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.

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.

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.

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.

Characterization of a p(66)Be(49) neutron therapy beam II: skin-sparing and dose transition effects.

Results of buildup measurements in A-150 tissue equivalent plastic are presented for a p(66)Be(49) neutron beam. These measurements were taken in air and behind various materials to answer questions about skin-sparing, bolussing materials, recovery of skin-sparing, and dosimetry in small radiobiological samples. The depth for Dmax for this beam is 1.6 g cm-2. An algorithm is also presented that reproduces the measured dose buildup curves.

Characterization of a p(66)Be(49) neutron therapy beam I: central axis depth dose and off-axis ratios.

Results of measurements of central axis depth doses, off-axis ratios, and wedge filter effects are presented for a p(66)Be(49) neutron beam. All measurements were made and are reported in tissue equivalent solution. Algorithms that reproduce the various measured characteristics of the beam are also discussed.

Conceptual design of beryllium targets for the generation of neutron beams for radiation therapy by the (p,n) reaction.

A conceptual design is presented showing that, by judiciously choosing the beryllium target thickness and the backstop material, improvements can be achieved in dose-rate, skin sparing, and penetration of neutron beams generated by the same proton accelerator.

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.

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.

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.

The influence of target thickness and backstop material on proton-produced neutron beams for radiotherapy.

Results are presented of measurements of skin sparing, penetration and total dose per unit of incident charge for various target thicknesses and filtrations for a neutron beam generated by 42 MeV protons on beryllium. These results are contrasted to predictions outlined in a previous paper. The differences from these predictions are attributed to the contribution of low-energy neutrons produced by the residual proton beam in the thick copper target backstop.

p(42)Be neutron therapy beams: dose rate and penetration as a function of target thickness and beam filtration.

It is shown that, in the production of p(42)Be neutron beams for clinical use, the use of semithick targets leads to more desirable beam characteristics when appropriate backstop materials are used. Furthermore, an algebraic representation of beam penetration and of dose per unit charge on target, including hardening by polyethylene filters, provides a method for target optimization.

Physical characterization of neutron beams produced by protons and deuterons of various energies bombarding beryllium and lithium targets of several thicknesses.

Protons of 35 and 65 MeV and deuterons of 35 MeV were used to bombard beryllium and lithium targets of various thicknesses. Four types of experiments were conducted in order to characterize the neutron fields. They were (1) central axis depth-dose measurements in a water phantom, (2) dose buildup at small depths in tissue-equivalent plastic, (3) microdosimetric measurements and LET distributions, and (4) neutron yields and energy spectra at an angle of 0 deg. The results generally show that (a) the central axis depth doses for the 35 and 65 MeV particles roughly approximate those of 60Co and 4-MeV bremsstrahlung photons, respectively, (B) the neutron dose buildups are more rapid than those of the above-mentioned photon sources, (C) the microdosimetric spectra show differences which are consistent with the measured neutron energy spectra, and (D) P-Li compared to p-Be neutron spectra have larger high-energy particle flux for similar target and beam configurations.

Calorimetric and ionimetric dosimetry intercomparisons I: U.S. neutron radiotherapy centers.

In the U.S. neutron radiotherapy trial centers, absorbed dose is routinely measured using commercially available A-150 tissue equivalent (TE) plastic ionization chambers. The collecting volumes of these chambers are filled with either methane-based tissue equivalent gas or air. Absorbed dose in A-150 plastic, determined with these ionization chambers, was compared to that measured by an A-150 plastic calorimeter in an A-150 plastic phantom. These comparisons have yielded the following information: (1) Agreement of the total absorbed dose measured using the ionization chambers was within 2.5% of the calorimeter at all the centers visited to date. (2) For all the neutron fields measured, the product of the stopping power ratio (sw,g)N' between the A-150 plastic chamber wall and TE gas, and the average energy expended in the gas per ion pair formed, WN/e, was computed assuming Bragg-Gray theory and found to be 31.0 +/- 0.7 J/C. (3) The displacement correction factor employed to normalize measurements at a depth in a phantom using the type IC-17 ionization chamber was verified to be approximately 0.97 +/- 0.01.

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.

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%.

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.