Author:

Simon Crompton

Abstract

Globally, around 350,000 people have been treated with proton therapy since the 1960s. Adults and more often children with cancer are generally referred for proton therapy when treatment is particularly challenging.

After the early use of proton beams to treat cancer patients in the 1950s at Berkeley and Harvard in the United States, pioneering proton therapy was introduced by physicists and oncologists working in Europe, particularly in Uppsala, Sweden, in the 1950s and 60s, then at the Paul Scherrer Institute in Villigen, Switzerland, from the 1980s to 2000s. Without their breakthroughs, the course of modern proton therapy might have been quite different.

The high cost of proton therapy limits its availability worldwide. However, there are now more than 100 proton therapy centres, which play a particularly important role in saving the lives of children with brain and spinal tumours.

Introduction

Globally, around 350,000 people have been treated with proton therapy since the 1960s ^[1]. Adults and (more often) children with cancer are generally referred for proton therapy when treatment is particularly challenging because their tumour is resistant to conventional radiation therapy or because other radiation techniques would prove too damaging for the patient.

It is a form of radiation therapy that is uniquely suited to treat hard-to-reach tumours located near sensitive organs such as the brain or the spinal cord. This is because it targets high radiation doses extremely precisely, giving maximum opportunity to neutralise even radiation-resistant cancers while minimising damage to surrounding tissues.

This has particularly important applications in the treatment of childhood cancer. Children are highly sensitive to radiation and conventional, less targeted, radiation therapy can bring significant side effects. Because children have many years ahead of them, they are also more prone to experience “late” adverse events caused by conventional radiotherapy.

Textbooks rightly stress the importance of the work of scientists at Berkeley and Harvard in the United States in the early use of proton beams to treat cancer patients in the 1950s. Less publicised, however, is the pioneering work of physicists and oncologists working in Europe – particularly in Uppsala, Sweden, in the 1950s and 60s, then at the Paul Scherrer Institute in Villigen, Switzerland, from the 1980s to 2000s. Without their breakthroughs, the course of modern proton therapy might have been quite different.

The first ground-breaking irradiation of a human cancer with protons actually took place in Uppsala in November 1957 – three years before the same procedure was performed in Berkeley. In Switzerland, between the 1970s and the 1990s, physicists worked with oncologists to perfect highly accurate ways of targeting protons using very narrow beams – which resulted in the first treatment of a cancer patient with “pencil beam scanning” using a “gantry” system in 1996.

The cost of proton therapy – because it requires complex proton-generating particle accelerators, gantries and a lot of space – means that its availability is limited worldwide. However, there are now more than 100 proton therapy centres around the world which play a particularly important role in saving the lives of children with brain and spinal tumours. Nearly all of them are equipped with the pencil-beam scanning technology developed at the Paul Scherrer Institute, which is now established as the “industry standard” for proton delivery.

Science and context

Since the 1930s, scientists have explored how to use different types of particle to deliver high energies into tumours, damaging and killing cancer cells in the process. The goal of their research has always been to administer a sufficiently high dose to the tumour while sparing the surrounding healthy tissue as much as possible.

The potential of accelerated protons to meet those requirements was first recognised in the 1940s by scientists at Harvard University in the USA, who concluded that protons had particular qualities that might make them a good means of conveying high energy to tumours. Harvard researchers had already experimented with accelerated electrons, but these light particles tended to scatter when passing through tissue before reaching their target.

Protons, on the other hand, were heavier and passed through tissue in straighter lines, making them more easily targeted. They also had a unique pattern of energy release when passing through tissue (known by physicists as the “Bragg curve”). They released their maximum energy (the Bragg peak) just before stopping. This meant, in theory, that if a beam of protons was of the correct energy, the maximum dose could be released at the target, leaving the tissue that the beams passed through before and after the tumour subject to much smaller energies.

The importance of these characteristics for treating cancer was first identified by Robert R. Wilson, Professor of Physics at Harvard University, in 1946. But when the Lawrence Berkeley Laboratory in California picked up on his work two years later, first treating mice and then humans with protons, they did not utilise the Bragg peak. Instead, scientists used a “cross-fire” technique, aiming the beam at the target from various angles so that the combined dose was concentrated on one spot. They treated the first cancer patient with the technique in 1954 – a woman with metastatic breast cancer. The beam was focused not on the tumour itself, but on the pituitary gland, for hormone suppression. Similar patients were treated in the same way at Berkeley until 1957.

