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2058 Background: Glioblastoma is the most common and aggressive primary brain tumor, with 75-85% of patients historically having recurrence within the original tumor site. We have shown in preclinical studies that inhibition of the SDF1/CXCR4 pathway by the CXCR4 inhibitor Plerixafor increases tumor response to irradiation by inhibition of the recovery of tumor blood vessels. Methods: Newly diagnosed glioblastoma patients were enrolled to the clinical trial using the investigational agent Plerixafor after standard radiation therapy and temozolomide (NCT01977677). To date, 28 patients out of the planned accrual of 29 have been enrolled to this study. Normalized relative cerebral blood volume (rCBV) ratios were calculated by the mean rCBV within the 95% isodose radiation field one month post-radiation as compared to contralateral white matter outside of the radiation field. Our imaging analysis compares patients treated with Plerixafor compared to a control group receiving standard therapy (chemo-RT). Results: There was a significant reduction in rCBV measured by DSC-MRI within the 95% isodose field one month after radiation therapy in patients receiving Plerixafor compared to control (p < 0.02). The rCBV out of the radiation field was similar between patients receiving Plerixafor compared to control patients one-month post radiation therapy. As of February 7, 2017, only 2 of the total of 9 recurrences occurred within the irradiated field. The rate of out of field recurrence (77%) was therefore much higher than expected (20%), with statistical significance (p < 0.03, Fisher’s exact test). Conclusions: We show that Plerixafor has a meaningful impact on local control of glioblastoma. Furthermore, DSC-MRI could be a useful biomarker of its efficacy.

Stereotactic Body Radiation Therapy (SBRT) was introduced clinically more than twenty years ago, and many subsequent publications have reported safety and efficacy data. The AAPM Working Group on Biological Effects of Hypofractionated Radiotherapy/SBRT (WGSBRT) extracted published treatment outcomes data from extensive literature searches to summarize and construct tumor control probability (TCP) and normal tissue complication probability (NTCP) models for six anatomical regions: Cranial, Head and Neck, Thoracic, Abdominal, Pelvic, and Spinal. In this session, we present the WGSBRT’s work for cranial sites, and recurrent head and neck cancer. From literature-based data and associated models, guidelines to aid with safe and effective hypofractionated radiotherapy treatment are being determined. Further, the ability of existing and proposed radiobiological models to fit these data is considered as to the ability to distinguish between the linear-quadratic and alternative radiobiological models such as secondary cell death from vascular damage, immunogenic, or bystander effects. Where appropriate, specific model parameters are estimated. As described in “The lessons of QUANTEC,” (1), lack of adequate reporting standards continues to limit the amount of useful quantitative information that can be extracted from peer-reviewed publications. Recommendations regarding reporting standards are considered, to enable such reviews to achieve more complete characterization of clinical outcomes. 1 Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, Constine LS, Deasy JO. The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S155–60. Learning Objectives: 1. Describe the techniques, types of cancer and dose schedules used in treating recurrent H&N cancers with SBRT 2. List the radiobiological models that compete with the linear-quadratic model in explaining the results of hypofractionated RT 3. Describe the dose/volume metrics that are considered safe in SBRT treatment of tumors near the optic structures. 4. Discuss the efficacy of hypofractionation and dosing schedules used in treating vestibular schwannomas 5. Identify some difficulties in modeling TCP and NTCP for cranial tumors treated with hypofractionation. One moderator, Dr. Grimm, designed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and can analyze some of this data. No others have relevant conflicts of interest.

Summary Despite the increasing use of postresection stereotactic radiosurgery targeting the operative cavity for brain metastases, deferring wholebrain irradiation, the risk of leptomeningeal disease (LMD) in this setting is unknown. Our retrospective review of 165 patients found a 1-year cumulative incidence rate of LMD of 24% for breast cancer compared to 9% for non-breast histology (PZ.004). We encourage all future reports of this technique to include the 3 compartments of failure: local, distant, and leptomeningeal. Purpose: We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients. Methods and Materials: We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), and histology (lung, colon, breast, melanoma, gynecologic, other). Results: With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (PZ.004). Conclusions: In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology. 2013 Elsevier Inc.

2068Background: Preclinical studies indicate that local recurrence after radiotherapy (RT) of Glioblastoma is dependent on recovery of tumor vasculature following RT via hypoxia-driven SDF-1 (CXCL12) secretion. We hypothesize that blocking the CXCL12/CXCR4 axis would improve local control. Methods: Newly diagnosed Glioblastoma patients were recruited to this Phase I study of a 4 week intravenous infusion of Plerixafor (Mozobil), a CXCR4 antagonist, with concurrent Temozolomide (TMZ) and radiation therapy. Three patients were treated with Plerixafor at 8.3 µg/kg/hr and six patients at 16.6 µg/kg/hr, while being monitored for dose limiting toxicities (DLTs) including grade ≥ 3 hematologic or non-hematologic adverse events. Patients underwent dynamic susceptibility contrast perfusion MRI (DSC-MRI) for quantification of relative cerebral blood volume (rCBV) values by region-of-interest analysis. Pharmacokinetic (PK) analysis of Plerixafor plasma levels were collected. Results: Since August 2014, 9 patients co...

