High-dose Stereotactic Radiosurgery Research Articles

Stereotactic radiosurgery in alveolar soft part sarcoma brain metastases: Case series and literature review

Alveolar soft part sarcoma (ASPS) has the highest incidence of brain metastasis amongst sarcomas. There is a paucity of literature published focusing on radiation therapy for this condition. This is a single centre retrospective review of the treatment of three patients with 12 ASPS brain metastasis using single dose stereotactic radiosurgery (SRS). Five lesions were treated with low (<25 Gy) and seven with high (≥25 Gy) dose. Four lesions had a volume of >1.5 cm3 and were defined as large, while seven had a volume of ≤0.5 cm3 and were defined as small. The local tumor control as well as the clinical complication rates were studied. There was a statistically significant relation between treatment dose and tumor control rate. All large tumors treated with low dose recurred and required surgical removal within two months following SRS, while the large lesion treated with high dose recurred after 11 months. Five of the six small tumors treated with high doses were controlled, while the sixth required retreatment and was stable thereafter. No patient suffered from undue symptomatic radiation effects. The success rate following SRS for small ASPS metastases treated with high doses seems to be sufficient to justify the treatment. The short time for large tumor to recur, significant increase in tumor size requiring surgical removal of the tumors, makes low dose SRS unattractive. Based on this limited patient population, it seems that high dose SRS should be used for all ASPS brain metastases except for large tumors deemed surgically accessible.

On the evaluation of edgeless diode detectors for patient-specific QA in high-dose stereotactic radiosurgery.

In this work, the potential of an innovative "edgeless" silicon diode was evaluated as a response to the still unmet need of a reliable tool for plan dosimetry verification of very high dose, non-coplanar, patient-specific radiosurgery treatments. In order to prove the effectiveness of the proposed technology, we focused on radiosurgical treatments for functional disease like tremor or pain. The edgeless diodes response has been validated with respect to clinical practice standard detectors by reproducing the reference dosimetry data adopted for the Treatment Planning System. In order to evaluate the potential for radiosurgery patient-specific treatment plan verification, the anthropomorphic phantom Alderson RANDO has been adopted along with three edgeless sensors, one placed in the centre of the Planning Target Volume, one superiorly and one inferiorly. The reference dosimetry data obtained from the edgeless detectors are within 2.6% for output factor, off-axis ratio and well within 2% for tissue phantom ratio when compared to PTW 60,018 diode. The edgeless detectors measure a dose discrepancy of approximately 3.6% from the mean value calculated by the TPS. Larger discrepancies are obtained in very steep gradient dose regions when the sensors are placed outside the PTV. The angular independent edgeless diode is proposed as an innovative dosimeter for patient quality assurance of brain functional disorders and other radiosurgery treatments. The comparison of the diode measurements with TPS calculations confirms that edgeless diodes are suitable candidates for patient-specific dosimetric verification in very high dose ranges delivered by non-isocentric stereotactic radiosurgery modalities.

A Comparison of Ramipril and Bevacizumab to Mitigate Radiation-Induced Brain Necrosis: An Experimental Study

Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, is a new treatment approach for radionecrosis. In our study, we compared the prophylactic and therapeutic usage of a promising agent, ramipril (an angiotensin-converting enzyme inhibitor), with that of bevacizumab for reducing radiation-induced brain injury after high-dose stereotactic radiosurgery (SRS). A total of 60 Wistar rats were used. The rats were irradiated with a single dose of 50 Gy using a Leksell Gamma Knife device. Bevacizumab and ramipril were administered in the prophylactic protocol (starting the first day of SRS) and in the therapeutic protocol (starting the fourth week of SRS). Their usage was continued until 12 weeks, and the right frontal lobes of the rats were examined histologically (hematoxylin and eosin stain) and immunohistochemically (hypoxia-inducible factor [HIF]-1α, VEGF, and CD31 antibody expression). The expression of VEGF, HIF-1α, and CD31 had significantly increased at 12 weeks after SRS compared with the control group. The addition of bevacizumab or ramipril to SRS significantly mitigated the histological severity of radiation injury and the expression of VEGF, HIF-1α, and CD31. However, the prophylactic use of bevacizumab and ramipril seemed to be more effective than therapeutic administration. Our results also revealed that the greatest benefit was achieved with the use of prophylactic administration of bevacizumab compared with other treatment protocols. Ramipril might be a promising agent for patients with radionecrosis. Clinical studies are required to investigate the effective and safe doses of ramipril, which is an inexpensive, well-tolerated drug that can cross the blood-brain barrier.

