FAST NEUTRON THERAPY
Cures for the Incurable

Dan T L Jones

Head : Medical Radiation Group
National Accelerator Centre, Old Cape Road
P O Box 72, Faure 7131, South Africa

email : jones@nac.ac.za

1. Cancer Incidence and Treatment

Cancer can broadly be defined as the uncontrolled growth and proliferation of groups of cells, the triggering of which is not yet fully understood. In industrialised societies about 30% of people suffer from cancer and about half of these die from the disease. More than half of all cancer sufferers receive radiation therapy (possibly in conjunction with surgery and chemotherapy). The prognosis in individual cases varies greatly and depends on tumour type, stage of diagnosis, general health of the patient, etc. A patient who survives for 5 years after commencement of treatment without further symptoms is regarded as having been cured. The overall 5-year survival rate of all treated cancer sufferers is about 45%.

Cells from the primary tumour can metastasize (spread to other parts of the body) and about 30% of all cancer patients have metastases at diagnosis. Radiotherapy and surgery are both localised forms of treatment. They are used, alone or in combination, to treat the primary tumour and are responsible for about 90% of cancer cures (50% surgery, 40% radiotherapy alone or combined with surgery). In addition, radiotherapy - even at moderate doses - is particularly effective for palliative treatment of metastases, especially for pain relief. Chemotherapy is used to treat metastases and the 5-year survival rate is about 5% (about 10% of all cures).

From the above statistics it is clear that even modest improvements in cancer treatment will benefit a large number of people. A very important factor to also consider when assessing the cost-benefit of cancer treatment is the cost of not curing a patient.

This can be very high and may involve risky salvage surgery, chronic health care costs, and other costs. These costs may be as much as 4-5 times the cost of curing a patient.

2. Radiation Therapy

The objective of radiation therapy is to maximise the effect of the radiation on the target lesion and to minimise the effect on surrounding normal tissue. This is done by increasing either the physical dose differential or the biological effect differential between the target and normal tissue. This requires accurate lesion delineation, proper treatment planning, precise patient positioning and other factors.

Radiation is usually not administered in a large single dose (except in special circumstances) but is divided into several treatment sessions or fractions (up to 30 or more, depending on the condition being treated and the modality used). This technique allows normal healthy cells which suffer sublethal damage (i.e. they sustain some damage but are not killed) in the previous session to repair and recover, while the unhealthy cancer cells are unable to recover during this period. The dose limiting factor in radiation therapy is the amount of damage which normal tissue can sustain.

Radiation therapy machines are expensive, high technology equipment, but a sterile environment is not required; few people are involved in patient treatment, which does not necessarily require the daily presence of a radiation oncologist or any other clinician; most patients are treated as out-patients and therefore do not occupy scarce and expensive hospital beds; irradiation is not traumatic for patients, who are not normally anaesthetized (except possibly in the case of small children) and usually do not get sick from the treatment; there is little after-care and usually no expensive intensive care or extended hospitalisation are necessary. Radiation therapy is therefore cost-effective and often cheaper than the alternatives of surgery, chemotherapy or health care for the chronically ill.

3. Rationales for Neutron Therapy

The biological effects of different radiations depend not only on the dose delivered, but also on the microscopic dose distribution which is expressed in terms of LET (linear energy transfer). Densely ionizing radiations such as neutrons, pions and heavy ions are high-LET radiations while photons, electrons and high-energy protons are low-LET radiations. The higher the LET, the greater the biological effect of a given type of radiation. The lower the energy of a particular radiation the higher is its LET and therefore its biological effect.

For a given physical dose high-LET radiations are more efficient at killing cells than low-LET radiations. This is quantified in terms of the rbe (relative biological effectiveness) which is defined as the ratio of the dose of a reference radiation (usually 60Co) required to produce a specified biological effect to the dose of the given radiation required to produce the same effect (Fig. 1). With low-let radiations a larger proportion of cells suffer sublethal (repairable) damage than with high-let radiations, where the damage is largely irreparable.

