Image problem – the CERN EndoTOFPET-US project

9 December 2017

The annual mortality rate for pancreatic cancer in the MENA region has increased by 77% since 1990. Pancreatic cancer is notorious for its poor survival rates. Only 5% of sufferers survive beyond five years after diagnosis, and most die within 12 months. While the prognosis is somewhat better for those identified at an early stage (rising to a 7–25% five-year survival rate), most cases are not detected until much later, by which time the cancer has metastasised.

While this poor outlook has several causes, it is mostly because the disease takes a while to become symptomatic. By the time the classic signs appear – back pain, jaundice and weight loss – the cancer is typically quite advanced. What is more, tumours are unlikely to be detected during routine physical exams because the pancreas is so deep in the body, and there are no screening programmes in place.

This means the medical imaging community has a conundrum on its hands: what can be done to improve diagnosis, enabling doctors to catch the disease while tumours are small and surgery is still possible?

Answers to this question may be set to arise from an unlikely source – namely, the European Organization for Nuclear Research (CERN). Better known for its high-energy physics work, such as the discovery of the Higgs boson in 2012, CERN is also a hub of biomedical enquiry.

Take a CERN view

“CERN is not only interested in physics research, but it is also deeply concerned with the societal impacts, and this is something I have been involved in since the very beginning,” says Dr Paul Lecoq, a senior physicist in the Geneva-based body’s experimental physics division, and the technical director of the European Center for Research in Medical Imaging in Marseilles. “I specialise in optical detectors and particle detectors, but it turns out that the technologies are very similar to the technologies used in PET.”

To be precise, CMS electromagnetic calorimeters (which are used in high-energy physics) and positron emission tomography (PET) use a method called scintillation that involves the absorption of high-energy protons and the emitting of visible light. Both techniques use crystals, although PET functions on a far smaller scale. 

“The crystal-based electromagnetic calorimeter is nothing but a gigantic PET scanner, looking to the decay of the Higgs boson into two gamma rays in the same way as a PET measures the two gamma rays from the positron decay,” says Lecoq. “The fundamental knowledge on crystals and photodetectors has been very useful to our medical projects, as well as showing us the way to characterise and assemble these components.”

In 1990, Lecoq founded the Crystal Clear Collaboration, a multidisciplinary consortium for the development of new scintillators for experimental, industrial and medical applications. It was here that he began to forge links with those involved in building PET scanners, and to embark on a number of projects targeted at specific areas of need. 

In 2003, he set to work on creating a dedicated mammography scanner, the ClearPEM. A multimodal device integrating ultrasound and PET into a single imaging system, this is designed to discern tumours in the breast and axial region as small as 1mm across.

Having been trialled in a small study in Marseilles, the machine was recently moved to San Gerardo Hospital near Milan, where it is undergoing a much larger investigation to see how it compares with other modalities.

If you want to detect a tumour before it is too large and starts to spread to different parts of the body, you need to go to a millimetre resolution, and the only way is to go as close as possible to the target.

While this device is still at the prototype stage, it has shown promising results to date, inspiring Lecoq to tackle something even more ambitious. Since 2011, he has been technical coordinator at the EndoTOFPET-US consortium based at CERN that aims to develop new diagnostic techniques for prostate and pancreatic cancers.

“The idea was to provide MDs with customised and optimised tools for the development of new biomarkers for pancreatic and prostate cancer,” he says. “We also wanted to introduce PET as an endoscopic imaging tool and to develop intra-operative interventional imaging techniques.”

Three-way collaboration

EndoTOFPET-US involves three groups of stakeholders – physicists, medics and SMEs – each of which plays a critical role. Lecoq is being assisted on the medical side by Professor John Prior, head of nuclear medicine at Lausanne University Hospital, and Professor Rene Laugier, head of the hepato-gastroenterology department at the University Hospital of Marseilles La Timone.

