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.

The lazaroid U74389G protects normal brain from stereotactic radiosurgery-induced radiation injury.

PURPOSE: To test an established model of stereotactic radiosurgery-induced radiation injury with pretreatments of either methylprednisolone or the lazaroid U74389G. METHODS AND MATERIALS: Nine cats received stereotactic radiosurgery with a linear accelerator using and animal radiosurgery device. Each received a dose of 125.0 Gy prescribed to the 84% isodose shell to the anterior limb of the right internal capsule. One animal received no pretreatment, two received citrate vehicle, three received 30 mg/kg of methylprednisolone, and three received 5 mg/kg of U74389G. After irradiation, the animals had frequent neurologic examinations, and neurologic deficits developed in all of them. Six months after the radiation treatment, the animals were anesthetized, and had gadolinium-enhanced magnetic resonance (MR) scans, followed by Evans blue dye perfusion, euthanasia, and brain fixation. RESULTS: Magnetic resonance scans revealed a decrease in the size of the lesions from a mean volume of 0.45 +/- 0.06 cm(3) in the control, vehicle-treated, and methylpredniosolone-treated animals to 0.22 +/- 0.14 cm(3) in the U74389G-treated group. The scans also suggested the absence of necrosis and ventricular dilatation in the lazaroid-treated group. Gross pathology revealed that lesions produced in the untreated, vehicle-treated, and methylprednisolone-treated cats were similar and were characterized by a peripheral zone of Evans blue dye staining with a central zone of a mature coagulative necrosis and focal hemorrhage. However, in the U74389G-treated animals, the lesions were found to have an area of Evans blue dye staining, but lacked discrete areas of necrosis and hemorrhage. CONCLUSION: These results suggest that the lazaroid U74389G protects the normal brain from radiation injury produced by stereotactic radiosurgery.

Treatment planning optimization for linear accelerator radiosurgery.

PURPOSE: Linear accelerator radiosurgery uses multiple arcs delivered through circular collimators to produce a nominally spherical dose distribution. Production of dose distributions that conform to irregular lesions or conformally avoid critical neural structures requires a detailed understanding of the available treatment planning parameters. METHODS AND MATERIALS: Treatment planning parameters that may be manipulated within a single isocenter to provide conformal avoidance and dose conformation to ellipsoidal lesions include differential arc weighting and gantry start/stop angles. More irregular lesions require the use of multiple isocenters. Iterative manipulation of treatment planning variables can be difficult and computationally expensive, especially if the effects of these manipulations are not well defined. Effects of treatment parameter manipulation are explained and illustrated. This is followed by description of the University of Florida Stereotactic Radiosurgery Treatment Planning Algorithm. This algorithm organizes the manipulations into a practical approach for radiosurgery treatment planning. RESULTS: Iterative treatment planning parameters may be efficiently manipulated to achieve optimal treatment plans by following the University of Florida Treatment Planning Algorithm. The ability to produce conformal stereotactic treatment plans using the algorithm is demonstrated for a variety of clinical presentations. CONCLUSION: The standard dose distribution produced in linear accelerator radiosurgery is spherical, but manipulation of available treatment planning parameters may result in optimal dose conformation. The University of Florida Treatment Planning Algorithm organizes available treatment parameters to efficiently produce conformal radiosurgery treatment plans.

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.

Treatment selection factors for stereotactic radiosurgery of intracranial metastases.

