Concurrent cisplatin therapy and iodine 125 brachytherapy for recurrent malignant brain tumors.

OBJECTIVE: Toxicity and safety study of concurrent cisplatin therapy and iodine 125 (125I) brachytherapy. BACKGROUND: Iodine 125 brachytherapy has an established role in surgically accessible recurrent tumors of brain. Cisplatin has antitumoral activity against glial neoplasms and has demonstrated sensitization of tumor to radiotherapy. DESIGN/METHODS: In 16 patients (age range, 13 to 68 years, median, 47 years), stereotactically placed catheters were afterloaded with 125I sources. A median 50-Gy minimum treatment volume dose was delivered during a 100-hour period along with cisplatin (20 mg/m2 per day for 5 days). Histologic diagnoses included glioblastoma multiforme (n = 11), anaplastic astrocytoma (n = 3), ependymoma (n = 1), and anaplastic oligodendroglioma (n = 1). Tumor volumes ranged from 7.0 to 73 cm3 (median, 25 cm3). RESULTS: Early complications included headache (n = 7), transient exacerbations of preexisting neurologic deficits (n = 5), seizures (n = 3), and nausea/vomiting (n = 3). Late complications included steroid dependency (n = 10), progressive dementia in the absence of recurrent tumor (n = 1), and radiation-induced necrosis (n = 9) requiring reoperation (n = 9). Fifteen of 16 patients were assessable, with a median follow-up time of 9.5 months. Brachytherapy was discontinued in one patient owing to an acute subdural hematoma. A partial response was seen in five patients, disease remained stable in seven patients, and disease progressed in three patients. CONCLUSIONS: We conclude that 125I brachytherapy with concurrent cisplatin therapy is associated with an acceptable level of toxic effects and warrants further investigation.

Dose volume histogram analysis of liver radiation tolerance.

Eleven patients with carcinoma of the pancreas or biliary system received heavy charged particle radiation treatments and whole liver heavy charged particle radiation at Lawrence Berkeley Laboratory. Doses to the whole liver ranged from 10 to 24 Gray-equivalent (the biological equivalent of 10 to 24 Gray of low-LET photon radiation), whereas the dose to the primary lesion ranged from 53.5 to 70 Gray-equivalent (GyE). The fraction size was 2 to 3 GyE. The liver received partial as well as whole organ irradiation. Integral dose volume histograms for the liver were obtained in all 11 patients. An integral dose volume histogram displays on the ordinate the percentage of liver that was irradiated in excess of the dose specified on the abcissa. In this study, the clinical liver radiation tolerance of these patients is correlated with the information contained in an integral dose volume histogram. One patient developed radiation hepatitis. The integral dose volume histogram of this patient differed from the dose volume histograms of the other 10 patients. This difference was greatest in the range of doses between 30 and 40 GyE. Our results suggest that liver doses in excess of 30 to 35 GyE should be limited to 30% of the liver or less when 18 GyE of whole liver radiation is delivered at 2 GyE per fraction in addition to primary radiation of the pancreas or biliary system.

Stereotactic radiosurgery for intracranial arteriovenous malformations using a standard linear accelerator.

We have previously described the development of a technique which utilizes a standard linear accelerator to provide stereotactic, limited field radiation. The radiation is delivered using a modified and carefully calibrated 6 MV linear accelerator. Precise target localization and patient immobilization is achieved using a Brown-Roberts-Wells (BRW) stereotactic head frame which is in place during angiography, CT scanning, and treatment. Seventeen arteriovenous malformations (AVMs) have been treated in 16 patients from February 1986 to July 1988. Single doses of 1500-2500 cGy were delivered using multiple non-coplanar arcs with small, sharp edged x-ray beams to lesions less than 2.7 cm in greatest diameter. The dose distribution from this technique has a very rapid dropoff of dose beyond the target volume. Doses were prescribed at the periphery of the AVMs, typically to the 80-90% isodose line. Eleven of 16 patients have been followed by repeat angiography at least 1 year following treatment. Five of 11 have had complete obliteration of their AVM in 1 year and an additional three patients have achieved complete obliteration by 24 months. There have been no incidences of rebleeding or serious complications in any patient. We conclude that stereotactic radiosurgery using a standard linear accelerator is an effective and safe technique in the treatment of intracranial AVMs and the results compare favorably to the more expensive and elaborate systems that are currently available for stereotactic treatments.

Treatment planning study for carcinoma of the esophagus: helium ions versus photons.

