Practical problems in neutron dosimetry.

The first problem discussed is the best phantom material. It is argued that tissue composition has a greater effect on dose distributions from photons than on those from neutrons. As water is normally used for photons, it should be satisfactory for neutrons, but checks are needed with high-energy neutron beams. Another serious problem is that of kerma ratios for neutrons above 20 MeV where highly discordant values have been calculated by several authors. Finally some suggestions are made about measurement of the gamma-ray component in beams of high-energy neutrons.

A comparison of clinical and laboratory data on neutron therapy for locally advanced tumors.

Experimental results suggest advantages for neutrons where cells are hypoxic, in tumors which are slowly growing and also in a relative sparing of bone damage. The neutrons available at Hammersmith were of 7.5 MeV energy and produced a poorly penetrating beam, unsuitable for treating tumors in the pelvis and abdomen. Patients with locally advanced tumors in superficial sites were therefore selected to assess the effects of neutrons on normal and malignant tissues. One hundred and eight-nine patients had between them 191 locally advanced (T4 N0-3) tumors in the oral cavity, paranasal sinuses, salivary glands, and breast. Neutron therapy resulted in complete regression in 84% of which 13% subsequently recurred. Median survival for the whole group was 32 months. Twenty-eight other patients had advanced tumors of the head and neck which were recurrent after X ray therapy and other treatments; 82% of these completely regressed for more than 1 year. Complications appeared in 27% of patients not previously treated and in 46% who had already undergone X ray therapy. Seventy-four per cent of complications started in the skin. With neutrons of this energy there is minimal sparing of the skin and uneven distribution of dose resulting in "hot" spots. These affected skin, subcutis, and muscle. The high rates of control in these large tumors, the low incidence of bone necrosis, and the repair of some bones eroded by tumor correlate well with the experimental data. There was rapid regression of the tumor and close correlation between early and late effects on skin and subcutis. These two observations may relate to the fractionation, total dose, and overall time of treatment of 1560 cGy neutron dose given in 12 fractions over 28 days.

Metabolic activity of sodium, measured by neutron activation, in the hands of patients suffering from bone diseases: concise communication.

Turnover of sodium in the human hand was studied by neutron activation. Patients suffering from various metabolic abnormalities affecting the skeleton, who were undergoing routine neutron activation for the measurement of calcium, were investigated along with a group of healthy volunteers. Neutron activation labels the sodium atoms simultaneously and with equal probability regardless of the turnover time of individual body compartments. The loss of sodium can be described either by a sum of two exponentials or by a single power function. Distinctions between patients and normal subjects were not apparent from the exponential model but were brought out by the power function. The exponent of time in the latter is a measure of clearance rate. The mean values of this parameter in (a) a group of patients suffering from acromegaly: (b) a group including Paget's disease, osteoporosis, Cushing's disease, and hyperparathyroidism; and (c) a group of healthy subjects, were found to be significantly different from each other.

Neutron-activation measurement of metabolic activity of sodium in the human hand.

Turnover of sodium in the human hand was studied by neutron activation. One hand of each subject was irradiated with a 1.5-rad dose of partially thermalized fast neutrons. The activity of 24Na was measured at intervals from 3 min to 48 hr after irradiation. The loss of sodium from the hand during this period can be described either by two exponentials or by a single power function. The latter description involves only two disposable factors compared with four in the former. The rate of loss of sodium was found, on the average, to be greater in patients suffering from bone disease than in normal subjects. Neutron activation is a powerful method for studying sodium turnover because the sodium atoms are labeled simultaneously and with equal probability, regardless of the turnover time of individual bodily compartments.

Fast neutrons in the treatment of locally advanced breast cancer.

The clinical investigation of fast neutrons at Hammersmith Hospital included 17 patients who between them had 20 T4 breast cancers. The majority of these tumours were ulcerated and all were painful. Ten had recurred after multiple other therapies. Complete local regression was achieved in all but one (95%) and no tumour recurred. Symptoms were relieved in all cases. Median survival was 26 months. Three patients developed small areas of skin necrosis following trauma of previous radiation. All the neutron treated breasts became fibrosed, but this was painless. Neutron treatment needed only 12 attendances over 28 days, in contrast to the best results from photon therapy which required 6-7 weeks followed by implant of radioactive wire and/or surgical excision. One patient who had bilateral tumours received neutrons to the left breast and X-ray therapy (photons) to the right. The photon treated tumour did not completely regress and recurred. The neutron treated one completely regressed and did not recur. Neutrons were also more effective than tamoxifen which causes complete regression in only about 30% of cases. It is suggested that neutron therapy is indicated for locally advanced tumours which do not respond to hormones. Since metastases were a common cause of death, there remains a need for an effective adjuvant treatment, acceptable to elderly patients.

Anthropomorphic models for checking the calibration of whole-body counters and activation analysis systems.

