Outcomes and the Role of Primary Histology Following LINAC-based Stereotactic Radiation for Sarcoma Brain Metastases.

OBJECTIVES: The brain is a rare site for sarcoma metastases. Sarcoma's radioresistance also makes standard whole-brain radiotherapy less appealing. We hypothesize that stereotactic radiation techniques (stereotactic radiosurgery [SRS]/stereotactic fractionated radiotherapy [FSRT]) may provide effective local control. MATERIALS AND METHODS: This single-institution retrospective analysis evaluated our experience with linear acceleator-based SRS/FSRT for sarcoma brain metastases. Time to event analysis was estimated via Kaplan-Meier. Univariable/multivariable Cox regression analyses followed to assess the impact of patient and disease characteristics on outcomes. RESULTS: Between 2003 and 2018, 24 patients were treated with 34 courses of SRS/FSRT to 58 discrete lesions. The median age at first treatment was 57 years (range: 25 to 87 y). Majority of patients had concurrent lung metastases (n=21; 88%), diagnosed spindle cell sarcoma (n=15; 25%) or leiomyosarcoma (n=12; 21%) histology, and were treated with either SRS (n=43; median dose=19 Gy, range: 15 to 24 Gy) or FSRT (n=17; 3/5 fractions, median dose=25 Gy, range: 25 to 35 Gy). With a median follow-up after brain metastasis of 7.3 months, the 6 month/12 month local control, distant brain control, and overall survival of 89%/89%, 59%/34%, and 50%/38%, respectively. All local failures were of primary spindle cell histology (P<0.001), which was associated with poorer distant control (hazard ratio=25.8, 95% confidence interval: 3.1-536.4; P=0.003) on univariable analysis, and OS (hazard ratio=7.1, 95% confidence interval: 2.0-26.1; P=0.003) on multivariable analysis. CONCLUSIONS: This is the largest patient cohort with sarcoma brain metastases treated with SRS/FSRT, it provides durable local control, despite a reputation for radioresistance. Further prospective evidence is required to determine the impact of primary histology on control and survival following brain metastasis diagnosis.

Postoperative Stereotactic Radiosurgery Using 5-Gy × 5 Sessions in the Management of Brain Metastases.

BACKGROUND: Multiple regimens for stereotactic radiosurgery (SRS) at the postoperative bed have shown a high local control rate and a low toxicity profile with no decrease in overall survival with the omission of whole-brain radiation therapy. METHODS: In this retrospective analysis, we evaluate our experience with postoperative SRS using a uniform regimen of 25 Gy in 5 sessions. RESULTS: Between April 2011 and May 2014, 75 patients were treated for 77 metastatic brain lesions with postoperative SRS in 5 sessions. The median planning target volume was 13.8 cm(3) (1.93-128.43 cm(3)) with a median follow-up for all lesions of 9.5 months (range, 1.2-38.2 months). Kaplan-Meier estimates of local control at 1 and 2 years were 88.8% and 83.9%, respectively. On univariate analysis, a trend in decreased survival with multiple brain lesions was noted (hazard ratio [HR] = 2; 95% confidence interval [CI], 0.87-4.53; P = 0.10). There was a trend towards decreased local control with radioresistant tumors (HR = 3.23; 95% CI, 0.7-22.6; P = 0.14) and planning target volume ≥17 cm(3) (HR = 3.07; 95% CI, 0.73-15.23; P = 0.12). Two (3%) patients developed radionecrosis, one of whom required craniotomy. CONCLUSIONS: SRS with a dose of 25 Gy in 5 sessions is associated with excellent local control at the resection site with minimal toxicity in the postoperative settings in our patient population. Further investigation is required to determine if dose escalation to the postoperative cavity of radioresistant tumors improves outcomes.

Outcomes Following Hypofractionated Stereotactic Radiotherapy in the Management of Brain Metastases.

