Subspecialization in radiation oncology: impact of stereotactic radiosurgery.
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Biomedical subjects
Publications and source records attributed to D A Larson.
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Between May 1977 and August 1989, 357 patients (199 male, 158 female; median age 40 years) with highly anaplastic astrocytomas other than glioblastoma multiforme were treated according to any of several protocols used in studies by the University of California, San Francisco, and the Northern California Oncology Group. The data evaluated were age, Karnofsky Performance Score, survival, time to tumor progression, therapy, and the effect of treatment at the time of progression. The records of 219 patients were taken from the University of California database, and those of the other 138 were taken from the Northern California Oncology Group computer files. Their median Karnofsky Performance Score was 90% (range 40-100%), the overall median survival was projected as 170.9 weeks, and the median time to first tumor progression was 127.3 weeks. The median survival time measured after the first progression was 41.3 weeks. Age and Karnofsky Performance Score had a significant influence on survival and on time to the first tumor progression, whereas extent of surgery and the use of interstitial brachytherapy in the initial therapy did not. We conclude that these patients can expect a median survival of over 3 years, that young age and high Karnofsky Performance Score have a positive influence on survival, and that salvage therapies can extend survival after the onset of tumor progression for nearly a year. Although it did not lengthen survival when used in initial therapy, interstitial brachytherapy used at the time of tumor progression was associated with increased survival.
Fifteen patients initially irradiated for pituitary adenoma were subsequently treated with a second course of radiotherapy at the University of California at San Francisco between 1961 and 1989. The re-irradiation followed surgery in all but two cases. The median time to recurrence was 9 years (range 2-17) and median follow-up after the second course of radiotherapy was 10 years (range 1-30). The median initial radiation dose was 4084 cGy; that at recurrence was 4200 cGy. Local control has been maintained in 12 patients. One failed locally with a benign adenoma that was surgically salvaged. Two developed pituitary carcinomas which were poorly controlled. Of the patients who presented with visual abnormalities at the time of recurrence, 50% improved and the remainder stabilized after re-irradiation. There are no long-term visual complications. Hypopituitarism was present in nine patients prior to the second course of radiotherapy and developed in the remaining six patients after re-irradiation. Temporal lobe injury was seen in two patients. Careful analysis of each patient's pituitary and temporal lobe doses, intervals between treatments, treatment volume, neurets, relative decay factors, absolute decay factors, TDF and modified LQF values, and dose-volume relationships, revealed no correlation with complication or likelihood of local control. Repeat radiotherapy for recurrent pituitary adenoma with the doses used in these patients appears to carry acceptable risk with good local control.
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.
Although interstitial brachytherapy appears to be effective in treating recurrent malignant gliomas, it has been studied less extensively in patients with newly diagnosed tumors. To examine the effect of this treatment when used at the time of primary diagnosis, we retrospectively reviewed the records of 88 patients who received temporary interstitial implants of 125I for newly diagnosed malignant gliomas. This brachytherapy was preceded by a course of external radiation therapy and followed, in some cases, by chemotherapy. The median duration of survival after the beginning of external radiation therapy was 87 weeks in patients with glioblastoma multiforme and 160 weeks in those with anaplastic gliomas. In 46% of patients with glioblastoma multiforme and 56% of those with anaplastic gliomas, a second operation was necessary to remove symptomatic radiation necrosis, recurrent tumor, or both. Our results support the conclusion that interstitial brachytherapy used at the primary diagnosis lengthens survival in selected patients with glioblastoma multiforme. However, the toxicity is significant in terms of the need for surgical resection of symptomatic necrosis. In patients with anaplastic gliomas, the toxicity associated with the treatment probably outweighs its advantages.