Spinal cord intramedullary metastases are uncommon and treatment options are limited. We reviewed our experience treating these lesions with radiosurgery to assess safety and efficacy, and to define preliminary treatment recommendations. With Institutional Review Board approval, we identified nine patients with 11 metastases treated with radiosurgery at Stanford University Hospital, between 2000 and 2010. We also reviewed all available published series discussing the treatment of spinal cord metastases. Our patients ranged in age from 33 years to 77 years (median 63 years) and included seven women and two men. Tumors ranged in size from 0.12 cm3 to 6.4 cm3 (median 0.48 cm3). Five were from breast cancer, two were non-small cell lung cancers, one was a cystic adenocarcinoma, and one was from an epithelioid hemangioepithelioma. All patients had neurologic deficits and multiple other metastases. We delivered 14 Gy to 27 Gy (median 21 Gy) in one to five (median 3) fractions. Complete follow-up was available for all nine patients. One patient remains alive 14 months after therapy. Of the eight deceased patients, survival ranged from one month and two days to nine months and six days (median four months and four days). There were no local recurrences or worsened neurological deficits. To our knowledge this is the largest reported series of spinal cord intramedullary metastases treated with radiosurgery. Survival was poor due to systemic disease, but radiosurgery appears to be safe and prevented local recurrences. With fewer sessions than conventional radiation and less morbidity than surgery, we feel radiosurgery is appropriate for the palliative treatment of these lesions.

Stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT) have emerged over the last decade as effective and safe approaches to the treatment of tumors of the spine and spinal cord. In this chapter we describe one of the technologies that have been involved in the development of this treatment modality, the CyberKnife® System (Accuray Incorporated, Sunnyvale, CA, USA). We also briefly review its use in the treatment of spinal metastases, primary malignant and benign tumors, and intramedullary tumors. The precise radiation delivery capability of the CyberKnife makes it uniquely valuable in the re-irradiation of lesions that have recurred or progressed after conventional radiotherapy. Although optimal treatment doses and radiation tolerance of the spinal cord are not known with certainty, published outcomes have shown very high levels of tumor control, pain relief, and halting and reversal of neurological deficit after spinal SBRT.

Chordomas are rare, malignant bone tumors of the axial skeleton, occurring particularly at the cranial base or in the sacro-coccygeal region. Although slow growing, chordomas are locally aggressive and challenging to treat. We evaluate the outcomes of skull base and spinal chordomas in 20 patients treated with CyberKnife (CK) stereotactic radiosurgery (SRS) (Accuray, Sunnyvale, CA, USA) between 1994 and 2010 at Stanford Hospital. There were 12 males and eight females (10–78 years; median age: 51.5 years). Eleven patients received CK as primary adjuvant therapy and nine patients received CK for multiple recurrences. The average tumor volume treated was 16.1 cm 3 (2.4–45.9 cm 3 ), with a mean marginal dose of 32.5 Gy (18–50 Gy). Median follow-up was 34 months (2–131 months). Overall, tumor control was achieved in 11 patients (55%), with eight patients showing tumor size reduction. However, nine patients showed progression and eventually succumbed to the disease (mean time from CK to death was 26.3 months). Of the patients treated with CK as the primary adjuvant therapy, 81.8% had stable or improved outcomes. Only 28.6% of those treated with CK for recurrences had stable or improved outcomes. The overall Kaplan–Meyer survival at five years from the first CK treatment was 52.5%. Moderate tumor control rates can be achieved with few complications with CK SRS. Poor control is associated with complex multiple surgical resections, long delay between initial resection and CK therapy, and recurrently aggressive disease uncontrolled by prior radiation.

Single-modality treatment of large brain metastases (2 cm) with whole-brain irradiation, stereotactic radiosurgery (SRS) alone, or surgery alone is not effective, with local failure (LF) rates of 50% to 90%. Our goal was to improve local control (LC) by using multimodality therapy of surgery and adjuvant SRS targeting the resection cavity.We retrospectively evaluated 97 patients with brain metastases2 cm in diameter treated with surgery and cavity SRS. Local and distant brain failure (DF) rates were analyzed with competing risk analysis, with death as a competing risk. The overall survival rate was calculated by the Kaplain-Meier product-limit method.The median imaging follow-up duration for all patients was 10 months (range, 1-80 months). The 12-month cumulative incidence rates of LF, with death as a competing risk, were 9.3% (95% confidence interval [CI], 4.5%-16.1%), and the median time to LF was 6 months (range, 3-17 months). The 12-month cumulative incidence rate of DF, with death as a competing risk, was 53% (95% CI, 43%-63%). The median survival time for all patients was 15.6 months. The median survival times for recursive partitioning analysis classes 1, 2, and 3 were 33.8, 13.7, and 9.0 months, respectively (p = 0.022). On multivariate analysis, Karnofsky Performance Status (≥80 vs.80; hazard ratio 0.54; 95% CI 0.31-0.94; p = 0.029) and maximum preoperative tumor diameter (hazard ratio 1.41; 95% CI 1.08-1.85; p = 0.013) were associated with survival. Five patients (5%) required intervention for Common Terminology Criteria for Adverse Events v4.02 grade 2 and 3 toxicity.Surgery and adjuvant resection cavity SRS yields excellent LC of large brain metastases. Compared with other multimodality treatment options, this approach allows patients to avoid or delay whole-brain irradiation without compromising LC.