“You have to remember what the situation was for cancer patients in the 1950s” says Erik Blomquist, retired Associate Professor and consultant radiation oncologist at Uppsala University Hospital. “There were almost none of the medicines we have today to treat cancer patients. So the idea was that they treated the pituitary gland of these patients to reduce the production of oestrogen, which could stimulate growth and cause more pain in the bone metastases. This was a substitute for a medicine that didn’t exist then.”

The “linear accelerator” machine or LINAC, the mainstay of modern radiotherapy departments, which uses high-energy x-rays to kill tumours, was still a way off being widely introduced into clinical practice. The first one was only trialled in London in 1953. In most locations, throughout the 1950s, the main sources of irradiation were low-energy x-ray machines, implanted radium-based radioactive sources or external beam teletherapy using gamma rays from the radioisotope cobalt-60.

It was in this environment that young researchers in Sweden were determined to think creatively about how best to use high energy particles such as protons, and how to direct them to kill the tumour itself.

Proton therapy at Uppsala

The Gustaf Werner Institute for Nuclear Chemistry was opened in Uppsala in 1949. Like many research centres established in the 1940s, 50s and 60s, its research revolved around examining the qualities of accelerated subatomic particles, generated from a particle accelerator – in the case of the Gustaf Werner Institute, a synchrocyclotron. Its main focus was investigating the effects of accelerated particles on both plant and animal tissue, and any medical or industrial applications that might arise. By 1955, a narrow external proton beam, fed by protons from the synchrocyclotron, had been extracted and became available for experiments. A young physicist named Börje Larsson began biological investigations, examining what happened to animal tissue when irradiated with this proton beam.

Larsson, born in 1931, trained as a civil engineer but during his university studies he developed an interest in interdisciplinary scientific issues. While still a student, he had been invited to come to Uppsala by the Nobel Prize laureate, Theodor Svedberg, one of the founders of the Gustaf Werner Institute, to work on biomedical applications of the newly developed external beams at the institute.

He started by examining the biological effect of proton radiation on animal tissue, and then living rabbits and goats. By 1957, Larsson and Svedberg, working in close collaboration with cancer clinicians at the Uppsala University Hospital, felt ready to treat a human cancer with the proton beam. On 23rd November 1957, Larsson – still only 26 – along with gynaecologist Stig Sténson, provided palliative radiotherapy to a 60 year-old woman with advanced cervical cancer. It was the first proton treatment of a cancer tumour in the world.

“The theory was that you could modulate the Bragg peak so that you could cover the whole tumour with a high dose of radiation,” says Anders Montelius, medical physicist and Associate Professor at Uppsala University Hospital, who worked with Larsson in the 1980s. “And Börje Larsson was the first one to do that in practice.”

“The woman was treated with a 3cm wide fixed proton beam where the Bragg peak was used to a maximum depth penetration of 2cm. The use of imaging to exactly locate the tumour was very primitive at the time. You could only take ordinary x-rays to see the skeleton. That is why they had started off treating the pituitary in Berkeley because that could be located using standard x-rays. So it was quite a daring step forward. For the gynaecological cancer treated at Uppsala, they went in through the perineum and you could actually see the tumour border.”

In a paper describing this first human irradiation, Larsson wrote: “No direct irradiation of human carcinoma with high energy atomic nuclei has, to our knowledge, been previously reported… The results indicate that human carcinomas may be successfully treated by irradiation with a beam of high energy protons.” ^[2]

Larsson later reviewed subsequent treatment of a series of women with similar gynaecological tumours in a 1985 paper: ^[3]

“The first series of patients included only such advanced tumours that curative treatment was judged impossible. Among these were 10 cases of verified recurrences of cervix carcinoma. A total dose of 30 Gy was given in a single fraction with a perineal portal to the pelvic region. Fractionated treatment of advanced genital carcinoma was also performed as a second series.”

“We had confidence in our technique and the equivalence of protons and cobalt radiation seemed fairly well established from the biological point of view. Further work was therefore concentrated on cases in which the geometrical advantages of the proton dose distribution could be better exploited.”

With this in view, the proton beam was also used for narrow beam irradiation of intracranial structures in the late 1950s and early 1960s. Proton beams were cross-fired through the cranium for the treatment of parkinsonism, intractable pain and large malignant tumours.

This work led to Larsson’s highly acclaimed doctoral dissertation on the proton irradiation of tumours, presented in 1962. He developed new methods of calculating radiation dose which are still in use today, and he continued to closely analyse the biological effects of protons on human tissue.

The impact of early proton therapy at Uppsala

According to Anders Montelius, the implications of what was being achieved at Uppsala was recognised almost immediately.

