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.

Distinguishing recurrent intra-axial metastatic tumor from radiation necrosis following gamma knife radiosurgery using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging.

BACKGROUND AND PURPOSE: MR image-guided gamma knife radiosurgery is often used to treat intra-axial metastatic neoplasms. Following treatment, it is often difficult to determine whether a progressively enhancing lesion is due to metastatic tumor recurrence or radiation necrosis. The purpose of our study was to determine whether relative cerebral blood volume (rCBV), relative peak height (rPH), and percentage of signal-intensity recovery (PSR) derived from dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging can distinguish recurrent metastatic tumor from radiation necrosis. MATERIALS AND METHODS: Twenty-seven patients with systemic cancer underwent gamma knife radiosurgery for metastatic lesions of the brain and subsequently developed enlarging regions of enhancement within the radiation field. Subsequent surgical resection or clinicoradiologic follow-up established a diagnosis of recurrent metastatic tumor or radiation necrosis. Perfusion MR imaging datasets were retrospectively reprocessed, and regions of interest were drawn around the entire contrast-enhancing region. The resulting T2* signal-intensity time curves produced rCBV, rPH, and PSR values for each examination. A Welch t test was used to compare imaging values between groups. RESULTS: The mean, minimum, and maximum PSR values were significantly lower (P < .01) in cases of recurrent metastatic tumor. The mean and maximum rCBV and rPH values were significantly higher (P < .02) in the recurrent metastatic tumor group. CONCLUSIONS: The findings of our study suggest that perfusion MR imaging may be used to differentiate recurrent intra-axial metastatic tumor from gamma knife-induced radiation necrosis.

Stereotactic radiosurgery and interstitial brachytherapy for glial neoplasms.

The application of focal radiation therapies in the management of malignant gliomas has gone through a number of stages. Earlier efforts to improve local control of malignant gliomas involved the use of brachytherapy. Despite some early encouraging results, Phase 3 studies did not prove a significant survival benefit for the addition of brachytherapy for newly diagnosed glioblastoma. Most recently radiosurgery has been employed using the same rationale in that improved local control may improve survival. Results of the RTOG Phase 3 study are pending final publication, but early abstracted reports are negative. While radiosurgery and brachytherapy continue to be used as a form of therapy for selected patients with recurrent gliomas, new information from metabolic imaging studies suggests our problem with these techniques in part may be related to targeting. This paper reviews the recent literature and results of the use of brachytherapy and radiosurgery in the management of newly diagnosed and recurrent malignant gliomas.

Dose conformity of gamma knife radiosurgery and risk factors for complications.

PURPOSE: To quantitatively evaluate dose conformity achieved using Gamma Knife radiosurgery, compare results with those reported in the literature, and evaluate risk factors for complications. METHODS AND MATERIALS: All lesions treated at our institution with Gamma Knife radiosurgery from May 1993 (when volume criteria were routinely recorded) through December 1998 were reviewed. Lesions were excluded from analysis for reasons listed below. Conformity index (the ratio of prescription volume to target volume) was calculated for all evaluable lesions and for lesions comparable to those reported in the literature on conformity of linac radiosurgery. Univariate Cox regression models were used to test for associations between treatment parameters and toxicity. RESULTS: Of 1612 targets treated in 874 patients, 274 were excluded, most commonly for unavailability of individual prescription volume data because two or more lesions were included within the same dose matrix (176 lesions), intentional partial coverage for staged treatment of large arteriovenous malformations (AVMs) (33 lesions), and missing target volume data (26 lesions). The median conformity indices were 1.67 for all 1338 evaluable lesions and 1.40-1.43 for lesions comparable to two linac radiosurgery series that reported conformity indices of 1.8 and 2.7, respectively. Among all 651 patients evaluable for complications, there were one Grade 5, eight Grade 4, and 27 Grade 3 complications. Increased risk of toxicity was associated with larger target volume, maximum lesion diameter, prescription volume, or volume of nontarget tissue within the prescription volume. CONCLUSIONS: Gamma Knife radiosurgery achieves much more conformal dose distributions than those reported for conventional linac radiosurgery and somewhat more conformal dose distributions than sophisticated linac radiosurgery techniques. Larger target, nontarget, or prescription volumes are associated with increased risk of toxicity.