Helium ion radiotherapy significantly reduces dose to adjoining critical structures in the treatment of carcinoma of the esophagus when the same treatment plan is compared with megavoltage photon therapy. A five-field 18 MV photon treatment plan, selected to minimize lung dose, is compared with helium ions using the same field configuration. Dose volume histograms show target coverage, as well as dose delivered to critical structures lung, heart, mediastinum, and spinal cord. Although both helium ions and photons deliver approximately the same lung dose for this treatment plan, radiation to the heart and spinal cord from this field arrangement is significantly reduced with the helium ion beam. The concentration of dose at the tumor site, while sparing surrounding normal tissue, is characteristic of charged particle therapy, particularly with light ions, which includes particles with Z from that of protons (Z = 1) through that of neon (Z = 10).

Radiosurgery for arteriovenous malformations of the brain using a standard linear accelerator: rationale and technique.

We have recently initiated a program for irradiating small, unresectable arteriovenous malformations (AVM's) in the brain. The treatments are delivered using a modified and carefully calibrated 6 MV linac. We are using high, single doses (15 to 25 Gy) with a goal of sclerosing the vessels and preventing hemorrhages. This technique, radiosurgery, is somewhat controversial in the radiotherapy community. Since the treatment is given in a single sitting, rather than in the more conventional pattern of multiple small daily fractions, there is some concern about late radiation damage to the normal brain tissue. However an extensive review of the literature leads us to the conclusion that if a technique is used that keeps the volume irradiated to high dose small, radiosurgery is a safe and efficacious treatment for small (less than 2.5 cm) AVM's. To decrease the risk of necrosis of normal brain tissue, it is important to confine the high dose region as tightly as possible to the target volume. Precise target localization and patient immobilization is achieved using a stereotactic head frame which is used during angiography, CT scanning, and during the radiation treatment. This minimizes the margin of safety that must be added to the target volume for errors in localization and set-up. The treatment is delivered using multiple noncoplanar arcs, with small, sharp edged X ray beams, and with the center of the AVM at isocenter. This produces a rapid dropoff of dose beyond the target volume. Early results in our first few patients are encouraging.

Precision, high dose radiotherapy: helium ion treatment of uveal melanoma.

We report on 75 patients with uveal melanoma who were treated by placing the Bragg peak of a helium ion beam over the tumor volume. The technique localizes the high dose region very tightly around the tumor volume. This allows critical structures, such as the optic disc and the macula, to be excluded from the high dose region as long as they are 3 to 4 mm away from the edge of the tumor. Careful attention to tumor localization, treatment planning, patient immobilization and treatment verification is required. With a mean follow-up of 22 months (3 to 60 months) we have had only five patients with a local recurrence, all of whom were salvaged with another treatment. Pretreatment visual acuity has generally been preserved as long as the tumor edge is at least 4 mm away from the macula and optic disc. The only serious complication to date has been an 18% incidence of neovascular glaucoma in the patients treated at our highest dose level. Clinical results and details of the technique are presented to illustrate potential clinical precision in administering high dose radiotherapy with charged particles such as helium ions or protons.

Precision, high dose radiotherapy. II. Helium ion treatment of tumors adjacent to critical central nervous system structures.

In this paper we present a technique for treating relatively small, low grade tumors located very close to critical, radiation sensitive central nervous system structures such as the spinal cord and the brain stem. A beam of helium ions is used to irradiate the tumor. The nearby normal tissues are protected by exploiting the superb dose localization properties of this beam, particularly its well defined and controllable range in tissue, the increased dose deposited near the end of this range (i.e., the Bragg peak), the sharp decrease in dose beyond the Bragg peak, and the sharp penumbra of the beam. To execute this type of treatment, extreme care must be taken in localization of the tumor and normal tissues, as well as in treatment planning and dosimetry, patient immobilization, and verification of treatment delivery. To illustrate the technique, we present a group of 19 patients treated for chordomas, meningiomas and low grade chondrosarcomas in the base of the skull or spinal column. We have been able to deliver high, uniform doses to the target volumes (doses equivalent to 60 to 80 Gy of cobalt-60) while keeping the doses to the nearby critical tissues below the threshold for radiation damage. Follow-up on this group of patients is short, averaging 22 months (2 to 75 months). Currently, 15 patients have local control of their tumor. Two major complications, a spinal cord transection and optic tract damage, are discussed in detail. Our treatment policies have been modified to minimize the risk of these complications in the future, and we are continuing to use this method to treat such patients. We are enthusiastic about this technique, since we believe there is no other potentially curative treatment for these patients.

