Features

Proton radiotherapy in ophthalmology

Disease Instruments
Dr Douglas Clarkson describes the use of proton beam radiotherapy as a specialist tool in the treatment of ocular cancers

Newly opened research room at the proton beam centre at the Christie Hospital Manchester (photo courtesy of Christie Hospital)

Conventional radiotherapy for ophthalmology involves use of high energy X-ray photon beams or so called plaque radiotherapy using implanted radioactive sources.

Such conventional radiotherapy, however, is associated with unavoidable collateral damage to adjoining tissues and where in particular damage to optic nerve and fovea region can be significant.  

Proton beam radiotherapy has become available as a specialist technique for the treatment of ocular cancers and where the principal advantage of such a mode of treatment is that it causes less damage to neighbouring tissues than conventional radiotherapy techniques and, consequently, has greater potential to preserve visual acuity. 

The technique of proton beam radiotherapy is also used to treat a wide range of commonly occurring cancers although proton radiotherapy is used in only around 1% for all such patients.  

Uveal melanoma is the most common type of eye cancer in adults where the uvea is considered to include the iris, ciliary body and choroid.  

Singh and Topham report an incidence of uveal melanoma of 4.3 cases per year per million of population in North America.1 Within Europe, Virgili et al report an incidence of as high as 8 cases per million per year in Norway to around 2 cases per year in Spain.2  

In Europe, this evidence of reducing incidence with decreasing latitude and is thought to be associated with increasing iris pigmentation with southern latitudes. Manchegowda et al report a reduced incidence for an Eastern population.3

  

A History of Development of Proton Radiotherapy 

Ernest Rutherford, the eminent New Zealand born physicist, had for some time suspected that atoms had at their centre a positively charged core surrounded by essentially empty space.  

It was an experiment undertaken around 1919 that detected hydrogen atoms ejected from nitrogen atoms after bombardment by alpha particles that finally provided evidence of protons as a building block of atoms.4  

This was the era in physics where major discoveries in particle physics could be achieved with basic tabletop experiments. The discovery of the proton paved the way for the discovery of the neutron by James Chadwick in 1932.  

The special characteristic of proton beam radiotherapy is indicated in the so called Bragg curves shown in figure 3 where a significant fraction of the dose of protons can be delivered close to an ‘end point’ of the beam beyond which no further radiation is delivered.5  

 

Figure 3: Depth dose characteristics (Bragg curves) of x-ray photons and protons. (~150 MeV).

 

This effect had been first identified by William Henry Bragg in 1903 from observation of the absorption of alpha particles in air. This is in contrast with conventional photon beams which can deliver a significant ‘exit dose’ beyond a target site in radiotherapy.  

However, Bragg’s greater claim to fame was the development of x-ray crystallography for which he was jointly awarded the Nobel prize for Physics in 1915 with his son Lawrence. 

In particle physics, the electron volt is the energy acquired by an electron accelerated through a potential of one volt. The commonly used unit of MeV is a million electron volts.  

The proton energies used in radiotherapy have significantly less energy that is achieved at the CERN research establishment, which can achieve energies of 6.8 TeV or 6.8 1012 eV. Cosmic rays, considered to be fast moving protons, are estimated to have energies in excess of 1018 eV. 

While the concept of a beam of high energy protons of a specific energy is by comparison simple, the technology to produce proton beams is significantly more complex. The cyclotron uses electrical and magnetic fields to accelerate protons to high velocities in a spiral-shaped path before they collide with their target.  

The story of the development of the cyclotron starts with the arrival of Ernst Lawrence in 1928 at the Physics Department on the Berkeley campus of the University of California, where he invented the principle of the cyclotron to accelerate protons.  

An initial cyclotron prototype system was capable of accelerating protons to energies of 0.08 MeV but progressively energies increased to 8 MeV in 1937 to 100 MeV by 1946, where the 100 MeV system was a major engineering project with the system magnet alone weighing several thousand tonnes.  

Lawrence, however, from an early stage in his work broadened the scope of his research to include chemists and clinicians, which stimulated the use of radioisotopes for both therapeutic and diagnostic purposes.  

He was awarded the 1939 Nobel prize for Physics with citation ‘for the invention and development of the cyclotron and for results obtained with it, especially with regard to artificial radioactive elements’.  

In the development of proton radiotherapy, the example of Ernst Lawrence at Berkeley to develop muti-discipline research teams was an excellent example of how to expand the horizons of science in a constructive and significant manner. 

