Relative biological effectiveness of 125I sources in a murine brachytherapy model.

The relative biological effectiveness of 125I and 192Ir has been determined in a murine brachytherapy model that uses a clonogenic cell assay as the end point. Removable 125I or 192Ir sources were implanted at right angles to the surface of RIF-1 tumors grown in the flanks of C3H/He mice. After irradiation for 1-5 days, mice were sacrificed and isodosed annuli of irradiated tumor tissue were sampled for the clonogenic cell assay. The slopes and intercepts of the two radiation survival curves for implanted sources with activities of 10 to 50 Gy for 125I (dose rate = 39.8 +/- 4.3 cGy/hr) and 192Ir (dose rate = 42.3 +/- 2.7 cGy/hr) were identical; the relative biological effectiveness was 1.

Combined total body X-ray irradiation and total skin electron beam radiotherapy with an improved technique for mycosis fungoides.

Twelve consecutive patients with advanced stage mycosis fungoides (MF) were treated with combined total body X ray irradiation (TBI) and total skin electron beam radiotherapy (EBRT). Six had generalized plaque disease and dermatopathic nodes, three had tumor stage disease and node biopsy positive for mycosis fungoides, and three had erythroderma/Sezary syndrome. The treatment regimen consisted of split course total body X ray irradiation, given in twice weekly 15 cGy fractions to 75 cGy, then total skin electron beam radiation therapy given in once weekly 400 cGy fractions to a total dose of 2400 cGy. Underdosed areas and areas of greatest initial involvement were boosted 400 cGy twice weekly for an additional 1200 cGy. This was followed by a second course of total body X ray irradiation, to a total dose of 150 cGy. The total skin electron beam radiotherapy technique is a modification of an established six position EBRT technique for mycosis fungoides. Measurements to characterize the beam with and without a lexan scattering plate, demonstrated that the combination of no-plate beams produced better dose uniformity with a much higher dose rate. This improved technique is particularly advantageous for elderly and/or frail patients. Nine (75%) of the 12 patients achieved complete response (CR). The other three had significant improvement with greater than 80% clearing of their disease and resolution of symptoms. All six patients with generalized plaque disease achieved complete response and remained free of disease from 2 to 16 months. Two of three node positive patients also achieved complete response; one, with massive biopsy-documented mycosis fungoides nodal disease and deep open tumors, remained relapse-free over 2 years. Only one of the three patients with erythroderma/Sezary syndrome achieved a complete response, which was short lived. Therapy was well tolerated. No significant hematological toxicity occurred. Although total body X ray irradiation and total skin electron beam radiotherapy produced excellent palliation of patients with advanced stage mycosis fungoides, new strategies to provide more effective systemic treatment are needed.

The effect of combination treatment with cis-platinum and low dose rate 125I radiation in a murine brachytherapy model.

We studied the effect of combination treatment with cis-platinum during low dose rate irradiation from 125I sources in the RIF-1 murine flank tumor model. Cell survival measured with a colony forming efficiency assay was used as the experimental endpoint. Sources implanted into tumors delivered 25 Gy of radiation to isodosed annuli of tissue at a dose rate of 1.3 Gy/hr. When 3 mg/kg of cis-platinum was administered 24, 12, and 1 hr before or 0, 12 and 24 hr after irradiation, the effect on cell kill was additive. Thus in the RIF-1 model there is no particular advantage gained by treatment with the combinations of cis-platinum and 125I radiation used in these studies.

Radiosensitization of the RIF-1 murine flank tumor by desmethylmisonidazole (Ro 05 9963) during interstitial brachytherapy.

We have investigated the interaction of the nitroimidazole radiosensitizer desmethylmisonidazole (Ro 05 9963) with interstitial radiation using a clonogenic cell assay as the endpoint. Removable I-125 sources were implanted at right angles to the outer surface of globular RIF-1 tumors grown in the flanks of C3H/He mice. Desmethylmisonidazole was administered by continuous intraperitoneal infusion at a rate of 2.7 mg/gm body weight /24 hr. Tumor and serum drug levels were measured by high performance liquid chromatography. Tumor drug levels of 40--100 mugm/gm tumor tissue were achieved consistently. No appreciable cytotoxicity was produced by desmethylmisonidazole alone, but a radiosensitization effect with a dose modifying factor of 1.6 was found.