Between February 1984 and September 1990, 60 patients with brainstem gliomas were treated with hyperfractionated radiotherapy in the Department of Radiation Oncology at the University of California, San Francisco. Forty-one children (< or = 18 years) and 19 adults were treated with 100 cGy twice daily with 4-8 hr between doses. Thirty-one patients (21 children and 10 adults) received total doses of 66-72 Gy and 29 patients (20 children and nine adults) received 74-78 Gy. Median follow-up was 208 weeks for all patients (214 weeks for children, 157 weeks for adults). Twenty-three patients (14 children and nine adults) were alive at the time of analysis, surviving 59-359 weeks following treatment. Median actuarial survival was 73.6 weeks overall (72 weeks for children, 190 weeks for adults; p = 0.43). Survival at 12 and 24 months was 65% and 38%, respectively (63% and 32%, for children; 68% and 53% for adults). All patients had pretreatment magnetic resonance imaging by which tumors were classified as either focal or diffuse. No significant pretreatment prognostic factors for adults were identified. In children, significant favorable prognostic factors on univariate analysis were older age (p = 0.001), tumor location in thalamus or midbrain (p = 0.002), focal appearance on MRI scan (p < 0.001) and duration of symptoms > 2 months prior to treatment (p < 0.001). Thirty-five patients had tumor biopsies, leading to a diagnosis in 33 (22 children and 11 adults). Children with moderately anaplastic astrocytomas survived significantly longer than those with glioblastoma multiforme or unbiopsied tumors (p < 0.001). Only duration of symptoms > 2 months remained significant as a favorable prognostic indicator for children on multivariate analysis (p < 0.001). Survival was not significantly different for patients receiving < or = 72 Gy and those receiving > 72 Gy (p = 0.18). No subgroup of patients showed significantly better survival with the higher dose. These findings indicate that hyperfractionated radiotherapy is effective treatment for adults and a subgroup of better prognosis children with brainstem gliomas. There is a subgroup of pediatric patients with extremely poor prognosis for whom even this aggressive treatment does little to extend survival. We conclude that there is no benefit to increasing total dose above 72 Gy for any of the groups analyzed.
A more precise radiation therapy technique to treat unilateral optic nerve sheath meningioma is presented. It uses an immobilization device to align the ipsilateral optic nerve with a vertical axis and employs three small half-beam blocked fields to deliver radiation to a small conformal volume, thereby reducing the dose to the optic chiasm and the contralateral optic nerve. Three patients were successfully treated with this technique, and a fourth patient with optic nerve glioma was also treated in a similar fashion and was included in this study. The new technique irradiates a much smaller volume of tissue to high dose levels: 58 cm3 is irradiated to the 80% isodose level and only 18 cm3 to the 95% level. In contrast, the opposed lateral technique irradiates 171 and 73 cm3 to these levels, respectively. Thus, a considerable reduction in the volume of normal tissue irradiated was accomplished. Doses to the pituitary and contralateral optic nerve were 4% of the treatment dose for the new technique, whereas these doses were 40% and 100% for opposed laterals and 10% and 3% for wedged pair, respectively. The average setup error for this technique was very small, 50% of the setups measured were less than 1 mm off, and 92.5% were less than 3 mm off. However, for the conventional setups without a mask, only 21% of the setups were less than 1 mm off and 55% less than 3 mm off. We recommend this technique for localized unilateral optic nerve sheath meningioma and other optic nerve lesions that may require radiation therapy.
Many new modalities and increasing data have become available in the treatment of brain tumors. We will review the growing experience with newer treatment modalities such as brachytherapy, radiosurgery, hyperthermia, and photodynamic therapy.
Radiation-induced optic neuropathy (RON) is a rare and catastrophic complication of currently employed radiation therapy regimens for meningiomas that have been partially resected and sampled for biopsy. Between 1972 and 1989, 49 patients received postoperative irradiation for partially resected or biopsy sampled meningiomas, with the optic nerve within the treatment field. One patient experienced RON. The latency period for this case was 23 months. A review of the literature disclosed few cases of RON after treatment for meningioma; however, 42 cases of RON have been reported after radiation therapy for other lesions. The authors constructed two approaches to predict optic nerve radiation tolerance. The first is modeled on a previous proposal for a neural tissue nominal standard dose term and enabled accurate prediction of safe treatment regimens and risk of RON. This approach compared favorably with previously employed nominal standard dose terms. The second approach, based on the linear-quadratic model, proved unsuccessful due to its failure to achieve statistical significance.