EGFR overexpression and radiation response in glioblastoma multiforme.

PURPOSE: Recent studies have suggested relative radioresistance in glioblastoma multiforme (GM) tumors in older patients, consistent with their shorter survival. Two common molecular genetic abnormalities in GM are age related: epidermal growth factor receptor (EGFR) overexpression in older patients and p53 mutations in younger patients. We tested whether these abnormalities correlated with clinical heterogeneity in GM response to radiation treatment. METHODS AND MATERIALS: Radiographically assessed radiation response (5-level scale) was correlated with EGFR immunoreactivity, p53 immunoreactivity, and p53 exon 5-8 mutation status in 170 GM patients treated using 2 prospective clinical protocols. Spearman rank correlation and proportional-odds ordinal regression were used for univariate and multivariate analysis. RESULTS: Positive EGFR immunoreactivity predicted poor radiographically assessed radiation response (p = 0.046). Thirty-three percent of tumors with no EGFR immunoreactivity had good radiation responses (>50% reduction in tumor size by CT or MRI), compared to 18% of tumors with intermediate EGFR staining and 9% of tumors with strong staining. There was no significant relationship between p53 immunoreactivity or mutation status and radiation response. Significant relationships were noted between EGFR score and older age and between p53 score or mutation status and younger age. CONCLUSION: The observed relative radioresistance of some GMs is associated with overexpression of EGFR.

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.

MR-spectroscopy guided target delineation for high-grade gliomas.

PURPOSE: Functional/metabolic information provided by MR-spectroscopy (MRSI) suggests MRI may not be a reliable indicator of active and microscopic disease in malignant brain tumors. We assessed the impact MRSI might have on the target volumes used for radiation therapy treatment planning for high-grade gliomas. METHODS AND MATERIALS: Thirty-four patients (22 Grade III; 12 Grade IV astrocytomas) were evaluated; each had undergone MRI and MRSI studies before surgery. MRI data sets were contoured for T1 region of contrast enhancement (T1), region of necrosis, and T2 region of hyperintensity (T2). The three-dimensional MRSI peak parameters for choline (Cho) and N-acetylaspartate (NAA), acquired by a multivoxel technique, were categorized based on an abnormality index (AI), a quantitative assessment of tissue metabolite levels. The AI data were aligned to the MRI and displayed as three-dimensional contours. AI vs. T conjoint and disjoint volumes were compared. RESULTS: For both grades, although T2 estimated the region at risk of microscopic disease as being as much as 50% greater than by MRSI, metabolically active tumor still extended outside the T2 region in 88% of patients by as many as 28 mm. In addition, T1 suggested a lesser volume and different location of active disease compared to MRSI. CONCLUSION: The use of MRSI to define target volumes for RT treatment planning would increase, and change the location of, the volume receiving a boost dose as well as reduce the volume receiving a standard dose. Incorporation of MRSI into the treatment-planning process may have the potential to improve control while reducing complications.

Relationship between pattern of enhancement and local control of brain metastases after radiosurgery.

PURPOSE: A desired goal in the radiosurgery (RS) of brain metastases is improved local control. Our earlier retrospective review identified pattern of enhancement on day-of-treatment imaging as a prognostic indicator for freedom from progression (FFP) after RS in 219 brain metastases. The current study was performed to corroborate this preliminary finding. METHODS AND MATERIALS: Records and imaging studies of patients treated with RS from 1991 to 1997 were reviewed. Each metastasis was categorized as homogeneously-, heterogeneously-, or ring-enhancing. Kaplan-Meier FFP was calculated from the date of RS to the first imaging showing tumor progression. Univariate and multivariate analyses were performed using Cox proportional hazard models stratified by primary site and type of RS (alone, as a boost, or for recurrence). RESULTS: Of 682 lesions in 258 patients, 518 lesions in 193 patients were evaluable. Pattern of enhancement was homogeneous in 59%, heterogeneous in 32%, and ring-like in 8% of lesions. One-year FFP probabilities for homogeneously-, heterogeneously-, and ring-enhancing lesions were 90% (95% confidence interval, 84-93%), 76% (64-84%), and 57% (35-74%), respectively. The p-value for pattern of enhancement from the stratified multivariate analysis was 0.019 adjusting for RS dose and treatment period (1991-1994 vs. 1995-1997). Similar results were achieved adjusting for tumor volume instead of RS dose. CONCLUSION: Pattern of enhancement is confirmed as a significant prognostic factor for FFP of brain metastases treated with RS, independent of dose and volume. A possible explanation is radioresistance of hypoxic tumor cells associated with necrotic regions, suggesting future investigations with radiosensitizers, hypoxic cell sensitizers, or strategies to improve tumor oxygenation.

