Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial.

BACKGROUND: Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH-) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH- was combined with temozolomide and radiotherapy. As P-AscH- relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH- therapy in glioblastoma participants. METHODS: Participants (n = 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory. RESULTS: Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival. CONCLUSIONS: This study analyzes iron-related biomarkers in the context of P-AscH- therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.

HIGHLIGHTS: Pharmacological ascorbate shows significant promise to enhance glioblastoma clinical outcomes. Transferrin receptor and ferritin heavy chain expression represent potential molecular markers to predict pharmacological ascorbate treatment response. Quantitative Susceptibility Mapping is an MRI technique that can serve as a non-invasive marker of iron metabolism to evaluate progression-free survival. Systemic iron metabolic markers are readily available diagnostic tests that can potentially be used to prognosticate overall survival.

Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate.

Ferumoxytol (FMX) is an FDA-approved magnetite (Fe3O4) nanoparticle used to treat iron deficiency anemia that can also be used as an MR imaging agent in patients that can't receive gadolinium. Pharmacological ascorbate (P-AscH-; IV delivery; plasma levels ≈ 20 mM) has shown promise as an adjuvant to standard of care chemo-radiotherapy in glioblastoma (GBM). Since ascorbate toxicity mediated by H2O2 is enhanced by Fe redox cycling, the current study determined if ascorbate catalyzed the release of ferrous iron (Fe2+) from FMX for enhancing GBM responses to chemo-radiotherapy. Ascorbate interacted with Fe3O4 in FMX to produce redox-active Fe2+ while simultaneously generating increased H2O2 fluxes, that selectively enhanced GBM cell killing (relative to normal human astrocytes) as opposed to a more catalytically active Fe complex (EDTA-Fe3+) in an H2O2 - dependent manner. In vivo, FMX was able to improve GBM xenograft tumor control when combined with pharmacological ascorbate and chemoradiation in U251 tumors that were unresponsive to pharmacological ascorbate therapy. These data support the hypothesis that FMX combined with P-AscH- represents a novel combined modality therapeutic approach to enhance cancer cell selective chemoradiosentization in the management of glioblastoma.

Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

Role of radiotherapy in adenoid cystic carcinoma of the head and neck.

This study retrospectively reviewed 183 cases of adenoid cystic carcinoma treated over 40 years. The local recurrence free survival rate was 68.2 per cent at five years and 40.8 per cent at 10 years. At 10 years, local recurrence free survival was significantly worse following radiotherapy alone (0 per cent), compared with surgery alone (41.8 per cent, p = 0.004) or combined with post-operative radiotherapy (43.5 per cent, p = 0.001). Neither tumour stage three or four, perineural invasion, solid subtype nor involved margins predicted local recurrence. Treatment with radiotherapy alone resulted in worse survival than surgery alone (p = 0.002) or combined with post-operative radiotherapy (p = 0.001). Survival rates following local recurrence (n = 34) were higher following surgery (p = 0.006) but not significantly improved following radiotherapy (p = 0.139). Chemotherapy for distant metastases did not prolong survival (p = 0.747) but did result in improved eating and aesthetics scores, while decreasing overall physical health. These results indicate that surgery is preferable for primary and recurrent adenoid cystic carcinoma of the head and neck. The incidence of local recurrence following surgery and postoperative radiotherapy was similar to surgery alone cases although the latter had less adverse prognostic features. Contemporary chemotherapy may benefit quality of life but not survival in patients with distant metastases due to adenoid cystic carcinoma of the head and neck.

Initial clinical experience with frameless stereotactic radiosurgery: analysis of accuracy and feasibility.

PURPOSE: To report on preliminary clinical experience with a novel image-guided frameless stereotactic radiosurgery system. METHODS AND MATERIALS: Fifteen patients ranging in age from 14 to 81 received radiosurgery using a commercially available frameless stereotactic radiosurgery system. Pathologic diagnoses included metastases (12), recurrent primary intracranial sarcoma (1), recurrent central nervous system (CNS) lymphoma (1), and medulloblastoma with supratentorial seeding (1). Treatment accuracy was assessed from image localization of the stereotactic reference array and reproducibility of biteplate reseating. We chose 0.3 mm vector translation error and 0.3 degree rotation about each axis as the maximum tolerated misalignment before treating each arc. RESULTS: The biteplates were found on average to reseat with a reproducibility of 0.24 mm. The mean registration error from CT localization was found to be 0.5 mm, which predicts that the average error at isocenter was 0.82 mm. No patient treatment was delivered beyond the maximum tolerated misalignment. The radiosurgery treatment was delivered in approximately 25 min per patient. CONCLUSION: Our initial clinical experience with stereotactic radiotherapy using the infrared camera guidance system was promising, demonstrating clinical feasibility and accuracy comparable to many frame-based systems.