Temporary implants of high-activity 125iodine sources have been used in the treatment of brain tumors since December 1979 at the University of California, San Francisco. For previously untreated patients who underwent external beam radiation therapy followed by implant boost, median survival from the date of diagnosis was 88 weeks for 34 patients with glioblastoma multiforme (GM) and 157 weeks for 29 patients with nonglioblastoma gliomas (NGM). For recurrent tumors treated with brachytherapy only, median survival from the date of the implant was 54 weeks for 45 patients with GM and 81 weeks for 50 patients with NGM. Finally, in 48 patients with recurrent tumors treated with combined hyperthermia and brachytherapy, median survival from the date of the implant was 46 weeks for 25 patients with GM and 44 weeks for 7 patients with metastases; 18-month survival was 65% for 16 patients with NGM. Brachytherapy appears to be a useful technique for the treatment of selected recurrent brain tumors and selected primary glioblastomas.
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Hyperfractionated irradiation appears to have improved survival for pediatric patients with brainstem gliomas. However, the efficacy and safety of this technique are less well established for adults with brainstem tumors. In 1984 the UCSF Department of Radiation Oncology began treating adults with brainstem gliomas using 100 cGy fractions given twice daily to total doses ranging between 6600-7800 cGy (median dose 7200 cGy). By the end of 1989, a total of 14 patients had been irradiated with follow-up times for surviving patients ranging between 4-69 months (median follow-up 33 months). Tumor histologies included five moderately anaplastic astrocytomas, one highly anaplastic astrocytoma, and eight which were unbiopsied. At the time of this analysis, six patients had failed locally, with five dying as a result of recurrent tumor. There were no deaths caused by complications or intercurrent illness. The 3-year actuarial survival rate was 59%, with a corresponding 3-year actuarial local control rate of 48%. The projected median survival was in excess of 5 years, whereas the actuarial median time to progression was 31 months (134 weeks). The treatments were well tolerated: the mean pretreatment Karnofsky Performance Status was 74% (range 60-90%); at the end of treatment the mean KPS was 78% (range 60-100%). In terms of neurologic status, six patients improved by the end of treatment, seven were stable, and one experienced only minor deterioration without change in KPS. There were no significant long-term complications (specifically, no instances of either radiation brain necrosis or myelitis). Seven patients required prolonged steroid administration after completing radiotherapy; six of these eventually recurred locally. These results appear to be substantially better than those achieved using conventional radiotherapy regimens, and suggest that this technique merits further investigation.
Radiosurgery at UCSF is performed with a 6-MV linear accelerator with tertiary collimation for improved small field definition. The dose delivery to the target relative to normal tissue is influenced by the number of arcs, the arc geometry, field size, and beam energy. The impact of arc number, arc geometry, and field size on the dose distribution from 6-MV X rays in a 16 cm spherical phantom has been evaluated through the use of cumulative dose volume histograms. Dose volume histograms were calculated for a) 1-5 and 10 arcs, and b) collimator sizes of 1.25, 2.0, and 3.0 cm. Differences between techniques were found at the 5-10% level for field sizes from 1.25 to 2.0 cm. It was shown that the finite dimension of the sphere and, by extension, head diminishes the differences between techniques for the larger field sizes. The effect of treating with two isocenters is also analyzed and an approach for improving the dose distribution is presented.
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.
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.
The term radiosurgery, originally applied to three-dimensional stereotactic irradiation of small intracranial targets with low-energy x-rays, has more recently been applied to widely differing techniques and radiation sources. These include gamma units using cobalt-60; beams of protons, helium ions and neutrons; and modified cobalt-60 or linear accelerator units. These techniques allow delivery of a high dose of radiation in a single fraction to a small and well-defined intracranial volume, without delivering significant radiation to adjacent normal tissue. The most usual targets for radiosurgery are arteriovenous malformations. It is occasionally used for acoustic neuromas and primary or metastatic brain malignancies as well. Although radiosurgery is not a new procedure, its use is becoming more widespread. Nurses, as critical members of radiosurgery teams, must be informed about all aspects of the procedures and associated nursing care skills.