PURPOSE: To define treatment selection criteria for patients with intracranial metastases treated with stereotactic radiosurgery. METHODS AND MATERIALS: Between August 1989 and July 1993, 25 patients with intracranial metastases (28 lesions) were treated with stereotactic radiosurgery at the University of Florida. Thirteen patients were treated for progressive intracranial disease after external-beam radiotherapy, and 12 were treated with radiosurgery as an adjunct to initial treatment. Minimum eligibility criteria included histologic verification of primary disease, Karnofsky performance status 50% or greater, three or fewer intracranial metastases, radiographically distinct lesion(s) 4 cm or less in diameter, and reasonably well-controlled primary disease. Univariate and multivariate analyses tested the prognostic significance of Karnofsky performance status, lesion volume, number of lesions, treatment dose (both external beam and stereotactic), histology, site of primary disease, and time interval (less than or greater than 1 year) from primary diagnosis to development of intracranial metastasis or from treatment of intracranial disease to recurrence. RESULTS: Local control was achieved in 84% of 28 lesions treated. The only significant prognostic indicator among the tested variables was the interval to development or recurrence of intracranial metastasis. CONCLUSION: Although stereotactic radiosurgery improves local control rates and is likely to offer improved palliation for a select cohort of patients, the selection criteria for such patients remain poorly defined. Our data suggest that an interval of greater than 1 year from primary disease diagnosis to development of intracranial metastasis, or from treatment of intracranial metastasis to its recurrence, defines a patient cohort that is more likely to benefit from this treatment technique.

Linac radiosurgery for high-grade gliomas: the University of Florida experience.

PURPOSE: Stereotactic radiosurgery has been reported as a promising boost technique for the treatment of selected patients with high-grade glioma. The first 11 patients given this treatment at the University of Florida are reported. METHODS AND MATERIALS: Six patients with glioblastoma multiforme and five with anaplastic astrocytoma were carefully selected for treatment with linac radiosurgery. All patients had a Karnofsky performance status > or = 90%. Median age of patients was 42.1 years. External-beam radiotherapy delivered a median dose of 60 Gy. Stereotactic radiosurgery was delivered to the enhancing tumor volume without margin. Median treatment volume was 14 cm3 (equivalent sphere diameter, 3 cm). The maximum volume of any tumor treated was 22.5 cm3 (equivalent sphere diameter, 3.5 cm). Median stereotactic radiosurgery boost dose was 12.5 Gy, and median prescription sphere was the 80% isodose shell. RESULTS: Despite rigorous selection and aggressive stereotactic boost irradiation, this patient cohort had a median actuarial survival of 17 months. All patients have had progression of intracranial disease within 1 year of radiosurgery, and only 3 of 11 remain alive with a median follow-up of 13 months. CONCLUSION: These results differ significantly from others reported. Comparative analysis suggests tumor volume may be an important prognostic factor in patients treated with stereotactic radiosurgery. Future studies need to define appropriate patient cohorts for the boost technique.

Accelerated hyperfractionated radiotherapy for malignant gliomas.

PURPOSE: To evaluate accelerated hyperfractionated radiotherapy for the treatment of malignant gliomas. METHODS AND MATERIALS: Between April 1985 and June 1994, 70 adult patients with pathologically confirmed malignant glioma (75% glioblastoma multiforme, 25% anaplastic astrocytoma) suitable for high-dose therapy were selected for treatment with accelerated hyperfractionated radiotherapy, 1.5 Gy twice daily to a total target dose of 60 Gy. Two patients were excluded from analysis (one patient had a fatal pulmonary embolism after 18 Gy; one patient discontinued therapy after 28.5 Gy against medical advice and without sequelae or progression). The 68 patients in the study group had a median age of 52 years and a median Karnofsky performance status of 90. Stereotactic implant (125I) or stereotactic radiosurgery boosts were delivered to 16 patients (24%) in the study group. Minimum follow-up was 6 months. RESULTS: Median survival was 13.8 months and median progression-free survival was 7.4 months. The absolute Kaplan-Meier survival rate was 16% at 2 years and 4% at 5 years. Multivariate analysis for the prognostic impact of age, gender, histology, Karnofsky performance status, symptomatology, surgical resection vs. biopsy, and boost vs. nonboost therapy revealed that Karnofsky performance status > or = 90, boost therapy, and surgical excision predicted significantly improved outcome. No severe toxicity occurred in patients treated with accelerated hyperfractionated radiotherapy alone, although 5% required steroids temporarily for edema. Progression occurred during treatment in one patient (1.5%). CONCLUSION: This regimen of accelerated hyperfractionated radiotherapy is well tolerated and leads to results comparable with those of standard therapy. The rate of disease progression during treatment is significantly better (p = 0.001) than is reported for patients treated with standard fractionation, with or without chemotherapy. This regimen is a reasonable starting point for future trials and may have some advantages over standard fractionation.