Isotropic beam bouquets for shaped beam linear accelerator radiosurgery.

In stereotactic radiosurgery and radiotherapy treatment planning, the steepest dose gradient is obtained by using beam arrangements with maximal beam separation. We propose a treatment plan optimization method that optimizes beam directions from the starting point of a set of isotropically convergent beams, as suggested by Webb. The optimization process then individually steers each beam to the best position, based on beam's-eye-view (BEV) critical structure overlaps with the target projection and the target's projected cross sectional area at each beam position. This final optimized beam arrangement maintains a large angular separation between adjacent beams while conformally avoiding critical structures. As shown by a radiosurgery plan, this optimization method improves the critical structure sparing properties of an unoptimized isotropic beam bouquet, while maintaining the same degree of dose conformity and dose gradient. This method provides a simple means of designing static beam radiosurgery plans with conformality indices that are within established guidelines for radiosurgery planning, and with dose gradients that approach those achieved in conventional radiosurgery planning.

Optically guided intensity modulated radiotherapy.

BACKGROUND AND PURPOSE: Previously, we reported on development of an optically guided system for 3D conformal intracranial radiotherapy using multiple noncoplanar fixed fields. In this paper we report on the extension of our system for stereotactic fractionated radiotherapy to include intensity modulated static ports. METHODS AND MATERIALS: A 3D treatment plan with maximum beam separation is developed in the stereotactic space established by an optically guided system. Gantry angles are chosen such that each beam has a unique entrance and exit pathway, avoids the critical structures, and has a minimal beam's eye view projection. Once, a satisfactory treatment plan is found using this geometric approach an inverse treatment plan is developed using the beam portals established previously. The purpose of adding inverse planing is two fold, on the one hand it allows further reduction of margins around the PTV, while on the other hand it affords the possibility of conformal avoidance of critical structures that are close to or abut the PTV. RESULTS: The use of the optically guided system in conjunction with intensity modulated noncoplanar radiotherapy treatment planning using fixed fields allows the generation of highly conformal treatment plans that exhibit smaller 90, 70, and 50% of prescription dose isodose volumes, improved PITV ratios, comparable or improved EUD, smaller NTD(mean) for the critical structures, and an inhomogeneity index that is within generally accepted limits. CONCLUSION: Because optically guided technology improves the accuracy of patient localization relative to the linac isocenter and allows real-time monitoring of patient position, the planning target volume needs to be corrected only for the limitations of image resolution. Intensity modulated static beam radiotherapy planning then provides the user the ability to further reduce margins on the PTV and to conform very closely to this smaller target volume, and enhances the normal tissue sparing, and high degree of conformality possible with 3D conformal radiotherapy. In addition, since optically guided technology affords improved patient localization and online monitoring of patient position during treatment delivery it allows for safe and efficient delivery of intensity modulated radiotherapy.

Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method.

PURPOSE: To estimate the potential improvement in survival for patients with brain metastases, stratified by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) class and treated with radiosurgery (RS) plus whole brain radiotherapy (WBRT). METHODS AND MATERIALS: An analysis of the RS databases of 10 institutions identified patients with brain metastates treated with RS and WBRT. Patients were stratified into 1 of 3 RPA classes. Survival was evaluated using Kaplan-Meier estimates and proportional hazard regression analysis. A comparison of survival by class was carried out with the RTOG results in similar patients receiving WBRT alone. RESULTS: Five hundred two patients were eligible (261 men and 241 women, median age 59 years, range 26-83). The overall median survival was 10.7 months. A higher Karnofsky performance status (p = 0.0001), a controlled primary (median survival = 11.6 vs. 8.8 months, p = 0.0023), absence of extracranial metastases (median survival 13.4 vs. 9.1 months, p = 0.0001), and lower RPA class (median survival 16.1 months for class I vs. 10.3 months for class II vs. 8.7 months for class III, p = 0.000007) predicted for improved survival. Gender, age, primary site, radiosurgery technique, and institution were not prognostic. The addition of RS boosted results in median survival (16.1, 10.3, and 8.7 months for classes I, II, and III, respectively) compared with the median survival (7.1, 4.2, and 2.3 months, p <0.05) observed in the RTOG RPA analysis for patients treated with WBRT alone. CONCLUSION: In the absence of randomized data, these results suggest that RS may improve survival in patients with BM. The improvement in survival does not appear to be restricted by class for well-selected patients.