BACKGROUND: The role of stereotactic radiosurgery in the treatment of benign intracranial lesions is well established. Although a growing body of evidence supports its role in the treatment of malignant spinal lesions, a much less extensive dataset exists for treatment of benign spinal tumors. OBJECTIVE: To examine the safety and efficacy of stereotactic radiosurgery for treatment of benign, intradural extramedullary spinal tumors. METHODS: From 1999 to 2008, 87 patients with 103 benign intradural extramedullary spinal tumors (32 meningiomas, 24 neurofibromas, and 47 schwannomas) were treated with stereotactic radiosurgery at Stanford University Medical Center. Forty-three males and 44 females had a median age of 53 years (range, 12-86). Twenty-five patients had neurofibromatosis. Treatment was delivered in 1 to 5 sessions (median, 2) with a mean prescription dose of 19.4 Gy (range, 14-30 Gy) to an average tumor volume of 5.24 cm 3 (range, 0.049-54.52 cm 3 ). RESULTS: After a mean radiographic follow-up period of 33 months (range, 6-87), including 21 lesions followed for ≥ 48 months, 59% were stable, 40% decreased in size, and a single tumor (1%) increased in size. Clinically, 91%, 67%, and 86% of meningiomas, neurofibromas, and schwannomas, respectively, were symptomatically stable to improved at last follow-up. One patient with a meningioma developed a new, transient myelopathy at 9 months, although the tumor was smaller at last follow-up. CONCLUSION: As a viable alternative to microsurgical resection, stereotactic radiosurgery provides safe and efficacious long-term control of benign intradural, extramedullary spinal tumors with a low rate of complication.

Objective Hemangiopericytoma is a rare and aggressive meningeal tumor. Although surgical resection is the standard treatment, hemangiopericytomas often recur with high incidences of metastasis. The purpose of this study was to evaluate the role of CyberKnife stereotactic radiosurgery (CK) in the management of recurrent, metastatic, and residual hemangiopericytomas. Methods In a review of the Stanford radiosurgery database between 2002 and 2009, the authors found 14 patients who underwent CK therapy for recurrent, metastatic, and residual hemangiopericytomas. A total of 24 tumors were treated and the median patient age was 52 years (range 29-70 years) at the time of initial CK therapy. The median follow-up period was 37 months (10-73 months) and all patients had been previously treated with surgical resection. Mean tumor volume was 9.16 cm3 and the mean marginal and maximum radiosurgical doses to the tumors were 21.2 Gy and 26.8 Gy, respectively. Results Of the 24 tumors treated, 22 have clinical follow-up data at this time. Of those 22 tumors, 12 decreased in size (54.5%), 6 remained unchanged (27.3%), and 4 showed recurrence (18.2%) after CK therapy. Progression-free survival rate was 95%, 71.5%, and 71.5% at 1, 3, and 5 years after multiple CK treatments. The 5-year survival rate after CK was 81%. Conclusions CK is an effective and safe management option for hemangiopericytomas. The current series demonstrates a tumor control of 81.8%. Other institutions have demonstrated similar outcomes with stereotactic radiosurgery, with tumor control ranging from 46.4% to 100%.

BACKGROUND Single-session stereotactic radiosurgery (SRS) treatment of vestibular schwannomas results in excellent tumor control. It is not known whether functional outcomes can be improved by fractionating the treatment over multiple sessions. OBJECTIVE To examine tumor control and complication rates after multisession SRS. METHODS Three hundred eighty-three patients treated with SRS from 1999 to 2007 at Stanford University Medical Center were retrospectively reviewed. Ninety percent were treated with 18 Gy in 3 sessions, targeting a median tumor volume of 1.1 cm3 (range, 0.02-19.8 cm3). RESULTS During a median follow-up duration of 3.6 years (range, 1-10 years), 10 tumors required additional treatment, resulting in 3- and 5-year Kaplan-Meier tumor control rates of 99% and 96%, respectively. Five-year tumor control rate was 98% for tumors < 3.4 cm3. Neurofibromatosis type 2-associated tumors were associated with worse tumor control (P = .02). Of the 200 evaluable patients with pre-SRS serviceable hearing (Gardner-Robertson grade 1 and 2), the crude rate of serviceable hearing preservation was 76%. Smaller tumor volume was associated with hearing preservation (P = .001). There was no case of post-SRS facial weakness. Eight patients (2%) developed trigeminal dysfunction, half of which was transient. CONCLUSION Multisession SRS treatment of vestibular schwannomas results in an excellent rate of tumor control. The hearing, trigeminal nerve, and facial nerve function preservation rates reported here are promising.

Purpose To assess the role of a planned neck dissection (PND) after sequential chemoradiotherapy for patients with head-and-neck cancer with N2–N3 nodal disease. Methods and Materials We reviewed 90 patients with N2–N3 head-and-neck squamous cell carcinoma treated between 1991 and 2001 on two sequential chemoradiotherapy protocols. All patients received induction and concurrent chemotherapy with cisplatin and 5-fluorocuracil, with or without tirapazamine. Patients with less than a clinical complete response (cCR) in the neck proceeded to a PND after chemoradiation. The primary endpoint was nodal response. Clinical outcomes and patterns of failure were analyzed. Results The median follow-up durations for living and all patients were 8.3 years (range, 1.5–16.3 year) and 5.4 years (range, 0.6–16.3 years), respectively. Of the 48 patients with nodal cCR whose necks were observed, 5 patients had neck failures as a component of their recurrence [neck and primary ( n = 2); neck, primary, and distant ( n = 1); neck only ( n = 1); neck and distant ( n = 1)]. Therefore, PND may have benefited only 2 patients (4%) [neck only failure ( n = 1); neck and distant failure ( n = 1)]. The pathologic complete response (pCR) rate for those with a clinical partial response (cPR) undergoing PND ( n = 30) was 53%. The 5-year neck control rates after cCR, cPR→pCR, and cPR→pPR were 90%, 93%, and 78%, respectively ( p = 0.36). The 5-year disease-free survival rates for the cCR, cPR→pCR, and cPR→pPR groups were 53%, 75%, and 42%, respectively ( p = 0.04). Conclusion In our series, patients with N2–N3 neck disease achieving a cCR in the neck, PND would have benefited only 4% and, therefore, is not recommended. Patients with a cPR should be treated with PND. Residual tumor in the PND specimens was associated with poor outcomes; therefore, aggressive therapy is recommended. Studies using novel imaging modalities are needed to better assess treatment response.

