Penny K. Sneed

Summary Report on the Graded Prognostic Assessment: An Accurate and Facile Diagnosis-Specific Tool to Estimate Survival for Patients With Brain Metastases

PURPOSEnOur group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians.nnnMETHODSnA multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis.nnnRESULTSnSignificant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined.nnnCONCLUSIONnPrognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.

Effect of Tumor Subtype on Survival and the Graded Prognostic Assessment for Patients With Breast Cancer and Brain Metastases

PURPOSEnThe diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype.nnnMETHODS AND MATERIALSnA multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index.nnnRESULTSnSignificant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype.nnnCONCLUSIONSnThe Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.

The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer

Our group has previously published the Diagnosis-Specific Graded Prognostic Assessment (GPA) showing the prognostic factors associated with survival in patients with brain metastases (BM). The purpose of this study is to investigate the relationship of breast cancer subtype to the time interval from primary diagnosis (PD) to development of BM (TPDBM), number of BM at initial BM presentation and survival. We analyzed our previously described multi-institutional retrospective database of 865 breast cancer patients treated for newly-diagnosed BM from 1993 to 2010. Several factors found to be associated with survival were incorporated into the Breast-GPA, including tumor subtype. The GPA database was further analyzed to determine if the subtype correlated with the TPDBM, number of BM, and survival from PD. After exclusions for incomplete data, 383 patients remained eligible for analysis. The subtypes were approximated as follows: Luminal B: triple positive; HER2: HER2 positive/ER/PR negative; Luminal A; ER/PR positive/HER2 negative; Basal: triple negative. Patients with Basal (90), HER2 (119), Luminal B (98) and Luminal A (76) tumor subtypes had a median TPDBM of 27.5, 35.8, 47.4 and 54.4xa0months (pxa0<xa00.01), median survival from PD of 39.6, 66.4, 90.3 and 72.7xa0months (pxa0<xa00.01) and median survival from BM of 7.3, 17.9, 22.9 and 10.0xa0months (pxa0<xa00.01), respectively. Tumor subtype is an important prognostic factor for survival in patients with breast cancer and BM. Although TPDBM is not an independent prognostic factor for survival (and thus not part of the Breast-GPA), the TPDBM does correlate with tumor subtype but does not correlate with the number of BM. Patients with Basal and HER2 tumor subtypes have short TPDBM. Prospective studies are needed to determine if screening brain MRIs are indicated in patients with Basal or HER2 subtypes.

Prognostic Factors for Survival in Patients Treated With Stereotactic Radiosurgery for Recurrent Brain Metastases After Prior Whole Brain Radiotherapy

PURPOSEnTo evaluate prognostic factors for survival after stereotactic radiosurgery (SRS) for new, progressive, or recurrent brain metastases (BM) after prior whole brain radiotherapy (WBRT).nnnMETHODS AND MATERIALSnPatients treated between 1991 and 2007 with Gamma Knife SRS for BM after prior WBRT were retrospectively reviewed. Potential prognostic factors were analyzed overall and by primary site using univariate and stepwise multivariate analyses and recursive partitioning analysis, including age, Karnofsky performance status (KPS), primary tumor control, extracranial metastases, number of BM treated, total SRS target volume, and interval from WBRT to SRS.nnnRESULTSnA total of 310 patients were analyzed, including 90 breast, 113 non-small-cell lung, 31 small-cell lung, 42 melanoma, and 34 miscellaneous patients. The median age was 56, KPS 80, number of BM treated 3, and interval from WBRT to SRS 8.1 months; 76% had controlled primary tumor and 60% had extracranial metastases. The median survival was 8.4 months overall and 12.0 vs. 7.9 months for single vs. multiple BM treated (p = 0.001). There was no relationship between number of BM and survival after excluding single-BM patients. On multivariate analysis, favorable prognostic factors included age <50, smaller total target volume, and longer interval from WBRT to SRS in breast cancer patients; smaller number of BM, KPS >60, and controlled primary in non-small-cell lung cancer patients; and smaller total target volume in melanoma patients.nnnCONCLUSIONSnAmong patients treated with salvage SRS for BM after prior WBRT, prognostic factors appeared to vary by primary site. Although survival time was significantly longer for patients with a single BM, the median survival time of 7.9 months for patients with multiple BM seems sufficiently long for salvage SRS to appear to be worthwhile, and no evidence was found to support the use of a cutoff for number of BM appropriate for salvage SRS.