Analysis of risk factors associated with radiosurgery for vestibular schwannoma.

OBJECT: The aim of this study was to identify factors associated with delayed cranial neuropathy following radiosurgery for vestibular schwannoma (VS or acoustic neuroma) and to determine how such factors may be manipulated to minimize the incidence of radiosurgical complications while maintaining high rates of tumor control. METHODS: From July 1988 to June 1998, 149 cases of VS were treated using linear accelerator radiosurgery at the University of Florida. In each of these cases, the patient's tumor and brainstem were contoured in 1-mm slices on the original radiosurgical targeting images. Resulting tumor and brainstem volumes were coupled with the original radiosurgery plans to generate dose-volume histograms. Various tumor dimensions were also measured to estimate the length of cranial nerve that would be irradiated. Patient follow-up data, including evidence of cranial neuropathy and radiographic tumor control, were obtained from a prospectively maintained, computerized database. The authors performed statistical analyses to compare the incidence of posttreatment cranial neuropathies or tumor growth between patient strata defined by risk factors of interest. One hundred thirty-nine of the 149 patients were included in the analysis of complications. The median duration of clinical follow up for this group was 36 months (range 18-94 months). The tumor control analysis included 133 patients. The median duration of radiological follow up in this group was 34 months (range 6-94 months). The overall 2-year actuarial incidences of facial and trigeminal neuropathies were 11.8% and 9.5%, respectively. In 41 patients treated before 1994, the incidences of facial and trigeminal neuropathies were both 29%, but in the 108 patients treated since January 1994, these rates declined to 5% and 2%, respectively. An evaluation of multiple risk factor models showed that maximum radiation dose to the brainstem, treatment era (pre-1994 compared with 1994 or later), and prior surgical resection were all simultaneously informative predictors of cranial neuropathy risk. The radiation dose prescribed to the tumor margin could be substituted for the maximum dose to the brainstem with a small loss in predictive strength. The pons-petrous tumor diameter was an additional statistically significant simultaneous predictor of trigeminal neuropathy risk, whereas the distance from the brainstem to the end of the tumor in the petrous bone was an additional marginally significant simultaneous predictor of facial neuropathy risk. The overall radiological tumor control rate was 93% (59% tumors regressed, 34% remained stable, and 7.5% enlarged), and the 5-year actuarial tumor control rate was 87% (95% confidence interval [CI] 76-98%). Analysis revealed that a radiation dose cutpoint of 10 Gy compared with more than 10 Gy prescribed to the tumor margin yielded the greatest relative difference in tumor growth risk (relative risk 2.4, 95% CI 0.6-9.3), although this difference was not statistically significant (p = 0.207). CONCLUSIONS: Five points must be noted. 1) Radiosurgery is a safe, effective treatment for small VSs. 2) Reduction in the radiation dose has played the most important role in reducing the complications associated with VS radiosurgery. 3) The dose to the brainstem is a more informative predictor of postradiosurgical cranial neuropathy than the length of the nerve that is irradiated. 4) Prior resection increases the risk of late cranial neuropathies after radiosurgery. 5) A prescription dose of 12.5 Gy to the tumor margin resulted in the best combination of maximum tumor control and minimum complications in this series.

Calibration of three-dimensional ultrasound images for image-guided radiation therapy.

