E. McTyre

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy

Background In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. Methods We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Results Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Conclusions Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death.

Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery

OBJECTIVE There are a variety of salvage options available for patients with brain metastases who experience local failure after stereotactic radiosurgery (SRS). These options include resection, whole-brain radiation therapy, laser thermoablation, and repeat SRS. There is little data on the safety and efficacy of repeat SRS following local failure of a prior radiosurgical procedure. This study evaluates the clinical outcomes and dosimetric characteristics of patients who experienced tumor recurrence and were subsequently treated with repeat SRS. METHODS Between 2002 and 2015, 32 patients were treated with repeat SRS for local recurrence of ≥ 1 brain metastasis following initial SRS treatment. The Kaplan-Meier method was used to estimate time-to-event outcomes including overall survival (OS), local failure, and radiation necrosis. Cox proportional hazards analysis was performed for predictor variables of interest for each outcome. Composite dose-volume histograms were constructed for each reirradiated lesion, and these were then used to develop a predictive dosimetric model for radiation necrosis. RESULTS Forty-six lesions in 32 patients were re-treated with a second course of SRS after local failure. A median dose of 20 Gy (range 14-22 Gy) was delivered to the tumor margin at the time of repeat SRS. Local control at 1 year was 79% (95% CI 67%-94%). Estimated 1-year OS was 70% (95% CI 55%-88%). Twelve patients had died at the most recent follow-up, with 8/12 patients experiencing neurological death (as described in Patchell et al.). Eleven of 46 (24%) lesions in 11 separate patients treated with repeat SRS were associated with symptomatic radiation necrosis. Freedom from radiation necrosis at 1 year was 71% (95% CI 57%-88%). Analysis of dosimetric data revealed that the volume of a lesion receiving 40 Gy (V40Gy) was the most predictive factor for the development of radiation necrosis (p = 0.003). The following V40Gy thresholds were associated with 10%, 20%, and 50% probabilities of radiation necrosis, respectively: 0.28 cm3 (95% CI 3%-28%), 0.76 cm3 (95% CI 9%-39%), 1.60 cm3 (95% CI 26%-74%). CONCLUSIONS Repeat SRS appears to be an effective salvage option for patients with brain metastases experiencing local failure following initial SRS treatment. This series demonstrates durable local control and, although rates of radiation necrosis are significant, repeat SRS may be indicated for select cases of local disease recurrence. Because the V40Gy is predictive of radiation necrosis, limiting this value during treatment planning may allow for a reduction in radiation necrosis rates.

Emerging Indications for Fractionated Gamma Knife Radiosurgery.

