Proton beam therapy: perspectives on the National Health Service England clinical service and research programme

Abstract

The UK has an important role in the evaluation of proton beam therapy (PBT) and takes its place on the world stage with the opening of the first National Health Service (NHS) PBT centre in Manchester in 2018, and the second in London coming in 2020. Systematic evaluation of the role of PBT is a key objective. By September 2019, 108 patients had started treatment, 60 paediatric, 19 teenagers and young adults and 29 adults. Obtaining robust outcome data is vital, if we are to understand the strengths and weaknesses of current treatment approaches. This is important in demonstrating when PBT will provide an advantage and when it will not, and in quantifying the magnitude of benefit.The UK also has an important part to play in translational PBT research, and building a research capability has always been the vision. We are perfectly placed to perform translational pre-clinical biological and physical experiments in the dedicated research room in Manchester. The nature of DNA damage from proton irradiation is considerably different from X-rays and this needs to be more fully explored. A better understanding is needed of the relative biological effectiveness (RBE) of protons, especially at the end of the Bragg peak, and of the effects on tumour and normal tissue of PBT combined with conventional chemotherapy, targeted drugs and immunomodulatory agents. These experiments can be enhanced by deterministic mathematical models of the molecular and cellular processes of DNA damage response. The fashion of ultra-high dose rate FLASH irradiation also needs to be explored.

Figure 1.

Gantry one at the Christie Proton Beam Therapy Centre

Figure 2.

Planned ramp up of patient treatments for the Christie Hospital, Manchester. Note that the service commenced with patients, paediatric and TYA, who are considered likely to derive the greatest benefit from PBT in place of XRT. The first patient, a child, was treated in December 2018. The first adult patient (>24 years of age) was treated a month later, and by April 2019 all tumour site teams were treating adult patients. Actual ramp up has matched the planned ramp up closely. Paed = paediatric, GA = general anaesthesia, TYA = teenagers and young adults (age 16–24).

Figure 3.

Treatment plans (PBT–left; X-ray IMRT–right) for a paediatric patient with a grade I/II astrocytoma. The patient was treated with PBT, to a dose of 50.4 Gy_(RBE=1.1). The PBT plan was delivered with two fields optimised with single field optimisation. The X-ray plan was prepared using fixed field IMRT, using four beams, and was intended to provide a backup in case of machine breakdown; it was not used clinically. Note the difference in medium and low dose to the brain between the plans, which may reduce neurocognitive effects in children. However, in adults, there is currently no evidence that this would deliver any clinical value, suggesting an opportunity for a clinical trial.

Figure 4.

Composite treatment plan for an adult patient with skull base chordoma, treated to a total of 73.8 Gy_(RBE=1.1) in 41 fractions of 1.8 Gy_(RBE=1.1)/fraction, in two phases using SFO. The first phase (54 Gy_(RBE=1.1)) used four fields, all slightly angled down which is apparent from the coronal section; the second phase (19.8 Gy_(RBE=1.1)) used two direct laterals.

Figure 5.

Dose plan report for the patient whose plan is shown in Figure 3, including doses planned under uncertainty. The magnifying glass shows the nominal doses received (for the prescription dose of 50.4 Gy_(RBE=1.1)), the minimum and maximum doses under uncertainty, where relevant, and the error scenario in which this worst case occurs (X, Y & Z refer to the three dimensions of patient positioning uncertainty, the percentage figure refers to the range uncertainty). Inset: dose-volume histogram (DVH) curves for the CTV showing the different uncertainty scenarios considered (dashed lines) which provide the basis for the uncertainty reporting.

Figure 6.

Three categories of clinical trial or study required to optimise creation of the evidence base for PBT, for patient and societal benefit.

Figure 7.

Schematic of the Manchester PBT centre, showing the main entrance and clinical areas to the front of the building (left side-of the diagram) with the cyclotron, beam line and gantries at the back (shown in red; right side). The beam line and entry to the gantries is located on the first floor, which avoided the need to excavate below ground level. Note that the beam line extends beyond the third gantry, and is shown stopping at the fourth bunker, which functions as the dedicated research room (top of the diagram).

Figure 8.

The Manchester PBT centre research room with the in vitro experimental beam line ending in the Varian engineering scanning nozzle. The nozzle is virtually identical to a clinical nozzle and allows the beam to be scanned across the whole field. Quadrupole magnets are located along the beam line to focus the beam, which is travelling at two-thirds of the speed of light.

Figure 9.

Diagram of the end of the experimental beam line and scanning nozzle in the research room at the Christie PBT Centre. Illustrated in front of the nozzle is a dedicated modular unit, in this case a hypoxia cabinet for accurately controlling oxygen concentration in the enclosed cell culture dishes. Note the robot which is designed to allow high throughput irradiation of a large number of cell culture dishes or flasks, without the need for the operator to enter the room to move flasks in and out of the beam. Funding for the radiobiology end-station from Cancer Research UK. Diagram courtesy of Dr Mike Merchant.