OBJECTIVE: To evaluate the outcomes of patients treated with hypofractionated stereotactic radiotherapy (HSRT) for radiosensitive and radioresistant brain metastases. METHODS: Between August 2006 and July 2013, a total of 56 lesions in 44 patients with brain metastases were treated with HSRT. Twenty-three (41.1%) lesions were radioresistant. Patients were treated to a total dose of 24 to 30 Gy in 3 to 5 fractions. Median planning target volume was 6.18 cm. The primary endpoint for this study was local control with secondary endpoints of overall survival, distant failure, performance status, and treatment toxicity. RESULTS: The median follow-up for all patients was 5 months (range, 0.4 to 58.3 mo). Six- and 12-month Kaplan-Meier estimates of local control for all lesions were 85.6% and 79.4%, respectively. Radioresistant tumors had a 6- and 12-month local control rate of 87.0%, whereas radiosensitive tumors had a 6- and 12-month local control rate of 82.5% and 72.2%, respectively (P=0.41). Six- and 12-month distant brain control rates were 56.8% and 46.9%, respectively. Overall survival was significantly associated with recursive partitioning analysis classes I, II, and III (P=0.0003) and graded prognostic assessment classes 2 to 3 and 1 to 1.5 (P=0.041). CONCLUSIONS: HSRT is a safe and feasible alternative to single-session stereotactic radiosurgery for brain metastases. No difference was observed in local control rates between radioresistant and radiosensitive tumors.

Potential role for LINAC-based stereotactic radiosurgery for the treatment of 5 or more radioresistant melanoma brain metastases.

OBJECT: Linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) is a treatment option for patients with melanoma in whom brain metastases have developed. Very limited data are available on treating patients with ≥5 lesions. The authors sought to determine the effectiveness of SRS in patients with ≥5 melanoma brain metastases. METHODS: A retrospective analysis of metastatic melanoma treated with SRS in a single treatment session for ≥5 lesions was performed. Magnetic resonance imaging studies were reviewed post-SRS to evaluate local control (LC). Disease progression on imaging was defined using the 2009 Response Evaluation Criteria in Solid Tumors (RECIST). Survival curves were calculated from the date of brain metastases diagnosis or the date of SRS by using the Kaplan-Meier (KM) method. Univariate and multivariate analysis (UVA and MVA, respectively) were performed using the Cox proportional-hazards model. RESULTS: The authors identified 149 metastatic brain lesions treated in 28 patients. The median patient age was 60.5 years (range 38-83 years), and the majority of patients (24 [85.7%]) had extracranial metastases. Four patients (14.3%) had received previous whole-brain radiotherapy (WBRT), and 11 (39.3%) had undergone previous SRS. The median planning target volume (PTV) was 0.34 cm3 (range 0.01-12.5 cm3). Median follow-up was 6.3 months (range 1-46 months). At the time of treatment, 7% of patients were categorized as recursive partitioning analysis (RPA) Class I, 89% as RPA Class II, and 4% as RPA Class III. The rate of local failure was 11.4%. Kaplan-Meier LC estimates at 6 and 12 months were 91.3% and 82.2%, respectively. A PTV volume≥0.34 cm3 was a significant predictor of local failure on UVA (HR 16.1, 95% CI 3.2-292.6, p<0.0001) and MVA (HR 14.8, 95% CI 3.0-268.5, p=0.0002). Sixteen patients (57.1%) were noted to have distant failure in the brain with a median time to failure of 3 months (range 1-15 months). Nine patients with distant failures received WBRT, and 7 received additional SRS. Median overall survival (OS) was 9.4 and 7.6 months from the date of brain metastases diagnosis and the date of SRS, respectively. The KM OS estimates at 6 and 12 months were 57.8% and 28.2%, respectively, from the time of SRS treatment. The RPA class was a significant predictor of KM OS estimates from the date of treatment (p=0.02). Patients who did not receive WBRT after SRS treatment had decreased OS on MVA (HR 3.5, 95% CI 1.1-12.0, p=0.03), and patients who did not receive WBRT prior to SRS had improved OS (HR 0.11, 95% CI 0.02-0.53, p=0.007). CONCLUSIONS: Stereotactic radiosurgery for ≥5 lesions appears to be effective for selected patients with metastatic melanoma, offering excellent LC. This is particularly important for patients as new targeted systemic agents are improving outcomes but still have limited efficacy within the central nervous system.