BACKGROUND: Surgical resection of nonvestibular cranial schwannomas carries a considerable risk of postoperative complications. Stereotactic radiosurgery (SRS) offers a non-invasive treatment alternative. The efficacy and safety of multi-session SRS of nonvestibular cranial schwannomas has not been well studied. OBJECTIVE: To analyze the results of single- and multi-session SRS of nonvestibular cranial schwannomas. METHODS: From 2001 to 2007,42 lesions in 40 patients were treated with SRS at Stanford University Medical Center, targeting schwannomas of cranial nerves IV (n =1 1), V (n = 18), VII (n = 6), X (n = 5), XII (n = 2), jugular foramen (n = 8), and cavernous sinus (n = 2). SRS was delivered to a median marginal dose of 18 Gy (range, 15-33 Gy) in 1 to 3 sessions, targeting a median tumor volume of 3.2 cm 3 (range, 0.1-23.7 cm 3 ). The median doses for treatments in 1 (n = 18), 2 (n = 9), and 3 (n = 15) sessions were 17.5, 20, and 18 Gy, respectively. RESULTS: With a median follow-up of 29 months (range, 6-84 months), tumor control was achieved in 41 of the 42 lesions. Eighteen of 42 lesions (43%) decreased in size; 23 tumors (55%) remained stable. There were 2 cases of new or worsening cranial nerve deficits in patients treated in single session; no patient treated with multi-session SRS experienced any cranial nerve toxicity (P = 0.18). CONCLUSION: SRS of nonvestibular cranial schwannomas provides excellent tumor control with minimal risk of complications. There was a trend towards decreased complications with multi-session SRS.

Purpose: We sought to determine if dosimetric differences exist between Ray-Trace (RT) and Monte-Carlo (MC) calculation algorithms for radiosurgery for tumors of the clivus, given their proximity to air-tissue inhomogeneity. Methods: We retrospectively identified 10 patients with a tumor of the clivus where the target was located near an air-tissue interface. CyberKnife treatment was delivered in 1 to 5 fractions. Plans originally calculated with the RT algorithm were re-calculated with the same monitor units (MU) with the MC algorithm. Similarly, plans originally calculated with MC were recalculated with RT. MC calculations were performed using High Resolution with 2% uncertainty on the MultiPlan 4.6 planning system. If the RT plans were originally calculated using water-air density model, they were re-calculated with Body standard density model, and then compared with MC plans computed with Body standard density model. The maximum dose (Dmax) to the planning target volumes (PTV) and critical structures, minimum dose (Dmin) and coverage percentage for the PTV were calculated. Results: For 8 cases, MC PTV Dmin was a median 5% (range 0–10%) and Dmax a median 6% (range 3–9%) higher than for RT. For 2 cases, MC PTV Dmin was 6 and 2% and Dmax was 1 and 3%more » lower than for RT. MC PTV Dmin and Dmax maybe higher or lower than for RT even though the target coverage for MC was less than for RT (median 4%, range 0–13%) with the same MU used. The degree of differences depends on the location of the target relative to the air-tissue inhomogeneity. Examples are shown that the targets are underdosed near the air-tissue inhomogenity. Conclusion: Monte Carlo dose calculations are recommended for targets near tissue homogeneity such as the clivus. Assuming that Monte Carlo more closely approximates the true dosimetry, the use of Ray Trace could overestimate target coverage.« less

Background The optimal management of subtotally resected atypical meningiomas is unknown. Objective To perform a retrospective review of patients with residual or recurrent atypical meningiomas treated with stereotactic radiosurgery (SRS). Methods Twenty-five patients were treated, either immediately after surgery (n = 15) or at the time of radiographic progression or treatment failure (n = 10). SRS was delivered to with a median marginal dose of 22 Gy (range, 16-30) in 1 to 4 fractions (median, 1), targeting a median tumor volume of 5.3 cm³ (range, 0.3-26.0). Results With a median follow-up time of 28 months (range, 3-67), the 12-, 24-, and 36-month actuarial local and regional control rates for all patients were 94%, 94%, 74%, and 90%, 90%, 62%, respectively. There were 2 cases of radiation toxicity. On univariate analysis, the number of recurrences before SRS (P = .046), late SRS (ie, waiting until tumor progression to initiate treatment) (P = .03), and age at treatment ≥ 60 years (P = .01) were significant predictors of recurrence. Of the 20 radiation-naive patients, 2 patients failed with the targeted lesion and 3 elsewhere in the resection bed, resulting in 12-, 24- and 36-month actuarial local and regional control rates of 100%, 100%, 73% and 93%, 93%, 75%, respectively. The overall locoregional control rates at 12, 24, and 36 months were 93%, 93%, and 54%, respectively. Conclusion Irradiation of the entire postoperative tumor bed may not be necessary for the majority of patients with subtotally resected atypical meningiomas. Patients in this series achieved outcomes comparable to that of historical control rates for larger volume, conventionally fractionated radiotherapy.