Background Gamma Knife radiosurgery (GKRS) allows for the treatment of intracranial tumors with a high degree of dose conformality and precision. There are, however, certain situations wherein the dose conformality of GKRS is desired, but single-session treatment is contraindicated. In these situations, a traditional pin-based GKRS head frame cannot be used, because it precludes fractionated treatment. Objective To report our experience in treating patients with fractionated GKRS using a relocatable, noninvasive immobilization system. Methods Patients were considered candidates for fractionated GKRS if they had 1 or more of the following indications: a benign tumor >10 cc in volume or abutting the optic pathway, a vestibular schwannoma with the intent of hearing preservation, or a tumor previously irradiated with single-fraction GKRS. The immobilization device used for all patients was the Extend system (Leksell Gamma Knife Perfexion, Elekta, Kungstensgatan, Stockholm). Results We identified 34 patients treated with fractionated GKRS between August 2013 and February 2015. There were a total of 37 tumors treated including 15 meningiomas, 11 pituitary adenomas, 6 brain metastases, 4 vestibular schwannomas, and 1 hemangioma. At last follow-up, all 21 patients treated for perioptic tumors had stable or improved vision and all 4 patients treated for vestibular schwannoma maintained serviceable hearing. No severe adverse events were reported. Conclusion Fractionated GKRS was well tolerated in the treatment of large meningiomas, perioptic tumors, vestibular schwannomas with intent of hearing preservation, and reirradiation of previously treated tumors.BACKGROUND Gamma Knife radiosurgery (GKRS) allows for the treatment of intracranial tumors with a high degree of dose conformality and precision. There are, however, certain situations wherein the dose conformality of GKRS is desired, but single session treatment is contraindicated. In these situations, a traditional pin-based GKRS head frame cannot be used, as it precludes fractionated treatment. OBJECTIVE To report our experience in treating patients with fractionated GKRS using a relocatable, noninvasive immobilization system. METHODS Patients were considered candidates for fractionated GKRS if they had one or more of the following indications: a benign tumor >10 cc in volume or abutting the optic pathway, a vestibular schwannoma with the intent of hearing preservation, or a tumor previously irradiated with single fraction GKRS. The immobilization device used for all patients was the Extend system (Leksell Gamma Knife Perfexion, Elekta, Kungstensgatan, Stockholm). RESULTS We identified 34 patients treated with fractionated GKRS between August 2013 and February 2015. There were a total of 37 tumors treated including 15 meningiomas, 11 pituitary adenomas, 6 brain metastases, 4 vestibular schwannomas, and 1 hemangioma. At last follow-up, all 21 patients treated for perioptic tumors had stable or improved vision and all 4 patients treated for vestibular schwannoma maintained serviceable hearing. No severe adverse events were reported. CONCLUSION Fractionated GKRS was well-tolerated in the treatment of large meningiomas, perioptic tumors, vestibular schwannomas with intent of hearing preservation, and in reirradiation of previously treated tumors.BACKGROUND Gamma Knife radiosurgery (GKRS) allows for the treatment of intracranial tumors with a high degree of dose conformality and precision. There are, however, certain situations wherein the dose conformality of GKRS is desired, but single-session treatment is contraindicated. In these situations, a traditional pin-based GKRS head frame cannot be used, because it precludes fractionated treatment. OBJECTIVE To report our experience in treating patients with fractionated GKRS using a relocatable, noninvasive immobilization system. METHODS Patients were considered candidates for fractionated GKRS if they had 1 or more of the following indications: a benign tumor >10 cc in volume or abutting the optic pathway, a vestibular schwannoma with the intent of hearing preservation, or a tumor previously irradiated with single-fraction GKRS. The immobilization device used for all patients was the Extend system (Leksell Gamma Knife Perfexion, Elekta, Kungstensgatan, Stockholm). RESULTS We identified 34 patients treated with fractionated GKRS between August 2013 and February 2015. There were a total of 37 tumors treated including 15 meningiomas, 11 pituitary adenomas, 6 brain metastases, 4 vestibular schwannomas, and 1 hemangioma. At last follow-up, all 21 patients treated for perioptic tumors had stable or improved vision and all 4 patients treated for vestibular schwannoma maintained serviceable hearing. No severe adverse events were reported. CONCLUSION Fractionated GKRS was well tolerated in the treatment of large meningiomas, perioptic tumors, vestibular schwannomas with intent of hearing preservation, and reirradiation of previously treated tumors. ABBREVIATIONS CNS, central nervous systemGKRS, Gamma Knife radiosurgerySRS, stereotactic radiosurgery.

A cortical thickness and radiation dose mapping approach identifies early thinning of ribs after stereotactic body radiation therapy

BACKGROUND AND PURPOSE High rates of spontaneous rib fractures are associated with thoracic stereotactic body radiation therapy (SBRT). These fractures likely originate within the cortical bone and relate to the cortical thickness (Ct.Th). We report the development and application of a novel Ct.Th and radiation dose mapping technique to assess early site-specific changes of cortical bone in ribs. MATERIALS AND METHODS Rib Ct.Th maps were constructed from pre-SBRT and 3month post-SBRT CT scans for 28 patients treated for peripheral lung lesions. The Ct.Th at approximately 50,000 homologous points within the entire rib cage was determined pre- and post-SBRT. Each rib was then divided into 30 homologous regions. The mean dose and thinning were determined per section. RESULTS Regions of ribs that received ⩾10Gy exhibited significant thinning of cortical bone (p=0.001). The mean Ct.Th percent difference (95% CI) in regions receiving 10-20Gy, 20-30Gy, 30-40Gy, and ⩾40Gy were -7% (-4%,-11%), -14% (-18%,-11%), -15% (-19%,-11%), and -18% (-22%,-15%) respectively. Regions receiving >20Gy experienced significantly more thinning than regions receiving lower doses. CONCLUSIONS Substantial early cortical bone thinning was observed post-SBRT in regions of ribs that received ⩾10Gy. The rapid thinning of ribs may predispose ribs to fracture after SBRT.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients’ DBF risk within the validation dataset (c-index = 0.631) and Heller’s explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.

