Lawrence Kleinberg

Inter- and intrafraction patient positioning uncertainties for intracranial radiotherapy: a study of four frameless, thermoplastic mask-based immobilization strategies using daily cone-beam CT.

PURPOSEnTo determine whether frameless thermoplastic mask-based immobilization is adequate for image-guided cranial radiosurgery.nnnMETHODS AND MATERIALSnCone-beam CT localization data from patients with intracranial tumors were studied using daily pre- and posttreatment scans. The systems studied were (1) Type-S IMRT (head only) mask (Civco) with head cushion; (2) Uni-Frame mask (Civco) with head cushion, coupled with a BlueBag body immobilizer (Medical Intelligence); (3) Type-S head and shoulder mask with head and shoulder cushion (Civco); (4) same as previous, coupled with a mouthpiece. The comparative metrics were translational shift magnitude and average rotation angle; systematic inter-, random inter-, and random intrafraction positioning error was computed. For strategies 1-4, respectively, the analysis for interfraction variability included data from 20, 9, 81, and 11 patients, whereas that for intrafraction variability included a subset of 7, 9, 16, and 8 patients. The results were compared for statistical significance using an analysis of variance test.nnnRESULTSnImmobilization system 4 provided the best overall accuracy and stability. The mean interfraction translational shifts (± SD) were 2.3 (± 1.4), 2.2 (± 1.1), 2.7 (± 1.5), and 2.1 (± 1.0) mm whereas intrafraction motion was 1.1 (± 1.2), 1.1 (± 1.1), 0.7 (± 0.9), and 0.7 (± 0.8) mm for devices 1-4, respectively. No significant correlation between intrafraction motion and treatment time was evident, although intrafraction motion was not purely random.nnnCONCLUSIONSnWe find that all frameless thermoplastic mask systems studied are viable solutions for image-guided intracranial radiosurgery. With daily pretreatment corrections, symmetric PTV margins of 1 mm would likely be adequate if ideal radiation planning and targeting systems were available.

STEREOTACTIC RADIOSURGERY IN THE MANAGEMENT OF BRAIN METASTASES: AN INSTITUTIONAL RETROSPECTIVE ANALYSIS OF SURVIVAL

PURPOSEnThe objective of this study was to report our experience with stereotactic radiosurgery performed with the Gamma Knife (GK) in the treatment of patients with brain metastases and to compare survival for those treated with radiosurgery alone with survival for those treated with radiosurgery and whole-brain radiotherapy.nnnMETHODS AND MATERIALSnProspectively collected demographic and clinical characteristics and treatment and survival data on 237 patients with intracranial metastases who underwent radiosurgery with the GK between 2003 and 2007 were reviewed. Kaplan-Meier and Cox proportional hazards regression analyses were used to compare survival by demographic and clinical characteristics and treatment.nnnRESULTSnThe mean age of the patient population was 56 years. The most common tumor histologies were non-small-cell lung carcinoma (34.2%) and breast cancer (13.9%). The median overall survival time was 8.5 months from the time of treatment. The median survival times for patients with one, two/three, and four or more brain metastases were 8.5, 9.4, and 6.7 months, respectively. Patients aged 65 years or greater and those aged less than 65 years had median survival times of 7.8 and 9 months, respectively (p = 0.008). The Karnofsky Performance Score (KPS) at the time of treatment was a significant predictor of survival: those patients with a KPS of 70 or less had a median survival of 2.9 months compared with 10.3 months (p = 0.034) for those with a KPS of 80 or greater. There was no statistically significant difference in survival between patients treated with radiosurgery alone and those treated with radiosurgery plus whole-brain radiotherapy.nnnCONCLUSIONSnRadiosurgery with the GK is an efficacious treatment modality for brain metastases. A KPS greater than 70, histology of breast cancer, smaller tumor volume, and age less than 65 years were associated with a longer median survival in our study.