Impact of cochlear modiolus dose on hearing preservation following stereotactic radiosurgery for non-vestibular schwannoma neoplasms of the lateral skull base: a cohort study.

Radiation dose to the cochlea has been proposed as a key prognostic factor in hearing preservation following stereotactic radiosurgery (SRS) for vestibular schwannoma (VS). However, understanding of the predictive value of cochlear dose on hearing outcomes following SRS for patients with non-VS tumors of the lateral skull base (LSB) is incomplete. The authors investigated rates of hearing loss following high-dose SRS in patients with LSB non-VS lesions compared with patients with VS. Patients with LSB meningioma or jugular paraganglioma and serviceable pretreatment hearing who underwent SRS treatment during 2007-2016 and received a modiolus dose > 5 Gy were included in a retrospective cohort study, along with a similarly identified control group of consecutive patients with sporadic VS. Sixteen patients with non-VS tumors and a control group of 43 patients with VS met study criteria. Serviceable hearing, defined as American Academy of Otololaryngology-Head and Neck Surgery class A/B, was maintained in 13 non-VS versus 23 VS patients (81% vs 56%, p = 0.07). All 3 instances of hearing loss in non-VS patients were observed in cerebellopontine angle (CPA) meningiomas. Non-VS with preserved hearing had a median modiolus dose of 6.9 Gy (range 5.7-19.2 Gy), versus 7.4 Gy (range 5.4-7.6 Gy) in those patients with post-SRS hearing loss (p = 0.53). Sporadic VS patients received an overall median modiolus point-dose of 6.8 Gy (range 5.4-11.7 Gy). The modiolus dose threshold of 5 Gy does not predict hearing loss in patients with non-VS tumors undergoing SRS, suggesting that dosimetric parameters derived from VS may not be applicable to this population. Differential rates of hearing loss appear to vary by pathology, with paragangliomas and petroclival meningiomas demonstrating decreased risk of hearing loss compared to CPA meningiomas that may directly compress the cochlear nerve similarly to VS.

Evaluation of Clinical and Histologic Effects of High-Dose Radiosurgery on Rat Dorsal Root Ganglion

Stereotactic radiosurgery (SRS) is an effective technique to create lesions of the trigeminal nerve to treat refractory trigeminal neuralgia. In the lumbar spine, the dorsal root ganglion (DRG) contains the body of the sensory neurons responsible for pain sensitivity. Neuromodulation of the DRG might therefore improve chronic peripheral pain. This study was performed to determine the feasibility, clinical, and histologic effects of delivering high-dose SRS targeted to the lumbar DRG in a rat model. Four Sprague Dawley male rats underwent 80 Gy maximum-dose single-fraction SRS to the left L5 and L6 DRG using the Leksell Gamma Knife Icon (Elekta, Atlanta, Georgia, USA). The right L5 and L6 DRGs served as controls. The animals were evaluated for motor and sensory deficits every 2 weeks and were sacrificed at 3 and 6 months after SRS. Common histologic techniques were used to assess for fibrosis and demyelination at the target levels. No detectable motor or sensory deficits were seen in any animal. Histologic changes including fibrosis and loss of myelin were noted to the left L5 and L6 DRGs, but not the right side control DRGs. Fibrotic changes within the vertebral body were also evident on the treated sides of the vertebral bodies. We were able to detect a demyelinating response from SRS delivered to the DRG in rats. Because such changes mimic those seen after trigeminal SRS in experimental animals, we hypothesize that radiosurgery may be a potential option in chronic spinal radicular pain amenable to neuromodulation.

