A. Byron Young

Risk of symptomatic brain tumor recurrence and neurologic deficit after radiosurgery alone in patients with newly diagonised brain metastases: results and implications

PURPOSE A single-institution experience using primary stereotactic radiosurgery (SRS) alone in the management of newly diagnosed brain metastases was analyzed to identify the risk of symptomatic brain tumor recurrence (BTR) and neurologic deficit associated with such a treatment strategy. METHODS AND MATERIALS Thirty-six patients were treated for newly diagnosed single/multiple brain metastases using SRS alone followed by planned observation. SRS minimum tumor dose ranged from 8 to 25 Gy (median: 20 Gy). Factors evaluated in analysis of treatment outcome included number of metastases, site of metastasis, primary tumor site, histology, extent of intracranial and extracranial disease, and interval to diagnosis of brain metastasis. RESULTS Median and 1-year survival for the entire group was 9 months and 36%, respectively. BTR anywhere in the brain occurred in 47% (17/36) of patients. Forty-seven percent of BTR (8/17) recurred at the site of original metastasis; 35% (6/17) recurred at both original [corrected] and distant sites in the brain, and 18% (3/17) recurred at distant only [corrected] brain sites. Seventy-one percent (12/17) of the patients were symptomatic at the time of recurrence, and 59% (10/17) had an associated neurologic deficit. Multivariate analysis found that only the extent of disease was a predictor of BTR. Patients who had disease limited to the brain only had a BTR rate of 80% (8/10) vs. 35% (9/26) who had disease involving the brain, primary site, and/or other extracranial metastatic sites (p = 0.03). CONCLUSIONS Use of primary SRS alone in this setting is associated with an increasingly significant risk of BTR with increasing survival time. In addition, the majority of such recurrences are symptomatic and associated with a neurologic deficit, a finding not analyzed in recently reported experiences withholding whole brain radiation therapy as part of the primary treatment of brain metastasis.

Recursive partitioning analysis classifications I and II: Applicability evaluated in a randomized trial for resected single brain metastases

Purpose:Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) prognostic classes I and II for patients with brain metastases is derived from a database made up primarily of patients with unresected and multiple metastases. An analysis of a previously published randomized trial was performed to determine the applicability of these RPA prognostic classes in the setting of resection of single metastases to the brain. Patients and Methods:Ninety-five patients with single metastases to the brain that were treated with complete surgical resection entered this study. Patients were randomly assigned to treatment with postoperative whole brain radiotherapy (WBRT) (n = 49 patients) or no further brain treatment (n = 46 patients). All patients entered on this study had a Karnofsky performance status of ≥70. Therefore, although the RTOG RPA has 3 classes, only patients with RPA classes I (n = 26) or II (n = 69) were eligible for this study analysis. Results:For RPA class I, the median survival was 10.9 months versus 9.8 months for class II patients (P = 0.45). Multivariate analysis showed that only postoperative WBRT, independent of RPA class I or II, lessened the risk of brain tumor recurrence (P < 0.0001). Conclusion:This analysis of a randomized trial evaluating postoperative WBRT in the treatment of single metastases to the brain showed no difference in survival between RPA class I or II patients. In addition, the use of postoperative WBRT after complete surgical resection of single brain metastases results in substantially better control of disease in the brain independent of RPA classes I or II.

The prognostic significance of midline shift at presentation on survival in patients with glioblastoma multiforme

PURPOSE While patients with glioblastoma multiforme (GBM) who present with midline shift have a presumably worse prognosis, there is little literature evaluating the prognostic significance of this presentation in multivariate analysis in the context of other known prognostic factors. METHODS AND MATERIALS From March 1981 to September 1993, 219 patients underwent irradiation for intracranial glioma at our institution. One hundred fourteen patients with a diagnosis of a primary GBM were analyzed for the influence of the presence of midline shift at diagnosis on survival with respect to other known prognostic factors, including age, Karnofsky performance status (KPS), and extent of surgery. Eighty-five patients (74%) presented with midline shift. Surgical treatment consisted of subtotal/total resection in 86 patients (75%). Among patients presenting with midline shift, 68 (80%) underwent subtotal/total resection before irradiation. RESULTS Multivariate analysis of the entire cohort of patients found none of the potential prognostic factors analyzed to significantly influence survival. The overall median survival was 6 months. However, when multivariate analysis was limited to patients with a KPS of > or = 70, only the presence of midline shift and age were found to significantly influence survival. Patients with a KPS > or = 70 and with midline shift present at diagnosis had a median survival of 8 months, as compared to 14 months for those not having midline shift at presentation (p = 0.04). Patients with a KPS > or = 70 and age > 50 years had a median survival of 5 months as compared to 11 months for those < or = 50 (p = 0.02). CONCLUSION In this series, where 80% of patients who presented with a midline shift underwent decompressive resection of GBM before irradiation, the presence of midline shift at diagnosis remained an independent prognostic factor influencing survival among good performance status patients. While the role of decompressive surgery in this setting is likely of some benefit, the extent of this benefit remains to be defined.

