Proton Beam Radiotherapy: Advancing Targeted Cancer Treatment So That It Doesn't Affect Non-Cancerous Cells

by Dr. Nick Plowman
28th Jul 2018

To the layman, if you discover a lump in your breast, prostate, lung or colon, then surgery (mastectomy, prostatectomy, lobectomy, colectomy) is the obvious treatment – cut it out! Whilst this is often the case for early disease, unfortunately, cancer tends to spread – cancer cells shed off and migrate around the body to grow at multiple body sites – this is the main threat to life in most cancers and surgery is not the solution.

Modern cancer therapy relies on chemotherapy (drugs that kill dividing cells), ‘smart’ drugs (targeting particular genetically mutated pathways specific to specific cancers), anti-hormonal therapy (particularly the frequently driven breast and prostate cancers) and immunotherapy (raising the body’s defence systems particularly for heavily mutated/antigenic cancers) – all four of which share the ability to target cancer wherever it is in the body. We refer to them as systemic therapies. If they were perfect, then there would be no need for surgery or radiotherapy. Unfortunately, they are not.

Apart from surgery, radiotherapy (RT) is the main alternative as ‘local’ therapy and, if the disease is caught early, sometimes it is preferable (e.g. for early larynx cancer – because it allows cure without loss of the voice box). It is also useful to consolidate the work of systemic therapy when one or two sites are not in remission after a systemic programme. RT consists of beams of high energy, ionising radiation which break bonds in DNA and thereby kill cells. Cross-firing beams allow concentration of the maximum deposition of energy on the cancer and avoid much normal tissue – collateral damage. So it’s easy to see why RT remains an important tool in cancer therapy.

Did you know? RT is usually given in lots of little daily doses (fractionation)? The rationale for this is that normal cells can raise their ‘repair game’ after sub-lethal dosages, whereas cancer cells have lost this homeostatic reflex. This allows some selectivity for RT on cancer cells (which in other respects may not be more sensitive to the lethal effects of RT than normal cells).

But is RT progressing as fast as other areas of Oncology?

At present, RT relies on high energy x-rays (photons). Now: everyone knows that, if your doctor requests a chest x-ray, then an x-ray beam (low energy) is shone from your back and it darkens an x-ray photographic plate placed against the front of your chest. The x-rays travel through a corridor of you to reach the other side being absorbed more by some structures (e.g. the ribs) than others (e.g. the lung) – hence the appearance on the film.

In radiotherapy, where we are using much higher voltage beams and perhaps dosages thousands higher than diagnostic x-rays, this corridor of dose to collateral normal tissues in unwanted and can be harmful. An objective of next generation RT is to avoid the low dose ‘bath’ of radiation that accompanies modern x-ray (photon) beam radiotherapy. Nowhere is this more important than in the field of childhood cancer where late growth impairment and induction of late second cancers is a real problem.

So what is the solution?

Enter Protons

Proton beam radiotherapy (PBT) does not create a corridor of dose through the patient and represents the most exciting new development in RT. As this charged particle beam enters the patient it starts to interact with the tissues and deposit ionising dose, which makes it slow down, which (interestingly) makes it more likely to interact further and deposit more dose, making it slow down further etc. etc. The consequence is that the dose is deposited at a depth (which can be controlled by varying the energy of the beam) and is concentrated heavily at the end of the proton beam’s range (called the Bragg peak) and there is no dose (as there is no further ‘beam’) deposited beyond that depth (Fig 1). The cancer is obviously placed within this Bragg peak range. So: little entry dose, then a heavy deposit of ionising energy at the target depth and no exit dose – it is the dream ticket for avoiding collateral dose/damage.

Fig 1. Plots of the deposition of ionising energy versus depth into the body. Note the low dose at entry of the proton beam (red) and absence of exit dose beyond the cancer/target. By contrast, the Xray beam (blue) gives a continuous deposition of dose through the uninvolved body.

For paediatric RT, this lack of potential collateral damage has been a game changer and the UK Government sends 150 selected children to the USA each year for this therapy at $100,000-130,000 per child, but adults would like this too! The problem with PBT to the present time has been that the cost has been circa ten times or more than that of Photon/x-ray RT. The UK Government has commissioned two PBT machines at a cost of £0.5 billion or more – to be placed in Manchester and London and hopefully will start treating patients by 2019-2020. The procurement of these two cyclotron based machines will have taken almost a decade from first decision to first clinical treatment – the problem is that, during this time, there have been advances in the subject that may allow better machines at lesser cost. Next generation machines, using linear accelerator (linac) technology, have been developed and will bring the cost of PBT down to much closer that of traditional RT.

Furthermore, the ability to conform the deposition of the high dose delivery more tightly to the confines of (often irregularly shaped) cancers and the faster delivery (with faster energy changes) make the linac based PBT look a potentially better form of PBT to cyclotron-based methods.

Whilst PBT may be approximately the same as x-ray/photon based RT in terms of killing cancer cells, the minimal collateral damage is a tremendous advantage and additionally may often allow the therapy team to escalate the dose to the cancer itself, increasing the cure rate. Once established, we foresee this method of RT supplanting traditional RT methods in all major RT departments across the world. It has a long way to go but in the fight to curing cancer, it’s an exciting time.

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