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Protontherapy and heavy ion therapy offer bespoke treatment of tumours


21 July, 2010  

New radiotherapy devices using protons and ions can target tumours precisely and match the shape of rays to the tumour’s mass without harming surrounding tissue, making them ideal for use on children and on head and neck cancers

Andrzej Kacperek
PhD, FIPEM

Douglas Cyclotron
Clatterbridge Centre for Oncology Wirral, UK

The peculiarity of the Bragg peak phenomenon in the radiotherapy field is now well known. Heavier charged particles, such as protons, deposit their energy gradually with increasing penetration in tissue; this reaches a maximum in ionisation, at maximum penetration, when proton energy is virtually zero, hence the renowned Bragg peak (fig.1) with sharp distal
fall-off.

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Unlike conventional radiation beams (fig.1), proton beams can be adjusted to a prescribed depth in tissue, either by fixed-energy absorbers or accelerator adjustment. Furthermore, by means of ‘modulating’ the energy of the monoenergetic
proton beam, a spread-out Bragg peak (SOBP) is created, to envelope a tumour within a constant dose volume (fig.2 overleaf), thus proton beams can be termed a ‘bespoke’  radiation.
While high-energy photons offer important ‘skin sparing’ where maximum dose appears below the skin surface, proton SOBPs can demonstrate significant anterior dose volume sparing.
X-ray beam techniques have now achieved much more tumour conformality, combining gantry beams with multi-leaf  collimation (intensity modulated radiation therapy, IMRT), with image guidance and dose verification techniques such as electronic portal imaging devices (EPID), in addition to rapidly exploiting the potential of physiological gating of the beam. However, the use of multiple X-ray beams to reduce high doses
to normal tissue generally results in lower doses but spread over a larger volume of normal tissue; this is termed integral dose.
As shown in Figure 2, a modulated clinical proton beams can offer significant sparing in the tissue volume anterior to the tumour, with no dose ‘behind’ the tumour. The range and modulation depth are determined from the treatment planning  system with appropriate safety margins. The anterior sparing effect is particularly advantageous when using multi-directional proton beams – whether by a rotating gantry or patient positioning – in reducing integral dose compared with conventional radiation techniques. Generally, this has permitted higher tumourcidal doses, thus better local tumour control, while reducing dose to critical organs and normal tissue.[10]

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There are two main types of ion beam delivery: firstly, passive-scattered beams in which foils are used to produce a homogeneous beam (similar to electron beams in Linacs), which is then collimated (machined brass or multi-leaf collimation) to produce the prescribed field shape; a depth compensator is also used to conform the depth-dose to the distal (back-edge) shape of the tumour. However, some anterior volumes may receive full dose and there are considerations of neutron contamination of the beam.[9]
Secondly, a ‘pencil’ beam of protons, or ions may be scanned, by fast-acting magnets, to produce a dose plane of required area; changing the energy of the pencil beam adds another dose plane or ‘slice’. Thus, a true 3-dimensional dose distribution can be produced which delivers full dose only to the tumour volume. While quite complex to plan, verify and deliver, this technique does not require the use of collimators and has been shown to be very effective in treating irregular-shaped tumours. Work at the Paul Scherrer Institute (PSI) in Villingen, Switzerland, has shown that this method of beam delivery affords a reduction of integral dose between 2-5 times less than advanced X-ray Linac treatments, depending on clinical case.

