rates of 100%, 98.7%, and 93.5% at 3, 5, and 10 years and patients with biopsy-proven grade I meningioma showed rates of 100% after 3 years, 91.7% after 5 years and 85.9% after 10 years. Patients with adjuvant radiotherapy showed significantly worse progression-free survival rates than patients who had been treated with primary radiotherapy (P = 0.043), progression-free survival rates were independent of tumour size. The most common acute grade I symptoms were headache, fatigue, and local alopecia. The most common chronic grade I symptoms were fatigue and headache.ConclusionsThis large study showed that fractionated stereotactic radiotherapy is an effective and safe treatment modality with high progression-free survival rates for intracranial meningioma. We identified “prior surgery” as significant poor prognostic factor.