“I would say we did understand what an impact it would have,” he says. “One of the doctors who worked with Larsson on the first patient was Stig Stenson, a doctor here at the university hospital. He told me that when the people from Berkeley came to Uppsala to see what they were doing in the 1950s, they were a bit, shall we say, disappointed that they had come up with the idea of using the Bragg peak and that we at Uppsala were the first to use it.”

Between 1957 and 1968, over 50 patients were treated at Uppsala with large-field, range-modulated proton beams (the number of treatments was limited because the proton beam often had to be made available for other experiments in the research centre). In his 1985 review, Larsson said that the work had demonstrated that high energy protons can safely be used for radical radiotherapy and that “flexibility of the proton field permits an accurate dose distribution in good conformance to generally accepted clinical criteria”.

“The reason for recalling the old situation is that the clinical work in Uppsala paved the way for the later, technically more advanced, studies at Harvard, Berkeley and Moscow,” he wrote.

Larsson became Professor of Physical Biology at Uppsala in 1979, and Professor of Medical Radiation Biology at Zurich in 1991. He contributed to the development of innovative particle therapy cancer centres in the USA, Europe and Japan and continued pioneering new techniques – including the development of the “[gamma knife]”(@leksell-gamma-knife) in the 1960s.

Jörgen Carlsson, Professor Emeritus at Uppsala University, knew Larsson from the early 1970s when he was working as an engineer and plans for a proton therapy clinic at Uppsala were taking shape. Larsson supervised his PhD in 1978 and influenced his move into radiation biology and nuclear medicine.

“He was always positive and at the lab it was said that each week he could come up with five new research ideas, and sometimes one of these ideas took place,” says Carlsson. “He was very humble, a very nice person to be with and he was very open with his ideas. He stimulated everyone he could stimulate, and he was not interested in patenting or business.”

Pencil beam scanning at the Paul Scherrer Institute: the context

Twenty years after the Gustaf Werner Institute for Nuclear Chemistry was founded in Uppsala, another research institute opened in Switzerland – the Swiss Institute of Nuclear Research (SIN), near the town of Villigen. Like Uppsala, its programme of research centred on better understanding the qualities and potential applications of subatomic particles, based around its particle accelerator (in this case a cyclotron). Investigating potential medical applications was always part of the aim.

At first, biomedical research at SIN focused on the potential therapeutic use of particles called pions, and in 1981 the first human cancer patients were treated with accelerated pions in a machine named the piotron, designed by Georg Vecsey. Ultimately, the pion experiments reached a dead-end – the machinery was hard to maintain, and the radiation-induced side effects on patients were sometimes severe. The inherent characteristics of the pion particle itself caused problems with controlling the dose distribution and concentrating their high energy at the target.

But the project laid the groundwork for important developments in proton therapy that followed. It had made two important advances. First, it treated patients in three dimensions using three-dimensional dose calculations from CT scan data. Second, it delivered this three-dimensional treatment by concentrating particle delivery into a targeted pattern of “spots” rather than a wide beam scattered across the whole tumour.

Conventionally, radiation therapy was delivered via a single particle beam, shaped to the target tumour using “collimators” – metal devices, often specially made for each patient. In contrast, the piotron utilised 60 identical beams fixed in a ring around the patient. The pions from all 60 beams released their intense energy at a single “hot spot” within the tumour and then the patient position was carefully adjusted – forwards and backwards, up and down – by means of a moveable couch, so that each “spot” in the treatment plan could be treated accurately and the dose delivered homogenously across the tumour.

This new “spot scanning” approach to radiation therapy was devised by a young Swiss physicist called Eros Pedroni who had joined SIN in 1977.

In January 1988, SIN became the Paul Scherrer Institute, and took on a new emphasis on applied physics rather than basic science. It also had a new proton beam line for scientific experimentation with the right energy range for treating deep-seated tumours. Pedroni saw a new opportunity to develop the spot scanning principle, but with protons rather than pions.

His motivation was more than scientific curiosity. He was haunted by the dire situation of many of the patients with advanced cancer who came to SIN for treatment with pions, particularly one young man in 1985.

Talking in 2021 ^[4], Pedroni said: “I felt sad and angry seeing the life of a young cancer patient being destroyed by a blind injustice from ‘Mother Nature’. The experience remained in my mind.”