Findings on Surveillance Imaging After Preoperative Partial Breast Irradiation for Early Stage Breast Cancer

To evaluate the mammographic sequelae of preoperative accelerated partial breast irradiation (APBI) delivered via either stereotactic radiosurgery or a conventionally fractionated regimen. This multicenter, retrospective study evaluated surveillance mammograms from patients enrolled in 2 prospective, preoperative APBI clinical trials. At 1 site, 31 patients with cT1N0 invasive carcinomas or low- or intermediate-grade ductal carcinoma in situ (<2cm) received preoperative stereotactic radiosurgery and had a total of 186 mammograms available for review. At the second site, 180 mammograms from 25 patients with cT1-2 (<3cm) unifocal invasive carcinomas treated with conventionally fractionated, preoperative APBI were reviewed. Findings were compared with those of 26 early stage breast cancers treated with conventional postoperative whole breast radiation therapy. At a median follow-up of 61months, 17 patients (55%) treated with single-dose APBI exhibited exuberant fat necrosis at the lumpectomy site. Fat necrosis was believed to be clinically palpable in 5 (16%) of these patients within the first 3years of follow-up. Exuberant fat necrosis developed in 5 patients (20%) treated with fractionated APBI over a median 68-month follow-up period but only 2 of those patients (8%) who underwent conventional whole breast radiation therapy. In situ tumor targeting in the preoperative setting allows relative sparing of normal tissue but results in a larger and more vigorous area of change on surveillance imaging, potentially reflecting the interaction of surgical resection with an irradiated tissue bed. High-dose stereotactic radiosurgery in particular increases the risk of developing a uniquely robust and well-demarcated pattern of fat necrosis onmammogram that may also present clinically. With many ongoing studies evaluating the preoperative treatment approach, defining the landscape of expected imaging sequelae will provide useful anticipatory guidance for clinicians and patients.

Prophylactic Bevacizumab May Mitigate Radiation Injury: An Experimental Study

Stereotactic radiosurgery (SRS) is widely used to treat brain pathologies alone or in concert with other treatment modalities. However, there are some side effects, such as radiation injury characterized by edema and necrosis in peripheral tissues, that must be managed. A new treatment agent against this side effect is bevacizumab, which targets increased vascular endothelial growth factor (VEGF) as a prominent etiologic factor in radiation injury. In this study, we created a rat experimental model to describe the effects of both radiation and the anti-VEGF monoclonal antibody bevacizumab following high-dose SRS, and to compare the effects of prophylactic and delayed-onset bevacizumab treatment. Fifty-four adult male Wistar rats were allocated into 9 groups based on differing Gamma-knife surgery (GKS) doses and bevacizumab treatment protocols. After 12 weeks, the rats' right frontal lobes were examined with hematoxylin and eosin staining and immunohistochemistry analysis via VEGF and CD31 antibodies. Radiation necrosis occurred to varying degrees in all irradiated animals between 3 and 10 weeks post-SRS. Higher GKS dose (50% isodose of 100 Gy) led earlier necrosis and prophylaxis of bevacizumab at this dose was associated with delayed onset of necrosis. Moreover, prophylactic bevacizumab mitigated the effects of radiation necrosis following GKS at both doses, whereas this effect was not prominent with late initiation of bevacizumab (treatment protocol). Our findings show that the onset and degree of radiation injury are affected by the GKS dose and protocol of bevacizumab administration.

Stereotactic radiosurgery for spinal metastases with or without separation surgery.

