The lethal effects of Fermilab fast neutrons vary with the depth of cells in a water phantom.

Using V79 Chinese hamster lung fibroblast cells grown in culture we have examined the lethal effects of fast neutrons from the Fermilab therapy facility as a function of depth in a water phantom. Exposures and dosimetry were performed from 3 to 24 cm deep in the phantom along the central axis of the neutron beam, using various collimator configurations. The results indicate that the relative biological effect (RBE), using 60Co gamma rays as the standard radiation, varies with depth in the neutron beam. Starting from d-max (approx. 3 cm), the RBE appears to decrease continuously with depth. At 24 cm deep, the relative effectiveness is 10-15% lower than at 3 cm deep. There appears to be no systematic variation of relative effectiveness with shape or size of collimator. If a hydrogenous filter is added before the beam passes into the water phantom, the variation with depth is greatly reduced.

The Clatterbridge high-energy neutron facility: dosimetry intercomparisons.

Dosimetry intercomparisons have been performed between the Clatterbridge high-energy neutron facility and the following institutions, all employing beams with similar neutron energies: Université Catholique de Louvain, Belgium; University of Washington, Seattle, USA; MD Anderson Hospital, Houston, USA; and Fermi National Accelerator Laboratory, Batavia, USA. The purpose of the intercomparison was to provide a basis for the exchange of dose-response data and to facilitate the involvement of Clatterbridge in collaborative clinical trials. Tissue-equivalent ionization chambers were used by the participants in each intercomparison to compare measurements of total (neutron plus gamma) absorbed dose in the host institution's neutron beam, following calibration of the chambers in a reference photon beam. The effects of differences in exposure standards, chamber responses in the neutron beams and protocol-dependent dosimetry factors were all investigated. It was concluded that the overall difference in the measurement of absorbed dose relative to that determined by the Clatterbridge group was less than 2%.

Response of pancreatic cancer to local irradiation with high-energy neutrons.

Seventy-seven patients with locally advanced, nonresectable, biopsy-proven adenocarcinoma of the pancreas were treated by palliative bypass surgery followed by intensive neutron beam irradiation of the primary tumor site. Three dose levels, under 20, 21 to 23, and 24 to 25 Gy, were studied with the use of a treatment plan that included all known disease within a limited target volume, generally under 2 l. Symptomatic palliation was achieved in the majority of patients. The median survival time was 6 months. One patient remained alive and well without evidence of tumor 5 years after irradiation. Two were free of tumor at autopsy (one had died of intercurrent disease and one of radiation-related complications). A common cause of death was metastatic dissemination. Complication rates were dose-dependent; life-threatening complications did not exceed 12% with doses of less than 23 Gy. Autopsies from 19 patients were reviewed. In all, the pancreatic tumor site showed extensive reactive fibrosis. Local control was achieved in two patients, but most had both residual tumor in the pancreas and metastases. Six patients had centrolobular veno-occlusive liver disease. These patients had all received the higher (22-24 Gy) neutron doses. Six patients had hemorrhagic radiation gastroenteritis. Mild skin atrophy and bone marrow hypoplasia were seen in the irradiated volumes. The kidneys and spinal cord showed no radiation effects. The authors conclude that neutron irradiation can provide a good local response with marked regression and fibrosis of the tumor. This response, coupled with many deaths due to metastases, suggests that combined treatment with neutrons and chemotherapy would be worth exploring.

Tolerance of the human spinal cord to high energy p(66)Be(49) neutrons.

The risk of post irradiation myelopathy was evaluated in 76 patients followed for 1-5 years after neutron irradiation of the cervical and thoracic regions. No overt myelopathy was observed. Forty-six patients received doses (central cord dose) in excess of 10 Gy, 9 received doses in excess of 12 Gy, and 5 received doses between 13 and 17 Gy, all without any evidence of spinal cord injury. On careful questioning, a subjective transient neuropathy (a tingling sensation in one extremity) was reported by 6 patients, but this was apparently unrelated to dose. A review of available literature revealed a total of 14 patients with myelopathy, 13 of whom received doses in excess of 13 Gy delivered with relatively low energy neutrons generated by the deuteron + beryllium reaction. It is concluded from these studies that the tolerance limit for the human spinal cord irradiated with high energy [p(66)Be(49)] neutrons is close to 15 Gy, above which the risk of cord injury becomes significant. Central cord doses of 13 Gy or less appear to be well tolerated with little, if any, risk of myelopathy. These conclusions are valid for a treatment time of 4 weeks or more with two or more fractions per week (9 or more fractions). The RBE for the human spinal cord irradiated under the above conditions compared with conventionally fractionated photon therapy does not exceed 4.0.