Preliminary report of a phase I study of combined fractionated stereotactic radiosurgery and conventional external beam radiation therapy for unfavorable gliomas

PURPOSE To determine the tolerance and toxicities of fractionated stereotactic radiosurgery (FSRS) given in combination with conventional external beam radiation therapy (CEBRT). METHODS AND MATERIALS From March 1995 to September 1998, 14 patients with previously unirradiated and unfavorable glioma (malignant glioma, n = 8; unfavorable low-grade glioma, n = 5; and recurrent glioma, n = 1) were stratified into 3 groups according to tumor volume (TV) to determine the initial FSRS dose schedule: Group A (n = 3): TV </= 5 cc (7 Gy x 2 pre- and post-CEBRT]; Group B (n = 6): 5 cc < TV </= 15 cc [7 Gy x 2 pre- and 7 Gy x 1 post-CEBRT]; and Group C (n = 5): 15 cc < TV </= 30 cc (7 Gy x 1 pre- and post-CEBRT). All patients received CEBRT to 59.4 Gy at 1.8 Gy/fraction. Dose escalation was planned, if toxicity was acceptable. RESULTS All patients were able to complete CEBRT without interruption or experiencing disease progression. Unacceptable toxicity has been limited to patients in groups B (grade 4, n = 2/6) and C (grade 4, n = 2/5). Eight patients required reoperation, with 3 (38%) having necrosis without evidence of tumor. Eleven patients (79%) have had objective partial (>/=50% reduction, n = 2) or minor (>20% reduction, n = 9) imaging response. Follow-up ranged from 9 to 51 months (median 15 months), with 7 patients alive at 22-51 months. CONCLUSIONS Imaging response and the ability of these patients with unfavorable intracranial gliomas to complete therapy without interruption or experiencing disease progression is very encouraging. Excessive toxicity of combined FSRS and CEBRT as evaluated thus far in this study was seen for patients with group B/C lesions. Evaluation of this novel treatment strategy with dose modification is ongoing.

Comparison of Administration of Two Standard Intravenous Amino Acid Formulas to Severely Brain-Injured Patients

Twenty severely brain-injured patients with Glasgow Coma Scale scores of 4–9 were prospectively randomized to receive one of two standard amino acid formulas, starting with the first day of hospital admission up to day 14 postinjury. Formula 2 (patient group 2) had 54 percent more leucine, 53 percent more isoleucine, 74 percent more valine, 28 percent less phenylalanine, 31 percent less methionine, 111 percent more proline, 38 percent less alanine, and 38 percent less glycine than formula 1 (patient group 1). Groups 1 and 2 received statistically equal overall mean parenteral nutrition calories and protein (2173 ± 147 vs. 2059 ± 143 kcal, and 77 ± 12 vs. 83.1 ± 6 g, respectively). There was a significant difference in overall mean urinary urea nitrogen excretion (group 1 = 24.6 ± 1.3 vs. group 2= 18.3 ± 1.1, p = 0.02) and nitrogen balance (group 1 = −8.0 ± 2.1 vs. group 2 = + 1.8 ± 1.2, p = 0.01). Mean overall isoleucine values were significantly higher in group 2 (overall mean 77 μmol/L vs. 62 μmol/L, p = 0.04). Phenylalanine levels were significantly higher in group 1 (107 μmol/L) versus group 2 (82 μmol/L) patients (p = 0.01). Arginine levels were significantly higher in group 1 (78 μmol/L) versus group 2 (49 μmol/L) patients (p = 0.0002). This observation suggests that some standard intravenous amino acid formulas may be more apt to promote positive nitrogen balance than others.

A template for rigid stereotaxic afterloading brachytherapy of the brain

PURPOSE This paper describes a system for the implantation of rigid stainless steel afterloading tubes into the brain using a stereotaxic head frame for both localization and treatment. METHODS AND MATERIALS The stereotaxic frame is attached to the skull throughout the treatment, and the afterloading tubes are both rigid and fixed to the frame. The source positions are therefore fixed relative to the skull throughout the irradiation. Design and construction of templates, afterloading tubes and clamps are discussed in detail. RESULTS The rigidity of the resulting implant provides accurate and immobile positioning of the planned isodose distribution relative to the defined treatment volume and makes it possible to carefully and rapidly plan a source loading which will best cover the volume of interest. The source template is not in contact with the patient at any time. The afterloading tubes are held strictly parallel during treatment, allowing for rapid and versatile preplanning prior to surgical placement. Placement options are enhanced by using a set of rotating templates. CONCLUSION This system has been used for over 60 procedures without any mechanical or safety problems and has provided a significant improvement in both the speed and confidence of localization and treatment planning. There are significant advantages of such a system for High Dose Rate Afterloading Brachytherapy.

A Comparative Study of Laboratory Parameters in Head-Injured Patients Receiving Either Phenytoin or Placebo for 24 Months

The effects of chronic phenytoin therapy on serum calcium, phosphorus, folate, and various hematological indices were assessed. One hundred and fifty-one patients, ages 18 months to 81 years, received phenytoin in a previously-conducted, double-blind, placebo-controlled study. Of the patients receiving phenytoin, initially 127 were evaluable while for control patients receiving placebo, 116 were evaluable. All patients had various laboratory parameters monitored at one day post-loading dose, one week, 1,3,6,9,12,15,18,21, and 24 months. Laboratory values examined were serum calcium, phosphorus, folate, white blood cell count with differential, hemoglobin, hematocrit, and red blood cell and platelet counts. A statistical analysis using the t-test method was employed to evaluate data. Data are reported as mean values ± standard deviation. Patients suffering early hypersensitivity, manifested by a morbilliform skin rash, were removed from the drug by day 30 and were not included in the chronic therapy review. Results indicate that the various laboratory values examined were not significantly affected by phenytoin administration in the patient population. Therefore, chronic phenytoin therapy following the initial hypersensitivity period does not cause abnormal laboratory values as followed in this study.