  

Clinical Applications 

The first description of the possible use of protons in radiotherapy is credited to Wilson in 1924 though it was not until 1954 that the first patients received clinical treatments.6, 7 This first use was to irradiate the pituitary gland as an adjuvant treatment for breast cancer.  

The key to successful use of proton beam radiotherapy is to deliver an incident beam of an incident energy appropriate for the tumour depth and where more superficial targets will require less initial energy and the deeper targets increased energy.  

In the case of ophthalmic treatments, the maximum energy is relatively low, at around 60 MeV, while for a proton radiotherapy system to treat a wide range of cancers a maximum beam energy of 250 MeV is typical and corresponds to an approximate treatment depth of 38cm. 

In terms of current generation of proton beams, this can either be undertaken by use of a cyclotron or a synchrotron. The cyclotron typically generates a proton beam with an upper energy limit value and which is reduced to a prescribed value by use of absorbing structures.  

This beam attenuation system can add significantly to the radiation shielding required for safe system operation. The synchrotron, by contrast, can be configured to deliver a specific output beam energy and where this configuration is also more compact. Synchrotron systems also typically operate at lower levels of electrical power.    

Figure 4 indicates the relationship between proton beam energy and penetration depth for a standard water target. This confirms the beam energy of around 60 MeV for the beam line to treat to a depth of around 31mm for ophthalmic applications.

 

Figure 4: Outline of the relationship between proton beam energy and penetration depth for a standard water target. 

  

 

The National Centre for Eye Proton Therapy 

The National Centre for Eye Proton Therapy, which started operating in 1989, is a separate clinical facility based within Clatterbridge Hospital in the United Kingdom and is the only dedicated proton therapy facility in the United Kingdom for the treatment of eye cancers.

Protons of energy 62 MeV are generated by a cyclotron, which provides treatment to an equivalent depth of water of around 31 mm. Funding for the initial facility was provide by a range of national and local charities.  

Specialist eye centres in the United Kingdom acting as key referral centres include Moorfields Eye Hospital, St Paul’s Eye Unit at the Royal Liverpool University Hospital, the Royal Hallamshire Hospital and Gartnavel General Hospital in Glasgow.  

Currently, up to 40% of proton radiotherapy for ocular cancers in the United Kingdom are treated at the Clatterbridge facility.  

Hussain et al outline a summary of referral patterns for the Clatterbridge facility where referring centres reflect the balance of use of conventional radiotherapy techniques in relation to use of proton radiotherapy treatments.8 

  

Other UK Proton Radiotherapy Centres in the United Kingdom 

The first proton beam treatment facility in the UK to deliver a range of beam energies to treat a wide range of cancers is at the Proton Beam Centre at the Christie Hospital in Manchester.  

An important milestone in the site commissioning was the delivery in June 2017 of the cyclotron manufactured by Varian Medical Systems as a key component of Varian’s ProBeam system.

The first patients received treatment in December 2018. When the facility was completed, it represented the largest building in the world dedicated to proton radiotherapy.  

The cyclotron, as pictured at the Christie Hospital, directs proton beams to three treatment gantries which can rotate around the patients in the treatment rooms for tumour targeting.   

Only one gantry can receive the proton beam at a time whilst treatments are prepared in the other two rooms. Provision was made for a fourth gantry to provide a unique facility for future research and development and which became operational in April 2023.  

The cyclotron produces protons with a consistent energy of 230 MeV. The proton beam is injected into the Energy Selection System (ESS) which consists of mechanical carbon wedges that can reduce the beam energy to a value appropriate for a specific location within the tumour.  

Initially, the most distant regions of the tumour are treated and then progressively the whole tumour is treated with protons of reducing energy.  

A year later, a similar system was installed at the proton beam therapy centre therapy centre at University College Hospital in London, with first patients receiving treatment in December 2021 with some delay caused by the Covid-19 pandemic. The government committed £250 million capital investment for both major NHS proton beam therapy centres.  

This includes the buildings, the cyclotron units and gantries, providing six NHS treatment rooms (three at each centre). It is anticipated the two centres will each treat up to 750 patients per year. A complex system of referral/patient selection is in place to manage treatment schedules. 

  

Treatment of Iris Melanoma 

In a review of proton beam irradiation as a treatment of iris melanoma for 13 patients, Hauzinger et al report the general effectiveness of the treatment.9 Local tumour control after a mean follow-up of 25 months was 92%.  