Radiation therapy of pathologically confirmed newly diagnosed glioblastoma in adults

Hypo-fractionated radiation schemes may be used for patients with a poor prognosis and limited survival without compromising response. Hyper-fractionation and accelerated fractionation have not been shown to be superior to conventional fractionation and are not recommended. Brachytherapy or stereotactic radiosurgery as a boost to external beam radiotherapy have not been shown to be beneficial and are not recommended in the routine management of newly diagnosed malignant glioma.

A dosimetric comparison between Gamma Knife and CyberKnife treatment plans for trigeminal neuralgia.

Object The Leksell Gamma Knife and the Accuray CyberKnife systems have been used in the radiosurgical treatment of trigeminal neuralgia. The 2 techniques use different delivery methods and different treatment parameters. In the past, CyberKnife treatments have been associated with an increased incidence of treatment-related complications, such as facial numbness. The goal of this study was to develop a method for planning a CyberKnife treatment for trigeminal neuralgia that would reproduce the dosimetric characteristics of a Gamma Knife plan. A comparison between Gamma Knife and CyberKnife treatment plans obtained with this method is presented. Methods Five patients treated using the Gamma Knife Perfexion Unit were selected for this study. All patients underwent CT cisternography to accurately identify the position of the trigeminal nerve. The Gamma Knife plans used either one 4-mm-diameter collimator or two coincident 4-mm collimators (one open and one with sector blocking) placed at identical isocenter ...

High­precision volume­staged Gamma Knife surgery and equivalent hypofractionation dose schedules for treating large arteriovenous malformations

OBJECTnThe goal of this study was to develop a technique for performing submillimeter high-precision volume-staged Gamma Knife surgery and investigate its potential benefits in comparison with hypofractionated stereotactic radiotherapy (SRT) for treating large arteriovenous malformations (AVMs).nnnMETHODSnThe authors analyzed 7 pediatric AVM cases treated with volume-staged stereotactic radiosurgery (SRS) using the Gamma Knife Perfexion at the University of California, San Francisco. The target and normal tissue contours from each case were exported for hypofractionated treatment planning based on the Gamma Knife Extend system or the CyberKnife SRT. Both the Gamma Knife Extend and CyberKnife treatment plans were matched to yield the same level of target coverage (95%-98%) and conformity indices (1.24-1.46). Finally, hypofractionated treatment plans were compared with volume-staged treatment plans for sparing normal brain by using biologically equivalent 12-Gy normal brain volumes.nnnRESULTSnHypofractionated Gamma Knife Extend and CyberKnife treatment plans exhibited practically identical sparing of normal brain for the studied cases. However, when matching such values with volume-staged treatments for the biological effective dose, only conservative dose fractionation schemes, such as 27.3 Gy in 5 fractions and 25 Gy in 4 fractions, were found to be comparable to the volume-staged treatments. On average, this represents a mean 18.7% ± 7.3% reduction in the single-fraction biologically equivalent dose for hypofractionated treatments versus the reference volume-staged treatments (p < 0.001).nnnCONCLUSIONSnVolume staging remains advantageous over hypofractionation in delivering a higher dose to the target and for better sparing of normal brain tissue in the treatment of large AVMs. More clinical data are needed, however, to justify the clinical superiority of this increased dose when compared with a hypofractionated treatment regimen.

