The Clinical Radiobiology of High LET Radiotherapy with Particular Reference to Proton Radiotherapy

Many countries throughout the world will soon possess high linear energy transfer (LET) charged particle radiotherapy facilities. These have the advantage of a superior dose distribution, due to the Bragg peak effect, when compared with conventional X-ray based radiotherapy of equal complexity in terms of field arrangements and treatment planning sophistication. This paper concentrates on the subtle effects caused by relative biological efficiency or effect (RBE) that can occur in the context of high LET therapy. Higher RBE values than those associated with protons are found with light ions, which also have the potential advantage of a reduced oxygen enhancement ratio. Clinicians should remember that although neutrons are high LET particles, they are uncharged and do not possess the dose localizing advantages of a Bragg peak. Radioresistance, from whatever cause, will be opposed by an increase in tumour dose. The sigmoidal shapes of radiation dose–response curves show that increasing the total dose will produce an enhanced tumour cure probability (TCP), but with diminishing returns at the very highest doses [1]. If the normal tissue receives the same dose as the tumour then normal tissue complications (NTCPs) also escalate. However, if tumour dose can be increased whilst normal tissue doses are simultaneously reduced we effectively follow the normal tissue curve downwards and to the left, and beneficially increase the cure:complication ratio. The ratio of cure:complication is a measure of the therapeutic ratio associated with a given treatment. The advantage of proton therapy stems from the extra tumour dose that can be delivered in association with a reduced dose to normal tissues [2]. Newer forms of X-ray therapy [e.g., intensity-modulated radiation therapy (IMRT) or X-ray IMRT (IMXT)] may also facilitate a similar degree of dose escalation, but proton dose distributions are usually better due to the absence of any dose beyond the Bragg peak. Proton IMRT techniques may also be used to further improve the dose distribution. Such progressive dose reduction in normal tissues should produce benefits to patients in terms of reduced low-grade, radiation-related morbidity, e.g., specific organ dysfunction related to stem cell depletion, reduced vascular function, fibrosis and a reduction in stochastic effects such as second malignancies. Both short- and long-term quality of life is expected to be superior in proton-irradiated patients than after X-ray therapy, although this difference needs to be measured in comparative studies. High LET Particle Radiobiology Charged particle beams have a higher LET and thus deposit more energy per unit length of beam than megavoltage X-rays [3]. The additional biological effect is quantified in terms of RBE, the ratio of the iso-effect dose for a high-LET radiation to that required with low-LET cobalt gamma rays or orthovoltage X-rays. RBE increases with LET until the phenomenon of overkill occurs.