Author:

Anna Wagstaff

Introduction

The Gamma Knife machine is an alternative to conventional surgery – it delivers gamma rays to brain tumours and other brain abnormalities by focusing about many tiny beams of radiation on a tumour or other target with sub-millimetre accuracy. Although each beam has little effect on the brain tissue it passes through, a strong dose of radiation is delivered to the place where all the beams meet. It is a type of stereotactic radiosurgery; other stereotactic methods use linear accelerators (X-rays) and proton beams and can treat not just the brain but other organs.

Radiosurgery with the Gamma Knife was developed by Lars Leksell (1907–1986), a Swedish neurosurgeon who was a pioneer in stereotactic functional neurosurgery, a method for producing tiny regions of damage within diseased regions of brain to block abnormal nerve impulses and relieve symptoms such as tremor or pain.

The stereotactic technique uses a frame fixed to the head to provide a finely calibrated navigation system to introduce instruments to a precisely defined location in the brain. Leksell wanted to reduce further the already minimal damage to the brain caused by surgical instruments and saw the potential of radiation.

The ideas behind the Gamma Knife were developed during his time as head of the neurosurgery unit in Lund, Sweden, and were first published in 1951 in a paper ^[1] that introduced the term radiosurgery. In this seminal paper, he suggested using ionising radiation as a non-invasive alternative to surgery. After a lengthy period of research he developed the first Gamma Knife, which delivered 179 fine beams of gamma radiation which intersected at a location in the brain. The cross-section of the beams was rectangular, because this produced the best shape of the region of damage to improve symptoms. The first patient was treated in 1967.

Until the early 1980s, the Karolinska in Stockholm was the only centre in the world practising radiosurgery. Today, the technique had become so successful that 321 centres in 56 countries are practitioners.

Applications have evolved. Functional neurology indications have reduced as a result of progress in medical treatment, such as levodopa for Parkinson's disease. But it has become an increasingly important tool in the management of brain malignancies.

Gamma Knife in oncology

Leksell was reluctant to treat cancer with the Gamma Knife because he worried that it would not perform as well in severe diseases and could damage the reputation of the new method.

Lack of high-quality imaging also made it hard to target lesions that were not part of normal brain anatomy. Visualisation at that time was limited to plain X-rays, which could be enhanced by injecting air into the fluid filled spaces in the brain or by contrast injected into blood vessels. This limited the lesions which could be treated to tumours of the pituitary region, tumours on the hearing nerve and blood vessel malformations.

Furthermore, the technique is not suited to treating primary brain tumours – those such as glioblastomas that arise in the brain – as it works best if the target has a clear-cut margin from the surrounding brain, which is rarely the case in primary tumours.

But with modern computed tomography (CT) and magnetic resonance (MR) imaging techniques the Gamma Knife now has a major role in treating brain metastases that have spread from primary cancers elsewhere in the body, such as the lung, breast, skin, colon or kidney. This is now the most common indication for treatment.

Before the Gamma Knife, these tumours were treated with fractionated whole brain radiotherapy, which is effective but has a number of disadvantages. For patients who survive long enough there is a substantial risk of dementia due to radiation of the healthy brain, and whole brain radiotherapy has to be carried out over a number of sessions over about four weeks. This can be a considerable burden for patients who have a limited time to live. The Gamma Knife treatment takes one day and, thanks to its precision, does not cause dementia.

Such was Leksell's caution though that while CT and MR scans capable of showing the location of brain metastases emerged in the 1970s, serious treatment of brain metastases did not begin until after his death in 1986.

How Gamma Knife was developed

Geometric principles

The concept of stereotactic devices to help guide surgeons to a precise location in the dense and delicate organ that is the brain was not invented by Leksell. Credit for that goes to Victor Horsley and Robert Henry Clark ^[3], British surgeons and physiologists, who in 1905 constructed a cage-shaped 'stereoscopic instrument employed for excitation and electrolysis', which was detailed in a paper published in 1908 paper published in 1908 and later described here.

While their equipment was only used for research on animals, it introduced a 3D construct that, when fixed around the skull, could define the location of any point using 3D Cartesian coordinates.