Radiotherapy for recurrent epidermoid cyst

Intracranial epidermoid cysts are rare benign congenital lesions for which the mainstay of treatment has been surgical resection. Due to a propensity to grow along the skull base, subtotal resection is often elected to avoid excessive surgical morbidity, but it comes with an increased risk of recurrence with its associated treatment difficulties. We here present the cases of three patients with recurrent epidermoid cyst who underwent multiple surgical resections followed by external beam radiation therapy with excellent results to date.

In Regard to Yamamoto et al

To the Editor: We commend Dr Yamamoto and colleagues for their work on a modified Recursive Partitioning Analysis (RPA) classification for patients with brain metastases (1). Several important points warrant discussion. The authors acknowledge 2 weaknesses of their study: the heterogeneity of the patient populations, and the high number of patients with 5 or more metastases treated with stereotactic radiosurgery (SRS) alone. The first is not a weakness. Heterogeneity is a well-known characteristic of this patient population. The weakness is that the authors fail to account for this heterogeneity in their methodology. The Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) has shown, in a larger database, that prognosis for patients with newly diagnosed brain metastases varies by diagnosis (and by tumor subtype in breast cancer), and that the factors that influence prognosis differ by diagnosis (2-4). The second weakness is important in the context of patient selection for SRS. The authors acknowledge that SRS alone for patients with more than 4 metastases is not the standard of care in Japan or in Western countries. Their study included 1463 patients (39%) with 5 or more brain metastases and 775 patients (21%) with 10 or more brain metastases. Beyond these 2 issues, there are additional points to consider. First, 239 patients (6%) had prior radiation (Table 1) and thus had recurrent, not newly diagnosed, brain metastases and should be excluded from a series of patients with newly diagnosed disease. Second, their system requires assessment of primary tumor control, which is dependent on the type and timing of imaging studies. These were not detailed in their article. This was one of many reasons the DS-GPA, which does not use control of primary as a factor, is considered preferable to the RPA. Third, to their credit, the authors compare their modified RPA to other prognostic indices, including the Score Index for Radiosurgery (SIR), Basic Score for Brain Metastases (BSBM), and the original GPA. The authors reference the DS-GPA, but curiously do not compare their results to it. A user-friendly worksheet for calculation of the DS-GPA has now been published (2). The DS-GPA has also been adopted for purposes of stratification in 2 Radiation Therapy Oncology Group (RTOG) randomized trials. Finally, we again commend the authors for their work, and encourage them to apply the DS-GPA to their data to determine whether the DS-GPA would retain its prognostic validity in patients managed with SRS alone.

A Two-Step Optimization Method for Improving Multiple Brain Lesion Treatments with Robotic Radiosurgery:

Planning robotic radiosurgery treatments for multiple (n > 3) metastatic brain lesions is challenging due to the need of satisfying a large number of dose-volume constraints and the requirement of prescribing different dose levels to individual targets. In this study, we developed a sequential two-step optimization technique to improve the planning quality of such treatments. In contrast to the conventional approach of where all targets are simultaneously planned, we have developed a two-step optimization method. In this method, the first step was to create treatment plans for individual targets. In the second step, the 3D dose matrices associated with each plan were exported to Dicom-RT digital files and subsequently optimized. For the optimization, a singular-value-decomposition (SVD) algorithm was implemented to minimize the dose interferences among different targets. Finally, we compared the optimized treatment plans with the treatment plans created using the conventional method to determine the effectiveness of the new method. Large improvements in target dose distributions as well as normal brain sparing were found for the two-step optimization treatment plans as compared with the conventional treatment plans. The two-step optimization significantly lowered the volume of normal brain receiving relatively low doses. For example, the normal brain volume receiving 12-Gy was reduced by averaged 42% (range 34%–47%) with the two-step optimization. Such improvements generally enlarged with increasing number of targets being treated regardless of target sizes. Of note, normal brain dose was found to increase non-linearly with increasing number of targets. In summary, a two-step optimization technique is demonstrated to significantly improve the treatment plan quality as well as reduce the planning effort for multi-target robotic radiosurgery.