by ecancer reporter Will Davies

2017 has been a… complicated year in many corners of the world. As a company, ecancer has celebrated our 10th year, and mourned the passing of our co-founder Umberto Veronesi late last year. In wider oncology, approvals have come through for the first CAR-T cell based gene therapies, alongside myriad other targeted therapies. CAR-T cell therapy made waves not only for its landmark approval, but also for the cost associated with a single course.

In news which ties together the threads of ecancer, cost and cutting-edge technology, this May also saw the installation of the cyclotron for what will become the UK's first proton beam centre in Newport, under the direction of Proton Partners International, of which ecancer Founding Editor Prof. Gordon McVie is also chairman

Since our coverage of the Proton Therapy Congress last September, I confess to having been both baffled and enamoured by the technologies discussed there – oxygen ions and laser-accelerators – tapping into my wildest childhood sci-fi dreams. Of course, in a year where biohackers livestream their injection of experimental HIV gene therapy, CRISPR-based muscle boosters are self-tested, and small cells of info-tactics units are ascribed with influencing elections across the globe, engineered immune cells and elemental ion radiotherapy are hardly the most fictional of sciences…

Over a year on from the Proton Congress, and much of our conference coverage has been following themes of personalised medicine and immunotherapies, which are also indistinguishable from magic in the eyes of much of the lay-public. Still, those talks have stuck with me. While construction continues in Newport, and with further centres planned for Manchester and London, I have found myself thinking: Did everyone ever agree if this was all a good idea?

The main selling point of proton therapy (or hadron therapy, or heavy element radiography, depending on who you ask) is the specificity with which radiation is delivered – the Bragg peak of energy transfer delivering a surgical strike to the core of a tumour versus the hole-punch penetration of photon therapy to and through tumours, collateral damage be damned. This is why, randomised clinical trials or no, proton therapy is a top choice for paediatric, brain and spinal tumours, in which delicacy and damage limitation are of the utmost importance. In adults, cardiac and pulmonary damage can also be avoided, lending it to breast cancer treatment (at three times the price). Similar local control also recommends it for small lung and prostate cancers, the latter of which is the main target of proton centers in the US despite uncertainty over GI toxicity.  The benefits of improved locoregional control can be said for all of the above with even-more-targeted carbon therapy, where Japan has taken a commanding role in development and distribution.

In short, the thinking is that you get a more precise, durable, tumour-specific bang for your buck. The latest ecancermedicalscience special issue on radiobiology featured a critique of this particular intersection of maths, physics and biology, with Dr Bleddyn Jones warning that “medical physicists often overemphasise the Bragg peak placement issues and minimise the radiobiology uncertainties, so that it becomes difficult to determine the cause of toxicity or failure to cure”. And it sure would be a shame to for so many people to have built their livelihoods around one misplaced assumption. This seems to especially be the case in paediatric cancer care where, having dodged the risk of brain damage or paralysis thanks to highly active, highly accurate proton/carbon beams, later toxicities are becoming more apparent. Others fielding toxicity argue that data is incomplete or that techniques are still being refined.

Here is where the second strike against proton implementation can be laid alongside cost – a looming, long-recognised lack of clinical superiority in a randomised control trial.

The absence of proven superiority in RCTs seems to have come to a most severe of conclusions in the US, home to over 20 proton facilities, where insurance providers have refused to compensate any further treatments without them. This has led to facilities shuttering until those results come through, with an estimated due date of… 7 years time.

Will this be too late? Or rather, have other health systems committed too early?

Now that proton therapy is coming to the UK, through the aforementioned Proton Partners facility in Newport, Prof Gordon McVie provided a few words.

“From 1956, protons have been known, along with several other ions that have different characteristics, that when they hit a certain object, they stop. But what has stopped that all getting into the clinic would be the cost. The brief history of proton therapy is that it's only really come to light because of a university in Belgium, where the professor of physics said how come nobody's doing any research into ions, in particular protons, because it seemed obvious. And he was told it costs €300m to produce a machine. So he set about miniaturizing it, and found you could get it down to €30m- because I've just bought four, as chairman of proton partners. That's for one cubicle. It's still very, very expensive, about 4 times more than your average radiotherapy machine.”

“While people have been waiting to get proton installations miniaturized and made cheaper, radiation therapists have developed a lot of other ways of improving their success rate and targeting only the tumour with IMRT. They are now state of the art, so that's important because when you come to look at other ions and protons, you’ve got to beat IMRT. That's the standard. So the cost is going to be the main issue and the cost will depend on the evidence base. The Americans who led the massive expansion are now retracting.”

  - And if the trials come back with unclear or mixed results?

“We do the meta-analysis. I am absolutely dead against scientists saying it's cost effective or not if they haven't done the cost measurement in the trials. And so few clinical trials have got cost assessments built into them. Now that we’ve got all these expensive medicines, people like NICE are saying ‘Show us the data. What's the total cost per patient package?’”

  - So if protons are lacking in evidence grounding, would it be worth following the Japanese route and pursuing carbon or oxygen radiotherapy instead?

“That wouldn't happen because there's less evidence on carbon. I’d say they’re even further behind, maybe five years off protons in terms of the radiobiology.”

“At the minute there is still a big question mark over the whole thing. One approach which the Dutch government has agreed in terms of funding is proposed by Johannes Langendyke from Groningen. He has said why don't we have a map with CT and MRI design and the plan with photons and then, apparently, it's not that difficult to ask the same question of the protons using different capacity, different characteristics of the ion and then send those digitized images to a panel of 10 experts anywhere in the world. And if they agree that it’s better to use protons because the safety is proven better, then pay for the protons. If not…”

While many at the 2016 congress were, of course, positive on the topic, a few speakers offered words of warning over misplaced enthusiasm without proven clinical benefits.  A year on, and trial data is starting to come in, though many remain active. By the time they deliver, market demand may well have driven costs down. Equally, clinical experience with pencil-beam scanning and IMRT may have made photon therapy even trickier to surpass for cost-effectiveness. Perhaps, as some consider, a two-stream approach of adding proton capability to photon-based therapies and centres offers more utility than diving into full ionic armaments. As breakdowns of benefit by disease indication and geography have shown, a one-beam-fits-all approach is not likely to be forthcoming.

And so, 60 years into their clinical history and 154203 patients later, we are close to finding out if there’s any future for proton beams. Considering how much the world has changed in the time, there is strange irony in having caught up to the future in one aspect, and surpassed it in so many others.

Just think, when those first cyclotrons were spinning up in the late 50s, the world was mired in cold nuclear trepidation, with deep social rifts along the lines of race and class in the West and conflict tearing down the Korean peninsula…

It's been a complicated year.