To treat patients, this stereotactic approach had to wait for developments in imaging, such as adding contrast enhancement to X-rays, so surgeons could identify the coordinates they were aiming for. A key contribution came from the Temple Medical School in Philadelphia, US, where Ernest Spiegel, an Austrian neurologist trained in Vienna, and his student Henry Wycis devised a 'brain atlas' to aid in navigating the brain using cerebral landmarks.

Spiegel and Wycis used a modified version of the Horsley and Clark frame to plan and conduct neurosurgery, starting in 1947 with a procedure conducted on a patient with Huntingdon's disease (see here for how they introduced stereotactic surgery in people). Leksell visited them that year, and he started thinking about ways to improve the apparatus to provide surgeons with a more simple and accurate method to guide them to the location of interest.

The answer he came up with was to introduce the principle of 'centre-of-arc' ‒ the point at which all straight lines entering at a tangent from any point on the surface of the arc would converge. This was the principle behind the frame Leksell designed, which was first described in a paper published in 1949 (see this later paper for this and other references). Without this, directing an instrument to a location had been clumsy and complicated. By fixing an arc to the frame, which could be rotated forwards and backwards, an instrument could be introduced from any number of directions and angles, thus optimising the approach to the anatomy of a patient.

Source: courtesy of Jeremy Ganz, ©Jeremy Ganz

Leksell’s original frame and arc design for stereotactic surgery. The rectilinear frame that contains the Cartesian coordinates locating the precise point of interest is located within the arc. The geomtery of the arc and instruments fixed to it ensure the instrument top reaches the precise point determined by the frame. This historic instrument is located at Haukeland University Hospital in Bergen, Norway, which in 1988 installed the fifth Gamma Knife ever made. The picture is by Jeremy Ganz, who joined the hospital as chief of Gamma Knife in 1989, and published with his permission.

From surgery to radiosurgery

At the time, radiotherapy was in widespread use to treat cancer, but only for relatively wide fields, and its capacity to kill cancer cells was limited by the damage done to healthy tissue. Lars Leksell recognised that his 'stereotactic apparatus for intracerebral surgery' could overcome the limitations of conventional radiotherapy. The centre-of-arc design that allowed surgeons to choose from any number of points/angles of entry could also be used to target multiple beams of radiation from multiple angles, giving an effective therapeutic dose where they all met, while subjecting healthy tissue to much safer doses along each trajectory. Using radiation as an alternative to surgery also avoided the damage that surgical entry routes may cause even with the most accurate navigation systems.

Then in 1951 Leksell published his seminal paper, 'The stereotaxic method and radiosurgery of the brain'. Here he set out the concepts that would lead to the development of the Gamma Knife. Though listed as sole author, the paper was accredited to both the neurosurgery and physics departments of the University of Lund, indicating it was the product of close collaboration. The influence of that paper is clear from a review of all publications on stereotactic radiosurgery published between 1951 and 2010, which found that Leksell's 1951 article was the only one out of more than 5,500 that met the criteria for a 'citation classic'.

By 1953, Lars Leksell had completed a series of experiments using his new radiosurgery techniques on cats, and was starting to put the theory into practice in treating patients, using an industrial X-ray unit delivering doses through multiple portals at different positions over the head. Three cases are reported from that year. The first two patients, treated for trigeminal neuralgia, were not reported until 1971, when the 18-year follow-up showed a lasting relief of pain with no sensory loss. The third case report concerned a patient with schizophrenia treated with bilateral tractotomies, which involved spreading the dose to the right side across 15 portals and to the left via 17 portals.

The case was published only two years later, in 1955, with the head of the Lund University physics department Kurt Lidén named this time as co-author. It reported on a positive outcome for the patient, and concluded that applying radiation to deep cerebral structures was practical and seemingly safe. It also discussed the need for more research on whether the dose (around 40 Gy) was sufficient to destroy cerebral tissue, and raised concerns over the damage to the skin and the relatively poor penetration of the X-rays. This 1955 paper suggests that cobalt 60 – which emits higher-energy (gamma) radiation – and heavy particles such as protons, should both be considered as possible alternatives to X-rays.

