Gadolinium neutron capture in glioblastoma multiforme cells.

PURPOSE: A proof of principle for cell killing by Gadolinium (Gd) neutron capture in Magnevist preloaded Glioblastoma multiforme (GBM) cells is provided. MATERIALS AND METHODS: U87cells were pre-loaded with 5 mg/ml Magnevist (Gd containing compound) and irradiated using an enhanced neutron beam developed at NIU Institute for Neutron Therapy at Fermilab. These experiments were possible because of an enhanced fast neutron therapy assembly designed to use the fast neutron beam at Fermilab to deliver a neutron beam containing a greater fraction of thermal neutrons and because of the development of improved calculations for dose for the enhanced neutron beam. Clonogenic response was determined. RESULTS: U87 cell survival after gamma irradiation, fast neutron irradiation and irradiation with the enhanced neutron beam in the presence or absence of Magnevist were determined. CONCLUSIONS: U87 cells were the least sensitive to gamma radiation, and increasingly sensitive to fast neutron irradiation, irradiation with the enhanced neutron beam and finally a significant enhancement in cell killing was observed for U87 cells preloaded with Magnevist. The sensitivity of U87 cells pre-loaded with Magnevist and then irradiated with the enhanced neutron beam can at least in part be attributed to the Auger electrons emitted by the neutron capture event.

Neutron irradiation of human pelvic tissues yields a steep dose-response function for late sequelae.

PURPOSE: Analysis of the dose-response function in normal tissues following pelvic irradiation for carcinoma of the prostate. METHODS AND MATERIALS: A homogeneous group of 136 patients with locally advanced carcinoma of the prostate were treated with the Fermilab high-energy neutron beam at three dose levels: 19, 20.4, and 21 Gy, using the same treatment plan and fractionation scheme for all patients. RESULTS: Tumor control rates were about 83% at the three dose levels studied. However, the normal tissue complication rate (late sequelae) varied with dose: 0 out of 5 at 19 Gy, 5 out of 58 (8.6%) at 20.4 Gy, and 9 out of 73 (12.3%) at 21 Gy. CONCLUSIONS: Neutron therapy to the pelvis reveals a steep dose-response function for late effects with a coefficient of variation of only 11%. This is lower than that usually observed with photons or with less uniform clinical data sets, and may be characteristic for well-planned high-LET radiotherapy.

Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council.

PURPOSE: To compare the efficacy of fast neutron radiotherapy versus conventional photon and/or electron radiotherapy for unresectable, malignant salivary gland tumors a randomized clinical trial comparing was sponsored by the Radiation Therapy Oncology Group in the United States and the Medical Research Council in Great Britain. METHODS AND MATERIALS: Eligibility criteria included either inoperable primary or recurrent major or minor salivary gland tumors. Patients were stratified by surgical status (primary vs. recurrent), tumor size (less than or greater than 5 cm), and histology (squamous or malignant mixed versus other). After a total of 32 patients were entered onto this study, it appeared that the group receiving fast neutron radiotherapy had a significantly improved local/regional control rate and also a borderline improvement in survival and the study was stopped earlier than planned for ethical reasons. Twenty-five patients were study-eligible and analyzable. RESULTS: Ten-year follow-up data for this study is presented. On an actuarial basis, there continues to be a statistically-significant p = 0.009) but there is no improvement in overall survival (15% vs. 25%, p = n.s.). Patterns of failure are analyzed and it is shown that distant metastases account for the majority of failures on the neutron arm and local/regional failures account for the majority of failures on the photon arm. Long-term, treatment-related morbidity is analyzed and while the incidence of morbidity graded "severe" was greater on the neutron arm, there was no significant difference in "life-threatening" complications. This work is placed in the context of other series of malignant salivary gland tumors treated with definitive radiotherapy. CONCLUSIONS: Fast neutron radiotherapy appears to be the treatment-of-choice for patients with inoperable primary of recurrent malignant salivary gland tumors.

Prognostic implications of prostate-specific antigen in patients with locally advanced prostate cancer treated with high energy neutron beam therapy: preliminary results.

Serial serum prostate-specific antigen (PSA) levels were analyzed retrospectively for prognostic implications in 70 patients with locoregional (Stages B2, C, and D1) prostate cancer who were managed with high energy neutron beam therapy. Three groups of patients were identified. Group I included 30 patients whose serum PSA level decreased to the reference range (0-4 ng/mL) following neutron therapy and remained so subsequently: 28 (93%) remained disease-free and 2 (7%) have failed distantly. All 30 patients (100%) had no evidence of locally progressive disease. This group was categorized as having a good prognosis. The mean time for serum PSA value to decline to reference range was six months; calculated mean time to achieve a stable base-line PSA was 53 +/- 37 days. Follow-up period ranged from twelve to fifty-six months (median: 21 months). Group II consisted of 13 patients in whom there was an initial decrease in serum PSA to reference range followed by a subsequent increase: 6 of 13 (46%) have no overt clinical progression of disease; 7 (54%) have either persistent locoregional or distant metastatic disease. Follow-up period was from twelve to seventy-two months (median: 39 months). Calculated mean time to achieve stable baseline PSA for serum PSA in this group was 61 +/- 21 days. Group III patients had a persistently elevated or rising serum PSA concentration. Of 27 patients in this group, only 9 (33%) have no evidence of disease progression, while 18 patients (67%) have failed already, either locoregionally or distantly. Follow-up period ranged from twelve to sixty-nine months (median: 21 months). Mean time to achieve stable baseline of serum PSA in this cohort of patients with a poor prognosis was 108 +/- 76 days. We conclude that PSA has a predictable prognostic value in patients with locally advanced prostate cancer managed with high energy neutron beam therapy. Rapid normalization of PSA after therapy indicates a good prognosis. Persistent elevation signifies either presence of persistent locoregional disease or development of distant metastases. Subsequent elevation of the serum PSA concentration after definitive therapy signals progression of prostate cancer.