Linac radiosurgery for benign meningiomas.

PURPOSE: To review outcomes for patients treated with linac radiosurgery for benign meningiomas. METHODS AND MATERIALS: Between January 1989 and July 1997, 70 patients with 76 meningiomas were treated with LINAC-based radiosurgery. In 38 patients, radiosurgery was the initial treatment. In 32 patients, radiosurgery followed surgery or conventional radiotherapy. The average treatment volume was 10.0 cm3 (range, 0.6 to 28.6 cm3). The mean peripheral dose was 12.7 Gy (range, 10 to 20 Gy). The mean clinical follow-up period was 23 months. No patient was lost to follow-up. RESULTS: No lesions enlarged during the follow-up period; of 48 lesions in patients who had follow-up for at least one year and hence had follow-up imaging, 27 tumors remained unchanged and 21 tumors were reduced in size. Two patients experienced transient radiation-induced neurological deficits. One was treated with surgical excision of the tumor; the other responded to prolonged steroid therapy. Both patients, treated early in our experience, received doses higher than we would currently recommend. CONCLUSIONS: Early results suggest that stereotactic radiosurgery is an effective treatment for meningiomas. Long-term follow-up will be necessary to fully evaluate its efficacy.

Ependymoma: results, prognostic factors and treatment recommendations.

PURPOSE: To review the University of Florida experience in treating ependymomas, analyze prognostic factors, and provide treatment recommendations. METHODS AND MATERIALS: Forty-one patients with ependymoma and no metastases outside the central nervous system received postoperative radiotherapy with curative intent between 1966 and 1989. Ten patients had supratentorial lesions, 22 had infratentorial lesions, and 9 had spinal cord lesions. All patients had surgery (stereotactic biopsy, subtotal resection, or gross total resection). Most patients with high-grade lesions received radiotherapy to the craniospinal axis. Low-grade intracranial lesions received more limited treatment. Spinal cord lesions were treated using either partial spine or whole spine fields. RESULTS: Of 32 intracranial tumors, 21 recurred, all at the primary site; no spinal cord tumors recurred. Overall 10-year survival rates were 51% (absolute) and 46% (relapse-free); by tumor site: spinal cord, 100%; infratentorial, 45%; supratentorial, 20% (p = 0.002). On multivariate analysis, tumor site was the only factor that influenced absolute survival (p = 0.0004); other factors evaluated included grade, gender, age, duration of symptoms, resection extent, primary tumor dose, treatment field extent, surgery-to-radiotherapy interval, and days under radiotherapy treatment. CONCLUSIONS: Patients with supratentorial or infratentorial tumors receive irradiation, regardless of grade. Craniospinal-axis fields are used when spinal seeding is radiographically or pathologically evident. Spinal cord tumors are treated using localized fields to the primary site if not completely resected. Failure to control disease at the primary site remains the main impediment to cure.

Pterygium treated with excision and postoperative beta irradiation.

A retrospective study was done of 338 patients with pterygia treated between October 1974 and May 1990. These patients resided in the desert of the southwestern United States, where the hot, dry, dusty climate is thought to predispose to pterygium formation and subsequent recurrence. The pterygia were excised, and the administration of beta irradiation was initiated within 24 hr of surgery. Sixteen percent of the pterygia were recurrent. Ninety-five percent of the beta irradiation prescriptions consisted of 3 weekly 800 cGy fractions. For patients with a minimum of 6 months follow-up, the crude local control rate was 225/258 (88%). The Kaplan-Meier estimate of the 5-year local control rate was 84% (95% confidence interval: 79-89%). Ten of 33 recurrences were diagnosed within 6 months, and 32/33 recurrences were diagnosed within 5 years of treatment. Previously untreated pterygia were controlled more easily than were recurrent pterygia (p = 0.005). In 86% of the cases, patients judged the cosmetic results to be satisfactory. No severe complications developed. This study and others, when compared with studies involving excision alone, suggest that postoperative beta irradiation reduces the likelihood for pterygium recurrence. When the beta irradiation is fractionated, satisfactory cosmetic results can be achieved with low morbidity.