Early dose-dependent cortical thinning of the femoral neck in anal cancer patients treated with pelvic radiation therapy

BACKGROUND AND PURPOSE Anal cancer patients treated with radiation therapy (RT) have an increased risk of hip fractures after treatment. The mechanism of these fractures is unknown; however, femoral fractures have been correlated with cortical bone thinning. The objective of this study was to assess early changes in cortical bone thickness at common sites of femoral fracture in anal cancer patients treated with intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS RT treatment plans and computed tomography (CT) scans from 23 anal cancer patients who underwent IMRT between November 2012 and December 2014 were retrospectively reviewed. Cortical thickness (Ct.Th) was mapped at homologous vertices within the proximal femur using pre-RT and post-RT (≤4months) CT scans. The bone attenuation measurements were collected at homologous locations within the trabecular bone of the right femoral neck (FN). The percent change in Ct.Th and trabecular bone mineral density (trBMD) were assessed. FN cortical thinning was correlated to RT dose using linear regression. A logistic model for dose dependent cortical thinning was constructed. RESULTS Twenty-two patients were analyzed. Significant post-treatment cortical thinning was observed in the intertrochanteric crest, subcapital and inferior FN (p<0.05). FN volume receiving ≥40Gy (V40Gy) was a significant predictor of focal cortical thinning ≥30% (p=0.03). A significant decrease in FN trBMD was observed (-6.4% [range -34.4 to 3.3%]; p=0.01). CONCLUSION Significant early decrease in Ct.Th and trBMD occurs at the FN in patients treated with RT for anal cancer. FN V40Gy was predictive of clinically significant focal FN cortical thinning.

Early or late radiotherapy following gross or subtotal resection for atypical meningiomas: Clinical outcomes and local control

We report a single institution series of surgery followed by either early adjuvant or late radiotherapy for atypical meningiomas (AM). AM patients, by WHO 2007 definition, underwent subtotal resection (STR) or gross total resection (GTR). Sixty-three of a total 115 patients then received fractionated or stereotactic radiation treatment, early adjuvant radiotherapy (≤4months after surgery) or late radiotherapy (at the time of recurrence). Kaplan Meier method was used for survival analysis with competing risk analysis used to assess local failure. Overall survival (OS) at 1, 2, and 5years for all patients was 87%, 85%, 66%, respectively. Progression free survival (PFS) at 1, 2, and 5years for all patients was 65%, 30%, and 18%, respectively. OS at 1, 2, and 5years was 75%, 72%, 55% for surgery alone, and 97%, 95%, 75% for surgery+radiotherapy (log-rank p-value=0.0026). PFS at 1, 2, and 5years for patients undergoing surgery without early adjuvant radiotherapy was 64%, 49%, and 27% versus 81%, 73%, and 59% for surgery+early adjuvant radiotherapy (log-rank p-value=0.0026). The cumulative incidence of local failure at 1, 2, and 5years for patients undergoing surgery without early External Beam Radiation Therapy (EBRT) was 18.7%, 35.0%, and 52.9%, respectively, versus 4.2%, 13.3%, and 20.0% for surgery and early EBRT (p-value=0.02). Adjuvant radiotherapy improves OS in patients with AM. Early adjuvant radiotherapy improves PFS, likely due to the improvement in local control seen with early adjuvant EBRT.