Experimenting with radiobiology

By 1956 Lars Leksell was looking into these possibilities, and over the next few years much of the action moved to the Gustaf Werner Institute in Uppsala. The institute was home to the most advanced particle accelerator in Europe ‒ a synchrocyclotron ‒ where physicists were carrying out research in high-energy physics under the leadership of Theodor Svedberg, a physical chemist and Nobel laureate.

Among them was Börje Larsson, a young physicist who went on to play a key role in the Gamma Knife story. Working in collaboration with Lars Leksell, he spent many years experimenting with accelerated protons in animal models, using the stereotactic surgery frame, to learn about their impact on central nervous system tissue and how best to target their destructive energy. This work formed the basis for a paper on high energy protons for neurosurgery, which was published in Nature in 1958. In 1960, Leksell left Lund for Stockholm, where he took over from the renowned Swedish neurosurgeon Herbert Olivecrona as chair of neurosurgery at the Karolinska Institute, and was closer to the research at the Gustaf Werner Institute.

By 1962, Larsson and Leksell [reported on the cases] of the first three patients treated with proton therapy for neurological conditions. The treatments, for depression, pain and Parkinson's disease, used procedures that targeted different parts of the brain: a bilateral radio-capsulotomy, a radio-mesencephalotomy and a radio-thalamotomy. "The present investigation," they concluded, "demonstrates that ionising radiation of low scattering can be used to advantage for the production of therapeutically effective lesions in man. Radiosurgery of the brain has now been proven therefore to be a clinical useful and effective operation procedure."

About 20 patients with neurological conditions were treated with proton therapy using Leksell's stereotactic frame but the team were to conclude that proton therapy was not the best solution for these indications.

Switching to gamma rays

Radiosurgery of the brain had proved to be clinically useful in a clinical research setting. Yet Leksell had doubts about the suitability of proton therapy in everyday clinical practice. His early stereotactic radiosurgery treatments had involved preparing and delivering the radiation in a hospital setting to a static patient.

The immense size of the equipment used to deliver proton therapy required moving the patient rather than the beam to set up each new angle of delivery and it was harder to be precise, took longer and involved long journeys between hospital and proton facility for patients who were often severely ill.

In 1963, Larsson and Lidén reported on how well other forms of radiation compared with protons in dose strength, acceptability for patients, minimising damage to healthy brain tissue, and protecting against radiation leaks from the equipment. Electrons, neutrons and high-energy X-rays were all rejected on various grounds. But gamma rays ‒ from a cobalt 60 source ‒ could work.

Protons have the advantage of carrying a positive electric charge and can therefore be directed. Gamma rays are emitted in all directions, which requires a heavy protective shield to prevent radiation from escaping. It also means using long, tubular collimators to make the cross-section of the beam smaller and more focused.

And for Leksell's requirements for ease of use and acceptability to patients, the equipment needed to deliver a beam of various dimensions to be moved precisely and quickly in three directions around the patient's head. It was still a major engineering challenge.

From concept to reality

The story of how Leksell and the supporters of the Gamma Knife concept convinced the engineering group Axel Johnson ‒ one of the few companies in Europe capable of doing the job at one of its subsidiaries ‒ is told by Jeremy Ganz in his book The History of the Gamma Knife. Ganz also provides details of how the engineers and radiation physicists worked on the design, and how funding was found ‒ with no help from the Swedish state ‒ and how the safety regulations (rightly somewhat onerous) were addressed to the satisfaction of the authorities.

It took four years from the 1963 paper setting out the detailed concept, to the delivery of the first Gamma Knife. It was installed in Sophiahemmet Hospital, a small private hospital in Stockholm, which gave Leksell an independent hand in developing its clinical use.

The design of the first Gamma Knife was based on the same principles as the frame and the arc. The patient's head, attached to a frame, is placed in the instrument, which has frame holders that ensure the desired target is centred in the machine. The rays cannot be moved around, so 179 sources ‒ tiny pieces of radioactive Cobalt-60 ‒ were distributed over the surface of a hemispherical helmet. This is equivalent to the multiple positions available to the frame with the arc in open procedures (see image). The direction, number, and cross-section of the beams have changed in the latest machines but the principle remains the same.