IRLED-based patient localization for linac radiosurgery.

PURPOSE: Currently, precise stereotactic radiosurgery delivery is possible with the Gamma Knife or floor-stand linear accelerator (linac) systems. Couch-mounted linac radiosurgery systems, while less expensive and more flexible than other radiosurgery delivery systems, have not demonstrated a comparable level of precision. This article reports on the development and testing of an optically guided positioning system designed to improve the precision of patient localization in couch-mounted linac radiosurgery systems. METHODS AND MATERIALS: The optically guided positioning system relies on detection of infrared light-emitting diodes (IRLEDs) attached to a standard target positioner. The IRLEDs are monitored by a commercially available camera system that is interfaced to a personal computer. An IRLED reference is established at the center of stereotactic space, and the computer reports the current position of the IRLEDs relative to this reference position. Using this readout from the computer, the correct stereotactic coordinate can be set directly. RESULTS: Bench testing was performed to compare the accuracy of the optically guided system with that of a floor-stand system, that can be considered an absolute reference. This testing showed that coordinate localization using the IRLED system to track translations agreed with the absolute to within 0.1 +/- 0.1 mm. As rotations for noncoplanar couch angles were included, the inaccuracy was increased to 0.2 +/- 0.1 mm. CONCLUSIONS: IRLED technology improves the accuracy of patient localization relative to the linac isocenter in comparison with conventional couch-mounted systems. Further, the patient's position can be monitored in real time as the couch is rotated for all treatment angles. Thus, any errors introduced by couch inaccuracies can be detected and corrected.

The University of Florida frameless high-precision stereotactic radiotherapy system.

PURPOSE: To develop and test a system for high precision fractionated stereotactic radiotherapy that separates immobilization and localization devices. METHODS AND MATERIALS: Patient localization is achieved through detection and digital registration of an independent bite plate system. The bite plate is made and linked to a set of six infrared light emitting diodes (IRLEDs). These IRLEDs are detected by an infrared camera system that identifies the position of each IRLED within 0.1 to 0.15 mm. Calibration of the camera system defines isocenter and translational X, Y, and Z axes of the stereotactic radiosurgery subsystem and thereby digitally defines the virtual treatment room space in a computer linked to the camera system. Positions of the bite plate's IRLEDs are processed digitally using a computer algorithm so that positional differences between an actual bite plate position and a desired position can be resolved within 0.1 mm of translation (X, Y, and Z distance) and 0.1 degree of rotation. Furthermore, bite plate misalignment can be displayed digitally in real time with translational (x, y, and z) and rotational (roll, pitch, and yaw) parameters for an actual bite plate position. Immobilization is achieved by a custom head mold and thermal plastic mask linked by hook-and-loop fastener tape. The head holder system permits rotational and translational movements for daily treatment positioning based on the bite plate localization system. Initial testing of the localization system was performed on 20 patients treated with radiosurgery. The system was used to treat 11 patients with fractionated stereotactic radiotherapy. RESULTS: Assessment of bite plate localization in radiosurgery patients revealed that the patient's bite plate could be positioned and repositioned within 0.5 +/- 0.3 mm (standard deviation). After adjustments, the first 11 patients were treated with the bite plate repositioning error reduced to 0.2 +/- 0.1 mm. CONCLUSIONS: High precision stereotactic radiotherapy can be delivered using separate localization and immobilization systems. Treatment setup and delivery can be accomplished in 15 min or less. Advantages compared with standard systems require further study.

Benign meningiomas: primary treatment selection affects survival.