The single case of subsequent tumour development was in a sector of the iris that did not receive initial proton radiotherapy. The authors indicate the importance of detailed initial examination of the iris as part of the initial clinical assessment.  

Specific complications identified after treatment are described as cataract (46%), secondary glaucoma (31%), superficial keratitis (15%) and madarosis (8%). A higher level of complications was associated with treatment of the complete iris rather than selected sectors.  

The observations of Hauzinger et al are essentially confirmed in a previous study by Lumbroso-Le Rouic et al9, 10 In a larger cohort of 192 patients, Gollard et al identify proton radiotherapy for iris melanoma provides an effective, non-invasive treatment option though identify treatments in excess of 10 clock hours were associated  with an increased incidence of secondary glaucoma and consequent significant decline in visual acuity.11 

  

Treatment of Choroidal Melanomas 

Patel et al describe visual outcomes of a relatively large group of patients treated for choroidal melanomas within a disc diameter of the fovea using proton radiotherapy.12  

Within a subgroup receiving a higher disease of radiation of 70 Gray (unit of radiation dose) around 45% of patents retained 20/200 or better 5 years after initial treatment. In a subgroup that received a reduced dose of 50 Gray, the corresponding figure was 70.4%.  

Riechardt et al describe the incidence of neovascular glaucoma after proton beam therapy of choroidal melanoma.13 Within the study group of 629 patients, 20.8% developed neovascularization of the iris after a mean time of 2 years.  

While a number of clinical risk factor were identified, the authors indicate the reduction of proton irradiation of the iris and ciliary body during treatments by beam management would assist in prevention of the development of neovascular glaucoma.  

Papakostas et al report the findings of a study of long-term outcomes for patients receiving proton beam radiotherapy as a treatment for large choroidal melanomas.14 It was shown that eye conservation was possible in most cases, with ambulatory vision retained in a small proportion of patients 10 years after radiotherapy.  

Tumour recurrence rates were low and mortality rates similar to those observed with enucleation. 

  

Evaluation of Patient Perceptions 

In addition to formal studies of clinical outcomes of proton radiotherapy, various quality of life studies have been undertaken to quantify patient perceptions of the treatment process.

The study of Gollrad et al for example identified that patients found the surgical procedure to insert positioning clips in the sclera more distressing than the actual sessions of proton radiotherapy.15 

The authors indicated that patient acceptance of the overall procedure could be improved by development of technologies such as non-invasive eye tracking during treatment sequences.

Rabsahl et al indicate that the majority of patients undergoing proton therapy for uveal melanoma experienced mild, transient depressive symptoms and anxiety.16  

Specific sets of patients, however, were identified where additional support during initial disease stages would benefit from additional support mechanisms. 

  

The Proton Therapy research Group at University College London  

While proton radiotherapy provides the potential for improved modes of patient treatment, there are always potential developments to improve the quality of treatments based on accurate management of delivery modes.  

Such enhancements, however, are complex at a technical and scientific level and require a high levels of scientific expertise to implement. This is a key role of the Proton Therapy Research Group at University College London.  

Research within the group involves a wide range of disciplines, such as physics, engineering, computer science, imaging science, biology, nanotechnology and oncology. One area of work relating to proton radiotherapy in Ophthalmology has been a detailed analysis of the 62 MeV proton therapy beamline at the Clatterbridge Cancer Centre. 

Such analysis can provide insight into parameters describing beam characteristics and resulting degrees of quality of delivered treatments.17  

  

Challenges in Proton Radiotherapy 

It had been identified in some respects proton radiotherapy presents a greater challenge than conventional x-ray radiotherapy in terms of variability of the relative biological effectiveness of treated tissues.18, 19 Coupled to this is the as yet incomplete understanding of energy deposition effects in proton beam delivery at the nano scale.  

However, this uncertainty is the subject of various research initiatives to improve beam delivery. Part of this uncertainty relates also to changes in tissue characteristics between fractions and even within fraction of delivered radiotherapy. With the pace of uptake of proton radiotherapy increasing around the world, the present advantages of the technology will hopefully continue to be refined and further developed.  

  • Douglas Clarkson is Research Fellow in Department of Clinical Physics and Bioengineering at UHCW NHS Trust, Coventry. 

