Cyclotron vs. cancer: cyclotron wins, and an industry is born

Adrien Reymond / Managing Director, PETNET Solutions’ Lab (Paris area) / 2014-10-11

Significant tech breakthroughs, a growing number of applications, mature industrial processes: in recent years many factors have boosted the development of nuclear medicine. Not so long ago, it was a matter of R&D. Now it’s an industry. One of its most interesting business lines is the production of FDG, the most widely used radioactive tracer in nuclear medical imaging. Adrien Reymond, managing director of an industrial BU for PETNET Solutions Inc., details the highly sophisticated production process of this radioactive isotope of fluorine. He outlines the prospects of both the FDG market and nuclear medicine as a whole.

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ParisTech Review – Nuclear medicine has evolved considerably over the past decade. It has undergone significant growth across the world. What exactly triggered of this development?

Adrien Reymond – This development is the result of new features offered by nuclear medicine imaging and more particularly, by positron emission tomography (PET). Used to visualise the activity of cells, this tool has brought significant progress. More specifically, PET helps detect pathologies resulting from an alteration of normal physiology. Images provided by PET help us understand how an organism works, as well as many dysfunctions. Through a camera linked to the PET device, we can visualise a tumour with millimetre scale.

Beyond diagnosis capabilities, PET is also interesting for therapeutic monitoring, to identify remaining lesions after a treatment. Examination is often coupled with a scanner. PET Scan, for example, merges two images and allows you to locate precisely metabolic dysfunctions. In a close future, these techniques will guide surgeons during their interventions. Thanks to the higher degree of precision allowed by the next-generation imaging, surgery operations will evolve. They will be less intrusive and increasingly automated.

To obtain an image through PET, you need to inject a radioactive tracer. The production of these indicators of a new kind is a specific line of business, led by the same manufacturers who designed and manufactured different models of PET on the market today – rather than by the pharmaceutical industry. Siemens, for instance, has diversified very soon into the production of the products needed to make their devices work: in 1995, the company acquired PETNET Solutions, a U.S. firm specialized in this field, and has supported its expansion.

Since 2012, this company has a subsidiary in France. It produces fluorodeoxyglucose, also known as FDG. Could you tell us a bit more about this product and what it is used for during PET scans?

In nuclear medicine, 95% of PET scans today use FDG. This pharmaceutical product is made of a radioactive atom (fluorine 18) and a carrier molecule. Fluorine 18 is a radioactive isotope of fluorine with a half-life of slightly less than two hours. This means that in two hours, half of the radioactive atoms will decay (and after a dozen hours there remain only a few thousandths).

This decay is interesting for us, because during the process fluorine atoms emit positrons. The emitted radiation will help build the medical image. This mode of decay yields stable oxygen-18, an element that does not interfere with the body.

In Nature, there is only non-radioactive fluorine-19. But different isotopes can be produced. Why fluorine-18? Heavier isotopes (fluorine 21, for example) decay releasing neon, a dangerous product for the body. Lighter isotopes have a half-life of a few minutes, making them unusable for medical imaging.

The principle of this operation is that radioactive atoms have time enough to bind to the tumour, and help us determine its outline when atoms decay. For this they need a vector. In the case of FDG, the vector is simply sugar. Sugar reveals the metabolic dysfunction of cancer cells: given the speed and anarchy of their development, they consume much more energy and sugar than healthy cells. When decaying, radioactive fluorine 18 coupled with a sugar molecule inside the cancer cells will emit a radiation that will be detected by the PET camera. This allows to identify and differentiate cancer cells.

Today, oncology – i.e. the diagnosis and treatment of cancer – is one of the main fields of application for PET scans using FDG. But FDG is increasingly used in cardiology and neurology. Just as for cancer diagnosis, FDG can reveal other types of dysfunctions. In neurology, for example, brain imaging with FDG is used for the diagnosis of some forms of dementia. In cardiology, PET scanning provides valuable information for doctors and assists in developing personalized treatments.

How is fluorine-18 produced?

unedoseF18 FDGInside labs, through a sophisticated process, but at an industrial scale in terms of volumes: PETNET Solutions will produce 20,000 doses this year. Its radiation is measured with extreme precision in mega-becquerels. This extremely sensitive production process requires high-end equipment.

The laboratory has two cyclotrons, i.e. particle accelerators. Cyclotrons are controlled remotely by two computers. To produce fluorine 18, we don’t use fluorine 19 but enriched water with oxygen-18. Oxygen is a neighbour element of fluorine in the periodic table (neon could also be used). Oxygen-18 nuclei are bombed with accelerated light particles (i.e. protons), a nuclear reaction takes place, which transforms them into fluorine-18. After two or three hours of irradiation, the radioactive fluorine-18 is transferred to the synthesis insulator. Fluorine 18 is then fed into a reactor where we proceed with a nucleophilic substitution to attach the isotope on a glucose molecule. This is a fully automated step. The insulator doors are made of lead, with a thickness of 75 mm in order to protect from radiations.