Purpose To determine whether normal tissue complication probability (NTCP) analyses of the human spinal cord by use of the Lyman-Kutcher-Burman (LKB) model, supplemented by linear–quadratic modeling to account for the effect of fractionation, predict the risk of myelopathy from stereotactic radiosurgery (SRS). Methods and Materials From November 2001 to July 2008, 24 spinal hemangioblastomas in 17 patients were treated with SRS. Of the tumors, 17 received 1 fraction with a median dose of 20 Gy (range, 18–30 Gy) and 7 received 20 to 25 Gy in 2 or 3 sessions, with cord maximum doses of 22.7 Gy (range, 17.8–30.9 Gy) and 22.0 Gy (range, 20.2–26.6 Gy), respectively. By use of conventional values for α/β, volume parameter n , 50% complication probability dose TD 50 , and inverse slope parameter m , a computationally simplified implementation of the LKB model was used to calculate the biologically equivalent uniform dose and NTCP for each treatment. Exploratory calculations were performed with alternate values of α/β and n . Results In this study 1 case (4%) of myelopathy occurred. The LKB model using radiobiological parameters from Emami and the logistic model with parameters from Schultheiss overestimated complication rates, predicting 13 complications (54%) and 18 complications (75%), respectively. An increase in the volume parameter ( n ), to assume greater parallel organization, improved the predictive value of the models. Maximum-likelihood LKB fitting of α/β and n yielded better predictions (0.7 complications), with n = 0.023 and α/β = 17.8 Gy. Conclusions The spinal cord tolerance to the dosimetry of SRS is higher than predicted by the LKB model using any set of accepted parameters. Only a high α/β value in the LKB model and only a large volume effect in the logistic model with Schultheiss data could explain the low number of complications observed. This finding emphasizes that radiobiological models traditionally used to estimate spinal cord NTCP may not apply to the dosimetry of SRS. Further research with additional NTCP models is needed.

Objective: Intramedullary spinal cord arteriovenous malformations (AVMs) are very rare lesions which are characteristically associated with recurrent hemorrhage and progressive ischemia. Although favorable location, size and vascular anatomy make it sometimes possible to manage this condition with embolization and/or microsurgical resection, there are no good treatment options for many, if not most, of these lesions. Given such poor prospects, the senior author began in 1997 investigating CyberKnife radiosurgical ablation as a tool for managing selected patients with intramedullary spinal cord AVMs. Although a previous paper in 2006 reported the preliminary experience from Stanford, our understanding has grown significantly as follow-up was extended and more patients were treated. Herein, we retrospectively analyze our longer term experience with a primary radiosurgical approach to spinal cord AVM. Methods: Thirty patients (17 females: 13 males) with a median age of 33 years and intramedullary spinal cord AVMs (18 cervical, nine thoracic, and three conus medullaris) were treated with CyberKnife SRS between 1997 and 2008. A history of hemorrhage was present in 57% of cases, while in 50% of patients previous treatment included microsurgery (6/29) or embolization (11/29). The mean AVM volume was 2.8 cc (0.2-15cc) and was treated to mean marginal dose of 20Gy in one to four sessions (median 2). Based on our growing experience, the biologically effective dose (BED) of radiation was escalated gradually over the course of this study. Clinical and magnetic resonance imaging follow-up were carried out annually, and spinal angiography was repeated at three years. Results: After a mean follow-up period of 63 months (median 54), the treated AVM was completely obliterated in eight cases (27%) and significantly decreased in size in an additional 11 cases (64%) among the 22 angiographically studied patients with more than three years of followup. Pre-radiosurgery neurologic symptoms improved in more than 50% of cases, but worsened in three (10%). There was one instance (3%) of radiation-induced myelopathy occurring within one year of radiosurgery. Notably, after 158 years of collective post-SRS follow-up, no patient suffered a hemorrhage. Conclusions: Although our understanding is still incomplete, CyberKnife radiosurgery results in total obliteration or shrinkage for most intramedullary spinal cord AVM, a phenomenon that may be accompanied by a marked decrease in the risk of bleeding. Symptom improvement is also 1 2 3 4 5 6 7 Open Access Original Article DOI: 10.7759/cureus.14 How to cite this article Adler J R., Gupta G, Chang S D., et al. (2010-08-17 16:30:35 UTC) CyberKnife Ablation for Intramedullary Spinal Cord Arteriovenous Malformations (AVMs): A Promising New Therapeutic Approach. Cureus 2(8): e14. DOI 10.7759/cureus.14 common in most cases. More experience is required to determine the optimal radiosurgical dosing and consequent related efficacy. Given the significant therapeutic challenges inherent to spinal cord AVM patients, the rate of radiosurgical complications appears acceptable. Categories: Radiation Oncology, Neurosurgery

There are 2 Cyberknife units at Stanford University. The robot of 1 Cyberknife is positioned on the patient's right, whereas the second is on the patient's left. The present study examines whether there is any difference in dosimetry when we are treating patients with trigeminal neuralgia when the target is on the right side or the left side of the patient. In addition, we also study whether Monte Carlo dose calculation has any effect on the dosimetry. We concluded that the clinical and dosimetric outcomes of CyberKnife treatment for trigeminal neuralgia are independent of the robot position. Monte Carlo calculation algorithm may be useful in deriving the dose necessary for trigeminal neuralgia treatments.