Radiosurgery for brain metastases from primary lung carcinoma.

PURPOSE: Brain metastases are a common problem in patients with lung cancer. This retrospective review was performed to describe the efficacy and toxicity of stereotactic radiosurgery for brain metastases from lung carcinoma and to evaluate prognostic factors for survival. PATIENTS AND METHODS: A retrospective review was performed of 113 patients with the diagnosis of lung carcinoma who underwent radiosurgery with or without whole-brain radiotherapy for management of newly diagnosed or recurrent, single, or multiple brain metastases from 1991 through 1998 at the University of California, San Francisco. Freedom from progression and survival were measured from the date of radiosurgery and estimated using the Kaplan-Meier method. Prognostic factors were evaluated with the log-rank test and Cox proportional hazards models. RESULTS: The median patient age at the time of radiosurgery was 59 years (range, 37-82 years), and the median Karnofsky performance score was 90 (range, 50-100). The median survival time from radiosurgery was 12.0 months overall, 13.9 months for 41 patients treated with radiosurgery alone initially, 14.5 months for 19 patients treated with radiosurgery and whole-brain radiotherapy initially, and 10.0 months for 53 patients with recurrent brain metastases. Among newly diagnosed patients, multivariate analysis showed that improved survival was associated with absence of extracranial metastases and fewer brain metastases. Among patients with recurrent brain metastases, improved survival was associated with higher Karnofsky performance score, control of the primary tumor, and fewer metastases. Measured by lesion, 1-year local freedom from progression probabilities were 81% for radiosurgery alone, 86% for radiosurgery and whole-brain radiotherapy, and 65% for radiosurgery performed after recurrence. In patients with newly diagnosed brain metastases, there was a significantly greater risk of developing subsequent brain metastases and of worse overall brain freedom from progression after radiosurgery alone versus radiosurgery and whole-brain radiotherapy. One-year brain freedom from progression probabilities were 13% without salvage therapy and 62% with salvage therapy in the 41 patients treated initially with radiosurgery alone, versus 67% without salvage therapy and 89% with salvage therapy in the 19 patients treated initially with radiosurgery plus whole-brain radiotherapy. DISCUSSION: Radiosurgery is an effective therapy for selected patients with newly diagnosed or recurrent brain metastases from lung carcinoma. Initial whole-brain radiotherapy with radiosurgery appears to improve brain control but not survival. Prospective, randomized trials are needed to further investigate the role of radiosurgery with and without whole-brain radiotherapy for brain metastases.

Phase III trial of accelerated hyperfractionation with or without difluromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme.