Treatment of pituitary adenomas using radiosurgery and radiotherapy: a single center experience and review of literature

Fractionated radiotherapy (FRT) and gamma knife stereotactic radiosurgery (GKSRS) are used as adjuvant therapies to surgical resection for functional and non-functional pituitary adenomas, although their optimum role in the treatment algorithm, as well as long-term safety and efficacy, still awaits further study. We report a single center experience with 33 patients with non-functional (16 patients), ACTH- (five patients), GH- (four patients), or prolactin-secreting (eight patients) tumors treated with FRT or SRS. The median tumor diameter was 1.9xa0cm, and the median follow-up was 36xa0months. For GKSRS, the median dosage was 16xa0Gy for non-functional adenomas and 23xa0Gy for hormone-secreting tumors. The median total dose for FRT was 50.4xa0Gy over 28 fractions (median). Two patients (6%) demonstrated radiographic evidence of tumor progression, three patients (9%) demonstrated radiation-induced visual field deficits on neuro-ophthalmic evaluation, and two patients (6%) suffered from radiation-induced hypopituitarism. Biochemical control, defined as normalized hormone values in the absence of medical therapy, was achieved in five out of eight prolactinoma patients and two out of five patients with Cushing’s disease, but none of the four patients with acromegaly. These results are presented with a review of the relevant literature on the differential characteristics of FRT versus SRS in the treatment of functional and non-functional pituitary adenomas and validate postoperative irradiation as a potentially safe and effective means for tumor control.

Invasive adenoma and pituitary carcinoma: a SEER database analysis

Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable until identification of metastases. Optimal management and survival outcomes for both are not clearly defined. The purpose of this study is to use the Surveillance, Epidemiology, and End Results (SEER) database to report patterns of care and compare survival outcomes in a large series of patients with invasive adenomas or pituitary carcinomas. One hundred seventeen patients diagnosed between 1973 and 2008 with pituitary adenomas/adenocarcinomas were included. Eighty-three invasive adenomas and seven pituitary carcinomas were analyzed for survival outcomes. Analyzed prognostic factors included age, sex, race, histology, tumor extent, and treatment. A significant decrease in survival was observed among carcinomas compared to invasive adenomas at 1, 2, and 5xa0years (pu2009=u20090.047, 0.001, and 0.009). Only non-white race, male gender, and age ≥65 were significant negative prognostic factors for invasive adenomas (pu2009=u20090.013, 0.033, and <0.001, respectively). There was no survival advantage to radiation therapy in treating adenomas at 5, 10, 20, or 30xa0years (pu2009=u20090.778, 0.960, 0.236, and 0.971). In conclusion, pituitary carcinoma patients exhibit worse overall survival than invasive adenoma patients. This highlights the need for improved diagnostic methods for the sellar phase to allow for potentially more aggressive treatment approaches.

A radiotherapy technique to limit dose to neural progenitor cell niches without compromising tumor coverage

Radiation therapy (RT) for brain tumors is associated with neurocognitive toxicity which may be a result of damage to neural progenitor cells (NPCs). We present a novel technique to limit the radiation dose to NPC without compromising tumor coverage. A study was performed in mice to examine the rationale and another was conducted in humans to determine its feasibility. C57BL/6 mice received localized radiation using a dedicated animal irradiation system with on-board CT imaging with either: (1) Radiation which spared NPC containing regions; (2) Radiation which did not spare these niches; or (3) Sham irradiation. Mice were sacrificed 24xa0h later and the brains were processed for immunohistochemical Ki-67 staining. For the human component of the study, 33 patients with primary brain tumors were evaluated. Two intensity modulated radiotherapy (IMRT) plans were retrospectively compared: a standard clinical plan and a plan which spares NPC regions while maintaining the same dose coverage of the tumor. The change in radiation dose to the contralateral NPC-containing regions was recorded. In the mouse model, non-NPC-sparing radiation treatment resulted in a significant decrease in the number of Ki67+ cells in dentate gyrus (DG) (Pxa0=xa00.008) and subventricular zone (SVZ) (Pxa0=xa00.005) compared to NPC-sparing radiation treatment. In NPC-sparing clinical plans, NPC regions received significantly lower radiation dose with no clinically relevant changes in tumor coverage. This novel radiation technique should significantly reduce radiation doses to NPC containing regions of the brain which may reduce neurocognitive deficits following RT for brain tumors.