Diagram of the first gamma unit. The inner helmet contained the rectangular beam-shaping collimators, which were 5×3 mm or 7×3 mm in cross section. The patient was drawn into the machine and then upward. This design minimised the amount of radiation escaping from the machine into the room. The diagram shows the arrangement of five of the 179 cobalt sources and their channels. The inner helmet was heavy and required two people to screw it into the outer helmet before the patient was put on the couch. The patient’s head was then raised into the inner helmet.

Evolution of Gamma Knife radiosurgery

The second Gamma Knife was installed in 1974 in Stockholm's Radiumhemmet, the non-surgical cancer treatment and radiotherapy research department of the Karolinska University Hospital. There were a number of small design changes. The radius of the opening of the helmet to which the patient was attached was increased from 12 to 14 cm. The major function of the original design had been to treat functional indications: the targets for these all lay close to the centre of the brain. Experience at Sophiahemmet had shown that a major use of the Gamma Knife would be the treatment of vascular malformations which can occur anywhere in the brain and so a larger opening was needed. The beam channels were changed from rectangular to circular to better treat malformations and tumours.

Doctors visited to learn about Leksell's methods. Of these, David Forster in the UK and Hernan Bunge from Argentina acquired the first Gamma Knife equipment outside Sweden. The fourth was in Pittsburgh, US under the direction of Dade Lunsford. This resulted in more papers that convinced colleagues of the value of the technology.

In 2009, the machine was reconfigured to overcome a limitation with multiple brain metastases that are widely spread. The Gamma Knife Perfexion can target any location or combination of locations of tumours.

Developers have also released a machine that can treat larger tumours than was possible in the past. Doing so requires a division of treatment into fractions, and to avoid the discomfort of repeated frame applications a frameless method has been introduced in 2015 with the Gamma Knife ICON; it permits repeated treatments without a frame. It checks the patient's position during each treatment session for stereotactic accuracy.

A Swedish story**

Leksell was not the only one to consider focused radiation to treat brain conditions. The Berkeley Radiation Laboratory in California became a major centre for humanitarian uses of radiation after World War 2, and worked with the group in Sweden on radiation types and dosage limits. Berkeley did the first medical treatment using high-energy protons in 1954 but the introduction of a new machine using gamma radiation was solely a Swedish invention and it was used only in Sweden for over a decade. The country held a leading position in knowledge relevant to the research behind and construction of the machine.

Sweden had a strong track record in radiation physics. The Sievert ‒ the SI unit used to quantify radiation dose ‒ is named after the Swedish medical physicist Rolf Sievert, reflecting his contribution to the study of the biological effects of ionising radiation. Radiation physics was a well-respected and active field of research in the country.

At the time of its inauguration in 1951, the Gustave Werner Institute synchrocyclotron, located in the university town of Uppsala, was more advanced than particle accelerators located in any of Europe's university physics departments. Furthermore, unlike most particle accelerators, which were seen primarily as tools for researching particle physics, it was under the control of the Nobel Prize winning physical chemist, Theodor Svedberg.

According to Swedish physicist Sven Kullander, writing in the CERN Courier in 2000, "For a few years, scientists in Uppsala could access protons of the highest energy in Western Europe. Several foreign physicists visited to familiarise themselves with these high-energy projectiles." It proved to be the ideal instrument on which to perform the radiobiological research necessary for the construction of the Gamma Knife.

The task of getting the Gamma Knife off the drawing board and into production required capacity and expertise in large-scale precision metal engineering, in which Sweden excelled. The prototype was built by the Axel Johnson company, Motala Verkstad, a long established Swedish precision engineering firm, which at the time was so famous for the precise shaping of tough steel that it was name-checked by Jules Vernes as one of the sources of components for Captain Nemo's submarine in his book _20,000 leagues under the sea. _

Motala, now part of a new group, still produces the Gamma Knife for Elekta, a company founded by Leksell's brothers. The channels that shape the radiation beams are drilled through a hemispherical helmet and require exquisite accuracy, or the beams would be distorted. See here for more on the story of Elekta and the Gamma Knife.

And the other key ingredient was of course Lars Leksell.

Acknowledgements

This article draws on The History of the Gamma Knife by Jeremy Ganz, published by Elsevier in 2014. We also acknowledge input from Jeremy Ganz, particularly to the sections on the evolution of Gamma Knife radiosurgery.