Brief history
The use of proton beams for treatment of large tumours was developed at Uppsala, Sweden, using modulation of the Bragg peak to obtain a uniform dose over the tumour volume, in depth. Further developments in proton stereotactic and fractionated proton treatment of tumours, including eye tumours, took place at the Harvard Cyclotron Laboratory (HCL) between 1961 and 2002. The development of 3-D treatment with first CT and then MRI cemented the progress of protontherapy in better localising the tumour volume, especially adjacent to critical organs, and significantly minimising normal tissue dose.
Initially, ion therapy facilities were located in existing nuclear physics laboratories such as Berkeley, HCL, Tsukuba and PSI. Low-energy proton facilities were built in for combination with neutrontherapy such as Louvain, CAL (Nice) and at  Clatterbridge (UK); the latter was the first hospital-based proton service, albeit only for eye tumours.
At Loma Linda (LLUMC) in California, the first purpose-built protontherapy centre, with three gantry rooms, was opened in 1990. The use of 360º gantries is ubiquitous in Linac X-ray therapy. Steering ion beams through gantries is technically
very demanding, but is also fundamental in optimising the benefits of proton beams, particularly in clinical demanding cases. A further important development step in improving dose conformality to a tumour came with the commissioning of spot-scanning beam delivery in a gantry, at PSI (Villigen) in 1996.
The following year at GSI (Darmstadt), a raster-scanning of carbon ions commenced for clinical research, albeit with fixed beam-line. Both centres represent the world’s largest clinical
experience with this form of beam delivery. They have been followed by commercially constructed systems, at MDA (Houston) and the Rinecker PTC (Munich). The newly opened HIT (Heidelberg Ion Therapy) facility offers clinical research with a gantry and two fixed-beam treatment rooms, but with the additional capability of accelerating ions from protons to oxygen. In fact, Germany will boast four multi-treatment room proton/ion centres – Marburg, Essen and Kiel, in addition to proton eye therapy in Berlin. Japan has embraced ion beam therapy since 1994, with the fixed-beam carbon ion system at NIRS (Chiba); there are now eight ion-therapy centres, three of which treat with carbon beams.
Treatment planning studies between the best linear  accelerator-based X-ray radiotherapy (such as IMRT) and proton beams are being used by clinical research centres such as PSI to demonstrate potential improvements in terms of tumour coverage, dose to critical organs and integral non-tumour dose.
While Linac X-ray therapy has progressed particularly with IMRT and gating techniques, the PSI group has pioneered ‘intensity modulated’ protontherapy (IMPT) with their spot-scanning
beam delivery. Narrow proton beams of irregular intensity are used to envelope the tumour volume with a uniform dose while reducing dose to adjacent critical organs, as in the case brain or spinal tumours. Future development is aimed at reducing further the spot diameter below 3mm, and also the speed of scanning, which would allow ‘repainting’ of a treatment volume.
The principal advantage of proton beams lies in their physical conformity – radiobiological effect of protons is only slightly more elevated than MV photons, and the relative biological
effectiveness (RBE) compared to photons has been designated a generic value of 1.1 based on clinical and experimental data.[11] Proton dose is delivered by ionisation along individual particle tracks; this ionisation density increases with decreasing energy, attaining a maximum in the Bragg peak region. This has been shown to result in an elevated biological effect towards the end of range; some of which may be due partially to beamline design.
No effect on clinical outcomes has been observed, however international protocols recommend radiobiological  characterisation when commissioning protontherapy. Carbon ion tracks have far greater ionisation intensity due to a greater charge; this is reflected in the RBE of carbon beams which depends on tumour type and ion energy, but is assumed to be 3.0. Thus carbon ion beams have the theoretical advantage
of high biological effect, similar to neutrons, and excellent physical conformity. Clinical research centres in Japan and Germany are in the process of testing the promise of these advantages.