PURPOSE: To report the results of a prospective Phase III trial for patients with newly diagnosed glioblastoma multiforme (GBM), treated with either accelerated hyperfractionated irradiation with or without difluromethylornithine (DFMO) or standard fractionated irradiation with or without DFMO. METHODS AND MATERIALS: Adult patients with newly diagnosed GBM were registered and randomized following surgery to one of 4 treatment arms: Arm A, accelerated hyperfractionation alone using 2 fractions a day of 1.6 Gy to a total dose of 70.4 Gy in 44 fractions; Arm B, accelerated hyperfractionation as above plus DFMO 1.8 gm/m2 by mouth every 8 h beginning one week before radiation until the last fraction was given; Arm C, single-fraction irradiation of 1.8 Gy/day to 59.4 Gy; Arm D, single-fraction irradiation as in Arm C plus DFMO given as in Arm B. Patients were followed for progression-free survival (PFS) and overall survival (OS), as well as for toxicity. Eligibility required histologically proven GBM, age > or =18, Karnofsky performance status (KPS) > or =60, and no prior chemotherapy or radiotherapy. Adjuvant chemotherapy was not used in this protocol. RESULTS: A total of 231 eligible patients were enrolled. There were 95 men and 136 women with a median age of 57 years, and median KPS of 90. Extent of resection was total in 23, subtotal in 152, and biopsy only in 56 patients. The 4 arms were balanced with respect to age, KPS, and extent of resection. Times to event measurements are from date of diagnosis. Median OS and PFS were 40 and 19 weeks for Arm A; 42 and 22 weeks for Arm B; 37 and 16 weeks for Arm C; and 44 and 19 weeks for Arm D (p = 0.48 for survival; p = 0.32 for PFS). Comparison of the 2 arms treated with DFMO to the 2 arms without DFMO revealed no difference in OS (37 weeks vs. 42 weeks, p = 0.12) or PFS and thus no benefit to the use of DFMO. Comparison of the 2 standard fractionation arms to the 2 accelerated hyperfractionation arms also resulted in no difference in OS (42 weeks vs. 41 weeks, p = 0.75) or PFS, showing no benefit to accelerated hyperfractionated irradiation. CONCLUSION: In this prospective Phase III study, no survival or PFS benefit was seen with accelerated hyperfractionated irradiation to 70.4 Gy, nor was any benefit seen with DFMO as a radiosensitizer. Standard fractionated irradiation to 59.4 Gy remains the treatment of choice for newly diagnosed patients with glioblastoma multiforme.

Radiosurgery and radiotherapy for non-small-cell lung cancer metastatic to brain.

Non-small-cell lung cancer metastatic to brain represents a common problem in oncology. Treatment modalities include stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), surgical resection, supportive care, or a combination of these options. This review outlines therapeutic strategies for treatment with particular attention to the use of SRS. Radiosurgical technique, radiobiology, dose prescription, patient selection, and results of therapy are discussed. The term SRS describes a radiation procedure that utilizes a three-dimensional stereotactic localization system to precisely treat small intracranial targets with a single, large, highly focal radiation dose. Stereotactic radiosurgery is appealing for several reasons; it is minimally invasive, easily tolerated, and highly effective, and patients return to normal baseline function within 24 hours. Stereotactic radiosurgery provides much higher control rates of treated lesions than does WBRT. Randomized trials are underway to ascertain the optimal role and timing of SRS in relation to WBRT in order to maximize control, survival, quality of life, and neuropsychological outcome.

Age and radiation response in glioblastoma multiforme.

OBJECTIVE: Advanced age is a strong predictor of shorter survival in patients with glioblastoma multiforme (GM), especially for those who receive multimodality treatment. Radiographically assessed tumor response to external beam radiation therapy is an important prognostic factor in GM. We hypothesized that older GM patients might have more radioresistant tumors. METHODS: We studied radiographically assessed response to external beam radiation treatment (five-level scale) in relation to age and other prognostic factors in a cohort of 301 GM patients treated on two prospective clinical protocols. A total of 223 patients (74%) were assessable for radiographically assessed radiation response. A proportional odds ordinal regression model was used for univariate and multivariate analysis. RESULTS: Younger age (P = 0.006), higher Karnofsky Performance Scale score before radiotherapy (P = 0.027), and more extensive surgical resection (P = 0.028) predicted better radiation response in univariate analyses. Results were similar when clinical criteria were used to classify an additional 61 patients without radiographically assessed radiation response (stable versus progressive disease). In multivariate analyses, age and extent of resection were significant independent predictors of radiation response (P < 0.05); Karnofsky Performance Scale score was of borderline significance (P = 0.07). CONCLUSION: Older GM patients are less likely to have good responses to postoperative external beam radiation therapy. Karnofsky Performance Scale score before radiation treatment and extent of surgical resection are additional predictors of radiographically assessed radiation response in GM.

A preliminary study of the prognostic value of proton magnetic resonance spectroscopic imaging in gamma knife radiosurgery of recurrent malignant gliomas.