Imaging changes following stereotactic radiosurgery for metastatic intracranial tumors: Differentiating pseudoprogression from tumor progression and its effect on clinical practice

Stereotactic radiosurgery has become standard adjuvant treatment for patients with metastatic intracranial lesions. There has been a growing appreciation for benign imaging changes following radiation that are difficult to distinguish from true tumor progression. These imaging changes, termed pseudoprogression, carry significant implications for patient management. In this review, we discuss the current understanding of pseudoprogression in metastatic brain lesions, research to differentiate pseudoprogression from true progression, and clinical implications of pseudoprogression on treatment decisions.

Controversies in the Therapy of Brain Metastases: Shifting Paradigms in an Era of Effective Systemic Therapy and Longer-Term Survivorship

Opinion statementWith the development of therapies that improve extracranial disease control and increase long-term survival of patients with metastatic cancer, effective treatment of brain metastases while minimizing toxicities is becoming increasingly important. An expanding arsenal that includes surgical resection, whole brain radiation therapy, radiosurgery, and targeted systemic therapy provides multiple treatment options. However, significant controversies still exist surrounding appropriate use of each modality in various clinical scenarios and patient populations in the context of cancer care strategies that control systemic disease for increasingly longer periods of time. While whole brain radiotherapy alone is still a reasonable and standard option for patients with multiple metastases, several randomized trials have now revealed that survival is maintained in patients treated with radiosurgery or surgery alone, without upfront whole brain radiotherapy, for up to four brain metastases. Indeed, recent data even suggest that patients with up to 10 metastases can be treated with radiosurgery alone without a survival detriment. In an era of dramatic advances in targeted and immune therapies that control systemic disease and improve survival but may not penetrate the brain, more consideration should be given to brain metastasis-directed treatments that minimize long-term neurocognitive deficits, while keeping in mind that salvage brain therapies will likely be more frequently required. Less toxic therapies now also allow for concurrent delivery of systemic therapy with radiosurgery to brain metastases, such that treatment of both extracranial and intracranial disease can be expedited, and potential synergies between radiotherapy and agents with central nervous system penetration can be harnessed.

Clinical Results of a Pilot Study on Stereovision-Guided Stereotactic Radiotherapy and Intensity Modulated Radiotherapy

Real-time stereovision-guidance has been introduced for efficient and convenient fractionated stereotactic radiotherapy (FSR) and image-guided intensity-modulated radiation therapy (IMRT). This first pilot study is to clinically evaluate its accuracy and precision as well as impact on treatment doses. Sixty-one FSR patients wearing stereotactic masks (SMs) and nine IMRT patients wearing flexible masks (FMs), were accrued. Daily target reposition was initially based-on biplane-radiographs and then adjusted in six degrees of freedom under real-time stereovision guidance. Mean and standard deviation of the head displacements measured the accuracy and precision. Head positions during beam-on times were measured with real-time stereovisions and used for determination of delivered doses. Accuracy ± precision in direction with the largest errors shows improvement from 0.4 ± 2.3 mm to 0.0 ± 1.0 mm in the inferior-to-superior direction for patients wearing SM or from 0.8 ± 4.3 mm to 0.4 ± 1.7 mm in the posterior-to-anterior direction for patients wearing FM. The image-guidance increases target volume coverage by >30% for small lesions. Over half of head position errors could be removed from the stereovision-guidance. Importantly, the technique allows us to check head position during beam-on time and makes it possible for having frameless head refixation without tight masks.