In patients with significant epidural spinal cord compression, initial surgical decompression and stabilization of spinal metastases, as opposed to radical oncological resection, provides a margin around the spinal cord that facilitates subsequent treatment with high-dose adjuvant stereotactic radiosurgery (SRS). If a safe margin exists between tumor and spinal cord on initial imaging, then high-dose SRS may be used as the primary therapy, eliminating the need for surgery. Selecting the appropriate approach has shown greater efficacy of tumor control, neurological outcome, and duration of response when compared with external beam radiotherapy, regardless of tumor histology. This study evaluates the efficacy of this treatment approach in a series of 57 consecutive patients. Patients treated for spinal metastases between 2007 and 2011 using the Varian Trilogy Linear Accelerator were identified retrospectively. Each received SRS, with or without initial surgical decompression and instrumentation. Medical records were reviewed to assess neurological outcome and surgical or radiation-induced complications. Magnetic resonance images were obtained for each patient at 3-month intervals posttreatment, and radiographic response was assessed as stability/regression or progression. End points were neurological outcome and local radiographic disease control at death or latest follow-up. Fifty-seven patients with 69 lesions were treated with SRS for spinal metastases. Forty-eight cases (70%) were treated with SRS alone, and 21 (30%) were treated with surgery prior to SRS. A single fraction was delivered in 38 cases (55%), while a hypofractionated scheme was used in 31 (45%). The most common histological entities were renal cell, breast, and lung carcinomas. Radiographically, local disease was unchanged or regressed in 63 of 69 tumors (91.3%). Frankel score improved or remained stable in 68 of 69 cases (98.6%). SRS, alone or as an adjunct following surgical decompression, provides durable local radiographic disease control while preserving or improving neurological function. This less-invasive alternative to radical spinal oncological resection appears to be effective regardless of tumor histology without sacrificing durability of radiographic or clinical response.

Dosimetric verification of stereotactic radiosurgery/stereotactic radiotherapy dose distributions using Gafchromic EBT3

Aim of this study is to examine the feasibility of using the new Gafchromic EBT3 film in a high-dose stereotactic radiosurgery and radiotherapy quality assurance procedure. Owing to the reduced dimensions of the involved lesions, the feasibility of scanning plan verification films on the scanner plate area with the best uniformity rather than using a correction mask was evaluated. For this purpose, signal values dispersion and reproducibility of film scans were investigated. Uniformity was then quantified in the selected area and was found to be within 1.5% for doses up to 8Gy. A high-dose threshold level for analyses using this procedure was established evaluating the sensitivity of the irradiated films. Sensitivity was found to be of the order of centiGray for doses up to 6.2Gy and decreasing for higher doses. The obtained results were used to implement a procedure comparing dose distributions delivered with a CyberKnife system to planned ones. The procedure was validated through single beam irradiation on a Gafchromic film. The agreement between dose distributions was then evaluated for 13 patients (brain lesions, 5Gy/die prescription isodose ~80%) using gamma analysis. Results obtained using Gamma test criteria of 5%/1mm show a pass rate of 94.3%. Gamma frequency parameters calculation for EBT3 films showed to strongly depend on subtraction of unexposed film pixel values from irradiated ones. In the framework of the described dosimetric procedure, EBT3 films proved to be effective in the verification of high doses delivered to lesions with complex shapes and adjacent to organs at risk.