OBJECTIVE: The goal of this study was to investigate the use of proton magnetic resonance spectroscopic imaging as a prognostic indicator in gamma knife radiosurgery of recurrent gliomas. METHODS: Thirty-six patients with recurrent gliomas were studied with proton magnetic resonance spectroscopic imaging at the time of radiosurgery, and with conventional magnetic resonance imaging examinations at regular time intervals until the initiation of a new treatment strategy. Patients were categorized on the basis of their initial spectroscopic results, and their performance was assessed in terms of change in contrast-enhancing volume, time to further treatment, and survival. RESULTS: The trends in the overall population were toward more extensive increase in the percent contrast-enhancing volume, a decreased time to further treatment, and a reduced survival time for patients with more extensive initial metabolic abnormalities. Statistical analysis of the subpopulation of patients with glioblastoma multiforme found a significant increase in relative contrast-enhancing volume (P < 0.01, Wilcoxon signed-rank test), a decrease in time to further treatment (P < 0.01, log-rank test), and a reduction in survival time (P < 0.01, log-rank test) for patients with regions containing tumor-suggestive spectra outside the gamma knife target, compared with patients exhibiting spectral abnormalities restricted to the gamma knife target. Further studies are needed to establish statistical significance for patients with lower-grade lesions and to confirm the results observed in this study. CONCLUSION: The pretreatment spectroscopic results provided information that was predictive of outcome for this patient pool, both in local control (change in contrast-enhancing volume) and global outcome (time to further treatment and survival). This modality may have an important role in improving the selection, planning, and treatment process for glioma patients.

Radiosurgery for malignant meningioma: results in 22 patients.

OBJECT: The initial treatment of malignant meningiomas in the past has included surgical removal followed by fractionated external-beam radiotherapy. Radiosurgery has been added to the options for treatment of primary or recurrent tumors over the last 10 years. The authors report their results of using gamma knife radiosurgery (GKS) to treat 22 patients over an 8-year period. METHODS: Twenty-two patients who underwent GKS for malignant meningioma between December 1991 and May 1999 were evaluated. Three patients were treated with GKS as a boost to radiotherapy and 19 for recurrence following radiotherapy. Outcome factors including patient survival, freedom from progression, and complications were analyzed. In addition, in the recurrent group, variables such as patient age, sex, tumor location, target volume, margin dose, and maximum dose were also analyzed. Univariate and multivariate analyses were performed. Overall 5-year survival and progression-free survival estimates were 40% and 26%, respectively. Age (p < or = 0.003) and tumor volume (p < or = 0.05) were significant predictors of time to progression and survival in both univariate and multivariate analyses. Five patients (23%) developed radiation necrosis. Significant relationships between complications and treatment variables or patient characteristics could not be established. CONCLUSIONS: Tumor control following GKS is greater in patients with smaller-sized tumors (< 8 cm3) and in younger patients. Gamma knife radiosurgery can be performed to treat malignant meningioma with acceptable toxicity. The efficacy of GKS relative to other therapies for recurrent malignant meningioma as well as the value of GKS as a boost to radiotherapy will require further evaluation.

Radiosurgery for brain metastases: is whole brain radiotherapy necessary?

PURPOSE: Because whole brain radiotherapy (WBRT) may cause dementia in long-term survivors, selected patients with brain metastases may benefit from initial treatment with radiosurgery (RS) alone reserving WBRT for salvage as needed. We reviewed results of RS +/- WBRT in patients with newly diagnosed brain metastasis to provide background for a prospective trial. METHODS AND MATERIALS: Patients with single or multiple brain metastases managed initially with RS alone vs. RS + WBRT (62 vs. 43 patients) from 1991 through February 1997 were retrospectively reviewed. The use of upfront WBRT depended on physician preference and referral patterns. Survival, freedom from progression (FFP) endpoints, and brain control allowing for successful salvage therapy were measured from the date of diagnosis of brain metastases. Actuarial curves were estimated using the Kaplan-Meier method. Analyses to adjust for known prognostic factors were performed using the Cox proportional hazards model (CPHM) stratified by primary site. RESULTS: Survival and local FFP were the same for RS alone vs. RS + WBRT (median survival 11.3 vs. 11.1 months and 1-year local FFP by patient 71% vs. 79%, respectively). Brain FFP (scoring new metastases and/or local failure) was significantly worse for RS alone vs. RS + WBRT (28% vs. 69% at 1 year; CPHM adjustedp = 0.03 and hazard ratio = 0.476). However, brain control allowing for successful salvage of a first failure was not significantly different for RS alone vs. RS + WBRT (62% vs. 73% at 1 year; CPHM adjusted p = 0.56). CONCLUSIONS: The omission of WBRT in the initial management of patients treated with RS for up to 4 brain metastases does not appear to compromise survival or intracranial control allowing for salvage therapy as indicated. A randomized trial of RS vs. RS + WBRT is needed to assess survival, quality of life, and cost in good-prognosis patients with newly diagnosed brain metastases.