“Very often, technologies are being developed, but they have a hard time finding their way to users, so the idea was to set up a collaboration,” Lecoq explains. “First, physicists develop the technology and build the device. Second, the three hospitals involved in the project guide us with the design, enabling us to put the technologies together in a system that works under their constraints, as well as validating the tool at the end.

“Finally, you have the SMEs, small imaging enterprises that are involved in some technical development and will be ready to exploit the technologies once they’re ready.”

In the five years since the project got under way, the team has developed two prototype scanners – one for the prostate, the other for the pancreas. Now, under the technical commissioning stage at CERN, the devices will soon be delivered to hospitals in Munich and Marseilles respectively.

These scanners are far removed from traditional, whole-body PET machines. Much like the ClearPEM scanner for breast imaging, they combine morphological information (the shapes and sizes of tumours) from ultrasound and metabolic information (the presence of cancerous cells) from PET. Through merging the two images, they are able to convey more information than would be possible with one modality.

They are also endoscopic, with a bimodal imaging probe. One PET detector remains outside the body, while the other is positioned in front of the ultrasound transducer at the tip of a probe. This means the detector can be positioned very close to the organ of interest, providing higher sensitivity. Consequently, a lower dose of radioactive tracer is required.  

“If you want to detect a tumour before it is too large and starts to spread to different parts of the body, you need to go to a millimetre resolution, and the only way is to go as close as possible to the target,” says Lecoq. “Endoscopies that are efficacious in the stomach and the first duodenum require a very high level of miniaturisation, which is what we had to do.”

While PET is extremely sensitive (around a million times more so than MRI), its spatial resolution is unexceptional, typically around 5mm. To increase the resolution, the internal PET detector head needed to be highly granular. It is composed from a matrix of tiny scintillating crystal fibres, each one 0.75×0.75×10.00mm in size.

Flight path

There were other complications too, not least the difficulty, common to all endoscopy, of dealing with constant motion and erratic background signals. The team responded by creating a time of flight (ToF) sensor that produces a direct three-dimensional reconstruction of the area under scrutiny. With a timing resolution of 200 picoseconds, it is the fastest and most precise scanner of its kind ever developed, adeptly filtering background noise.

“That was a very important challenge that was resolved through a number of enabling technologies we have developed for that purpose,” Lecoq explains.

Building the devices, however, was only one piece of the puzzle. The researchers are now turning their focus towards the project’s true endpoint: using these sensitive, custom-built scanners to find new biomarkers for pancreatic cancer.

“It would be very nice if we could discover a molecule that is produced in the early stages of the development of pancreatic cancer before it becomes symptomatic,” says Lecoq. “You could perform some medical imaging if you saw something specific in the blood test.”

It would be very nice if we could discover a molecule that is produced in the early stages of the development of pancreatic cancer before it becomes symptomatic.

At present, pancreatic cancer has no such biomarkers. Whereas prostate cancer can be flagged up through an abnormal level of prostate specific antigen (PSA) in the blood, pancreatic cancer cannot reliably be detected through a blood test. The researchers are hoping that, through using their new tool, they will be able to hone in on a few biomarker candidates that are sufficiently sensitive and specific to indicate when something has gone amiss.

While EndoTOFPET-US was funded for four years by the EU as part of the Seventh Framework Programme, the funding has now come to an end, and the project is being sustained through the goodwill of its partner institutions. From Lecoq’s point of view, this is a source of frustration, meaning the second phase is not progressing as fast as desired.

He has no doubt, however, that the project needs to continue, with or without EU funding. “The instrument is still a prototype, so the medical doctors still need us to solicit their feedback and repair it if there are some non-functioning parts,” he says. “We know very well that it takes a few years to create an instrument and then a few years to explore it clinically and create some results. The process of getting the authorisation to test a new device on patients is long and complex.”

Despite the challenges ahead, he is optimistic about the potential for the device, which is poised to break new technical and medical ground. 

“When you have achieved your technical goals, you have only gone halfway. What is important now is to see how the machine behaves in the hands of the medical doctors,” Lecoq explains. “The machine will hopefully be shipped to Marseilles in September to start clinical research on the pancreas.”

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