Killing cancer cells in a laboratory environment is considerably easier than curing a malignant tumour situated within or close to essential organs and tissues of the body, which can be seriously harmed by collateral radiation effects. In the context of future radiotherapy developments, particularly the use of proton and ion-beam therapy, this tale is highly relevant.

The saga began with the finding that neutrons inflict much greater biological damage than the same dose of 250 keV X-rays. The difference can be quantified by the relative biological effect (RBE), defined as the ratio of the doses of two forms of radiation required to produce the same biological effect. Fast-neutron RBE values of 1.5 to 5 were found in many biological systems, including bacteria, plants and transplanted animal cancers.

The immediate inference from this finding was that neutrons would be ideal for cancer therapy. Yet the first human experiments in the US showed severe toxicity because the relationship between the exposure dose and RBE was not yet known. Further interest arose upon the discovery that high-linear-energy-transfer (LET) radiation, such as fast neutrons, with increased ionization events along micron distances of their tracks, are less dependent than X-rays upon the presence of oxygen to produce cell death.

Many cancers contain zones of very low oxygen tension, which are considered an important cause of radio-resistance. High-pressure oxygen was tested as a means to overcome this problem, but this required patients to be placed within compression tanks. An attractive alternative was the use of cyclotrons to accelerate protons to around 20 MeV or higher and then bombard them onto beryllium targets to produce fast neutrons with high-LET properties.

Trial and error
During the 1970s and 80s, the Medical Research Council in the UK funded three important projects investigating neutron therapy. Firstly, at Hammersmith Hospital in London, clinical studies were conducted using a fixed horizontal beam with relatively poor tissue penetration. However, despite clear evidence that neutron RBE is inversely related to dose-per-fraction in a wide variety of animal tissues, the clinical dose prescriptions used a constant RBE. Thus the dose plan took no account of the increased RBE in normal tissues receiving doses lower than those prescribed to the tumour.

Attempts at randomized trials involved control patients treated with X-rays or cobalt beams at other hospitals. However, no control protocol was specified, resulting in an inappropriately wide variation in applied dose. Much was learned about how to conduct cancer trials properly.

Researchers at the Western General Hospital in Edinburgh carried out stricter in-house randomized trials comparing megavoltage X-rays (with superior tissue penetration) and relatively poorly penetrating fast neutrons. For both radiation classes the beams could be rotated on a gantry. However, the neutron tumour-control rates were disappointing and were accompanied by enhanced normal-tissue toxicity.

Finally, randomized trials at Clatterbridge Hospital in the Wirral, some of which were jointly undertaken with the University of Washington (Seattle, WA), showed that neutrons conferred no clinical advantage.1,2 These studies used an extended fast-neutron energy (obtained using 64 MeV protons) that produced neutron depth-dose distributions equivalent to 5 MeV X-rays.

In other countries, therapy with relatively low-energy neutrons had been tried without recourse to formal comparative trials, and with little convincing success. One small randomized trial showed the benefits of neutrons in controlling unresectable cancers of the parotid gland,3 although it is possible that a higher dose of X-rays or electrons in the control arm might have produced the same result.

Relatively superficial air sinus cancers were also thought to be better controlled, although there was always concern that neutrons were particularly damaging to the tissues of the underlying brain, where the RBE is around 5 rather than 3. In retrospect, neutron therapy failed for the following reasons:

• Computations of absorbed dose did not include additional neutron capture in hydrogen-rich tissues, which results in higher energy release in hydrogen-rich tissues. Such tissues include white matter in the brain and the fat that surrounds most important organs, which is closely associated with their blood supply.
• The well-established finding that RBE varies in different tissues was dismissed, along with the important fact that RBE increases with falling dose, which mitigates the effect of a reduction in physical dose beyond the region of cancer.
• The fact that RBE also varies with cell proliferation rate, so that slow-growing cells have higher values, was not appreciated. It is the slow-growing cells that make up the majority of normal tissue and which contribute to severe tissue damage at extended time periods after irradiation.

Recent mathematical modelling that includes RBE effects shows that neutron therapy would only have worked well for very superficial, slow-growing cancers with little normal tissue coverage,4 as is the case for the parotid gland. There now remain very few advocates for fast-neutron therapy in the world, although there is some promise for boron neutron capture therapy (BNCT).

BNCT is a complex binary therapy that involves low-dose exposure to thermal or epithermal neutrons. Neutrons of such energies are selectively captured by boron-labelled bio-molecules administered to the patient and taken up by rapidly growing tumour cells. When a boron atom absorbs a neutron, the reaction creates more intense localized ionization by generating an alpha particle and a lithium ion, which have tissue ranges of around 10 µm (around one cell diameter).

Some pilot studies using BNCT show promise in treating highly malignant forms of brain tumours, either as a boost with conventional treatment or for recurrent tumours. Nuclear reactors have been used as the neutron source, but there is increasing interest in specifically designed or modified accelerators.

Charged particles
Following the fast-neutron cancer trials, the UK funding authorities decided not to invest in further ambitious radiation projects, resulting in a decline in radiotherapy research and scepticism of high-LET radiotherapy. In other countries, more progress has been achieved with charged particle therapy (CPT) using protons or light ions, again produced from cyclotrons or synchrotrons.

Protons of over 60 MeV have an RBE that's only slightly higher (by about 10%) than megavoltage X-rays, whereas carbon ions have an RBE value of around 3, similar to that of neutrons. The big advantage of CPT, however, is that as these charged particles traverse through tissue they initially deposit energy at a low LET, followed by a sharp increase to high-LET deposition at the Bragg peak. The tissue depth of this peak can be tailored to each treatment.

At distances beyond the target, there is little or no charged-particle dose, whereas X-rays and neutron beams pass through the entire body thickness. In this way, CPT reduces the total energy deposited in a patient by a factor of between two and 10, depending on location. Because of this superior dose distribution, which allows dose escalation and/or normal-tissue dose reduction to a wider volume of tissue than X-rays, CPT is likely to be more effective than X-ray therapy.

There can be no complacency about X-ray-based radiotherapy, as some patients continue to develop severe, chronic and debilitating side effects following such treatment. But it's important that the mistakes made with neutrons are not repeated with CPT. New forms of radiotherapy need to be tested in high-quality centres, using the best input from physics, biology and medicine. The major radiotherapy research question over the next few decades will be whether carbon ions are superior to protons in specific cancers.5

Advances in understanding the molecular biology of cancer might allow more accurate, earlier diagnosis of cancer. Safe sterilization of small cancers by a few, or even single, exposures might then be possible using CPT. Further fundamental advances in particle physics, including matter-antimatter reactions, may yet provide even more selective forms of radiation therapy. Watch this space.

• See also Neutron capture targets the treatment, IMRT: for neutrons too, Proton therapy: practice makes perfect and Antiprotons are four times as potent on medicalphysicsweb.