  

References 

  1. Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973-1997. Ophthalmology. 2003 May;110(5):956-61 
  2. Virgili G, Gatta G, Ciccolallo L, Capocaccia R, Biggeri A, Crocetti E et al; EUROCARE Working Group. Incidence of uveal melanoma in Europe. Ophthalmology. 2007 Dec;114(12):2309-15 
  3. Manchegowda P, Singh AD, Shields C, Kaliki S, Shah P, Gopal L et al. Uveal Melanoma in Asians: A Review. Ocul Oncol Pathol. 2021 Jun;7(3):159-167 
  4. Rutherford E. (1919) LIV. Collision of α particles with light atoms. IV. An anomalous effect in nitrogen, The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science, 37:222, 581-587 
  5. Brown A, Suit H. The centenary of the discovery of the Bragg peak. Radiother Oncol. 2004 Dec;73(3):265-8. doi: 10.1016/j.radonc.2004.09.008. PMID: 15588869 
  6. Wilson RR. Radiological use of fast protons. Radiology. 1946 Nov;47(5):487-91 
  7. Lawrence JH, Tobias CA, Born JL, McCombs RK, Roberts JE, Anger HO et al. Pituitary irradiation with high-energy proton beams: a preliminary report. Cancer Res. 1958 Feb;18(2):121-34 
  8. Hussain RN, Chiu A, Pittam B, Taktak A, Damato BE, Kacperek A et al.Proton beam radiotherapy for choroidal and ciliary body melanoma in the UK-national audit of referral patterns of 1084 cases. Eye (Lond). 2023 Apr;37(5):1033-1036 
  9. Hauzinger JA, Blatsios G, Haas G, Zehetner C, Velez-Escola L, Nowosielski Y et al. Proton beam radiation for iris melanoma: case series and review of literature. BMJ Open Ophthalmol. 2021 Dec 23;6(1):e000683. 
  10. Lumbroso-Le Rouic L, Delacroix S, Dendale R, Levy-Gabriel C, Feuvret L, Noel G et al. Proton beam therapy for iris melanomas. Eye (Lond). 2006 Nov;20(11):1300-5. 
  11. Gollrad J, Böker A, Vitzthum S, Besserer A, Heufelder J, Gauger U et al. Therapy for 166 Patients with Iris Melanoma: Side Effects and Oncologic Outcomes. Ophthalmol Retina. 2023 Mar;7(3):266-274 
  12. Patel AV, Lane AM, Morrison MA, Trofimov AV, Shih HA, Gragoudas ES, Kim IK. Visual Outcomes after Proton Beam Irradiation for Choroidal Melanomas Involving the Fovea. Ophthalmology. 2016 Feb;123(2):369-377 
  13. Riechardt AI, Pilger D, Cordini D, Seibel I, Gundlach E, Hager A, Joussen AM. Neovascular glaucoma after proton beam therapy of choroidal melanoma: incidence and risk factors. Graefes Arch Clin Exp Ophthalmol. 2017 Nov;255(11):2263-2269 
  14. Papakostas TD, Lane AM, Morrison M, Gragoudas ES, Kim IK. Long-term Outcomes After Proton Beam Irradiation in Patients With Large Choroidal Melanomas. JAMA Ophthalmol. 2017 Nov 1;135(11):1191-1196  
  15. Gollrad J, Rabsahl C, Riechardt AI, Heufelder J, Stroux A, Goerling U et al.Quality of life and treatment-related burden during ocular proton therapy: a prospective trial of 131 patients with uveal melanoma. Radiat Oncol. 2021 Sep 8;16(1):174.  
  16. Rabsahl C, Boehmer D, Boeker A, Gauger U, Goerling U, Gollrad J. Depression and anxiety in patients with uveal melanoma undergoing curative proton treatment-A prospective study. Cancer Rep (Hoboken). 2023 Apr;6(4):e1780. 
  17. Yap, J, Resta-López, J, Kacperek, A, Schnuerer, R, Jolly, S, Boogert, S et al. (2020). Beam characterisation studies of the 62 MeV proton therapy beamline at the Clatterbridge Cancer Centre. Physica Medica, 77, 108-120 
  18. Underwood TS, McMahon SJ. Proton relative biological effectiveness (RBE): a multiscale problem. Br J Radiol. 2019 Jan;92(1093):20180004. 
  19. Mohan R. A Review of Proton Therapy - Current Status and Future Directions. Precis Radiat Oncol. 2022 Jun;6(2):164-176