Gamma knife radiosurgery for malignant melanoma brain metastases.

PURPOSE: To evaluate the efficacy and toxicity of gamma knife radiosurgery in the treatment of melanoma metastases to the brain. PATIENTS AND METHODS: We retrospectively reviewed 55 patients with single or multiple intracranial melanoma metastases treated at the University of California, San Francisco, with gamma knife radiosurgery from 1991 through 1995. Sixteen patients were treated with gamma knife radiosurgery for recurrence following previous radiation therapy, 11 received radiosurgery as a boost to whole-brain radiation therapy, and 28 had radiosurgery alone for initial management of brain metastases. The median minimum radiosurgery tumor dose for 140 treated lesions was 19 Gy (range, 10-22 Gy) prescribed at the 35% to 90% isodose contour (median, 50%). The median total target volume per patient was 6.1 cc (range, 0.25-28.3 cc). RESULTS: With a median follow-up of 75 weeks in living patients, the median survival times were 35 weeks overall: 35 weeks for patients with solitary metastases versus 33 weeks for those with multiple metastases. A factor that was significant in univariate analysis of survival was total target volume treated. This parameter remained significant on multivariate analysis. The actuarial median freedom from progression analyzed by lesion for 113 lesions in 46 patients with imaging follow-up was 89 weeks with 6-month and 1-year actuarial freedom from progression rates of 89% (95% confidence interval, 80%-95%) and 77% (95% confidence interval, 62%-87%). In univariate analysis, improved freedom from progression was associated with smaller target volume treated, smaller maximum diameter, or higher prescribed dose. Four patients (7%) developed acute Radiation Therapy Oncology Group grade > or = 2 morbidity, and five patients (9%) developed late grade > or = 2 morbidity. DISCUSSION: Median survival and freedom from progression in patients treated with radiosurgery for melanoma metastatic to the brain are comparable to results in published radiosurgery series of grouped histologies. For melanoma patients, total intracranial tumor volume appears to be of greater prognostic significance than the absolute number of metastases treated. We conclude that gamma knife radiosurgery is effective and should be considered among various management strategies.

Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost +/- hyperthermia for glioblastoma multiforme.

PURPOSE: To determine if adjuvant interstitial hyperthermia (HT) significantly improves survival of patients with glioblastoma undergoing brachytherapy boost after conventional radiotherapy. METHODS AND MATERIALS: Adults with newly-diagnosed, focal, supratentorial glioblastoma < or = 5 cm in diameter were registered postoperatively on a Phase II/III randomized trial and treated with partial brain radiotherapy to 59.4 Gy with oral hydroxyurea. Those patients whose tumor was still implantable after teletherapy were randomized to brachytherapy boost (60 Gy at 0.40-0.60 Gy/h) +/- HT for 30 min immediately before and after brachytherapy. Time to progression (TTP) and survival from date of diagnosis were estimated using the Kaplan-Meier method. RESULTS: From 1990 to 1995, 112 eligible patients were entered in the trial. Patient ages ranged from 21-78 years (median, 54 years) and KPS ranged from 70-100 (median, 90). Most commonly due to tumor progression or patient refusal, 33 patients were never randomized. Of the patients, 39 were randomized to brachytherapy ("no heat") and 40 to brachytherapy + HT ("heat"). By intent to treat, TTP and survival were significantly longer for "heat" than "no heat" (p = 0.04 and p = 0.04). For the 33 "no heat" patients and 35 "heat" patients who underwent brachytherapy boost, TTP and survival were significantly longer for "heat" than "no heat" (p = 0.045 and p = 0.02, respectively; median survival 85 weeks vs. 76 weeks; 2-year survival 31% vs. 15%). A multivariate analysis for these 68 patients adjusting for age and KPS showed that improved survival was significantly associated with randomization to "heat" (p = 0.008; hazard ratio 0.51). There were no Grade 5 toxicities, 2 Grade 4 toxicities (1 on each arm), and 7 Grade 3 toxicities (1 on "no heat" and 6 on the "heat" arm). CONCLUSION: Adjuvant interstitial brain HT, given before and after brachytherapy boost, after conventional radiotherapy significantly improves survival of patients with focal glioblastoma, with acceptable toxicity.