Fast neutrons and misonidazole for malignant astrocytomas.

Twenty-five patients with biopsy proven malignant supratentorial astrocytomas were entered into a Phase I/II study of misonidazole combined with neutron radiation at Fermilab Neutron Therapy Facility (NTF) between August 1979 and April 1981. The main objectives were to determine tissue tolerance in terms of acute and late effects, and to estimate tumor clearance and survival rates. The total dose was 18.0 Gy given in weekly fractions of 3.0 Gy over 39 days. Four hours before each irradiation, 2.5 gm/m2 misonidazole was administered orally. Patients' ages ranged from 28-69 years. Karnofsky status for most patients was 80 or 90; the lowest grade was 60. The majority of patients had glioblastoma multiforms. Most were already on steroids prior to initiation of therapy. The median survival for the whole group was 12.0 months; 25% were alive at 18 months with some neurological compromise. The median survival remained unchanged for subgroups of patients with ages between 40-60 years and with Karnofsky performance status above 80. Among the 19 patients with glioblastoma multiforme, the median survival was 10 months. Acute toxicity was within tolerable limits. Details of toxicity and tissue analysis from post mortems and second craniotomy samples are presented.

Clinical evaluation of neutron beam therapy. Current results and prospects, 1983.

Some 9000 patients throughout the world have been treated by some form of neutron beam therapy. These include patients with advanced nonresectable tumors in many different sites treated with a variety of neutron beam generators varying widely in beam energy. Protocols were largely nonrandomized and included both mixed beam studies (neutrons + photons) and neutrons alone in varying doses. In spite of wide variation in equipment, treatment technique, and philosophy, some consistent trends have been identified: (1) in general, the neutron results have been at least as good as those of the photon controls measured in terms of local control, although the incidence of significant side effects have been higher; (2) in none of the randomized studies conducted so far, largely comprising epidermoid carcinomas of the head and neck, has a clear survival advantage for neutrons over photon controls been demonstrated at a statistically significant level; (3) results with mixed beam studies have been uniformly equivocal, with marginally significant differences in favor of the experimental groups compared with the photon controls; (4) adenocarcinomas of the gastrointestinal tract (GI) tract, including tumors of the salivary gland, pancreas, stomach, and bowel, appear to be responsive to high linear energy transfer (LET) radiation; (5) nonepidermoid, radioresistant tumors (sarcoma of bone and soft tissue and melanoma) yield a consistantly high local control rate, with neutron irradiation strikingly superior to those reported with photon therapy; and (6) in the central nervous system, both normal tissues and tumors appear to be exceptionally sensitive to neutron irradiation, therapeutic ratios are small, and the prospect of cure remains remote. It is concluded that neutrons are efficacious for certain specific tumor types, but that essentially new study designs, based on nonrandomized matched case comparisons, will be required to prove the merit of the new modality.

Absolute neutron dosimetry: effects of ionization chamber wall thickness.

To assess the effect of ionization chamber wall thickness on absolute neutron absorbed dose determinations, measurements were made of the charge collected by an A-150 tissue-equivalent plastic ionization chamber irradiated by a p(66)Be(49) neutron therapy beam as a function of chamber wall thickness both in air and in four different media: tissue-equivalent solution, water, motor oil, and glycerin. Wall thicknesses ranged from 1 to 31 mm, where isolation of the chamber gas volume from protons originating outside the chamber wall was assured. The in-air measurements compare favorably with earlier buildup measurements performed with an A-150 extrapolation chamber in an A-150 phantom. The in-phantom results may be explained if the effect of charged particles reaching the gas volume from the medium and the wall as well as the differences in neutron attenuation by the wall and the medium displaced by the wall are taken into account. The errors in absolute absorbed dose determination caused by ignoring the above processes are assessed.

Response of sarcomas of bone and of soft tissue to neutron beam therapy.

A total of 51 patients were treated at Fermilab for sarcoma of bone (25 patients) and soft tissue (26 patients). Neutrons were delivered in twice weekly fractions over 6-7 weeks to total doses between 18 and 26 Gy. Long-term local control (greater than 2 years) was achieved in 24 patients (47%). Overall local control rates were 44% in the bone sarcomas and 50% in the soft tissue tumors. Chondrosarcoma appeared relatively more responsive with 9 out of 16 (56%) controlled, compared to osteogenic sarcoma with 2 out of 9 (22%) controlled. Among the soft tissue tumors, liposarcoma (5/7 controlled) and neurogenic sarcoma (3/3 controlled) appear to be more responsive than other tumors. The overall survival rate was 40% in the entire series. These results are comparable with international experience in neutron therapy of sarcomas of bone and soft tissues. Out of 263 soft tissue sarcomas treated with neutrons only to full dosage throughout the world, 152 (58%) were locally controlled. Similarly out of 74 sarcomas of bone so treated, 44 (60%) were controlled.