Progressive Low-Grade Glioma: Assessment of Prognostic Importance of Histologic Reassessment and MRI Findings

BACKGROUNDnIn patients with progressive low-grade glioma (LGG), the presence of new magnetic resonance imaging (MRI) enhancement is commonly used as an indicator of malignant degeneration, but its accuracy in this setting is uncertain.nnnOBJECTIVEnWe characterize the ability of new MRI enhancement to serve as a surrogate for histologic grade in patients with progressive LGG, and to explore the prognostic value of new MRI enhancement, pathologic grade, and extent of resection.nnnMETHODSnPatients at our institution with World Health Organization grade II glioma diagnosed between 1994 and 2010 and who underwent repeat biopsy or resection at progression were retrospectively reviewed (nxa0= 108). The positive predictive value, negative predictive value, sensitivity, and specificity of new MRI enhancement were characterized. A multivariable proportional hazards model was used to test associations with overall survival (OS), and Kaplan-Meier curves were constructed to compare OS between patient subsets.nnnRESULTSnThe positive predictive value, negative predictive value, sensitivity, and specificity of new MRI enhancement were 82%, 77%, 92%, and 57%, respectively. In patients without malignant degeneration, new MRI enhancement was associated with inferior median OS (92.5 months vs. not reached; Pxa0= 0.03). In patients with malignant degeneration, gross or near total resection was associated with improved median OS (58.8 vs. 28.8 months; Pxa0= 0.02).nnnCONCLUSIONnIn patients with progressive LGG, new MRI enhancement and pathologic grade were discordant in greater than 20% of cases. Pathologic confirmation of grade should therefore be attempted, when safe, to dictate management. Beyond functioning as a surrogate for pathologic grade, new MRI enhancement may predict for worse outcomes, a concept that merits prospective investigation.

Timely stereotactic body radiotherapy (SBRT) for spine metastases using a rapidly deployable automated planning algorithm

Purpose/objectivesThe complex planning and quality assurance required for spine SBRT are a barrier to implementation in time-sensitive or limited resource clinical situations. We developed and validated an automated inverse planning algorithm designed to streamline planning and allow rapid delivery of conformal single fraction spine SBRT using widely available technology.Materials/methodsThe Rapid Spine (RaSp) automated script successfully generated single fraction SBRT plans for fourteen complex spinal lesions previously treated at a single high-volume institution. Automated RaSp plans were limited to 5 beams with a total of 15 segments (allowing calculation-based verification) and optimized based on RTOG 0631 objectives. Standard single fraction (16xa0Gy) stereotactic IMRT plans were generated for the same set of complex spinal lesions and used for comparison. A conservative 2xa0mm posterior isocenter shift was used to simulate minor set-up error.ResultsAutomated plans were generated in under 5xa0min from target definition and had a mean dose to the PTV of 1663xa0cGy (SD 131.5), a dose to 90xa0% of PTV (D90) of 1358xa0cGy (SD 111.0), and a maximum point dose (Dmax) to the PTV of 2055xa0cGy (SD 195.2) on average. IMRT plans took longer to generate but yielded more favorable dose escalation with a mean dose to the PTV of 1891xa0cGy (SD 117.6), D90 of 1731xa0cGy (SD 126.5), and Dmax of 2218xa0cGy (SD 195.7). A 2xa0mm posterior shift resulted in a 20xa0% (SD 10.5xa0%) increase in cord dose for IMRT plans and a 10xa0% (SD 5.3xa0%) increase for RaSp plans. The 2xa0mm perturbation caused 3 cord dose violations for the IMRT plans and 1 violation for corresponding RaSp plans.ConclusionThe Rapid Spine plan method yields timely and dosimetrically reasonable SBRT plans which meet RTOG 0631 objectives and are suitable for rapid yet robust pretreatment quality assurance followed by expedited treatment delivery. RaSp plans reduce the tradeoff between rapid treatment and optimal dosimetry in urgent cases and limited resource situations.