Pencil-beam scanning at Villigen: development

Pedroni, with radiobiologist Hans Blattmann and radiation oncologist Gudrun Goitein, continued experiments on spot scanning – now re-named “pencil beam scanning” – using a fixed horizontal beam line, with ultrafast magnet systems for switching the beam on and off and deflecting it to different positions. In 1992, PSI announced that it would build a new proton therapy centre, with a view to administering treatment using the new pencil beam scanning technique via a compact rotating gantry. Patients were already being treated with protons in research facilities in the USA, Sweden (Uppsala), USSR, Japan, England, France and Belgium. The American research centre at Loma Linda had pioneered the use of a 360-degree rotating gantry – a means of effectively rotating the proton beam to different positions around the patient, rather than moving the patient him/herself into the right position for a fixed beam.

But none of these initiatives were using an “active scanning” technique like Pedroni’s, and most were using “beam widening” or “passive scattering techniques”.

As Hans Blattmann explained, speaking in 2021: ^[5] “We wanted something new, to go a step further than they had in the US,” he says. “The fast scanning of the beam was the most important thing. The beam could move very quickly and exactly deposit the maximal dose at specific points where we predicted we wanted the dose distribution, covering a three-dimensional volume. Before, using collimators, people had been irradiating two-dimensional areas. The new thing we started was three-dimensional point irradiations.”

The aim of research throughout the world was to find a way of conforming a high dose of radiation to every point in an irregularly shaped tumour, while at the same time protecting surrounding cells as much as possible. PSI believed that the pencil beam scanning gantry system was the best way to achieve this.

The first test proton beam was sent through the new gantry in April 1994, and work continued on investigating the radiobiological effects of administering a high radiation dose at the proton spot. A programme of treating animals with spontaneous tumours – mainly household pets such as dogs and cats with cancer – was established, advised by Börje Larsson who was at the time Professor of Medical Radiation Biology in Zurich.

Finally, on 25th November 1996, a man with brain metastases became the first ever patient to receive proton therapy treatment using a pencil beam scanning system, delivered via what became known as Gantry 1. In the following year nine further patients, referred from Swiss university hospitals, were treated. None of the primary tumours treated showed signs of progression after irradiation.

PSI backed its confidence in proton beam scanning and gantry systems by building a new multi-million proton therapy facility, with its own dedicated cyclotron, based around pencil beam scanning via a gantry, begun in 1999 and completed in 2008.

By 2002, PSI could report to an international particle therapy conference that 99 patients had been treated on the gantry since 1996, with 86 still alive, and local control achieved in 72 out of 78 curatively irradiated patients and 10 out of 20 palliative cases.

But the institute was still ploughing a lone furrow. Damien Weber, current Head of the Center for Proton Therapy at PSI, who joined the staff as a radiation oncologist in 2002, remembers the cool reception he got in 2003 when he gave a presentation on pencil beam scanning for spinal tumours at an international conference.

“People were saying that pencil beam scanning was too complicated, and that scattering was a much better way to go,” he says.

Impact of pencil beam scanning

By 2008, four years after PSI started successfully treating young children for brain and spinal tumours, the climate had changed. Despite worries about the capital costs and complexity of proton beam scanning, people began to realise that, on the ground, it was more cost-effective than using scattering technologies. Key institutions, such as Massachusetts General Hospital and MD Anderson Cancer Center in the United States began to make the shift from scattering to scanning.

“As enthusiasm for spot-scanning-based particle therapy continues worldwide,” read the 2009 PSI Scientific Report, “and as other centres implement first generation systems, the issue of the ‘safety and efficacy’ of spot-scanning-based proton therapy, compared with the historically used passive scattering technology, becomes of paramount importance… Our data provide the medical evidence for the ‘safety and feasibility’ of spot-scanning technology for the clinical indications presently treated at PSI [mainly difficult-to-treat tumours of at the skull base and next to the spinal cord, and tumours in infants and children].”

“From initial design and treatment concepts, to early research, manufacturing and clinical implementation, to ultimately routine use and now proof of not only principal, but actual, readiness for widespread clinical implementation, is an outstanding accomplishment by literally one generation of researchers at PSI.”

A paper by Damien Weber and colleagues published in Radiotherapy and Oncology in 2016 capitalised on PSI’s long history of providing pencil beam scanning with protons, and records going back to 1998. Looking back at outcomes of 222 patients with skull-base tumours, at a mean follow-up period of over four years, it found that long-term local tumour control was achieved in more than 70 per cent of patients, with the long-term toxicity-free survival rate being 87 per cent. ^[6]

Today, virtually all new proton systems manufactured, and all new proton therapy centres, provide pencil beam scanning exclusively.

“The pencil beam scanning that was pioneered on our gantries has served as the model for facilities around the world, and fast scanning has become the leading method of proton delivery,” says Damien Weber.

Reproduced with permission: David Meer, Paul Scherrer Institute