Three models of the human body have been made for checking the calibration of whole-body counters and activation analysis systems. Their weights are 41, 67 and 110 kg. Each contains simplified forms of lungs, bones, thyroid, kidneys and liver and has a chemical composition similar to that of the ICRP standard man. In addition traces of toxic elements such as Cd and Hg have been included in various organs. The composition of the manikins has been measured at four centres where activation analysis in vivo has been carried out. The potassium contents have been measured at three other centres. Differences between measured and actual contents have often been much larger than quoted uncertainties of the measurements, 20-50% for Na, Cl and P. For K, differences did not exceed 17% but are still often greater than the expected uncertainty. The greatest errors usually occurred with the smallest manikin.

X-ray emission analysis of human plasma by proton excitation of thick samples in air.

Thick plasma samples have been irradiated in air by 2.3 MeV protons for trace elemental analysis by proton-induced X-ray emission spectroscopy. Accurate calibration curves were obtained for Fe, Zn and Sr and detection limits in dry plasma were estimated to be 0.08 PPM for Fe, 0.065 PPM for Zn and 0.12 PPM for Sr. Low temperature ashing of these samples improved the detection limits by a factor of 3 but reduced the precision and resulted in loss of bromine from the plasma. Mass absorption coefficients for low energy X-rays in dry plasma were measured and X-ray attenuation in the sample was found to prevent the detection of trace elements with Z less than 26. The method was used to determine Sr in plasma from a patient with bone disease, the Sr being a non-radioactive bone-seeking tracer element. The results, which were in the 3--13 PPM range, were in good general agreement with the analysis of the same samples by flame photometry.

New neutron sources for radiotherapy.

All existing neutron sources suffer from disadvantages which would not be tolerated in modern megavoltage X-ray equipment. Experimental work with 30-60 MeV protons on beryllium and other elements has shown how these difficulties can to a large extent be overcome. Angular distributions and kerma rates as a function of proton energy are presented for various targets. Thin targets are found to be a better method than filtration for improving the penetration of the beam. A 237Np fission counter and a GM counter have been used to decompose stray radiation into its neutron and gamma-ray components. A model of a treatment head was found to attenuate the neutron component to less than 1% of its value in the useful beam.

Neutron beams from protons on beryllium.

Measurements of dose rate and penetration in water have been made for neutron beams produced by 30--75 MeV protons on beryllium. The effects of Polythene filters added on the target side of the collimator have also been studied. A neutron beam comparable with a photon beam from a 4--8 MeV linear accelerator can be produced with p/Be neutrons plus 5 cm Polythene filtrations, with protons in the range 50--75 MeV. This is a more economical method than use of the d/Be reaction.

The use of 10B to enhance the tumour dose in fast-neutron therapy.

Incorporation of 10B in tumours treated by fast-neutron therapy would increase the tumour dose via the reaction 10B(n, alpha)7Li which occurs with partially thermalised neutrons. The extent of the dose enhancement was measured for neutron beams with median energies of 2.4, 3.3, 7.0 and 9.0 MeV by two techniques: with a BF3 proportional counter in three beams and activation of 23Na in the fourth. The results obtained with the two techniques are in good agreement. The magnitude of the dose enhancement depends upon the depth, field size and neutron beam energy. The dose enhancement at a depth of 8 cm varied from 0.32% with the lowest-energy beam to 0.07% with the highest-energy beam for each microgram of 10B uptake per gram of tissue. The products of the reaction in 10B would, however, have an RBE about twice that of the fast-neutron dose in the absence of boron. The method may be useful if drugs providing adequate uptake of 10B can be synthesised.

The 8 MeV linear accelerator at the MRC Cyclotron Unit, Hammersmith Hospital, London.

This machine was the first linear accelerator designed for medical use and the first to be installed in a hospital. The first patient was treated in 1953 and the last in 1969. During this period the machine was used for research during the evenings and latterly it was available for research all day long. It was switched off for the last time in February 1984. In addition to the X-ray beam, electrons were used for treatment and for research, where the high dose rate and large field size were particularly useful. An account is given of some of the highlights of the clinical and research programmes.

On the nature and significance of the radiation outside the beam in neutron therapy.

Measurements have been made of beam profiles at 10 cm deep for the neutron beam of mean energy 7.5 MeV produced by the MRC cyclotron at Hammersmith Hospital. Neutron and gamma-ray doses in water were measured with a tissue-equivalent chamber and a Geiger-Müller counter. Far outside the beam the radiation consists mostly of gamma rays penetrating the shielding. Perfect shielding would reduce this but the profile of biologically effective dose would still be worse than that from conventional X- and gamma-ray generators owing to the high RBE of small doses of neutrons. The main hazard to the patient is probably that of carcinogenesis. An approximate assessment is made of this hazard which is compared with that estimated in previous publications.

The Clatterbridge high-energy neutron therapy facility: specification and performance.