LINAC-based stereotactic radiosurgery to the brain with concurrent vemurafenib for melanoma metastases.

While selective BRAF inhibitors have demonstrated improved outcomes in patients with metastatic BRAF V600E mutant melanoma, management of brain metastases prior to and during therapy presents challenges. Stereotactic radiosurgery (SRS) is an effective treatment for melanoma brain metastases, but there is limited safety and efficacy data on the use of SRS during BRAF therapy. An analysis was performed of patients with metastatic melanoma and brain metastases treated with SRS while on vemurafenib. MRI scans were reviewed post-SRS to evaluate local control (LC) as well as distant control. We identified 80 metastatic melanoma brain lesions treated in 24 patients. The median planning target volume was 0.28 cm(3) (range 0.05-4.19 cm(3)), and lesions were treated to a median dose of 24 Gy (range 15-24 Gy). The median follow up was 5.1 months (range 2-25.2 months). Eight (10 %) lesions showed progression at a median of 6.1 months (range 2-20.1 months) following SRS. Kaplan-Meier LC estimates at 6 and 12 months were 92 and 75 %, respectively. Fourteen (58 %) patients were noted to have distant brain failure at a median of 3.4 months (range 1.9-16.1 months) following treatment with SRS. Median overall (OS) from the date of SRS was 7.2 months (range 1.5-26.8 months) with a median of 11.9 months (range 1.5-28.5 months) since the date of brain metastases diagnosis. There was no evidence of increased toxicity with the combination of SRS and vemurafenib. SRS to brain metastases appears to be both safe and effective for patients treated concurrently with BRAF inhibitors.

Fractionated stereotactic radiotherapy to the post-operative cavity for radioresistant and radiosensitive brain metastases.

Following surgical resection for brain metastases, fractionated stereotactic radiotherapy (FSRT) has been used as an alternative to single dose treatment for large cavities and to reduce risks of late toxicity. The purpose of this study was to evaluate the outcomes of patients treated with FSRT to the post-operative bed for both radioresistant and radiosensitive brain metastases. Between December 2009 and May 2013 a total of 65 patients with newly diagnosed brain metastases were treated with resection followed by FSRT. Patients were treated to a total dose of 20-30 Gy in five fractions. Median planning target volume (PTV) was 16.88 cm(3) (range 4.87-128.43 cm(3)). The median follow-up for all patients was 8.5 months (range 1.1-28.6 months) with a median of 12.9 months for living patients. One and two year Kaplan-Meier estimates of local control were 87.0 and 70.0 %, respectively. Local control at 1 year was 85.6 and 88.0% for radioresistant and radiosensitive tumors, respectively (p = 0.44). A PTV ≥17 cm(3), was associated with local failure, HR 8.63 ((1.44-164.78); p = 0.02). One and two year distant control rates were 50.9 and 46.2%, respectively with six patients (9.2%) experiencing leptomeningeal disease. OS rates at 1 and 2 years were 65.2 and 47.5%, respectively. Survival was significantly associated with recursive partitioning analysis class (p = 0.001) and graded prognostic assessment score (p = 0.005). One case of radionecrosis was noted on follow-up imaging. FSRT in five fractions offers excellent local control in both radiosensitive and radioresistant tumors with minimal toxicity.

Clinical and dosimetric predictors of radiation pneumonitis in a large series of patients treated with stereotactic body radiation therapy to the lung.