PURPOSE: To examine the effect of primary treatment selection on outcomes for benign intracranial meningiomas at the University of Florida. METHODS AND MATERIALS: For 262 patients, the impact of age, Karnofsky performance status, pathologic features, tumor size, tumor location, and treatment modality on local control and cause-specific survival was analyzed (minimum potential follow-up, 2 years; median follow-up, 8.2 years). Extent of surgery was classified by Simpson grade. Treatment groups: surgery alone (n = 229), surgery and postoperative radiotherapy (RT) (n = 21), RT alone (n = 7), radiosurgery alone (n = 5). Survival analysis: Kaplan-Meier method with univariate and multivariate analysis. RESULTS: At 15 years, local control was 76% after total excision (TE) and 87% after subtotal excision plus RT (SE+RT), both significantly better (p = 0.0001) than after SE alone (30%). Cause-specific survival at 15 years was reduced after treatment with SE alone (51%), compared with TE (88%) or SE+RT (86%) (p = 0.0003). Recurrence after primary treatment portended decreased survival, independent of initial treatment group or salvage treatment selection (p = 0.001). Atypical pathologic features predicted reduced 15-year local control (54 vs. 71%) and cause-specific survival rates (57 vs. 86%). Multivariate analysis for cause-specific survival revealed treatment group (SE vs. others; p = 0.0001), pathologic features (atypical vs. typical;p = 0.0056), and Karnofsky performance status (> or = 80 vs. < 80; p = 0.0153) as significant variables. CONCLUSION: Benign meningiomas are well managed by TE or SE+RT. SE alone is inadequate therapy and adversely affects cause-specific survival. Atypical pathologic features predict a poorer outcome, suggesting possible benefit from more aggressive treatment. Because local recurrence portends lower survival rates, primary treatment choice is important.

Radiotherapy for pituitary adenoma: long-term outcome and sequelae.

PURPOSE: To review outcome and treatment sequelae in patients treated with external beam radiotherapy for pituitary adenomas. METHODS AND MATERIALS: One hundred forty-one patients with pituitary adenomas received radiotherapy at the University of Florida and had 2-year minimum potential follow-up. One hundred twenty-one had newly diagnosed adenomas, and 20 had recurrent tumors. Newly diagnosed tumors were treated with surgery and radiotherapy (n = 98) or radiotherapy alone (n = 23). Patients with recurrent tumors received salvage treatment with surgery and radiotherapy (n = 10) or radiotherapy alone (n = 10). The impact of age, sex, presenting symptoms, tumor extent, surgery type, degree of resection, hormonal activity, primary or salvage therapy, and radiotherapy dose on tumor control was analyzed. Tumor control is defined by the absence of radiographic progression and stable or decreased hormone level (in hormonally active tumors) after treatment. Effect of therapy on vision, hormonal function, neurocognitive function, life satisfaction, and affective symptoms were examined. A Likert categorical scale survey was used for assessment of neurocognitive, life satisfaction, and affective symptom status. Survey results from the radiotherapy patients were compared with a control group treated with transsphenoidal surgery alone. Multivariate analysis used the forward step-wise sequence of chi squares for the log rank test. RESULTS: At 10 years, tumor control for the surgery and radiotherapy group (S + RT) was 95% and not statistically different (p = 0.58) than for patients treated with radiotherapy alone (RT) (90%). Patients with prolactin- and ACTH-secreting tumors had significantly worse tumor control, as did patients treated for recurrent tumors. Multivariate analysis for tumor control revealed that only young age was predictive of worse outcome (p = 0.0354). Visual function was either unaffected or improved in most patients, although four patients developed visual loss due to treatment. Hormonal function was affected adversely in 46 of the 93 patients for whom detailed hormonal information was available. Neurocognitive function evaluation revealed that patients in the S + RT group were more likely (p = 0.005) to report difficulty with memory than those in the RT-alone or S-alone groups. No significant difference in life satisfaction or affective symptoms was evident. CONCLUSIONS: Pituitary adenomas are well controlled by external beam radiotherapy, either alone or in combination with surgery. Visual symptoms often improve after treatment. Hormonal sequelae require medical intervention in many patients. Neurocognitive sequelae may be different among treatment groups.

Preliminary experience with frameless stereotactic radiotherapy.