A new technique of patient positioning for radiotherapy/radiosurgery of extracranial tumours using three-dimensional (3D) ultrasound images has been developed. The ultrasound probe position is tracked within the treatment room via infrared light emitting diodes (IRLEDs) attached to the probe. In order to retrieve the corresponding room position of the ultrasound image, we developed an initial ultrasound probe calibration technique for both 2D and 3D ultrasound systems. This technique is based on knowledge of points in both room and image coordinates. We first tested the performance of three algorithms in retrieving geometrical transformations using synthetic data with different noise levels. Closed form solution algorithms (singular value decomposition and Horn's quaternion algorithms) were shown to outperform the Hooke and Jeeves iterative algorithm in both speed and accuracy. Furthermore, these simulations show that for a random noise level of 2.5, 5, 7.5 and 10 mm, the number of points required for a transformation accuracy better than 1 mm is 25, 100, 200 and 500 points respectively. Finally, we verified the tracking accuracy of this system using a specially designed ultrasound phantom. Since ultrasound images have a high noise level, we designed an ultrasound phantom that provides a large number of points for the calibration. This tissue equivalent phantom is made of nylon wires, and its room position is optically tracked using IRLEDs. By obtaining multiple images through the nylon wires, the calibration technique uses an average of 300 points for 3D ultrasound volumes and 200 for 2D ultrasound images, and its stability is very good for both rotation (standard deviation: 0.4 degrees) and translation (standard deviation: 0.3 mm) transformations. After this initial calibration procedure, the position of any voxel in the ultrasound image volume can be determined in world space, thereby allowing real-time image guidance of therapeutic procedures. Finally, the overall tracking accuracy of our 3D ultrasound image-guided positioning system was measured to be on average 0.2 mm, 0.9 mm and 0.6 mm for the AP, lateral and axial directions respectively.

Esthesioneuroblastoma: the University of Iowa experience 1978-1998.

OBJECTIVE: Esthesioneuroblastoma is rare and the best treatment has yet to be defined. The purpose of this study is to analyze the natural history, treatment, and patterns of failure of esthesioneuroblastoma treated at one institution. METHODS: Between 1978 and 1998, 13 patients with esthesioneuroblastoma were identified using the University of Iowa Tumor Registry. All patients were staged according to Kadish criteria. Mean follow-up was 6.3 years. Six patients had 5 or more years of follow-up and four had follow-up exceeding 9.5 years. One patient was lost to follow-up at 36 months. RESULTS: No patients had Kadish stage A disease, five were stage B, and eight stage C. Overall actuarial 5- and 10-year survival rate was 61% and 24%, respectively. Disease-free survival rate at 5 and 10 years was 56% and 42%, respectively. Seven patients have died, three of intercurrent disease and three of disease progression, one with an unknown disease status. Six patients remain alive, three without evidence of disease and three have experienced a local or regional recurrence. Five patients who were initially controlled developed recurrence, three local only, one locoregional, and one regional and distant. Median time to failure was 96 months. All patients with follow-up exceeding 12 years have experienced either a local or regional recurrence. Survival after salvage therapy in these patients ranged from 3 to 12 years. CONCLUSION: Esthesioneuroblastoma has a long natural history characterized by frequent local or regional recurrence after conventional treatment. Successful retreatment can lead to prolonged survival.

Ultrasonographic guidance for spinal extracranial radiosurgery: technique and application for metastatic spinal lesions.

OBJECT: The relatively stationary anatomy of the intracranial compartment has allowed the development of stereotactic radiosurgery as an effective treatment option for many intracranial lesions. Difficulty in accurately tracking extracranial targets has limited its development in the treatment of these lesions. The ability to track extracranial structures in real time with ultrasound images allows a system to upgrade and interface pretreatment volumetric images for extracranial applications. In this report the authors describe this technique as applied to the treatment of localized metastatic spinal disease. METHODS: The extracranial stereotactic system consists of an optically tracked ultrasonography unit that can be registered to a linear accelerator coordinate system. Stereotactic ultrasound images are acquired following patient positioning, based on a pretreatment computerized tomography (CT) simulation. The soft-tissue shifts between the virtual CT-based treatment plan and the actual treatment are determined. The degree of patient offset is tracked and used to correct the treatment plan. The ultrasonography-based stereotactic navigation system is accurate to within an approximate means of 1.5 mm based on testing with an absolute coordinate phantom. A radiosurgical treatment was delivered using the system for localization of a metastatic spinal lesion. Compared with the virtual CT simulation, the actual treatment plan isocenter was shifted 12.2 mm based on the stereotactic ultrasound image. The patient was treated using noncoplanar beams to a dose of 15.0 Gy to the 80% isodose shell in a single fraction. CONCLUSIONS: A system for high-precision radiosurgical treatment of metastatic spinal tumors has been developed, tested, and applied clinically. Optical tracking of the ultrasonography probe provides real-time tracking of the patient anatomy and allows computation of the target displacement prior to treatment delivery. The results reported here suggest the feasibility and safety of the technique.

