Keith A. Weaver

Survival and quality of life after interstitial implantation of removable high-activity iodine-125 sources for the treatment of patients with recurrent malignant gliomas.

Between January 1980 and January 1988, 95 evaluable patients with recurrent, unifocal, supratentorial malignant gliomas were reirradiated with high-activity iodine-125 sources implanted directly into tumor in afterloaded, removable catheters using computerized tomography-directed stereotaxy. A tumor dose of 5270-15,000 cGy was delivered at a maximum distance of 0.5 cm from the rim of the contrast-enhancing mass seen on CT scans. The median survival for the 50 patients with anaplastic astrocytoma was 81 weeks and for 45 patients with glioblastoma multiforme it was 54 weeks. The 18- and 36-month survival rates for patients with anaplastic astrocytoma were 46% and 28%, respectively; the 18- and 36-month survival rates for patients with glioblastoma multiforme were 22% and 8%, respectively. Because of clinical deterioration, increasing steroid dependency, and increasing mass effect at the implantation site seen on CT scans, necrotic tissue was excised from 47 patients (49%) at craniotomy; in some patients, tumor was mixed with necrotic tissue. The survival of reoperated patients was significantly longer compared with patients who did not undergo this procedure. Serial determination of the Karnofsky Performance Score (KPS) showed that there was no significant deterioration for the group as a whole during the 6 months immediately after implantation. At 18 months, 33 of the patients were alive; KPS ranged between 50 to 90 (mean 79) and 67% were steroid dependent. At 36 months, 18 patients were alive; 17 patients were evaluable with KPS that ranged between 40 to 90 (mean 76) and 53% were steroid dependent. Eleven of the 17 evaluable long-term survivors had a KPS of 80 or higher with a mean of 87. Interstitial brachytherapy may provide long-term survival in selected patients with recurrent malignant gliomas who have been irradiated previously with conventional teletherapy. The quality of life in the majority of long-term survivors appears to be quite satisfactory. Further attempts to control tumor growth using this modality appear to be warranted.

High activity iodine-125 interstitial implant for gliomas

A total of 307 adult patients with glioma were treated with high-activity removable iodine-125 interstitial brain implants at the University of California at San Francisco from December 1979 to June 1990. Recurrent gliomas underwent brain implant alone whereas previously untreated (primary) tumors underwent brain implant boost after external beam radiotherapy. Of these patients, 106 had primary glioblastoma multiforme, 68 had primary non-glioblastoma glioma, 66 had recurrent glioblastoma multiforme and 67 had recurrent nonglioblastoma glioma. Median follow-up for living patients was 143 weeks. Median survival from diagnosis for primary glioblastoma multiforme and high and low grade nonglioblastoma glioma was 88 weeks, 142 weeks, and 226 weeks, respectively. Median survival measured from the date of implant for recurrent glioblastoma multiforme and high and low grade nonglioblastoma glioma was 49 weeks, 52 weeks, and 81 weeks, respectively. Ninety-two percent of patients had no toxicity or transient acute side effects. Severe acute toxicity was seen in 6% of patients, life threatening acute toxicity in 1% of patients, and fatal toxicity in less than 1% of patients. Forty percent of patients with malignant glioma underwent reoperation at a median of 33 weeks after brain implant, with tumor found in 95% of specimens at reoperation. This large experience demonstrates that interstitial implant is well-tolerated and prolongs survival in patients with primary and recurrent glioblastoma multiforme, as evidenced by the 3-year survival rates of 22% and 15%, respectively.

Five year results of linac radiosurgery for arteriovenous malformations: outcome for large AVMS

PURPOSE For radiosurgery of large arteriovenous malformations (AVMs), the optimal relationship of dose and volume to obliteration, complications, and hemorrhage is not well defined. Multivariate analysis was performed to assess the relationship of multiple AVM and treatment factors to the outcome of AVMs significantly larger than previously reported in the literature. METHODS AND MATERIALS 73 patients with intracranial AVMs underwent LINAC radiosurgery. Over 50% of the AVMs were larger than 3 cm in diameter and the median and mean treatment volumes were 8.4 cc and 15.3 cc, respectively (range 0.4-143.4 cc). Minimum AVM treatment doses varied between 1000-2200 cGy (median: 1600 cGy). RESULTS The obliteration rates for treatment volumes < 4 cc, 4-13.9 cc, and > or = 14 cc were 67%, 58%, and 23%, respectively. AVM obliteration was significantly associated with higher minimum treatment dose and negatively associated with a history of prior embolization with particulate materials. No AVM receiving < 1400 cGy was obliterated. The incidence of post-radiosurgical imaging abnormalities and clinical complications rose with increasing treatment volume. For treatment volumes > 14 cc receiving > or = 1600 cGy, the incidence of post-radiosurgical MRI T2 abnormalities was 72% and the incidence of radiation necrosis requiring resection was 22%. The rate of post-radiosurgical hemorrhage was 2.7% per person-year for AVMs with treatment volumes < 14 cc and 7.5% per person-year for AVMs > or = 14 cc. CONCLUSION As AVM size increases, the dose-volume range for the optimal balance between successful obliteration and the risk of complications and post-radiosurgical hemorrhage narrows.

Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost

PURPOSE To study patterns of recurrence in patients with focal primary glioblastoma treated on Northern California Oncology Group protocol 6G-82-2 including surgery, focal external beam radiotherapy (59.4-60 Gy) with oral hydroxyurea followed by temporary brain implant with high-activity iodine-125 sources (50 Gy), and six cycles of chemotherapy with procarbazine, lomustine, and vincristine. METHODS AND MATERIALS Serial brain imaging scans were available for review in 25 of 34 patients with glioblastoma who underwent brain implant boost. Of 381 scans performed between the date of diagnosis and the date of death or last follow-up, 362 (95%) were re-reviewed. Disease progression was scored as local (within 2 cm of the implant site), separate within the brain parenchyma (> or = 2 cm from the implant site), subependymal, or systemic. Both initial and subsequent failures were scored. RESULTS Three patients are 5-year survivors, without evidence of disease, at 267, 292, and 308 weeks. Of the 22 initial sites of failure, 17 (77%) were local, three (14%) were separate brain lesions (one of which was due in retrospect to multicentric disease at diagnosis), one (5%) subependymal, and one (5%) systemic. Five patients with local failure later had other sites of failure, including a separate brain lesion in 1, subependymal spread in 3, and both in 1. One patient with separate brain failure later had local progression and then subependymal spread. CONCLUSION Although there was a significant risk of separate brain lesions or subependymal spread over time, local tumor progression was the predominant pattern of failure.

High intensity 125-Iodine (1251) plaque treatment of uveal melanoma☆

PURPOSE Episcleral 125I plaque therapy of uveal melanoma is an important treatment modality to control tumor, salvage the globe, and potentially preserve vision. We retrospectively analyzed our experience in 239 patients to assess treatment outcome with this technique. METHODS AND MATERIALS Between 1983 and 1990, 239 uveal melanoma patients were treated with 125I plaques at the University of California, San Francisco. High intensity 125I seeds in the range of 3-20 mCi were used to give a minimum tumor dose of 70 Gy in 4 days. Initial mean tumor size was 10.9 mm x 9.2 mm x 5.5 mm with a range in tumor diameter from 4 to 18 mm and tumor height from 1.9 to 11.1 mm. Best corrected pre-treatment visual acuity was 20/200 or better in 92% of patients. RESULTS Local tumor control was maintained in 91.7% of patients with a mean follow-up of 35.9 months; 19 patients had local tumor progression; mean time to progression was 27.3 mo (1.8 to 60.1 mo). Actuarial local control is 82% at 5 years. Multivariate analysis demonstrates significant correlation of local failure with larger maximum tumor diameter (p = 0.0008), closer proximity to the fovea (p = 0.0001), lower radiation dose (p = 0.0437), and smaller ultrasound height (p = 0.0034). The actuarial incidence of distant metastases is 12% at 5 years with multivariate analysis showing significant correlation only with maximum tumor diameter (p = 0.0064). Visual outcome is 20/200 or better in 58% of patients. CONCLUSION While the tumor control rates appear favorable, ocular morbidity is significant. A current randomized trial comparing 125I plaque with Helium ion therapy is in progress with specific comparison of tumor control, survival, and visual outcome.

Radiation Therapy for Thyroid Eye Diseases

Sixty-two patients (28 men and 34 women, 26 to 84 years old) with thyroid ophthalmopathy were treated with approximately 20 Gy of fractionated photon irradiation. Eight of 14 patients with motility problems improved after treatment. Ten of 14 with thyroid optic neuropathy improved or stabilized, but four had recurrences within five months after completion of irradiation. Generally, patients who had disease durations of less than six months responded better than those with more long-term ocular changes.

Large effect of age on the survival of patients with glioblastoma treated with radiotherapy and brachytherapy boost.

A retrospective review was undertaken to study the influence of age on the survival of patients undergoing brachytherapy boost for glioblastoma multiforme. From February 1981 through December 1992, 159 adults with primary glioblastoma multiforme underwent high-activity iodine-125 brain implant boost after external beam radiotherapy. There were 98 men and 61 women, ranging in age from 18 to 73 years (median, 52 yr). Karnofsky performance scores ranged from 70 to 100 (median, 90). Surgery before radiotherapy consisted of biopsy in 7% of patients, subtotal resection in 66%, and gross total resection in 27%. External beam radiotherapy doses ranged from 39.6 to 76.8 Gy, with 91% of patients receiving 59.4 to 61.2 Gy. Brachytherapy doses ranged from 35.7 to 66.5 Gy (median, 55.0 Gy) at 0.30 to 0.70 Gy per hour (median, 0.43 Gy/h). Reoperations were performed in 81 patients (51%). Information on quality of life was available for 13 of the 14 living 3-year survivors; 10 patients were steroid independent, and mean Karnofsky performance scores had decreased from 92 at the time of brachytherapy to 75 at the last follow-up. Univariate and multivariate analyses showed that age was the most important parameter influencing survival (P < 0.0005). The nine patients 18 to 29.9 years old had a 3-year survival probability of 78 +/- 14% (median survival was not yet reached at the time of this report), with a follow-up of 145 to 511 weeks in living patients (median, 322 wk).(ABSTRACT TRUNCATED AT 250 WORDS)