A phase I-II trial of heavy charged particle irradiation of malignant glioma of the brain: a Northern California Oncology Group Study.

Thirty-nine patients with primary or recurrent glioma of the brain were irradiated wholely or in part with heavy charged particle beams at the University of California Lawrence Berkeley Laboratory in a Phase I-II clinical trial of the Northern California Oncology Group. During the course of this trial, treatment techniques have been developed and tumor doses have been escalated in order to obtain data on normal brain toxicity and response of malignant glioma of the brain. Toxicity has been acceptable with a low level of brain injury. Survival and tumor control has been approximately the same as historical results in glioma of the brain. Further dose escalation is planned together with possible trial of combined modality therapy.

Treatment of cancer with heavy charged particles.

A clinical radiotherapeutic trial using heavy charged particles in the treatment of human cancers has accrued over 400 patients since 1975, 378 of whom were treated with particles and 28 with low LET photons as control patients. Heavy charged particle radiotherapy offers the potential advantages of improved dose localization and/or enhanced biologic effect, depending on particle selected for treatment. Target sites have included selected head and neck tumors, ocular melanomata, malignant gliomata of the brain, carcinoma of the esophagus, carcinoma of the stomach, carcinoma of the pancreas, selected juxtaspinal tumors and other locally advanced, unresectable tumors. A Phase III prospective clinical trial has been started in carcinoma of the pancreas using helium ions. Phase I-II studies are underway with heavier particles such as carbon, neon and argon ions in order to prepare for prospective Phase III trials. Silicon ions are also under consideration for clinical trial. These studies are supported by the United States Department of Energy and National Institutes of Health.

Correlation of visual field, treatment fields, and dose in helium ion irradiation of uveal melanoma.

We correlated predicted radiation distributions in 29 patients with uveal melanoma (treated with 5,000 to 8,000 rads of helium ion therapy) with fundus photography and visual field deficits. The tumor was entirely within the treatment region in all patients. The fraction of the predicted high-dose and low-dose regions corresponding with an absolute scotoma was fitted by a linear regression model (r2 = .721) with three independent variables: dose region, initial condition, and time since therapy. The defect in the maximum-dose region increased at an average rate of 0.270/year. This differed (P = .002) from the rate in the penumbra region: (0.104/year). The rate in the penumbra differed (P = .01) from that in the predicted low-dose region, where scotoma did not increase with time. The pattern and time course of visual field loss in the different radiation dose regions tended to support the conclusion that isodose calculations are accurate. The data were consistent with the hypothesis that visual loss secondary to irradiation results primarily from radiation vasculopathy and not from direct damage to photoreceptors or ganglion cells. Development of an absolute scotoma may require a dose in excess of 5,000 rads.

Early results of ion beam radiation therapy for sacral chordoma. A Northern California Oncology Group Study.

The authors report on eight patients with sacral chordoma treated with ion beam radiation therapy. Ion beams have favorable physical and biological characteristics when compared to conventional radiation therapy beams of x-rays, gamma rays, or electrons. This treatment technique has been developed to exploit those advantages. With this technique it is possible to deliver a much higher tumor dose than that usually given with conventional beams, and to date no significant normal-tissue morbidity has been noted. Seven of the eight patients currently have local control of their tumor; however, follow-up time is too short to judge the long-term local control rate of this treatment technique.

Helium charged-particle radiotherapy of locally advanced carcinoma of the esophagus, stomach, and biliary tract.

Sixty-five patients with squamous carcinoma of the esophagus (32 patients), carcinoma of the stomach (18 patients) and carcinoma of the biliary tract (15 patients) received from 6000 to 7000 equivalent rad (60-70 Gray-equivalents) of helium radiotherapy at 2.0 GyE per fraction, four fractions per day, using multiportal, spread-out Bragg peak therapy. All patients had locally advanced disease without evidence of distant metastases. Partial compensation for tissue inhomogeneities was accomplished. Although palliation of symptoms and regression of tumor was commonly seen, local failure occurred in most patients (77%). The median survival was 8 months. It does not appear that an increase in tumor dose relative to normal tissues can be achieved that would be high enough to increase locoregional control rates over historical control rates with low-LET irradiation. Further studies will be carried out with heavier particles such as neon or silicon in hopes of achieving greater biological effect on these difficult-to-control tumors.