Radiosurgery using a stereotactic headframe system for irradiation of brain tumors in dogs.

Radiation therapy of brain tumors in dogs typically involves administration of multiple fractions over several weeks. Fractionation is used to minimize damage to normal tissue. Radiosurgery uses multiple non-coplanar stereotactically focused beams of radiation in a series of arcs to deliver a single dose to the target with extreme accuracy. The large number of beams facilitates a high degree of conformation between the treatment area and the target tumor and allows for a steep dose gradient; the use of nonintersecting arcs minimizes exposure of normal tissue. Computed tomography with a stereotactic localizer secured to the skull allows generation of a 3-dimensional image of the target and provides accurate spatial coordinates for computerized treatment planning and delivery. Three dogs were treated with radiosurgery, using 1,000 to 1,500 cGy. A linear accelerator mounted on a rotating gantry was used to generate and deliver the radiation. Two dogs with meningiomas survived 227 and 56 weeks after radiosurgery. A dog with an oligodendroglioma survived 66 weeks. No complications were observed following the use of this technique.

Pixel analysis of MR perfusion imaging in predicting radiation therapy outcome in cervical cancer.

The purpose of this study was to assess heterogeneity of tumor microcirculation determined by dynamic contrast-enhanced magnetic resonance (MR) imaging and its prognostic value for tumor radiosensitivity and long-term tumor control using pixel-by-pixel analysis of the dynamic contrast enhancement. Sixteen patients with advanced cervical cancer were examined with dynamic contrast-enhanced MR imaging at the time of radiation therapy. Pixel-by-pixel statistical analysis of the ratio of post- to precontrast relative signal intensity (RSI) values in the tumor region was performed to generate pixel RSI distributions of dynamic enhancement patterns. Histogram parameters were correlated with subsequent tumor control based on long-term cancer follow-up (median follow-up 4.6 years; range 3.8-5.2 years). The RSI distribution histograms showed a wide spectrum of heterogeneity in the dynamic enhancement pattern within the tumor. The quantity of low-enhancement regions (10th percentile RSI < 2.5) significantly predicted subsequent tumor recurrence (88% vs. 0%, P = 0.0004). Discriminant analysis based on both 10th percentile RSI and pixel number (reflective of tumor size) further improved the prediction rate (100% correct prediction of subsequent tumor control vs. recurrence). These preliminary results suggest that quantification of the extent of poor vascularity regions within the tumor may be useful in predicting long-term tumor control and treatment outcome in cervical cancer. J. Magn. Reson. Imaging 2000;12:1027-1033.

A geometrically based method for automated radiosurgery planning.

PURPOSE: A geometrically based method of multiple isocenter linear accelerator radiosurgery treatment planning optimization was developed, based on a target's solid shape. METHODS AND MATERIALS: Our method uses an edge detection process to determine the optimal sphere packing arrangement with which to cover the planning target. The sphere packing arrangement is converted into a radiosurgery treatment plan by substituting the isocenter locations and collimator sizes for the spheres. RESULTS: This method is demonstrated on a set of 5 irregularly shaped phantom targets, as well as a set of 10 clinical example cases ranging from simple to very complex in planning difficulty. Using a prototype implementation of the method and standard dosimetric radiosurgery treatment planning tools, feasible treatment plans were developed for each target. The treatment plans generated for the phantom targets showed excellent dose conformity and acceptable dose homogeneity within the target volume. The algorithm was able to generate a radiosurgery plan conforming to the Radiation Therapy Oncology Group (RTOG) guidelines on radiosurgery for every clinical and phantom target examined. CONCLUSIONS: This automated planning method can serve as a valuable tool to assist treatment planners in rapidly and consistently designing conformal multiple isocenter radiosurgery treatment plans.

A high-precision system for conformal intracranial radiotherapy.