A new high-energy neutron therapy facility has been installed at the Douglas Cyclotron Centre, Clatterbridge Hospital, Merseyside, in order to extend the clinical trials of fast neutrons initiated by the Medical Research Council. The neutron beam is produced by bombarding a beryllium target with 62 MeV protons. The target is isocentrically mounted with the potential for 360 degrees rotation and has a fully variable collimator. This gives a range of rectilinear field sizes from 5 cm x 5 cm to 30 cm x 30 cm. Basic neutron beam data including output, field flatness, penumbra and depth-dose data have been measured. For a 10 cm x 10 cm field, the 50% depth dose occurs at 16.2 cm in water and the output is 1.63 cGy microA-1 min-1 at the depth of dose maximum. The effectiveness of the target shielding and the neutron-induced radioactivity in the treatment head have also been measured. It is concluded that the equipment meets both the design specifications and also fully satisfies criticisms of earlier neutron therapy equipment. A full radiation survey of the centre was also carried out and it was found that radiation levels are low and present no significant hazard to staff.

Changes in relative biological effectiveness with depth of the Clatterbridge neutron therapy beam.

We have measured the biological equivalence of the Clatterbridge neutron therapy beam [p(62)-Be] and the Hammersmith neutron therapy beam [d(16)-Be] using the mouse intestinal crypt assay. The ratio (NDR) of Clatterbridge neutron (n + gamma) dose relative to Hammersmith neutron dose (n + gamma) was found to be 1.2-1.13 over a dose/fraction range of 1.8-9 Gy at 2 cm deep in a Perspex phantom. It is shown that the effectiveness of the Clatterbridge beam was reduced with penetration into the phantom because of hardening of the beam to a maximum reduction of 11% at 12 cm deep in the phantom. The hardening of the beam with depth of penetration will need to be taken into account by clinicians in assessing the tumour dose and tissue tolerance. Relative biological effectiveness values for the Clatterbridge and Hammersmith neutron beams were also measured. All neutron doses for both Hammersmith and Clatterbridge beams are total doses (n + gamma) which comply with the European protocol for neutron dosimetry and include the gamma-ray component of dose.

A comparison for use in radiotherapy of neutron beams generated with 16 and 42 MeV deuterons on beryllium.

The physical and radiobiological properties of two neutron beams have been compared. The beams were generated by deuterons of 16 MeV at Hammersmith Hospital and 42 MeV at Harwell, in both cases falling on a Be/Cu target. The dose-rate and depth-dose characteristics at the higher energy were found to be superior to those at the lower energy. Collimation and shielding at the higher energy are facilitated by the greater degree of forward-peaking and by the fact that a higher dose-rate allows longer collimators to be used. Attenuation in iron was found to be similar at the two energies. The radiobiological properties of the two neutron beams are very similar. There is a difference of about 20 per cent in RBE for effects on mammalian tissues for doses between 300 and 2,000 rad of neutrons. The OER and the sparing effect of two large fractions are the same for the two beams.

Changes in biological effectiveness of the neutron beam at Clatterbridge (62 MeV p on Be) measured with cells in vitro.

Chinese hamster V79 cells have been used to assess changes in RBE of the p(62)Be neutron beam at the Clatterbridge Hospital with depth in a phantom and with use of a hydrogenous filter. The cells were exposed at depths of 2 and 12 cm and at a depth of 2 cm with a hydrogenous filter. Two groups of experimenters each conducted two experiments. The ratios of relative biological effectiveness (RBE) at a depth of 12 cm to that at 2 cm were found by the two groups to be 0.99 +/- 0.04 and 0.96 +/- 0.02 (standard errors). The effect of a polythene filter 4.5 cm thick was measured at a depth of 2 cm and the ratio of RBE with and without the filter was found by both groups to be 0.99 +/- 0.02. All the experiments suggest that there may be small effects of beam hardening by depth and filtration but these results are in marked contrast with those obtained using an in vivo system.

Prospects for the application of fast neutrons in cancer therapy. Radiobiological bases and survey of the clinical data.

The rationale for introducing fast neutrons in therapy initially was a reduction in the Oxygen Enhancement Ratio (OER). The recent radiobiological developments indicate that, more generally, fast neutrons tend to reduce the difference in radiosensitivity between cell lines, or related to the degree of oxygenation (Oxygen Gain Factor), the position of the cells in the mitotic cycle (Kinetics Gain Factor), etc. The reduction of the differences in radiosensitivity brings a benefit for certain types of tumours (normally resistant to photons), but a disadvantage for other types of tumours (those which can currently be controlled by photon treatment). A review of the available clinical data is presented. The tumour types or sites for which a benefit has been observed are discussed: locally advanced tumours of the salivary glands, paranasal sinuses, some tumours of the head and neck area with metastatic lymph nodes, slowly growing, well differentiated soft tissue sarcomas, inoperable/recurrent melanomas, locally extended (C, D1) prostatic adenocarcinomas. Selection of the patients suitable for neutron therapy remains the main problem. Collaboration between neutron therapy centres is essential to accelerate the acquisition of sufficient clinical data needed in order to improve patient selection, as well as the optimum modality of application of fast neutrons.