OBJECTIVE: Although radiosurgery plays an important role in managing benign cranial base lesions, the potential for increased toxicity with single-session treatment of large tumors is a concern. In this retrospective study, we report the intermediate-term rate of local control, morbidity, and clinical outcomes of patients with large cranial base tumors treated with multisession stereotactic radiosurgery with the CyberKnife (Accuray, Inc., Sunnyvale, CA). METHODS: Between 1999 and 2008, 34 consecutive patients with large (>15 cm 3 ), benign cranial base tumors (21 meningiomas, 9 schwannomas, 4 glomus jugulare tumors) underwent primary or postoperative radiosurgical treatment using a multisession approach at Stanford University and were considered in this retrospective study. Forty-four percent of these patients had undergone previous subtotal surgical resection or radiotherapy. CyberKnife radiosurgery was delivered in 2 to 5 sessions (median, 3 sessions) to a median tumor volume of 19.3 cm 3 (range, 15.8―69.3 cm 3 ). The median marginal dose was 24 Gy (range, 18―25 Gy) prescribed to a median 78% isodose line. RESULTS: After a median clinical follow-up of 31 months (range, 12―77 months), 21 % of patients experienced clinical improvement of neurological symptoms, whereas neurological status remained unchanged among the rest. Four patients experienced prolonged use of glucocorticoids owing to transient neurological worsening and radiographic signs of radiation injury. No permanent neurotoxicity was seen. To date, all tumors remain locally controlled. CONCLUSION: Over our modest length of follow-up, multisession radiosurgery appears to be a safe and effective option for selected large, benign brain and cranial base lesions.

OBJECTIVE: Stereotactic radiosurgery has been used for nearly 2 decades to treat hemangioblastomas, particularly those that are in surgically inaccessible locations or that are multiple, as is common in von Hippel-Lindau disease. There is a paucity of long-term published radiosurgical treatment outcomes, particularly for spinal lesions, in a large patient population. The purpose of this study was to provide a long-term retrospective evaluation of radiosurgical hemangioblastoma treatment effectiveness, with a special emphasis on the relatively recent use of frameless, image-guided radiosurgery in the treatment of spinal lesions. METHODS: From 1991 to 2007, 92 hemangioblastomas in 31 patients, 26 with von Hippel-Lindau disease, were treated with radiosurgery (27 tumors treated with framebased linear accelerator radiosurgery, and 67 tumors were treated with CyberKnife radiosurgery). The mean patient age was 41 years (range, 18―81 years). The radiation dose to the tumor periphery averaged 23.4 Gy (range, 12―40 Gy). The mean tumor volume was 1.8 cm 3 (range, 0.058―65.4 cm 3 ). Tumor response was evaluated in serial, contrast-enhanced, computed tomographic, and magnetic resonance imaging scans. RESULTS: Clinical and radiographic follow-up data were available for 82 hemangioblastoma tumors. Only 13 (16%) of the treated hemangioblastomas progressed, whereas 18 tumors (22%) showed radiographic regression, and 51 tumors (62%) remained unchanged in size. With median follow-up of 69 months (range, 5―164 months), the actuarial local control rates at 36 and 60 months were 85% and 82%, respectively. Radiosurgery improved lesion-associated symptoms in 36 of 41 tumors. During the follow-up period, 9 patients died of causes unrelated to the progression of their treated hemangioblastomas, and 5 patients developed radiation necrosis. CONCLUSION: Stereotactic radiosurgery is safe and effective in the treatment of hemagioblastomas and is an attractive alternative to surgery for patients, including those with von Hippel-Lindau disease.

Objective Although stereotactic radiosurgery is an established procedure for treating trigeminal neuralgia (TN), the likelihood of a prompt and durable complete response is not assured. Moreover, the incidence of facial numbness remains a challenge. To address these limitations, a new, more anatomic radiosurgical procedure was developed that uses the CyberKnife (Accuray, Inc., Sunnyvale, CA) to lesion an elongated segment of the retrogasserian cisternal portion of the trigeminal sensory root. Because the initial experience with this approach resulted in an unacceptably high incidence of facial numbness, a gradual dose and volume de-escalation was performed over several years. In this single-institution prospective study, we evaluated clinical outcomes in a group of TN patients who underwent lesioning with seemingly optimized nonisocentric radiosurgical parameters. Methods Forty-six patients with intractable idiopathic TN were treated between January 2005 and June 2007. Eligible patients were either poor surgical candidates or had failed previous microvascular decompression or destructive procedures. During a single radiosurgical session, a 6-mm segment of the affected nerve was treated with a mean marginal prescription dose of 58.3 Gy and a mean maximal dose of 73.5 Gy. Monthly neurosurgical follow-up was performed until the patient became pain-free. Longer-term follow-up was performed both in the clinic and over the telephone. Outcomes were graded as excellent (pain-free and off medication), good (>90% improvement while still on medication), fair (50-90% improvement), or poor (no change or worse). Facial numbness was assessed using the Barrow Neurological Institute Facial Numbness Scale score. Results Symptoms disappeared completely in 39 patients (85%) after a mean latency of 5.2 weeks. In most of these patients, pain relief began within the first week. TN recurred in a single patient after a pain-free interval of 7 months; all symptoms abated after a second radiosurgical procedure. Four additional patients underwent a repeat rhizotomy after failing to respond adequately to the first operation. After a mean follow-up period of 14.7 months, patient-reported outcomes were excellent in 33 patients (72%), good in 11 patients (24%), and poor/no improvement in 2 patients (4%). Significant ipsilateral facial numbness (Grade III on the Barrow Neurological Institute Scale) was reported in 7 patients (15%). Conclusion Optimized nonisocentric CyberKnife parameters for TN treatment resulted in high rates of pain relief and a more acceptable incidence of facial numbness than reported previously. Longer follow-up periods will be required to establish whether or not the durability of symptom relief after lesioning an elongated segment of the trigeminal root is superior to isocentric radiosurgical rhizotomy.