Impact of timing of radiotherapy in patients with newly diagnosed glioblastoma

OBJECTIVE To further evaluate if a delay in the start of radiation therapy (RT) affects patient outcomes for glioblastoma (GBM). PATIENTS AND METHODS From May 1999 to May 2010, a total of 161 patients underwent surgery followed by RT for GBM. We assessed overall survival (OS) and progression free survival (PFS), stratified by extent of surgical resection. Included in the analysis were genomic predictors of progression. RESULTS Median time from surgery to start of RT was 20days for biopsy alone, 28days for subtotal resection (STR) and 28days for gross total resection (GTR). For all patients, a delay >28days did not result in a difference in PFS when compared to no delay (6.7 vs. 6.9 months, p=0.07). PFS was improved in biopsy or STR patients with a >28day delay to start of RT (4.2 vs. 6.7 months, p=0.006). OS was also improved in patients receiving biopsy or STR with a >28day delay to start of RT (12.3 vs. 7.8 months, p=0.005). Multivariable analysis (MVA) demonstrated an improvement in OS and PFS with time to RT >28days for biopsy or STR patients (HR 0.52 p=0.008 and HR 0.48 p=0.02, respectively). CONCLUSION In this retrospective review of GBM patients treated at a single institution, OS and PFS were not different between time to RT >28days compared to <28 days. There was a modest improvement in both PFS and OS in patients who received biopsy or STR with time to RT >28 days.

Multi-institutional competing risks analysis of distant brain failure and salvage patterns after upfront radiosurgery without whole brain radiotherapy for brain metastasis

Background In this study, we use a competing risks analysis to assess factors predictive of early-salvage whole brain radiotherapy (WBRT) and early death after upfront stereotactic radiosurgery (SRS) alone for brain metastases in an attempt to identify populations that benefit less from upfront SRS. Patients and methods Patients from eight academic centers were treated with SRS for brain metastasis. Competing risks analysis was carried out for distant brain failure (DBF) versus death prior to DBF as well as for salvage SRS versus salvage WBRT versus death prior to salvage. Linear regression was used to determine predictors of the number of brain metastases at initial DBF (nDBF). Results A total of 2657 patients were treated with upfront SRS alone. Multivariate analysis (MVA) identified an increased hazard of DBF associated with increasing number of brain metastases (P < 0.001), lowest SRS dose received (P < 0.001), and melanoma histology (P < 0.001), while there was a decreased hazard of DBF associated with increasing age (P < 0.001), KPS < 70 (P < 0.001), and progressive systemic disease (P = 0.004). MVA for first salvage SRS versus WBRT versus death prior to salvage revealed an increased hazard of first salvage WBRT seen with increasing number of brain metastases (P < 0.001) and a decreased hazard with widespread systemic disease (P = 0.002) and increasing age (P < 0.001). Variables associated with nDBF included age (P = 0.02), systemic disease status (P = 0.03), melanoma histology (P = 0.05), and initial number of brain metastases (P < 0.001). Conclusions Patients with a higher initial number of brain metastases were more likely to experience DBF, have a higher nDBF, and receive early-salvage WBRT, while patients who were older, had lower KPS, or had more systemic disease were more likely to experience death prior to DBF or salvage WBRT.

Radiation-Induced Bone Toxicity

Purpose of ReviewNormal bone is commonly irradiated during radiation therapy (RT). The true impact of focal radiation on bone tissue remains unclear. The goal of this paper is to present the current understanding of radiation effects on the bone as it pertains to clinically observed radiation side effects.Recent FindingsAn increased risk of local fracture has been associated with RT-induced bone loss in the pelvis, vertebrae, and ribs. This bone loss appears to occur early after and/or during treatment, which suggests that reactive remodeling of the bone via osteoclast activity is a primary contributor to bone loss and fractures.SummarySeveral reports have quantified the structural and histological changes observed after bone irradiation. These include changes in bone density and cortical thickness, as well as alterations in both the number and activity of the cells responsible for bone turnover that arise from hematopoietic and mesenchymal lineages: namely, osteoclasts and osteoblasts. All of these changes likely play an important role in the increased risk of fracture reported with RT. However, more research is needed to fully understand the mechanisms of bone damage and its relationship to modifiable factors such as beam energy, dose, photon or charged particle radiation, linear energy transfer (LET), fractionation, and field size.