Dose parameters of 125I and 192Ir seed sources

As mandated by an NCI brachytherapy contract, we measured dosimetric parameters for 192Ir seeds and two models of 125I seeds. Measurements were with LiF powder in a water-equivalent phantom. Data were corrected for background, sample mass, and finite detector volume. Selected parameters were also investigated through Monte Carlo calculations. Results are presented in terms of a dose parametrization that is described in detail, and are compared to published data. Our results agreed well with published data for relative quantities such as radial and angular dose dependence. Our measured value for the 192Ir dose factor was 4.55 cGy(H2O) cm2 mCi-1 h-1, also in good agreement with commonly used values. However, the measured dose factors for 125I seed models 6702 and 6711 were 1.18 and 1.06 cGy(H2O) cm2 mCi-1 h-1, values well below those in general use.

Demonstration of brachytherapy boost dose-response relationships in glioblastoma multiforme

PURPOSE To evaluate brachytherapy dose-response relationships in adults with glioblastoma undergoing temporary 125I implant boost after external beam radiotherapy. METHODS AND MATERIALS Since June 1987, orthogonal radiographs using a fiducial marker box have been used to verify brain implant source positions and generate dose-volume histograms at the University of California, San Francisco. For adults who underwent brachytherapy boost for glioblastoma from June 1987 through December 1992, tumor volumes were reoutlined to ensure consistency and dose-volume histograms were recalculated. Univariate and multivariate analysis of various patient and treatment parameters were performed evaluating for influence of dose on freedom from local failure (FFLF) and actuarial survival. RESULTS Of 102 implant boosts, 5 were excluded because computer plans were unavailable. For the remaining 97 patients, analyses with adjustment for known prognostic factors (age, KPS, extent of initial surgical resection) and prognostic factors identified on univariate testing (adjuvant chemotherapy) showed that higher minimum brachytherapy tumor dose was strongly associated with improved FFLF (p = 0.001). A quadratic relationship was found between total biological effective dose and survival, with a trend toward optimal survival probability at 47 Gy minimum brachytherapy tumor dose (corresponding to about 65 Gy to 95% of the tumor volume); survival decreased with lower or higher doses. Two patients expired and one requires hospice care because of brain necrosis after brachytherapy doses > 63 Gy to 95% of the tumor volume with 60 Gy to > 18 cm3 of normal brain. CONCLUSION Although higher minimum tumor dose was strongly associated with better local control, a brachytherapy boost dose > 50-60 Gy may result in life-threatening necrosis. We recommend careful conformation of the prescription isodose line to the contrast enhancing tumor volume, delivery of a minimum brachytherapy boost dose of 45-50 Gy in conjunction with conventional external beam radiotherapy, and reoperation for symptomatic necrosis.

Interstitial irradiation and hyperthermia for the treatment of recurrent malignant brain tumors.

Between June 1987 and June 1989, 29 recurrent malignant gliomas or recurrent solitary brain metastases in 28 patients were treated in a Phase I study of interstitial irradiation and hyperthermia. Patient age ranged from 18 to 65 years, and the Karnofsky Performance Status scores ranged from 40 to 90%. There were 13 glioblastomas, 10 anaplastic astrocytomas, 3 melanomas, and 3 adenocarcinomas. Catheters were implanted stereotactically after computed tomography-based preplanning. Hyperthermia was administered before and after brachytherapy, using one to six 2450- or 915-MHz helical coil microwave antennas and one to three multisensor fiberoptic thermometry probes. The goal was to heat as much of the tumor as possible to 42.5 degrees C for 30 minutes. Within 30 minutes after the first hyperthermia treatment, implant catheters were afterloaded with high-activity iodine-125 seeds delivering tumor doses of 32.6 to 61.0 Gy. Most patients had no sensation of heating. Complications included seizures in 5 patients, reversible neurological changes in 9 patients, a scalp burn in 1, and infections in 3. Of 28 evaluable 2-month follow-up scans, 11 showed definite improvement in the radiological appearance of the tumor, 4 were slightly improved, 7 were stable, and 6 showed tumor progression. Ten patients underwent reoperation for persistent tumor and/or necrosis. Eleven of 28 patients are alive 40 to 97 weeks after treatment. Thirteen patients died of a brain tumor, 2 died of extracranial melanoma metastases, 1 died of new brain melanoma metastases, and 1 died of a pulmonary embolus. The median survival was 55 weeks overall. Median survival has not yet been reached for the anaplastic astrocytoma subgroup. We conclude that interstitial brain hyperthermia using helical coil microwave antennas is technically feasible. The level of toxicity is acceptable, and the computed tomographic response rate is encouraging.