One of the main rationales for high-LET therapy lies in the so-called oxygen effect. Because the rapidly proliferating tumour cells can reduce the blood supply to the centre of large tumours, the cells in this region can become deprived of oxygen. Cells which lack oxygen are resistant to low-LET radiations (photons and electrons) but are much less resistant to high-LET radiations which therefore have a better chance of effecting a cure. The oxygen effect is quantified in terms of the OER (oxygen enhancement ratio) which is defined as the ratio of the dose of radiation required to produce a specified biological effect under anoxic conditions to the dose required to produce the same effect under well-oxygenerated (aerated) conditions (Fig. 1).

Fig. 1 : Typical survival curves for cells irradiated in ⁶⁰Co and fast neutron
beams under well-oxygenerated (exposed to air) and anoxic conditions.
RBE and OER values are given at the survival level illustrated (1 Gray = 100 rads)

Another important reason for using these radiations concerns the cell cycle effect. Cells are most sensitive to radiation in the mitotic (dividing) phase of the cell cycle. However, they are relatively tolerant in the S (DNA synthesising) phase, and since slowly growing tumours contain a larger proportion of cells in this phase at any given time these tumours are resistant to conventional radiations. The variation in radio-sensitivity between cells in different stages of the cell cycle is much less for fast neutrons and other high-LET radiations (Fig. 2) which are therefore generally used for treating large, slow-growing or radioresistant tumours.

Fig. 2 : Typical survival curves for synchronised cells irradiated in⁶⁰Co
and fast neutron beams at three different positions in the cell cycle :
mitosis, late G1/early S, mid to late S phase.
The magnitude of the cell cycle-dependent variations in radiosensitivity is
about a factor of 4 less for neutrons in this case (1 Gray = 100 rads)

The physical characteristics of high-energy fast neutron beams are similar to those of high-energy x-ray beams (Figs. 3,4). A RBE value of about 3 is typically used for clinical fast neutron beams.

Fig. 3 : Depth dose curves for a p(66)+Be neutron therapy
beam compared with other radiotherapy beams

Fig. 4 : Isodose curves for a p(66)+Be neutron therapy beam (right)
compared with a typical 8 MV x-ray beam (left)

An additional advantage of fast neutron therapy lies in the fact that fractionation schedules are not as critical as with low-LET radiations. Neutron therapy can be delivered in a fewer number of fractions and therefore patient distress is reduced and patient throughput can be increased, resulting in more cost-effective treatments.

4. Historical Aspects

The story of neutron therapy began with the construction by Ernest Lawrence and his associates of the first cyclotrons at Berkeley in the early 1930s. Shortly after the discovery of the neutron by Chadwick in 1932 at the Cavendish Laboratory in Cambridge, Ernest and his brother John Lawrence (a physician) along with their co-workers at Berkeley were experimenting with the effects of fast neutrons on biological systems. In a remarkable paper in 1936, Locher postulated on the therapeutic possibilities of both fast and slow (by means of the thermal neutron capture process). On the 26 September 1938, the first patients were treated with neutrons on the 37 inch cyclotron at Berkeley. The neutrons were produced in the reaction of 8 MeV deuterons on a beryllium target [designated d(8)+Be]. Single fractions only were administered. This pilot study on 24 patients was regarded as most successful and led to the construction of the dedicated 60-inch Crocker Medical Cyclotron. A total of 226 patients were given fractionated treatments with neutrons [d(16)+Be] on this latter machine between 1939 and 1943, before the cyclotron was expropriated for the atomic bomb programme.

Although some remarkable cures were obtained, many patients suffered severe side effects and neutron therapy fell into disrepute. Later analyses of the treatments showed that the increase in RBE when fractionated treatments are given was not taken into account as the effect was not known at the time. Only after extensive radiobiological investigations of the effects of neutrons was neutron therapy started again in the mid-1960s at Hammersmith Hospital, London, and later at many other centres.

The most common accelerators currently used to produce neutron therapy beams are cyclotrons although a few electrostatic generators, linear accelerators and reactors have been used. Many of the early fast neutron therapy facilities were closed because of several factors: the physical beam properties were hopelessly inferior, the location of the facilities was inconvenient, beam configuration and collimation were inadequate or there were problems with patient accrual. Table 1 and Table 2 show existing low- and high-energy fast neutron therapy facilities respectively. The former have limited application because of inferior beam penetration.

As mentioned above high-LET radiations are most effective for treating large, slow growing or radiation resistant tumours such as those of the salivary gland, paranasal sinus, head and neck, prostate, bone and breast; soft tissue sarcoma, uterine sarcoma and melanoma. To date more than 20,000 patients are estimated to have been treated with fast neutrons.

