Medical imaging & patient care

The heat is on

Philips and the Eindhoven University of Technology have announced an important development in MRI-guided local drug delivery for cancer treatment, which has the potential to improve chemotherapy in certain cancers. The university’s Professor Holger Grüll, lead researcher, explains what this development – involving the non-invasive heating of tumours and the use of temperature-sensitive drugs – might mean for the future of oncology and how it differs from the alternatives currently available.

A patient lies still on a motorised bed, preparing to enter an MRI scanner. She is suffering from liver cancer of a particularly pernicious variety: the tumour is clinging to a critical mass of blood vessels, rendering surgery impossible. Nor is she eligible for radiation therapy, as the cancer has a necrotic core.

She is not here simply for a progress check, however, but for a radical new form of treatment. Over the course of the next few hours, her tumour will be non-invasively heated and temperature-sensitive drugs administered, unleashing their active ingredient (doxorubicin) to the tumour site at an unusually high dosage. The side effects should be low, the therapy intense.

Most importantly, the process will be visualised and measured in real time, so the physician will know instantaneously whether further treatment is required.

This scene, beguiling in its potential, is not yet a reality, but early signs suggest it isn’t far away. In February 2011, researchers announced that MRI-guided local drug delivery had reached a crucial milestone in its development. A proof-of-concept study had been published in the Journal of Controlled Release, which held great promise for the future of oncological care.

“I think the technique will add a new therapeutic option to the ones that are already established, and you will probably be able to help a patient group that doesn’t currently have a viable treatment,” says Professor Holger Grüll, who headed the research. “In the long run, you can think about replacing current therapies.”

New technologies

His team, from Royal Philips Electronics and Eindhoven University of Technology, is taking part in the EU-funded research project, Sonodrugs. Targeted towards an ageing population, this project aims to develop novel drug-delivery technologies, enabling much-needed localised treatments of cancer and heart disease.

This particular procedure has been touted as a possibility for nearly a decade, but not until 2011 were there compelling grounds to suggest that it should work. As detailed in the proof-of-concept study, researchers performed a similar procedure on rats, heating the animals’ tumour sites with ultrasound and injecting them with temperature-sensitive drugs. Compared with the control rats, whose tumours were not heated, a greater uptake of drug was achieved.

While people cannot be assumed to respond like rodents, Grüll points out that this was more than your average pre-clinical trial. “In typical studies, the rats were warmed with a hot water bath,” he says. “That’s not translatable to patients. What we did was to bring together a huge chain of technologies – MRI, ultrasound, chemistry – and show that ultrasound guidance gives a very clinically translatable approach.”

A creative mix

The beauty of this treatment is not that its technology is pioneering, but rather that it fuses existing elements in an unforeseen and ingenious way.

Heating, for example, takes place using magnetic resonance-guided focused ultrasound, which has been used across a panoply of applications for some 20 years. Briefly, the MRI scanner incorporates an ultrasound dish, which focuses sound waves into one spot. This raises the temperature dramatically: think of it as being like a magnifying glass, catching the rays of the sun.

Most frequently, this technique has been used for the purposes of thermal ablation. Uterine fibroids are commonly treated in this way, melting away tissues at around 65˚C. For chemotherapy purposes, however, the temperature needs to be lower, simulating a local fever as opposed to a destructive blast of heat.

“We took this machine and used it completely differently,” says Grüll. “We go down to around 42˚C, to the hyperthermia range. The MRI scanner functions as a very precise thermometer, measuring the temperature on the focus spot and giving a feedback loop back to the ultrasound.”

As well as hyperthermia, this treatment relies upon temperature-sensitive liposomes. Chemotherapy has always suffered from the problem that, once injected, the drugs circulate unrestrainedly in the blood. True, they attack the tumour, but they also ambush any other quickly dividing cells.

With hair follicles, bone marrow and digestive tract under siege, the patient may become very sick. The clinician faces a tricky balancing act between minimising side effects and eradicating the cancer.

Protective barrier

Liposomes, then, are designed to prevent the active pharmaceutical ingredient (API) from entering healthy tissues. Tiny fat-based spherical structures, in which the API is encapsulated, these particles are too large to escape from well-sealed blood vessels. Only in the tumour do they have ease of access, as tumour vessels are diagnostically ‘leaky’, with large gaps in the endothelial walls.

When you’re dealing with a heated tumour site, and temperature-sensitive liposomes, efficacy is improved on two counts. Firstly, cancer cells are structurally responsive to heat, so a warm tumour contains more gaps through which particles can invade. Secondly, the particles will break down and release their API when and only when they’re sufficiently warm. The chemotherapy will do its intended job at exactly the right spot.

“These liposomes open up only at 42˚C, so the other tissue is protected against them,” says Grüll. “You can imagine that you get quite a high concentration of drug in the tumour tissue, up to a tenfold dose increase, extending the therapeutic window of your chemotherapy. A treatment may have fewer side effects.”

The final advantage of this procedure is the ease with which radiologists can gauge success. Alongside the drug itself, the temperature-sensitive liposomes also include an MRI contrast agent to heighten visibility on the scan.

“As long as these contrast agents are actually in the particle, you can’t see them on the MRI, but when they open up in the warm tumour they induce a contrast change,” says Grüll. “What we showed in our proof-of-concept study was that this scaled nicely with the amount of drug that we find in the tissue.”

Testing treatment

Our hypothetical liver cancer sufferer belongs to the group in which this therapy may be pioneered. Many cancers are essentially inoperable, because their tumour has grown onto a vital structure. But, as long as the cancer has not metastasised (spread out in the body), a strong dose of chemotherapy at the appropriate location may provide her with an excellent prognosis.

Grüll does not see this treatment as a panacea. “We will never replace traditional chemotherapy, for a simple reason,” he says. “Most of the time, chemotherapy is used for systemic treatment when you already have metastasis, focussing more on a palliative than a curative approach. Once you have metastasis, our methods will not really work because we can only treat what is local and what we can see.”

Regrettably, this means that local drug delivery will prove redundant for a significant proportion of patients. With a disease such as pancreatic cancer, for instance, around 80% of cases presenting at the clinic have already spread. A treatment like this is applicable only if you catch the disease at a relatively early stage of its development.

Even then, certain cancers will have to be ruled out for other reasons. Lung tissue is problematic as lungs contain air, and the ultrasound is prone to echoing. Brain tissue is challenging too, and out of the question for the time being.

More reassuringly, this does leave a wide range of possible targets – Grüll cites liver, pancreatic, renal, prostate and breast cancers to name just a few. “Our strategy will depend on business model, patient numbers and so on, in terms of what we pick to begin with,” he says.

Further progress

In the year since the proof of concept was published, a good deal has been achieved. The researchers have developed a mathematical model, allowing the MRI image data to be used to predict drug concentration in the tumour. And while the previous study assessed chemotherapeutic uptake, a trial underway at present will determine its efficacy.

While more strategic work does needs to be carried out, Grüll envisages that the final hurdles are surmountable. “It’s difficult to say,” he concedes, “but looking at the typical pharmaceutical roadmap, there should be something in the clinic anywhere between the next two to five years.”

As the procedure edges ever closer to full clinical applicability, he also believes that the technologies may spearhead something more wide ranging. “I expect that there are many drugs candidates that are currently shelved because of pharmacological properties that render them useless as normal drugs,” he says. “But once local delivery is viable, we may have an option at hand that allows us to administer very potent drugs in a completely different way.”

This feature appears in the Autumn 2012 edition of Medical Imaging Technology


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