Interstitial brachytherapy for malignant brain tumors.

For nearly 20 years, interstitial brachytherapy has been used as adjuvant treatment for malignant brain tumors in both prospective clinical trials and as part of standard therapy. Numerous publications analyzing the results of this treatment seem to indicate an improvement in median survival for highly selected patients. Some newly diagnosed glioblastoma multiforme, recurrent malignant glioma, brain metastases and possibly low grade gliomas seem to benefit. While Iodine-125 (I-125) remains the most popular radionuclide for brachytherapy, there is a recent move away from temporary high-activity implants to permanent low-activity implants. This review article will concentrate on the results from the University of California, San Francisco, as well as recent series published since 1990. In spite of the increased availability of radiosurgery, interstitial brachytherapy still has a place in the management of these difficult tumors.

Radiation therapy and hydroxyurea followed by the combination of 6-thioguanine and BCNU for the treatment of primary malignant brain tumors.

PURPOSE: This study was designed to evaluate a combined modality treatment for malignant gliomas using radiation therapy with a radiosensitizer and an adjuvant chemotherapy regimen designed to modify resistance to BNCU. METHODS AND MATERIALS: Patients were eligible if they were 15 years of age or older, and had newly diagnosed glioblastoma multiforme (GBM), or anaplastic glioma (AG). Treatment consisted of external beam radiotherapy given to a dose of 60 Gy using a single daily fraction Monday to Friday. Concurrent hydroxyurea at a dose of 300 mg/m2 every 6 h every other day was given during radiation. Following radiotherapy, patients were then treated with BCNU and 6-Thioguanine (6TG). The 6-TG was given by mouth every 6 h for 12 doses prior to BCNU. Patients were initially treated with 60 mg/m2/dose of 6TG, with escalation to a maximum dose of 100 mg/m2/dose. The primary study end points were time to tumor progression and survival. RESULTS: A total of 245 eligible patients were enrolled from 1/18/88 to 12/26/91. The histologic subtypes included 135 GBM, and 110 with AG (103 with anaplastic astrocytoma, 7 with high-grade mixed oligoastrocytoma). For the GBM group, the median time to tumor progression (TTP) and median survival were 33 (95% CI 26, 39) and 56 (95% CI 49, 69) weeks, respectively. For the AG group the median TTP was 282 weeks (95% lower confidence bound = 155 weeks). Median survival for this group has not been reached (95% lower confidence bound = 284 weeks) with a median follow-up for surviving patients of 298 weeks. A proportional hazards model was used to look at potential prognostic factors for survival, including initial Karnofsky Performance Scale (KPS), age, and extent of surgery, as well as dose of 6TG. Higher KPS, and lower age, predicted for longer survival (p < 0.01, < 0.001) in GBM patients; lower age was significant (p = 0.05) for AG cases. A higher (greater than 95 mg/m2) or lower dose of 6TG was not statistically significant in this model. CONCLUSIONS: This therapy was no more effective in patients with GBM than other reported series. In patients with malignant gliomas other than GBM, prolonged progression-free and overall survival is noted, without a median survival reached at the time of this report. In this subset of AG patients, survival is comparable to recent studies using halogenated prymidines during radiation and Procarbazine, CCNU, and Vincristine (PCV) as adjuvant chemotherapy.