These were just some of the questions considered at the recent AAPM annual meeting in Charlotte, NC, where three experts in the field presented on the theme "Will proton therapy gradually replace photon therapy?"
Financial challenges
The first speaker, Richard Maughan from the University of Pennsylvania (Philadelphia, PA), took a look at the economic issues, and asked whether the high cost of proton therapy facilities will limit the availability of proton treatment. "People are so worried about capital costs that they are looking to new technologies that will reduce this," he said. "For proton therapy, don't expect to get your investment back for eight to 10 years."
Cost reduction has driven the introduction of compact single-room accelerators that require less initial expenditure and should make proton therapy more accessible to smaller institutions. Examples include Mevion's recently approved gantry-mounted superconducting synchrocyclotron, the still unproven dielectric wall accelerator being developed by CPAC and, at an early development stage, laser-based accelerators. The established vendors are also starting to offer smaller-footprint alternatives to compete with these one-room solutions.
Maughan estimated the initial set-up costs for a single-room facility as around $30 m, roughly half that of a two-room site. Annual running costs, meanwhile, are $4–5 m, $8–10 m and $19–24 m for one, two and five rooms, respectively. While costs are obviously lower for a one-room facility, Maughan pointed out that it's not clear whether the overall business plan is as attractive as for a large centre. "In the USA, high capital costs are compensated by high reimbursement, so provided reimbursement is maintained, current business plans remain feasible."
Other considerations when setting up a proton therapy centre include establishing milestones and timelines with the vendor, as well as an annual budget. Some degree of flexibility is essential as "it's highly probable that you'll make changes to the original plan," said Maughan. A core team of medical physicists, physicians and administrators is required from the start, and the time required for staff recruitment and training, as well as system testing and validation, must not be underestimated.
If proton therapy is to be a success, in the USA at least, successful deployment of one-room systems is essential, said Maughan. "The thing about a one-room system is you don't need $140 m to get into the game, you need proportionally less. If it's going to be all $140 m facilities, I don't think we're going to get there." It's also critical that reimbursement rates remain higher than those for photon therapy, which may require more evidence of proton therapy's superiority.
To answer his initial question, "will high costs limit proton therapy availability?", Maughan turned to the AAPM delegates. An interactive voting system introduced at this year's meeting enabled audience members to submit responses via a hand‐held device. Around 60% of those who voted answered "yes", 30% answered "no" and the remainder were undecided.
The limit of uncertainty
It's not just financial challenges that may stymie the increased uptake of proton therapy. Harald Paganetti from Massachusetts General Hospital (Boston, MA), examined whether uncertainties may prevent proton therapy from reaching its full potential. Proton therapy's main advantages stem from the finite range of the proton beam. "When it comes to dose conformality to the target volume, you may be able to do as well with IMRT," said Paganetti. "But the integral dose is always higher with photons."
But does lower integral dose translate to clinical gain? Is a small volume of high dose necessarily a better option than a large volume of low dose? "To use the integral dose to conclude superiority of protons might be too simplistic. We need to consider the distribution of dose and the distribution of organs-at-risk," Paganetti explained.
The proton delivery system can also impact clinical outcome. For example, the size of the spot used for ion beam scanning can considerably impact the dose distribution. Paganetti gave the example of a rhabdomyosarcoma treatment using scanned protons. If the scanning system used too large a beam spot, the proton plan proved inferior to IMRT for one of the organs-at-risk.
The finite beam range also gives rise to a major shortcoming: range uncertainties. For non-moving targets, such uncertainties arise from sources including commissioning errors, compensator design and patient set-up, as well as factors related to dose calculation. These add up to an average uncertainty for an average patient of 2.7% + 1.2 mm. In extreme cases – where local lateral inhomogeneities exist – this can increase to 4.6% + 1.2 mm.
"Symmetric margin expansion doesn't make sense for protons, you need specific uncertainty meshes that address the range," said Paganetti. Monte Carlo dose calculation can help reduce the uncertainty, but not to zero. He emphasized that proton treatments need to be planned by experienced planners who understand the impact of range uncertainties. Robust planning is also under investigation for mitigating uncertainties, although this is still at the research stage.
Paganetti concluded that for some cases, such as paediatric cancers, proton therapy could indeed replace photon therapy, as clear advantages can be expected. For other sites, there is potential of replacing photons, but this is reliant upon reducing planning and delivery uncertainties, understanding the clinical significance of improved dose distributions, and using optimized delivery systems.
Motion matters
The session's final speaker, Frank Van den Heuvel from KU Leuven in Belgium, addressed another key sticking point: patient and organ motion during treatment delivery. While motion affects the dose distribution of any radiation treatment, the implications can be particularly severe for proton therapy.
Geometric effects, such as out-of-plane rotations, result in a small penalty for photons, but a large penalty for protons. For example, pelvis tilt during prostate treatment leads to underdose at the distal edge. Proton therapy is also affected by physical effects, as the beam range is linearly dependent on density, making knowledge of the density of irradiated tissues essential.
Another problem arises from the fact that the linear energy transfer (LET) of the proton beam is variable, and reaches a maximum at the end of Bragg peak. If an organ-at-risk lies behind the Bragg peak, range errors can be particularly debilitating. "At the edge you could have double trouble: you're not only over-treating the organ-at-risk, but treating it with a beam that has higher LET," Van den Heuvel explained.
Organ motion can generally be classed as either periodic, such as heartbeat or respiration, or stochastic (random). When treating a lung tumour, for example, periodic changes in lung density with breathing can cause range differences of up to 5 cm. Stochastic non-periodic movements, such as changes in prostate position, are not predictable, though it may be possible to model the chance that a change will occur.
Motion during X-ray therapy is addressed using real-time imaging and tracking, beam gating and adding margins. So can these approaches be used for photon therapy? Tracking target motion requires high-speed scanning of the proton beam. This should be possible in the x–y plane, but altering the range requires rapid changes in beam energy, which may be harder to achieve. Gating may help alleviate the effects of periodic motion, but margins must be considered with great care, as described above.
In-room imaging techniques – many of which are not currently available for proton therapy – could prove vital for addressing target motion. Van den Heuvel also noted that scattering-based proton delivery might prove more robust to motion. In particular, for pencil-beam scanning, interplay effects due to the differing frequencies of breathing motion and beam motion will impact delivery accuracy.
And what did the AAPM delegates take away from this session? When asked what they considered as the main obstacle to proton therapy becoming mainstream, 33% of voters chose range uncertainties, while 35% thought the unproven clinical advantage of lower integral dose was the main hurdle. Interestingly, 19% believed that proton therapy would never become a mainstream treatment option. Clearly, there's work still to be done.