The central nervous system is one of the most common sites of cancer metastases; up to 40% of cancer patients develop brain metastasis in the course of their disease. Radiation plays an important role in the palliative treatment of brain metastasis. Whole brain irradiation following surgical resection (or stereotactic radiosurgery) is considered the mainstay treatment for solitary brain metastasis. Whole-brain irradiation with or without stereotactic radiosurgery is the choice of treatment for palliation in patients with more than one intracranial metastatic lesions. Stereotactic radiosurgery alone for 4 or fewer brain metastases is also a reasonable option in selected patients.

Purpose Dosimetric data are reported for five cases of radiation-induced myelopathy after stereotactic body radiotherapy (SBRT) to spinal tumors. Analysis per the biologically effective dose (BED) model was performed. Methods and Materials Five patients with radiation myelopathy were compared to a subset of 19 patients with no radiation myelopathy post-SBRT. In all patients, the thecal sac was contoured to represent the spinal cord, and doses to the maximum point, 0.1-, 1-, 2-, and 5-cc volumes, were analyzed. The mean normalized 2-Gy-equivalent BEDs (nBEDs), calculated using an α/β value of 2 for late toxicity with units Gy 2/2, were compared using the t test and analysis of variance test. Results Radiation myelopathy was observed at the maximum point with doses of 25.6 Gy in two fractions, 30.9 Gy in three fractions, and 14.8, 13.1, and 10.6 Gy in one fraction. Overall, there was a significant interaction between patient subsets and volume based on the nBED (p = 0.0003). Given individual volumes, a significant difference was observed for the mean maximum point nBED (p = 0.01). Conclusions The maximum point dose should be respected for spine SBRT. For single-fraction SBRT 10 Gy to a maximum point is safe, and up to five fractions an nBED of 30 to 35 Gy 2/2 to the thecal sac also poses a low risk of radiation myelopathy.

OBJECTIVE: Anecdotal evidence suggests that radiosurgical ablation of parasagittal meningiomas may be associated with increased risk of subsequent edema. Potential predictors of postradiosurgical peritumoral edema, including parasagittal tumor location, tumor size, and treatment dose, were evaluated. METHODS: We retrospectively reviewed records of 102 patients with 111 supratentorial meningiomas treated with CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery (SRS). A median marginal dose of 18.0 Gy (range, 11.3-25.0 Gy) was delivered in 1 to 5 sessions (fractions). Potential predictors of posttreatment symptomatic edema were evaluated using Fisher's exact test. RESULTS: Of the 102 patients followed for a mean of 20.9 months (range, 6-77 mo), 15 (14.7%) developed symptomatic edema after SRS. Nine of 31 with parasagittal meningiomas (29.0%) and 6 of 80 with nonparasagittal supratentorial meningiomas (7.5%) developed symptomatic edema (P = 0.0053). Compared with patients with meningiomas in nonmidline supratentorial locations, patients with parasagittal meningiomas were more than 4 times as likely to develop symptomatic edema after SRS (odds ratio, 4.1; 95% confidence interval, 1.5-11.5). The 6-, 12-, and 18-month actuarial rates of symptomatic edema development were significantly greater for patients with parasagittal meningiomas than for patients with nonparasagittal meningiomas (17.8 versus 1.3%, 25.4 versus 5.8%, and 35.2 versus 7.8%, respectively). CONCLUSION: Patients with parasagittal meningiomas are at greater risk of developing peritumoral symptomatic edema after SRS. Close follow-up after SRS may be particularly important in such patients. These results highlight the need to pursue strategies that could decrease the incidence of postradiosurgical edema in patients with parasagittal meningioma.

Pulmonary artery intimal sarcoma is an uncommon tumor with a poor prognosis. We report a case of a 75-year-old man with a pulmonary artery sarcoma, recurrent following surgical resection. To palliate symptoms of this recurrence, he underwent CyberKnife stereotactic radiosurgery with a clinical and radiographic response of his treated disease. No acute or sub-acute toxicity was seen until the patient's death due to metastatic disease 10 weeks following treatment. The feasibility and short-term safety of this technique are reviewed, with emphasis on the stereotactic planning considerations, such as mediastinal organ movement and radiation tolerance.