PURPOSE: To report initial clinical experience with a novel high-precision stereotactic radiotherapy system. METHODS AND MATERIALS: Sixty patients ranging in age from 2 to 82 years received a total of 1426 treatments with the University of Florida frameless stereotactic radiotherapy system. Of the total, 39 (65%) were treated with stereotactic radiotherapy (SRT) alone, and 21 (35%) received SRT as a component of radiotherapy. Pathologic diagnoses included meningiomas (15 patients), low-grade astrocytomas (11 patients), germinomas (9 patients), and craniopharyngiomas (5 patients). The technique was used as means of dose escalation in 11 patients (18%) with aggressive tumors. Treatment reproducibility was measured by comparing bite plate positioning registered by infrared light-emitting diodes (IRLEDs) with the stereotactic radiosurgery reference system, and with measurements from each treatment arc for the 1426 daily treatments (5808 positions). We chose 0.3 mm vector translation error and 0.3 degrees rotation about each axis as the maximum tolerated misalignment before treating each arc. RESULTS: With a mean follow-up of 11 months, 3 patients had recurrence of malignant disease. Acute side effects were minimal. Of 11 patients with low grade astrocytomas, 4 (36%) had cerebral edema and increased enhancement on MR scans in the first year, and 2 required steroids. All had resolution and marked tumor involution on follow-up imaging. Bite plate reproducibility was as follows. Translational errors: anterior-posterior, 0.01 +/- 0.10; lateral, 0.02 +/- 0.07; axial, 0.01 +/- 0.10. Rotational errors (degrees): anterior-posterior, 0.00 +/- 0.03; lateral, 0.00 +/- 0.06; axial, 0.01 +/- 0.04. No patient treatment was delivered beyond the maximum tolerated misalignment. Daily treatment was delivered in approximately 15 min per patient. CONCLUSION: Our initial experience with stereotactic radiotherapy using the infrared camera guidance system was good. Patient selection and treatment strategies are evolving rapidly. Treatment accuracy was the best reported, and the treatment approach was practical.

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.

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.

Image localization for frameless stereotactic radiotherapy.

PURPOSE: Infrared light-emitting diodes (IRLEDs) have been used for optic-guided stereotactic radiotherapy localization at the University of Florida since 1995. The current paradigm requires stereotactic head ring placement for the patient's first fraction. The stereotactic coordinates and treatment plan are determined relative to this head ring. The IRLEDs are attached to the patient via a maxillary bite plate, and the position of the IRLEDs relative to linac isocenter is saved to file. These positions are then recalled for each subsequent treatment to position the patient for fractionated therapy. The purpose of this article was to report a method of predicting the desired IRLED locations without need for the invasive head ring. METHODS AND MATERIALS: To achieve the goal of frameless optic-guided radiotherapy, a method is required for direct localization of the IRLED positions from a CT scan. Because it is difficult to localize the exact point of light emission from a CT scan of an IRLED, a new bite plate was designed that contains eight aluminum fiducial markers along with the six IRLEDs. After a calibration procedure to establish the spatial relationship of the IRLEDs to the aluminum fiducial markers, the stereotactic coordinates of the IRLED light emission points are determined by localizing the aluminum fiducial markers in a stereotactic CT scan. RESULTS: To test the accuracy of direct CT determination of the IRLED positions, phantom tests were performed. The average accuracy of isocenter localization using the IRLED bite plate was 0.65 +/- 0. 17 mm for these phantom tests. In addition, the optic-guided system has a unique compatibility with the stereotactic head ring. Therefore, the isocentric localization capability was clinically tested using the stereotactic head ring as the absolute standard. The ongoing clinical trial has shown the frameless system to provide a patient localization accuracy of 1.11 +/- 0.3 mm compared with the head ring. CONCLUSION: Optic-guided radiotherapy using IRLEDs provides a mechanism through which setup accuracy may be improved over conventional techniques. To date, this optic-guided therapy has been used only as a hybrid system that requires use of the stereotactic head ring for the first fraction. This has limited its use in the routine clinical setting. Computation of the desired IRLED positions eliminates the need for the invasive head ring for the first fraction. This allows application of optic-guided therapy to a larger cohort of patients, and also facilitates the initiation of extracranial optic-guided radiotherapy.