Re: Is spending on proton beam therapy for cancer going too far, too fast?
Proton beam therapy for cancer: An important development for patients with an explicit research agenda
The Editor, BMJ
We were a disappointed with in the recent BMJ article by Epstein  concerning protons. Although some of the points were reasonable, the report nevertheless misrepresented the approach being used in this country.
The article correctly reports that proton radiotherapy has an important place in the management of childhood cancers requiring radiotherapy, and for the treatment of skull base and spinal tumours such as chordoma. For childhood cancers, the value is that proton beam therapy (PBT) delivers a lower dose to tissues around the tumour than is possible with X-ray techniques, resulting in less disturbance of growth  and a lower risk of second malignancy . For many children with brain tumours, PBT has been predicted to result in reduced impact on subsequent neuropsychological and IQ development .
The decision to proceed with developing PBT facilities in this country has not been a rush. On the contrary, much work was undertaken by the National Radiotherapy Advisory Group (NRAG), whose report to ministers  was incorporated into the 2007 Cancer Reform Strategy . This was followed by the development of the Proton Overseas Programme (POP), managed by NHS Specialised Services. From April 2008 this has allowed appropriate patients to access PBT abroad, mainly in Switzerland and the USA, under the auspices of (and funded by) the NHS . The UK also has a considered, coherent approach to selection of patients. The criteria for acceptance are clear , concentrating on those tumour types where evidence of benefit is good, and where the radiotherapy component can be delivered safely, without adverse impact on the timing or integration of the other components of multidisciplinary treatment that are so vital to achieving the high cure rates, particularly in children’s cancers. Since 2008 over 300 patients have been formally assessed by a national clinical reference panel and 160 patients have completed treatment overseas, including 107 children.
However, some patients with conditions potentially suitable for PBT are unable or unwilling to travel abroad. In one study which predates the POP, 8 out of 12 patients with conditions approved for treatment were considered unlikely to be able to manage treatment abroad had it been available . The plan to develop a service in the UK will allow all suitable patients access to an important technical development, providing equity of access. It will allow expansion in the numbers of patients and range of tumour types to be treated, without extra cost.
The UK has a notable heritage in particle therapy, and has made international contributions. Key clinical research studies into the role of neutron therapy were performed here . The UK has for many years had a leading proton eye treatment facility in Liverpool, the first hospital-based proton treatment facility in the world, delivering the best eye-sparing treatment for ocular tumours . The commitment to research and evaluation of new radiotherapy treatments is an established part of our clinical oncology culture.
The UK approach to particle therapy has been driven by scientists, engineers and clinicians working together. Fundamental research is also underway in the UK, in part motivated by a desire to develop treatment approaches in readiness for the commissioning of clinical facilities [11, 12]. The UK is at the forefront of developing the next generation of accelerators for particle therapy, and a multidisciplinary doctoral training centre (funded by the Engineering and Physical Sciences Research Council - EPSRC) is in place, to provide staff with the necessary multidisciplinary skills ready for the clinical facilities .
A national PBT service, with networked centres based on two hospital sites, UCLH in London and The Christie Hospital in Manchester, with a capacity for up to 1500 patients a year is now planned. Queen Elizabeth Hospital Birmingham has been identified as a third centre, if (or when) capacity requires. Of crucial importance is that each PBT centre will be integrated within a major cancer treatment centre, unlike many facilities elsewhere. This provides for the best choice of patient treatment between different radiotherapy modalities (i.e. X-rays or PBT), and access to multi-disciplinary adult and paediatric medical care and support services for this highly selected group of patients, many of whom have complex medical problems.
This hospital base also provides the best environment for clinical research, including related investigative science such as imaging for target volume definition and response assessment. It is also the right environment for development and evaluation of technology. Most importantly, this provides the opportunity for comprehensive evaluation of the clinical value of the PBT, which would be impossible without facilities here.
The UK had an established commitment to proton research, ahead of the DH announcement . Evaluation of outcomes is already an essential component of the existing overseas and planned UK service. It is proposed that all patients treated in the new UK facilities would be treated within prospective evaluation studies and that a parallel programme of clinical and physics research should be supported to ensure that new evidence is available to develop future services and needs.
An important consideration is the need for imaginative approach to the methodologies required for evaluation. The randomised controlled trial (RCT) has been the cornerstone of robust evaluation of many new treatments and clinical interventions. RCTs remain the best method for avoiding bias and providing methodological and intellectual rigour, provided they are powered correctly. RCTs have provided important evidence of the value of some new RT technologies [15, 16], and where appropriate RCTs must be applied to PBT, as has already been proposed . However, RCTs are difficult to apply to a whole technology, and must be placed into context of the stage and specific disease being treated. They are especially problematic in rare cancers with low patient numbers, such as those to be treated with PBT. The value but also the limitations of RCTs have been eloquently explained by Rawlins , and endorsed by others . Thus considerable care will need to be used in defining appropriate research strategies, and funders as well as clinicians will need to be cognisant of this.
The UK has an excellent environment for the evaluation of PBT. Many pieces of the research jigsaw are already in place, and our purpose is to provide the best possible research evidence to support PBT as a new, valuable treatment to improve the outcome of patients with curable cancer.