PURPOSE: To report clinical and dosimetric factors predictive of radiation pneumonitis (RP) in patients receiving lung stereotactic body radiation therapy (SBRT) from a series of 240 patients. METHODS AND MATERIALS: Of the 297 isocenters treating 263 patients, 240 patients (n=263 isocenters) had evaluable information regarding RP. Age, gender, current smoking status and pack-years, O2 use, Charlson Comorbidity Index, prior lung radiation therapy (yes/no), dose/fractionation, V5, V13, V20, Vprescription, mean lung dose, planning target volume (PTV), total lung volume, and PTV/lung volume ratio were recorded. RESULTS: Twenty-nine patients (11.0%) developed symptomatic pneumonitis (26 grade 2, 3 grade 3). The mean V20 was 6.5% (range, 0.4%-20.2%), and the average mean lung dose was 5.03 Gy (0.547-12.2 Gy). In univariable analysis female gender (P=.0257) and Charlson Comorbidity index (P=.0366) were significantly predictive of RP. Among dosimetric parameters, V5 (P=.0186), V13 (P=.0438), and Vprescription (where dose=60 Gy) (P=.0128) were significant. There was only a trend toward significance for V20 (P=.0610). Planning target volume/normal lung volume ratio was highly significant (P=.0024). In multivariable analysis the clinical factors of female gender, pack-years smoking, and larger gross internal tumor volume and PTV were predictive (P=.0094, .0312, .0364, and .052, respectively), but no dosimetric factors were significant. CONCLUSIONS: Rate of symptomatic RP was 11%. Our mean lung dose was <600 cGy in most cases and V20<10%. In univariable analysis, dosimetric factors were predictive, while tumor size (or tumor/lung volume ratio) played a role in multivariable and univariable and analysis, respectively.

Dosimetric analysis of modulated and hybrid arcs in stereotactic radiosurgery.

PURPOSE: Forward-planned conformal arcs (termed dynamic arcs in the BrainLab iPlan system) have been routinely used in cranial stereotactic radiosurgery (SRS) for many yeras. This study compares dosimetric parameters of the newer, inversely-planned volumetric modulated arc therapy (VMAT) and VMAT-conformal hybrid plans with conformal arc plans. In the hybrid plans, various numbers of conformal arcs in a conformal plan are replaced with VMAT arcs. METHODS: Ten brain cancer cases previously treated on a Novalis accelerator for frameless cranial stereotactic radiosurgery using conformal arcs generated by BrainLab iPlan treatment planning system were retrospectively studied with various numbers of VMAT arcs replacing the conformal arcs. Pure VMAT plans of different numbers of arcs were also generated using the same angle and arc length setup for all or part of the conformal arcs and compared with both the original and hybrid plans. Pinnacle version 9.0 was used for treatment plan generation. SmartArc was used for the VMAT planning for a Novalis accelerator. The conformity index (CI), defined as the ratio of the isodose volume to the isodose covered target volume, gradient index (GI), defined as the ratio of the 50% isodose volume (V50) to the 100% isodose volume, volume covered by 12 Gy isodose (V12), mean dose and standard deviation of dose in target were studied. RESULTS: With one of the conformal arcs replaced with a VMAT arc of the same weighting and geometric setup, the average CI with one standard deviation was improved from 1.35 ± 0.18 to 1.29 ± 0.15 (p-value 0.03), while the average GI degraded from 3.8 ± 1.0 to 4.9 ± 1.5 (p-value < 0.01). The degraded GI in the VMAT plans is due to the absence of beam margin limit in SmartArc planning. Pure VMAT plans usually demonstrated better CI values than the hybrid and conformal arc plans when the number of arcs was greater than 2. The GI value was improved with increasing number of arcs in VMAT plans. For target volumes greater than 1 cc, VMAT plans demonstrated improved CI and smaller V50 and V12 than that in conformal arc plans. Better dose fall-off in normal tissue in VMAT plans is accompanied with higher dose heterogeneity in the target volume. CONCLUSION: VMAT and conformal-VMAT hybrid plans usually offer better target conformity. The dose fall-off in normal tissue is also better in VMAT plans when the number of arcs is greater than 3 and target volume is greater than 1 cc, but compromise the dose homogeneity in target volumes. VMAT plans are the best option for targets that are greater than 1 cc for cranial radiosurgery treatments, while for very small targets, conformal arc technique may still be the better choice based on data of dose fall-off in normal tissues.