Failure of accelerated neutron therapy to control high grade astrocytomas.

Sixty-two patients with high grade malignant astrocytoma were treated with fast neutrons using three different treatment schemes to evaluate the effect of shortening the overall time. Dose and fraction number were kept constant. The total dose was 16-18 neutron Gy delivered in six fractions, weekly for 6 weeks, twice a week over 3-4 weeks, or three times a week over 2 weeks. There were no obvious differences in survival times among the three groups. We conclude that accelerated neutron therapy does not improve survival of patients with grade 3 and 4 astrocytoma.

Normal tissue reactions and complications following high-energy neutron beam therapy: I. Crude response rates.

The incidence of significant complications (fibrosis, ulceration, necrosis of bone or soft tissue or serious functional impairment) was determined in relation to neutron dosage and follow-up time for 5 anatomical sites totalling 617 patients who had survived 2 or more years following treatment. The regions studied were head and neck (268 patients), thorax (lung and esophagus, 76 patients), upper abdomen (132 patients), pelvis (prostate and bladder, 114 patients) and extremities (27 patients). Neutron doses ranged from 16 to 28 Gy. All patients were followed until death or up to 10 years after treatment. A total of 109 complications were observed yielding a crude complication rate of 18% for the whole series. Observed complication rates were 7% in the 16-20 Gy dose range, 19% between 20 and 24 Gy, and 33% in patients receiving more than 24 Gy. Probit analysis of the data indicated a median effective dose (50% complications) of 29 (+/- 0.5) Gy with an estimated standard deviation of 8 Gy. A reasonable estimate of "tolerance" may then be taken as 29 - 8 = 21 Gy. Comparing the 5 anatomical sites revealed no significant differences in estimated tolerance doses. With the available data, no effect of field-size or target volume could be demonstrated. The incidence of complications apparently increases with time in long-term survivors. Although the overall incidence is only 18%, actuarial analysis of the data suggests that the complication rate might have exceeded 50% if all treated patients had survived 10 years. It is concluded that, with the exception of the nervous system and possibly other viscera, a neutron dose of 20 Gy (in 12 fractions over 4 weeks) represents a practical tolerance limit for all sites.

Re-irradiation of locally recurrent tumors with fast neutrons.

Forty-six patients with locally recurrent disease were re-irradiated with fast neutrons at Fermilab. All had received prior radical radiation therapy either with or without surgery. Six were palliative. Forty patients treated with curative intent were analyzed for local response, survival, and complications. The overall response rate was 78% (31/40); 50% (20/40) had a complete local response. Ten of 16 patients (63%) with non-epidermoid carcinomas in the head and neck regions had complete response, whereas only nine of twenty patients (45%) with epidermoid carcinomas were complete responders. In a subset of 12 patients with salivary gland type tumors, 10 had a complete response (83%). Two of these 10 patients are alive beyond 5 years. Observed median survival for the forty patients was 9.3 months, and for complete responders 14.4 months. Observed median survival for partial responders was only 7.5 months. Four of six patients treated for palliation had significant subjective improvement. Significant morbidity, Grade III or greater (EORTC/RTOG scale), was seen in only 10 patients (25%), and this was found to depend directly on the total dose delivered. We conclude that neutron beam therapy can be used as a therapeutic modality for patients with recurrent tumors with an acceptable degree of morbidity.

An update on malignant salivary gland tumors treated with neutrons at Fermilab.

One hundred and thirteen cases of recurrent and/or unresectable malignant salivary gland tumors, treated with fast neutron therapy at Fermilab between September 1976 and December 1984, are analyzed for local control, sites of failure, and treatment-related morbidity. Sixty-three patients had major and 55 had minor salivary gland tumors. Local control was achieved in 67% of patients with major and 58% of patients with minor salivary gland tumors. In the subgroup of patients with oropharyngeal and oral cavity lesions, 19/24 (80%) had local control. However, only four of 15 patients with maxillary antrum tumors had successful control of their disease. Seventy-four percent of patients with lesions measuring 5 cm or less and 30% of patients with larger lesions had their local disease controlled. Histology did not influence the local control rate. Both observed and adjusted median survival for patients with major salivary gland tumors was 36 months. Disease-free survival was 31 months. Observed and adjusted median survivals for patients with minor salivary gland tumors are 48 and 57 months respectively. Twenty of 86 patients (23%) had major morbidity; this was directly related to the total dose delivered. In the dose range 20-24 Gy the complication rate was 16%. Most of these complications were successfully managed with minimal functional disability. We have concluded that fast neutron irradiation is an appropriate treatment for malignant salivary gland tumors.