PURPOSE: Currently, optimally precise delivery of intracranial radiotherapy is possible with stereotactic radiosurgery and fractionated stereotactic radiotherapy. We report on an optimally precise optically guided system for three-dimensional (3D) conformal radiotherapy using multiple noncoplanar fixed fields. METHODS AND MATERIALS: The optically guided system detects infrared light emitting diodes (IRLEDs) attached to a custom bite plate linked to the patient's maxillary dentition. The IRLEDs are monitored by a commercially available stereo camera system, which is interfaced to a personal computer. An IRLED reference is established with the patient at the selected stereotactic isocenter, and the computer reports the patient's current position based on the location of the IRLEDs relative to this reference position. Using this readout from the computer, the patient may be dialed directly to the desired position in stereotactic space. The patient is localized on the first day and a reference file is established for 5 different couch positions. The patient's image data are then imported into a commercial convolution-based 3D radiotherapy planning system. The previously established isocenter and couch positions are then used as a template upon which to design a conformal 3D plan with maximum beam separation. RESULTS: The use of the optically guided system in conjunction with noncoplanar radiotherapy treatment planning using fixed fields allows the generation of highly conformal treatment plans that exhibit a high degree of dose homogeneity and a steep dose gradient. To date, this approach has been used to treat 28 patients. CONCLUSION: Because IRLED technology improves the accuracy of patient localization relative to the linac isocenter and allows real-time monitoring of patient position, one can choose treatment-field margins that only account for beam penumbra and image resolution without adding margin to account for larger and poorly defined setup uncertainty. This approach enhances the normal tissue sparing, high degree of conformality, and homogeneity characteristics possible with 3D conformal radiotherapy.

Calculation of cranial nerve complication probability for acoustic neuroma radiosurgery.

PURPOSE: Estimations of complications from stereotactic radiosurgery usually rely simply on dose-volume or dose-diameter isoeffect curves. Due to the sparse clinical data available, these curves have typically not considered the target location in the brain, target histology, or treatment plan conformality as parameters in the calculation. In this study, a predictive model was generated to estimate the probability of cranial neuropathies as a result of acoustic schwannoma radiosurgery. METHODS AND MATERIALS: The dose-volume histogram reduction scheme was used to calculate the normal tissue complication probability (NTCP) from brainstem dose-volume histograms. The model's fitting parameters were optimized to provide the best fit to the observed complication data for acoustic neuroma patients treated with stereotactic radiosurgery at the University of Florida. The calculation was then applied to the remainder of the patients in the database. RESULTS: The best fit to our clinical data was obtained using n = 0.04, m = 0.15, and alpha/beta = 2.1 Gy(-1). Although the fitting parameter m is relatively consistent with ranges found in the literature, both the volume parameter, n, and alpha/beta are much smaller than the values quoted in the literature. The fit to our clinical data indicates that brainstem, or possibly a specific portion of the brainstem, is more radiosensitive than the parameters in the literature indicate, and that there is very little volume effect; in other words, irradiation of a small fraction of the brainstem yields NTCPs that are nearly as high as those calculated for entire volume irradiation. These new fitting parameters are specific to acoustic neuroma radiosurgery, and the small volume effect that we observe may be an artifact of the fixed relationship of acoustic tumors to specific regions of the brainstem. Applying the model to our patient database, we calculate an average NTCP of 7.2% for patients who had no cranial nerve complications, and the average NTCP for was 66% for patients who sustained a cranial neuropathy. For the entire patient population, the actual percentage of patients suffering either facial or trigeminal neuropathy was 14.7%, whereas the calculated average NTCP was 14.8%. DISCUSSION: NTCP calculations using brainstem dose-volume histograms can be used to estimate the rate of cranial neuropathies from acoustic neuroma radiosurgery. More clinical data and further study will lead to refinement of the model with time.

Stereotactic radiosurgery: techniques and clinical applications.

Radiation is a common treatment modality for cancer. Although commonly used, the treatment techniques of radiation delivery have changed substantially. One of the most important changes in implementation is the widespread application of stereotactic techniques and their acceptance into the mainstream of radiotherapeutic delivery. The distinguishing characteristics of stereotactic radiosurgery and its current and future application are important for all physicians to understand. This article discusses these treatment techniques and applications from the perspective of a surgical oncologist.