The next step is a purification step. Once synthesised, FDG may be transferred to distribution insulators. The solution is then diluted to match the specifications prescribed by health authorities for marketing authorization. Then, it is distributed in vials, according to the specifications provided by the clients. All these operations are automated or performed remotely, with pliers. The bottle then falls automatically in a lead container. The first copy of each production is sent to quality control for analysis. Product conformity is then verified. This analysis takes about 30 minutes. When the pharmacist gives the green light, the packages are sent to the clients.

We produce an average of three batches each night. Production follows just-in-time requirements. The cyclotron starts half an hour after midnight. At five o’clock in the morning, the products are ready to leave for delivery. This way, the product is available for our customers (i.e. nuclear medicine hospitals or clinics) at the beginning of the day. The distinctive feature of FDG is that it can last twelve hours. That’s why we have installed two cyclotrons on our Parisian site. This allows us not to suffer downtime due to maintenance and to start two productions in parallel. This ensures our clients and patients improved reliability.

How fast does the FDG market grow?

The first production of fluorine-18 came out of the laboratories thirty years ago. But this medicine is used at a large scale since the mid-2000s. Today we are witnessing an explosion in demand and an increase in the number of production sites. In France for example, 240,000 patients benefit from FDG injection, and the country has around fifteen cyclotrons. At Lisses, during the first year, PETNET Solutions produced 4,000 doses of FDG. Today, we produce five times more. France should allow the installation of fifteen new PET cameras during the next four years. This will increase demand even more. The same development can be observed in the rest of Europe as well as in major emerging countries.

A cyclontron

The activity was first developed in the United States, but it has to spread to the rest of the world. PETNET Solutions, for example, now operates on 55 sites worldwide and has installed over 200 cyclotrons. We are also developing in Asia and India. The accuracy of diagnosis, the indications that PET scans can deliver and what it shows from a metabolic point of view offers significant growth prospects.

Are there other possible applications for nuclear medicine?

Yes, indeed. For example, in Lisses, we also produce other molecules such as sodium fluoride (FNa), produced in partnership with the Lilly laboratory, used for bone diseases and as a tracer for amyloid plaques which reveal symptoms of Alzheimer’s disease. Finally, we also work on a tracer of angiogenesis that detects revascularization of certain tumours (malignant tumours have the particularity, because of their pathological growth, to be highly vascularized).

The challenge is to develop new molecules able to detect and reveal metabolic disorders, paving the way for new applications. The products of the future will no doubt be the result of a collaboration between the medical community, which expects a treatment to cure a specific disease, and the R&D of large pharmaceutical companies and industrial manufacturers of medical equipment.

Laboratories will increasingly be based on functional imaging to validate new available therapies. Their goal is to guide appropriately medical treatment.

Does nuclear medicine help create new professions?

Yes, and very skilled ones, from the different segments of the production chain to use. At the hospital, in the relevant departments, the staff is highly-specialized. Radiographers receive patients, inject the products and operate the device. Radio-physicists are responsible for the calibration of the equipment. Nuclear medical physicians interpret the results of the scan. In addition, a specific curriculum has been created some15 years ago in the pharmacy internship. Radiopharmacists assume responsibility for the product release and conformity of the batches. On the industrial side, production technicians and cyclotron engineers are responsible for the maintenance of production equipment.

How do you see the development of nuclear medicine in the next twenty years?

20 years ago, it was impossible to imagine the applications we use today. Nuclear imaging was still very limited. The imaging of a 2-inches high and 1-inch wide thyroid took half an hour. Today, it takes less than a minute. 20 years ago, most tracers existed already but the computers that drove the cameras were too slow and unsophisticated to render a quality image. As other imaging methods, nuclear medicine will develop depending on the evolution of machines. In 20 years, computers will work ten times faster. We will also gain precision. The aim is to approach a millimetre resolution to visualise very small metabolic mechanisms.

Will the boundary between nuclear medicine and radiology eventually fade?

Yes, these are increasingly integrated disciplines, both for manufacturers and users. It is likely that in ten years, the images from the MRI and PET scanners will be merged and made by a single device. This is already the case with some devices such as the PET-MRI scanner, but the principle will become mainstream. Each of these techniques produces specific information: on the structure of organs or on how they work. The combination of these different information into one image has just begun and we will surely follow this direction.

For the benefit of patients, not only because the diagnoses will be more accurate and quicker, but it will also reduce the number of intrusive operations. Increased precision will also benefit patients by reducing doses and targeting closer to the area of interest. In the case of some tumour diseases for which examinations are frequent, it’s a very important feature, which should be emphasised: in the future, medicine – both diagnosis and therapy – will certainly have less impact on the body. This recent development, will undoubtedly shape the coming decades.

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Note: PETNET is a subsidiary of Siemens, which is a patron of ParisTech Review.