The UK situation:
The situation in the UK towards the development of high-energy protontherapy has been ambivalent in the past decades. Effort was concentrated on neutrontherapy to address radioresistant tumours, and more generally, the need to improve standards and access to conventional radiotherapy services, which were perceived to be lagging those in Europe. However, the pressure for high-energy ion therapy provision has increased, from several quarters: the success of the long standing low-energy proton service at Clatterbridge, the increasing debate in the literature, [3,4,5] an informed public, the increase in planned facilities in the USA and Europe, and not least, an increasing number of UK patients being treated in France, and in the USA.
Arguments still persist that published evidence for improved results in terms of tumour control and side-effects still remains sparse,[7] in  spite of the obvious advantages in isodose distribution. However, the eminent oncologist Herman Suit has pointed out that, in the past, randomised trials have not been performed to demonstrate the advantage of Co-60 units over 250kV X-ray beams, or in fact the advantage of high-energy
linear accelerators over cobalt units.[6]
In 2006, the National Radiotherapy Advisory Group reported to the Department of Health (DoH) on the improvements in  standards of radiotherapy required in the UK, which included a subgroup on Proton Therapy group. This recommended the need of two high-energy protontherapy facilities in England with a national referral pattern, reflecting the expected number of patients with the accepted clinical indications. It stated that the physical dose advantages of proton beams represented an improvement over the best X-ray therapy treatment for paediatric, skull-base and other clinically demanding cases. It also noted the benefit of protontherapy in reducing the risk of secondary tumour induction particularly in paediatric cases. In addition, a Proton Therapy Reference Panel was set-up to review high priority patients for possible referral to proton centres abroad, to provide fairer and more equitable access.
However, the rate of referrals has increased, far outstripping available funding; there were difficulties in integrating treatment pathways and with the limited capacity at centres abroad. In 2009, the DoH issued a ‘Framework for the Development of Proton Beam Therapy Services’ which outlined the requirements for protontherapy service provision. A particular aim was to address the treatment of 1,600 high-priority patients a year. Such a throughput is unlikely to be met by a single, multi-room centre even working extended shift patterns. Thus two or more national centres may be preferred, geographically sited to serve the main population centres of UK. Nine UK cancer centres have expressed their interest to the
DoH in bidding for a protontherapy centre.

The future
Well over 70,000 patients have been treated by proton and other ion beams. There are now 30 operating particle therapy centres worldwide – including four offering carbon beam therapy – however the majority are not hospital-based. The rapid expansion of clinical protontherapy facilities in Europe may have several important effects. Firstly, the increase in treatment experience, the refinement of existing indications[2] and increased patient indications, will contribute to improved patient
outcomes, particularly compared with improving X-ray techniques. Secondly, this expansion may encourage greater academic and industrial interest in this form of radiation therapy.
More compact, lower-cost methods of accelerating protons to high clinical proton energies are being developed; either cyclotron methods with high-field superconducting magnets (Still Rivers Inc, USA) or the fixed-field alternating gradient (FFAG) accelerators, and non-cyclotron methods such as high-intensity laser-induced particle beams and high-field dielectric wall accelerators. These may represent an expansion in the decades ahead into many more tertiary radiotherapy
centres, if the promise of proton and ion conformal therapy is realised in the present generation of large, multi-room therapy facilities. In the next five years, the UK may see the commissioning of one or even two new protontherapy treatment centres, reflecting the need to improve clinical outcomes in high-priority clinical cases, particularly in paediatric radiotherapy. 

References
1. PTCOG (Particle Therapy Cooperative Group) website, http://ptcog.web.psi.ch/
2. ‘Proton Treatment for Cancer’, A Report for the National Radiotherapy Advisory Group (NRAG), April 2006. www.cancer.nhs.uk/nrag.htm.
3. B. Jones and N. Burnet, BMJ 2005;330:979-80.
4. Munro AJ. Editorial – ‘Particle Matters’. Br J Radiol 2006;79:276–7.
5. Taylor R.E. Correspondence – ‘Particle Matters?’ Br J Radiol 2006;79:850-57.
6. Interview with H Suit MD. Community Oncology, October 2007. www.communityoncology.net/journal/articles/0410586.pdf.
7. Olsen D, Bruland Ø, Frykholm G, Norderhaug I. Radiotherapy and Oncology 2007;83(2):123-32.
8. Steneker M, Lomax A and Schneider U. Radiotherapy and Oncology 80;2:263-67.
9. Baumert BG, Lomax AJ, Miltchev V, Davis JB. Int. J. Radiat. Oncol. Biol. Phys. 2001;49(5):1439-49.
9. Miralbell R, Lomax A, Cella L,Schneider U. Int. J. Radiat. Oncol. Biol. & Physics 2002;54(3):824-9.
10. Schulz-Ertner D, Tsujii H. J. Clin. Oncol. 2007;25:953-64. Review.
11. Paganetti H, Niemierko A et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int.
J. Radiat. Oncol. Biol. & Physics 53;2: 407-21.