For fast neutron therapy, the reactions d+T, d+Be and p+Be are used. Neutrons from the d+T reaction have inferior properties in terms of beam penetration, lateral penumbra and dose rate and this reaction is currently used at only a few centres. For modern high energy facilities, the p+Be reaction is preferred (except for the Detroit d + Be facility ), since the same machine can accelerate protons to twice the energy of deuterons and thus provide more penetrating beams.

Although some fixed beam arrangements are still used, isocentric facilities are desirable. Nevertheless, with a versatile patient support system and good treatment planning, fixed beam facilities have given good clinical results for selected tumour types [eg. salivary gland, prostate, soft tissue sarcoma, bone sarcoma, paranasal sinus, adenocystic carcinoma, melanoma]. Flexible beam shaping (eg. multileaf and multirod collimators, multiblade trimmer) is desirable, but good dose conformation can be achieved with a variable rectangular collimator or fixed inserts if proper beam blocking is done. Sophisticated 3-dimensional treatment planning is essential.

6. National Accelerator Centre Faure, South Africa

Routine treatment began in 1989 on the neutron therapy unit. All the major facilities, with the exception of the neutron therapy unit, were locally designed. The main accelerator is a variable-energy separated-sector cyclotron, capable of accelerating protons to a maximum energy of 200 MeV. The medical complex includes three radiotherapy treatment vaults, a CT scanner, treatment planning stations, laboratories, offices, full medical physics and radiobiology facilities as well as a 30-bed on-site hospital. One of the treatment vaults contains the isocentric neutron therapy unit in which neutrons are produced by the reaction of 66 MeV protons on a thick beryllium target [p(66) +Be]. Neutron therapy is delivered in 3 fractions per week.

Most patients, including those from other parts of the country and from neighbouring territories, are referred to the NAC through one of the local university teaching hospitals, viz, Groote Schuur Hospital (University of Cape Town) or Tygerberg Hospital (University of Stellenbosch). Both hospitals are about 25 minutes by road from the NAC. Some private patients are also treated. Although many patients are housed in the on-site hospital for the duration of their treatments, others attend as out-patients.

The p(66)+Be neutron therapy facility incorporates an isocentric gantry (Fig. 5) capable of ± 185° rotation. A rotating collimator (360°) with a continuously variable rectangular aperture provides field sizes between 5.5 cm x 5.5 cm and 29 cm x 29 cm at a source-to-axis distance of 150 cm.

Fig. 5 : NAC neutron therapy gantry

A manually-controlled moving floor permits full rotation of the gantry. Downstream of the target are, in order, a pair of steel flattening filters (for small and large fields respectively), three tungsten wedge filters and a 2.5 cm thick polyethylene hardening filter, which removes unwanted low energy neutrons from the beam. A multiblade trimmer (blocking system) has recently been installed on the collimator to provide more flexible shielding (Fig. 6). Neutron dose rates are typically about 0.50-0.60 Gy/min. A portal x-ray tube in the treatment head upstream of the collimator can be inserted on the beam axis and is used in conjunction with a neutron beam exposure for verification of the treatment field. The physical characteristics of the NAC neutron beam are rather similar to those of an 8 MV x-ray beam (Figs. 1, 2).

Fig. 6 : The multiblade trimmer attached to the NAC collimator assembly

In order to verify the dosimetry and treatment prescriptions, international radiobiological and national and international dosimetry intercomparisons have been undertaken. The results obtained were highly satisfactory, showing good agreement between participating centres. Several other radiobiological measurements have been made and the RBE (relative biological effectiveness) and OER (oxygen enhancement ratio) of the NAC's neutron therapy beam have been found to be similar to those measured at other high-energy p+Be neutron therapy facilities. The energy spectra of the neutron beams for various irradiation conditions have been measured in air using the pulsed beam time-of-flight technique and in phantom using recoil methods and agree well with Monte Carlo calculations.

Several clinical trials are currently being undertaken at NAC, including treatments of tumours of the head and neck, salivary gland and breast and treatments of soft tissue and bone sarcomas, uterine sarcomas, paranasal sinuses and mesotheliomas. The results of a pilot study of prostate treatments are presently being evaluated. A significant number of non-trial patients are also being treated (Table 3).