High intensity 125-iodine (125I) 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.

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.

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.

External irradiation followed by an interstitial high activity iodine-125 implant "boost" in the initial treatment of malignant gliomas: NCOG study 6G-82-2.

Between January 1982 and January 1990, 107 patients with unifocal, circumscribed malignant gliomas participated in a non-randomized trial testing brachytherapy in their initial treatment. Focal external irradiation (6000 cGy) was combined with an implant of high-activity iodine-125 (5000-6000 cGy) and six courses of procarbazine, lomustine, and vincristine. Of the 101 evaluable patients, 63 received implants. Of these, 29 had non-glioblastoma anaplastic gliomas, and 34 had glioblastoma multiforme. The other 38 did not receive implants, in most cases because radiation therapy failed to reduce the size of the tumor. The median survival was 165 weeks for all evaluable patients with non-glioblastoma anaplastic gliomas, 157 weeks for those with implants, 67 weeks for all evaluable glioblastoma patients, and 88 weeks for those with implants. Of the glioblastoma patients with implants, nine were alive after 2 years, and three were alive after 3 years. In each of the groups, nearly half the patients underwent reoperation for clinical deterioration, increasing steroid dependency, and increasing mass effect at the implantation site after 46.1 weeks (median) for glioblastoma multiforme and 41.3 weeks for non-glioblastoma patients. Karnofsky Performance Scores showed only a small decline in performance after brachytherapy. Patients receiving implants for non-glioblastoma anaplastic gliomas had a mean Karnofsky Performance Score of 91% (range 90-100%) after 1 month and 78% (range 60-100%) 30 months after brachytherapy. Those treated for glioblastoma multiforme had a mean Karnofsky Performance Score of 86% (range 60-100%) at 1 month and 75% (range 60-100%) at 24 months. The quality of life of treated patients appears to be satisfactory. On the basis of comparisons with previous studies, we conclude that a brachytherapy "boost" after external irradiation may be valuable for some patients with glioblastoma multiforme but not for those with non-glioblastoma anaplastic gliomas.

Thermoradiotherapy of recurrent malignant brain tumors.

In an attempt to improve local control and survival over those achieved with brain implant alone, a Phase I/II study of interstitial thermoradiotherapy was undertaken for recurrent malignant gliomas and recurrent solitary brain metastases. Between June 1987 and September 1990, 49 tumors in 48 patients were treated with thermoradiotherapy, including 26 glioblastoma multiforme (GM), 16 anaplastic astrocytomas (AA), 4 adenocarcinomas, and 3 melanomas. Patient age ranged from 18 to 71 years and Karnofsky Performance Status from 40 to 90. Stereotactically implanted catheters were used for both hyperthermia and brachytherapy. Hyperthermia was administered immediately before and after brachytherapy, heating as much of the tumor as possible to 42.5 degrees C for 30 min using helical coil microwave antennas. High-activity iodine-125 sources delivered tumor doses of 32.6 to 63.3 Gy. Complications included reversible neurologic changes in 13 patients, 9 seizures, 4 infections, 1 deep venous thrombosis with pulmonary embolus, and 1 scalp burn. Eighteen patients underwent reoperation for tumor and/or necrosis. Follow-up ranged from 9 to 166+ weeks. The median follow-up for living patients with GM and AA was 37 weeks and 92 weeks, respectively. Actuarial median survival was 47 weeks for patients with GM. For patients with AA, actuarial survival was 65% at 18 months and median survival has not yet been reached. Multivariate analysis showed a strong correlation between freedom from local tumor progression and "T90" temperature or minimum tumor temperature. Interstitial brain thermoradiotherapy is now being evaluated in a randomized Phase II trial for previously untreated GM.

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.

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.

Response of LiF powder to 125I photons.

125I seeds are being used to treat a variety of diseases, including brain tumors. However, the uncertainty in the energy response of LiF for 125I photons relative to megavoltage radiation limits the accuracy of dosimetry with this material. An array of 12 40-mCi 125I seeds was used to irradiate LiF powder in throwaway capsules, and an ion chamber was used to measure the absorbed dose. A comparison of the response of these LiF dosimeters with the response of capsules given a similar dose of 60Co radiation has yielded values of 1.39 +/- 0.03 (dose to water) and 1.32 +/- 0.03 (dose to muscle) for the LiF response for 125I relative to that for 60Co. Details of the procedure and sources of uncertainty are discussed.