Editorial: Separation surgery

The management of patients with spine metastases from a functional and health-related quality of life (HRQOL) perspective is one of the most challenging issues faced by both oncologists and spine surgeons. Higher levels of evidence have been achieved over the past decade in defining the positive impact of surgery and/or conventional external beam radiation therapy (cEBRT) in these patients.1,3 More recently, stereotactic radiosurgery (SRS) has provided a successful treatment option for traditionally radioresistant tumors, but has been limited in a setting where extensive epidural disease restricts radiation dose due to the threat of cord toxicity.2 In this patient group, maximally invasive surgery to achieve gross-total resection of the tumor was often necessary to prevent local recurrence and optimize HRQOL. This surgery is resource intensive, with a not-insignificant adverse event rate, so it is not ideal in those patients who are systemically compromised and have limited life expectancy. To address this problem, Laufer et al.4 report on a treatment method of surgically removing the epidural disease (separation surgery) and then administering high-dose SRS to the remaining tumor, thus providing a means of potentially achieving local control while minimizing surgical insult and cord toxicity. The study has a strong rationale and clear purpose: to determine local recurrence rate after separation surgery and SRS. The study design is a retrospective case series involving a relatively large consecutive patient cohort treated at a specialized cancer center between 2002 and 2011. The study design is reasonable for the research question, given the complexity of the patient population and the evolution of the treatment method, but not optimal with the number of potential confounders, treatment variability, and difficulty in accurately determining the primary or dependent outcome. Unfortunately, the validity or accuracy of local recurrence determination is difficult due to changes in technology over time, reviewer variability (imaging reports were used as well as neuroradiology and neurosurgeon review), lack of technique standardization (CT myelogram and MRI), effect of spinal implant imaging artifact, lack of standardized time periods, and quantitative evaluation. With these limitations, the magnitude of the group without local recurrence (82% of the patients) is questionable; however, such an impressive effect change cannot be ignored, and the positive effect is probably a true finding. The authors use a very appropriate and robust statistical analysis to try and overcome the treatment variability and aforementioned limitations. The variability leaves the study underpowered on a number of secondary outcomes, but trends can be observed. The study does not include a patient-focused HRQOL instrument to ensure that impressive imaging outcomes are correlated with those of the patient. This omission is not critical, given the research question being asked, and using local recurrence rate as the primary outcome is a reasonable surrogate for HROQL outcome in prospective tumor research. Finally, the generalizability of the study’s findings must be considered. The breadth and variability of the cohort supports external validity, but the specialization and technology of the center and subspecialization of the surgeons and oncologists may limit it. The management of patients with symptomatic spinal metastases is difficult. Carrying out high-quality clinical research involving patients whose quality of life you are trying to optimize for their remaining time is even more demanding. The authors should be congratulated for giving us evidence for a treatment method that potentially fills a therapeutic void in this truly deserving patient population. Can we implement the findings from this study into our clinical practice despite its being at the lower level of study design hierarchy? Though the study is statistically sound and optimal within the restraints of a retrospective design, its limitations diminish its impact. The effect size, external validity within the context of large cancer centers, and the unique patient population probably support cautious implementation of this treatment method. As the technique evolves and is used by more centers, prospective evaluation will be essential. (http://thejns.org/doi/abs/10.3171/2012.10.SPINE12743)

Radiosurgery for pituitary adenomas

Radiosurgery for pituitary adenomas

Stereotactic irradiation for intracranial arteriovenous malformation using stereotactic radiosurgery or hypofractionated stereotactic radiotherapy.

To investigate the appropriateness of the treatment policy of stereotactic irradiation using both hypofractionated stereotactic radiotherapy (HSRT) and stereotactic radiosurgery (SRS) for arteriovenous malformations (AVMs) located in an eloquent region or for large AVMs and using SRS alone for the other AVMs. Included in this study were 75 AVMs in 72 patients, with a mean follow-up of 52 months. Of the 75 AVMs, 33 were located in eloquent regions or were >2.5 cm in maximal diameter and were given 25-35 Gy (mean, 32.4 Gy) in four daily fractions at a single isocenter if the patient agreed to prolonged wearing of the stereotactic frame for 5 days. The other 42 AVMs were treated with SRS at a dose of 15-25 Gy (mean, 24.1 Gy) at the isocenter. The 75 AVMs were classified according to the Spetzler-Martin grading system; 21, 23, 28, 2, and 1 AVM were Grade I, II, III, IV, V, and VI, respectively. The overall actuarial rate of obliteration was 43% (95% confidence interval [CI], 30-56%) at 3 years, 72% (95% CI, 58-86%) at 5 years, and 78% (95% CI, 63-93%) at 6 years. The actuarial obliteration rate at 5 years was 79% for the 42 AVMs <2.0 cm and 66% for the 33 AVMs >2 cm. The 5- and 6-year actuarial obliteration rate was 61% (95% CI, 39-83%) and 71% (95% CI, 47-95%), respectively, after HSRT and 81% (95% CI, 66-96%) and 81% (95% CI, 66-96%), respectively, after SRS; the difference was not statistically significant. Radiation-induced necrosis was observed in 4 subjects in the SRS group and 1 subject in the HSRT group. Cyst formation occurred in 3 patients in the SRS group and no patient in the HSRT group. A permanent symptomatic complication was observed in 3 cases (4.2%), and 1 of the 3 was fatal. All 3 patients were in the SRS group. The annual intracranial hemorrhage rate was 5.5-5.6% for all patients. Our treatment policy using SRS and HSRT was as effective as the policy involving SRS alone. The HSRT schedule was suggested to have a lower frequency of radiation necrosis and cyst formation than the high-dose SRS schedule. The benefit of HSRT compared with lower dose SRS has not yet been determined.