Clinical problems in radiotherapy of carcinoma of the pancreas.

Since 1975, 94 patients with localized unresectable carcinoma of the pancreas have been irradiated using helium and heavier particles at the University of California Lawrence Berkeley Laboratory. Despite surgical exploration and an extensive diagnostic workup including radiological, nuclear medicine, and computer-assisted tomographic studies, many patients proved to have occult liver metastases manifested within 9 months post treatment. In addition, local and regional control of the primary neoplasm (approximately 20%) has been difficult to obtain even with doses of 6000 equivalent rad in 7 1/2 weeks. Gastric and biliary obstruction have required surgical bypass procedures since irradiation has not been successful in relieving obstructive symptoms. Evidence of gastrointestinal injury has been present in postradiation therapy in approximately 10% of patients, a figure which might be higher if more patients had a longer survival (average 10 months). Some patients require pancreatic enzyme supplementation because of pancreatic deficiency either secondary to tumor or treatment. Further improvement in local control and survival requires better diagnostic methods for evaluation of local and metastatic spread, improved therapy for local and regional disease, as well as therapy directed at occult liver metastases that are frequently present.

The prevalence of problem drinking and alcoholism in the West of Scotland.

A 10 per cent probability sample of the population of Clydebank was interviewed, using an indirect questionnaire, to assess the extent of alcohol-related disabilities. Eighty-two per cent of 4,397 persons gave information and weighted symptom-scoring analysis showed 5.0 per cent of adult males and 1.1 per cent of adult females could be classified as problem drinkers and 5.2 per cent and 0.5 per cent respectively could be labelled alcoholics. These figures are compared to existing Scottish and English alcoholism prevalence statistics.

Structure-function dependence and allopurinol inhibition of radiosensitizer/nitroreductase interaction: approaches to improving therapeutic ratios.

Normal tissue toxicity of nitroaromatic radiosensitizers may originate in radiosensitizer/nitroreductase interaction. A study of two mammalian cell nitroreductases, xanthine oxidase and NADH cytochrome c reductase, shows that the efficiency of electron transfer is dependent on sensitizer electron affinity and not lipid solubility. Misonidazole and its demethylated metabolite (RO-05-9963), for example, are equally efficient as electron acceptors from xanthine oxidase. The only exception to the electron affinity correlation is m-nitrobenzamidine hydrochloride (MNBAM) which results because MNBAM inhibits electron donation to xanthine oxidase from its cofactor, xanthine. Allopurinol inhibits electron transfer and might be a useful adjuvant to the use of radiosensitizers. Evidence that allopurinol interacts with nitroreductases in vivo is deduced from the observation that allopurinol significantly alters the serum lifetimes in mice of misonidazole and RO-05-9963.

Neovascular glaucoma after helium ion irradiation for uveal melanoma.

Neovascular glaucoma developed in 22 of 169 uveal melanoma patients treated with helium ion irradiation. Most patients had large melanomas; no eyes containing small melanomas developed anterior segment neovascularization. The mean onset of glaucoma was 14.1 months (range, 7-31 months). The incidence of anterior segment neovascularization increased with radiation dosage; there was an approximately three-fold increase at 80 GyE versus 60 GyE of helium ion radiation (23% vs. 8.5%) (P less than 0.05). Neovascular glaucoma occurred more commonly in larger tumors; the incidence was not affected by tumor location, presence of subretinal fluid, nor rate of tumor regression. Fifty-three percent of patients had some response with intraocular pressures of 21 mmHg or less to a combination of antiglaucoma treatments.

Postmortem examination of 22 pancreatic carcinoma patients treated with helium ion irradiation.

Postmortem findings are available in this report in 22 patients with pancreatic carcinoma treated with helium ions at Lawrence Berkeley Laboratory; California. This represents the largest group evaluated histologically in the literature and is the first report evaluating effects of particle radiation in pancreatic tissue. Patient survival after therapy averaged 9 months. Most died of infection and/or pulmonary emboli. Local control was achieved in 27%. The pancreatic tumors had histologically more severe radiation changes than nontumor bearing pancreas. Irradiated bone marrow was severely hypocellular, and irradiated skin was atrophic. Five patients had radiation injury in the gastrointestinal tract. The spinal cord, liver, and kidneys showed no damage. This study demonstrates the safety of helium particle irradiation with present therapeutic planning. Injury to tumor was seen without excessive damage to adjacent tissues.