Response of epidermoid and non-epidermoid cancers of the head and neck to fast neutron irradiation: the Fermilab experience.

One hundred and six patients with locally advanced cancers of the head and neck were treated with neutrons at the Fermilab Neutron Therapy Facility. Of these, 44 patients were previously untreated, 33 were recurrent following attempted surgery and 29 patients had previously received a full course of radiation therapy with conventional radiation. Results were analyzed to study the influence of stage, previous management, site of origin and tumor histology on local control of the disease. The most significant factor determining the outcome in this series of patients is the histological type. For epidermoid carcinoma, long term local control was achieved in 17/35 patients (49%) in the previously unirradiated group. With non-epidermoid tumors (adenocarcinoma, cylindroma, muco-epidermoid carcinoma), the local control rate was 28/39 (72%). Disease-free survival analysis also shows a survival advantage in non-epidermoid lesions treated with neutrons. It is concluded that neutron beam therapy may probably be the treatment of choice for non-resectable or recurrent non-epidermoid cancers of the head and neck and requires a clinical trial to establish this observation.

Analysis of personnel exposures in neutron therapy facilities.

In conventional radiation-therapy facilities, radiation doses to medical personnel originate from the leakage radiation of 60Co teletherapy systems or from photoneutrons produced during the operation of x-ray generators at energies over 10 MeV in unsuitably shielded therapy rooms. In neutron-therapy facilities, during patient set-ups and position verifications, medical personnel are exposed to photons from remanent radioactivity induced in the shielding around the neutron-producing targets and in the beam collimators. At Fermilab, the use of an elevating platform limits personnel exposure periods to those times when collimators are being exchanged. Comparisons with other facilities are shown.

Activation of the major constituents of tissue and air by a fast neutron radiation therapy beam.

The production of 11C, 13N, 15O from C, N, O, and of 39Cl and 41Ar from Ar by a p(66)Be(49) clinical neutron therapy beam has been measured. The results of these measurements were used to estimate the production of other radionuclides, then to estimate airborne radioactivity in a typical neutron therapy room and radioactivity induced in body tissues during treatment. Only under special circumstances would airborne radioactivity necessitate a waiting period before entering a typical treatment room. The additional dose to a treatment volume due to decay products from radioactivity induced within that volume would amount to a few thousandths of the given dose and the additional body dose outside the treated volume would be a few millionths of the given dose.

Kermas for various substances averaged over the energy spectra of fast neutron therapy beams: a study in uncertainties.

Kermas for various substances averaged over the energy spectra of fast neutron therapy beams, as well as ratios of average kermas relative to muscle, were calculated in an attempt to estimate the uncertainties introduced in these quantities by the poor knowledge of the elemental kerma functions, actual neutron energy spectra, and composition of tissues and other materials. Average kermas have uncertainties of the order of 7%-25%, while for ratios of average kermas the uncertainties are of the order of 2%-5% for materials of clinical interest. It is concluded that the ratio of average kerma of muscle to A-150 tissue-equivalent plastic should be 0.93 +/- 0.03 for the new p + Be clinical neutron beams.

A new look at displacement factor and point of measurement corrections in ionization chamber dosimetry.

A new technique is presented for determination of the effective point of measurement when cavity ionization chambers are used to measure the absorbed dose due to ionizing radiation in a dense medium. An algorithm is derived relating the effective point of measurement to the displacement correction factor. This algorithm relates variations of the displacement factor to the radiation field gradient. The technique is applied to derive the magnitudes of the corrections for several chambers in a p(66)Be(49) neutron therapy beam.

Characteristics of A-150 plastic-equivalent gas in A-150 plastic ionization chambers for p(66)Be(49) neutrons.

The evaluation of a gas mixture having an atomic composition similar to that of A-150 tissue-equivalent (TE) plastic has been extended to a high-energy neutron therapy beam. "A-150" gas, air, and methane-based TE gas were each flowed through A-150 plastic-walled ion chambers of different sizes and irradiated with p(66)Be(49) neutrons. A tentative value for W(A-150) of 27.3 +/- 0.5 JC-1 was derived for this beam. The W value of the A-150 gas mixture is compared to those of methane-based TE gas and of air for the p(66)Be(49) neutron beam as well as to corresponding values found in similar experiments using 14.8-MeV monoenergetic neutrons.