Acromegaly is a disease characterized by GH hypersecretion, and is typically caused by a pituitary somatotroph adenoma. The primary mode of therapy is surgery, and radiotherapy is utilized as an adjuvant strategy to treat persistent disease. The aim of this study was to determine the efficacy and tolerability of CyberKnife stereotactic radiosurgery in acromegaly.A retrospective review of biochemical and imaging data for subjects with acromegaly treated with CyberKnife stereotactic radiosurgery between 1998 and 2005 at Stanford University Hospital.Nine patients with active acromegaly were treated with radiosurgery using the CyberKnife (CK).Biochemical response based on serum insulin-like growth factor-1 (IGF-1), anterior pituitary hormone function, and tumor size with MRI scans were analyzed.After a mean follow up of 25.4 months (range, 6-53 months), CK radiosurgery resulted in complete biochemical remission in 4 (44.4%) subjects, and in biochemical control with the concomitant use of a somatostatin analog in an additional subject. Smaller tumor size was predictive of treatment success: baseline tumor volume was 1.28 cc (+/- 0.81, SD) vs. 3.93 cc (+/- 1.54) in subjects with a normal IGF-1 vs. those with persistent, active disease, respectively (P = 0.02). The mean biologically effective dose (BED) was higher in subjects who achieved a normal IGF-1 vs. those with persistent, active disease, 172 Gy(3) (+/-28) vs. 94 Gy(3) (+/-17), respectively (P0.01). At least one new anterior pituitary hormone deficiency was observed after CK in 3 (33%) patients: two developed hypogonadism, and one developed panhypopituitarism.CK radiosurgery may be a valuable adjuvant therapy for the management of acromegaly.

Pancreatic cancer remains one of the most lethal cancer diagnoses. The high mortality rate is primarily related to its advanced stage at diagnosis and the high rate of distant metastases. The treatment results of resected and locally advanced pancreatic cancer via conventional chemoradiotherapy have been disappointing, with a high rate of local disease progression and metastases. Past investigation has suggested improved outcomes with radiotherapy dose escalation. Extracranial stereotactic radiosurgery using CyberKnife® (Accuray Incorporated, Sunnyvale, CA) technology is a novel approach to the administration of radiation in a single outpatient treatment, while minimizing the irradiation of surrounding normal structures. Phase I/II studies have shown it to be safe and effective in providing local tumor control and palliation of local symptoms. Furthermore, the decreased treatment time with radiosurgery minimizes the delay in initiation of systemic therapy. The role of pre-operative radiosurgery in combination with gemcitabine chemotherapy has many theoretical advantages over conventional neo-adjuvant or post-operative fractionated radiotherapy in combination with sensitizing chemotherapy. The movement of the pancreas due to respiration poses a challenge in the planning of stereotactic radiosurgery. In this chapter, the use of Image Guided Radiotherapy techniques (IGRT), such as the Synchrony® (Accuray Incorporated, Sunnyvale, CA) Respiratory Motion Tracking system and respiratory gated 4D PET-CT scanning for defining the tumor volume is reviewed.

Motivation: Early cancer detection has always been a major research focus in solid tumor oncology. Early tumor detection can theoretically result in lower stage tumors, more treatable diseases and ultimately higher cure rates with less treatment-related morbidities. Protein mass spectrometry is a potentially powerful tool for early cancer detection. We propose a novel method for sample classification from protein mass spectrometry data. When applied to spectra from both diseased and healthy patients, the ‘peak probability contrast’ technique provides a list of all common peaks among the spectra, their statistical significance and their relative importance in discriminating between the two groups. We illustrate the method on matrix-assisted laser desorption and ionization mass spectrometry data from a study of ovarian cancers. Results: Compared to other statistical approaches for class prediction, the peak probability contrast method performs as well or better than several methods that require the full spectra, rather than just labelled peaks. It is also much more interpretable biologically. The peak probability contrast method is a potentially useful tool for sample classification from protein mass spectrometry data. Supplementary Information: http://www.stat.stanford.edu/~tibs/ppc

Background Mutations of the p53 tumor-suppressor gene are common in squamous cell carcinoma of the head and neck (SCCHN) and may portend a worse prognosis. Human papillomavirus (HPV) represents another potential prognostic factor for SCCHN. The oncogenic potential of HPV may be due to the ability of its E6 oncoprotein to promote degradation of wild-type p53 protein. We wish to determine whether there is a lower incidence of p53 mutations in HPV-positive versus HPV-negative tumors, and if HPV and/or p53 status has an impact on survival. Methods Thirty-two SCCHN specimens were analyzed for mutations of the p53 gene using single-strand conformational polymorphism (SSCP) analysis followed by DNA sequencing. The HPV status of all specimens was evaluated by use of polymerase chain reaction with HPV consensus primers and Southern blot hybridization. Pertinent clinical information was obtained from chart review. Results Nonsilent p53 mutations were present in 2 of 15 (13%) of HPV-positive tumors compared with 6 of 17 (35%) of HPV-negative tumors (p = .229; Fisher's exact test, odds ratio .28). A survival advantage was found between HPV-positive compared with HPV-negative specimens (p = .0264) and between p53 wild type compared with p53 mutant specimens (p = .01) by univariate log rank analysis. When stratified according to both HPV and p53 status, a statistically significant survival difference was observed largely because of a 100% survival for the HPV-positive/p53 wild-type group (p = .003). Conclusions This preliminary study supports the notion that the presence of HPV confers a survival advantage among HNSCC patients, particularly when p53 is wild type. © 2002 Wiley Periodicals, Inc. Head Neck 24: 841–849, 2002