Neil G Burnet
Vice-Chair NCRI Clinical and Translational Radiotherapy Research Working Group (CTRad)
Roger E Taylor
Professor of Clinical Oncology.
Chair, Clinical Oncology Subcommittee of Welsh Scientific Advisory Committee
Karen J Kirkby
Scientific Director, Surrey ion Beam Centre
Chair, Radiotherapy Discipline Group, Children’s Cancer and Leukaemia Group
Ranald I Mackay
Co-Chair Workstream 4, NCRI Clinical and Translational Radiotherapy Research Working Group (CTRad)
Head of Department of Oncology and Director of Gray Institute for Radiation Oncology and Biology, Oxford
1. Epstein K. Is spending on proton beam therapy for cancer going too far, too fast? BMJ 2012; 344: 20-21
2. Lee CT, Bilton SD, Famiglietti RM, Riley BA, Mahajan A, Chang EL, Maor MH, Woo SY, Cox JD, Smith AR. Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques? Int J Radiat Oncol Biol Phys. 2005; 63(2): 362-72
3. Miralbell R, Lomax A, Cella L, Schneider U. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int J Radiation Oncology Biol Phys 2002; 54: 824-829.
4. Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer 2008; 51: 110-117.
5. Radiotherapy: developing a world class service for England. Report to Ministers from National Radiotherapy Advisory Group. 2007. http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/%40dh/%40en/...
6. Cancer Reform Strategy 2007. http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/di...
7. NHS Specialised Services. Proton Beam Therapy. http://www.specialisedservices.nhs.uk/info/proton-beam-therapy
8. Foweraker KL, Burton KE, Maynard SE, Jena R, Jefferies SJ, Laing RJ, Burnet NG. High-dose radiotherapy in the management of chordoma and chondrosarcoma of the skull base and cervical spine: Part 1--Clinical outcomes. Clin Oncol (R Coll Radiol) . 2007; 19(7): 509-16
9. Laramore GE, Krall JM, Griffin TW, Duncan W, Richter MP, Saroja KR, Maor MH, Davis LW. Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council. Int J Radiat Oncol Biol Phys. 1993; 27(2): 235-40
10. Damato B, Kacperek A, Chopra M, Campbell IR, Errington RD. Proton beam radiotherapy of choroidal melanoma: the Liverpool-Clatterbridge experience. Int J Radiat Oncol Biol Phys. 2005; 62(5): 1405-11
11. Barazzuol L, Jena R, Burnet NG, Jeynes JC, Merchant MJ, Kirkby KJ, Kirkby NF. In Vitro Evaluation of Combined Temozolomide and Radiotherapy Using X-Rays and High-Linear-Energy Transfer Radiation for Glioblastoma. Radiat Res. 2012 Apr 2. [Epub ahead of print]
12. Fiorini F, Kirby D, Borghesi M, Doria D, Jeynes JC, Kakolee KF, Kar S, Kaur S, Kirby KJ, Merchant MJ, Green S. Dosimetry and spectral analysis of a radiobiological experiment using laser-driven proton beams. Phys Med Biol. 2011; 56(21): 6969-82.
13. Centre for Doctoral Training in Next Generation Accelerators. http://ngacdt.ac.uk/about/
14. Maughan TS, Illidge TM, Hoskin P, McKenna WG, Brunner TB, Stratford IJ, Harrington KJ, Plummer R, Billingham LJ, Nutting C, Burnet NG, Mackay RI, Oliver A, Young C, Chan CS; on behalf of the NCRI Clinical and Translational Radiotherapy Research Working Group. Radiotherapy Research Priorities for the UK. Clin Oncol (R Coll Radiol). 2010; 22(8): 707-9
15. Dearnaley DP, Khoo VS, Norman AR, Meyer L, Nahum A, Tait D, Yarnold J, Horwich A. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet. 1999; 353(9149): 267–72.
16. Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, Miles EA, Miah AB, Newbold K, Tanay M, Adab F, Jefferies SJ, Scrase C, Yap BK, A'Hern RP, Sydenham MA, Emson M, Hall E; PARSPORT trial management group. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2011; 12(2): 127–36.
17. Macbeth FR, Williams MV. Proton therapy should be tested in randomized trials. J Clin Oncol. 2008; 26(15): 2590-1
18. Rawlins M. De testimonio: on the evidence for decisions about the use of therapeutic interventions. Lancet. 2008; 372(9656): 2152–61.
19. Sullivan R, Peppercorn J, Sikora K, Zalcberg J, Meropol NJ, Amir E, Khayat D, Boyle P, Autier P, Tannock IF, Fojo T, Siderov J, Williamson S, Camporesi S, McVie JG, Purushotham AD, Naredi P, Eggermont A, Brennan MF, Steinberg ML, De Ridder M, McCloskey SA, Verellen D, Roberts T, Storme G, Hicks RJ, Ell PJ, Hirsch BR, Carbone DP, Schulman KA, Catchpole P, Taylor D, Geissler J, Brinker NG, Meltzer D, Kerr D, Aapro M. Delivering affordable cancer care in high-income countries. Lancet Oncol. 2011; 12(10): 933–80.
Competing interests: No competing interests