The dosimetry of 125I seed eye plaques.

The ability of a brachytherapy treatment-planning computer program to calculate accurately the dose from 125I seeds at distances relevant to eye plaque therapy was investigated. Thermoluminescent dosimetry measurements were made in a plastic phantom at depths of 0.5, 0.97, and 1.5 cm, and results were corrected for finite dosimeter size and phantom effects. Doses were calculated at the same depths with an 125I seed linear source model that accounted for dose anisotropy. Measurements and calculations were found to agree within their mutual uncertainties. The presence of a gold plaque was found to reduce the dose at all measured depths by 8%.

Source localization for template implants with particular reference to stepping-source afterloaders.

Source localization from radiographs can be very difficult for template-guided implants if the needle images overlap. At UCSF several techniques to make this task easier have been developed. The techniques include selection of an optimum simulator gantry angle, use of different types of dummies, and differential dummy loading. In addition, several modifications have been made in our brachytherapy planning computer program to facilitate source entry. As a result of these improvements, source localization is now accomplished in much less time with improved accuracy.

Dosimetric properties of neutrons from 21-MeV deuteron bombardment of a deuterium gas target.

Spectra, yields, average energies, and kerma rates in tissue of neutrons from 21-MeV deuteron bombardment of deuterium gas targets have been calculated for target thicknesses of 1, 3.5, and 5 MeV. A high pressure gas cell was constructed and was filled with 33 atm of D2 gas (equivalent to an energy loss of 3.5 MeV for 21-MeV deuterons); dose rate, dose buildup, and depth-dose properties of neutrons produced by the D(d,n) reaction were measured. Dosimetric properties of these neutrons are superior to those of neutrons from a thick Be target bombarded by a deuteron beam of the same energy.

Dose distribution of 125I sources in different tissues.

The low-energy photons of 125I deposit energy in tissues primarily by the photoelectric effect, which is strongly dependent on the atomic number Z. Thus dose distributions of 125I sources in media of different Z are not the same. LiF and CaF2 thermoluminescent dosimeters were used for relative dose distribution measurements in materials that are equivalent to muscle, breast, and bone. The experimental data are in good agreement with published results for muscle, and in reasonable agreement with Monte Carlo calculations for all the tissues tested. These measured data provide the basis for dose distribution calculations when 125I seeds are implanted in or near inhomogeneous tissues.

A review of the discrepancy between the in-air and in-water calibration of cobalt-60 machines.

Causes for the discrepancy noted by Grant et al. between the in-water and in-air calibration of 60Co are discussed. Data are presented from measurements with a set of ionization chambers with thimbles of 0.5, 1.0, and 1.5 cm outside radii. These data include measurements of percentage depth dose, backscatter factors, and displacement factors. The results show that the discrepancy noted by Grant et al. is caused by a combination of small errors both in depth dose data and in the displacement factor incorporated into C lambda.

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.

Brachytherapy of recurrent tumors of the skull base and spine with iodine-125 sources.

Thirteen patients with recurrent, previously irradiated tumors of the skull base or spine were reirradiated with 125I sources implanted interstitially using microsurgical or stereotactic techniques. Patients harbored difficult, end-stage recurrences of chordoma, meningioma, malignant meningioma, fibrosarcoma, invasive pituitary adenoma, and malignant schwannoma. In two other patients with malignant meningioma, the dose of external radiation was augmented by implanting 125I sources during the initial operation for excision of the lesion or at a separate surgical procedure after conventional teletherapy. Microsurgical implantation of 125I sources into basal tumors was limited by the difficulties inherent in operating in this region; it is not possible to visualize the entire tumor that requires implantation. Three of five chordomas stabilized or regressed; these patients probably benefited from the procedure. Two patients with recurrent malignant meningiomas had long term remission after interstitial brachytherapy. Interstitial 125I brachytherapy for recurrent tumors at the base of skull or adjacent to the spine can be more successful only if more aggressive surgical exposures of these regions are attempted. Implantation of sources for a "boost" dose, either microsurgically during the initial surgical resection of the lesion before conventional teletherapy or stereotactically after conventional teletherapy, may be a valuable adjunct to external irradiation for the control of potentially devastating tumors (such as chordomas and malignant meningiomas) before they recur with the severe consequences seen in the patients reported here.