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Can physics save the day in the fight against cancer?

At the end of the old Bond films our hero and his accomplices would have to break into the villain’s secret hideout and disable the super-weapon, whilst fighting off an ensemble of disposable henchmen conveniently clad in orange jumpsuits to help distinguish them from the good guys. The bad guys all get shot, the good guys survive and the villain’s plans are foiled.

Real world combat isn’t nearly as simple as it is in the Bond films. Neither is the battle to fight cancer once it takes hold. Perhaps the single biggest challenge with cancer treatment, whether it be surgical, radiological or pharmaceutical, is distinguishing the bad cancer cells from the good healthy cells. They don’t wear orange jumpsuits, and in fact they are often indistinguishable – it would be far easier for a surgeon trying to remove cancer if all the cells wore matching boiler suits like 007’s adversaries. In practice, it’s enormously challenging for a surgical team to remove a tumour, as any cancer cells left behind can be fatal whilst removing healthy tissue unnecessarily can have severe functional or cosmetic consequences.

In this article we’ll look at the ways in which physics is being used to improve the targeting of various therapies by differentiating the good cells from the bad, explore the underlying science and consider the challenges of both use and adoption.

 
iKnife
 

iKnife

The iKnife, currently under development at Imperial College London, demonstrates a novel approach to real time determination of cancer margins. A hollow tube is attached to the tip of the standard electrosurgical knife used to cut and cauterise tissue during surgery. The tube sucks the emitted smoke and vaporised cell components up into an ionisation mass spectroscopy system which analyses the constituents and informs the surgeon if tell-tale cancer compounds are present. Mass spectroscopy is commonly used in analytical chemistry to identify unknown chemical compounds (and the principle is explained in the box above). The iKnife gives feedback to the surgeon in almost real time, advising them on whether they’re cutting into healthy or cancerous tissue.

The developers of the iKnife haven’t tried to identify all the possible molecules in cancer cells, but instead they’ve compared the characteristic patterns of molecules found in cancer and healthy cells. As a result, a computer analysis of the mass spectroscopy data pattern indicates the likelihood of tissue being healthy or cancerous. The iKnife is a nice idea and proof-of-concept has been demonstrated, but it requires significantly greater sensitivity and specificity before it could become a viable tool for routine cancer surgery.

How mass spectroscopy works

In mass spectroscopy, a mixture of vaporised ions (molecules with an electrical charge) is rapidly accelerated (using a strong electrical charge) towards a detector array which records the impact of each molecule. Before reaching the detector the ions pass through a strong magnetic field which deflects the path of the ions depending on their weight and charge (bigger, heavier molecules are deflected more). The magnitude of deflection, as recorded by the detector array, indicates the mass-charge ratio of each ion and as every molecule has a particular mass-charge ratio, it is possible to identify particular molecules.
 

mass-spectroscopy-illustration

 
Fluorescence guided surgery

Fluorescence guided surgery, or fluorescence molecular imaging, involves labelling cancer cells with a fluorescent dye, illuminating the surgical field to excite the dye, and observing the resultant fluorescence in-situ. The prospect of making cancer cells glow in the dark sounds appealing. Since visible light doesn’t penetrate very far into tissue, near infrared (IR) light is used instead, typically >780nm, as this can penetrate 2-3cm into tissue and creates virtually no auto fluorescence. Any cancer cells labelled with a chemical dye will emit fluorescent light of longer wavelength (>830nm) which can be visualised by a highly sensitive digital camera equipped with an optical filter to exclude the shorter wavelength excitation light.

The camera system superimposes the fluorescent image, in real time, onto a normal view of the surgical site so that the surgical team can see the tumour location and ensure the excised margins are clear of any cancer. A number of such fluorescence visualisation systems are now commercially available and have been granted marketing approval by the FDA.

fluorescence-guided-surgery

Cancer-specific dyes are more of a challenge than the hardware, however, and currently the non-specific dye indocyanine green (ICG) is the only useful approved fluorescence dye. A cancer-specific molecularly targeted dye has yet to be approved although a number are currently undergoing clinical evaluation. Fluorescently labelled, cancer-specific antibodies are a promising route to high specificity, but whilst they are widely used as an in-vitro research tool they have not yet been translated into an approved clinical product. The primary challenge is making the antibodies sufficiently specific so they don’t bind to healthy tissue yet bind strongly to cancer cells.

 
Intraoperative radioisotope visualisation

Radiopharmaceuticals play an important role in cancer therapy and diagnosis, and the combination of radioactively labelled glucose and PET scanning (positron emission tomography) is the de-facto tool for cancer visualisation. Glucose labelled with radioactive fluorine18 (FDG) is administered, and this accumulates in tissues which are metabolically active. Because tumour cells are rapidly dividing they accumulate relatively large amounts of tracer.

he patient is then placed inside a PET scanner – a circular array of x-ray detectors. When each radioactive fluorine18 isotope decays it emits a positron, a positively charged version of an electron. The positron immediately collides with a nearby electron and both particles are annihilated, emitting two gamma rays which fly off at 180 degrees to each other, and these two gamma rays are detected by the array of x-ray detectors surrounding the patient. This tells us that the tracer was somewhere along a straight line between the two detectors. The time at which the two gamma rays reach the detectors is then compared in order to work out how far the fluorine atom was from each side, thereby placing the location of the tracer molecule in three dimensions.

There are some drawbacks to using PET. Firstly, the patient is exposed to a small amount of radioactivity. Secondly, as the fluorine18 isotope has a very short half-life of just under two hours, radioactive FDG must be made on-site or transported very quickly to the hospital. Lastly, PET resolution isn’t as high as other imaging modalities such as CT or MRI, although by overlaying 3D PET images with CT itis possible to determine the location of tumours fairly accurately.

Whilst PET scanning is useful it can’t provide real-time feedback for a surgeon looking to remove a tumour. Scientists are therefore developing low light scanning technology to directly image the location of any radioactive glow within the body, during surgery. This definitely sounds like the stuff of Bond films but when radioisotopes decay in water, or inside the body, they do actually emit a characteristic blue glow, known as Cherenkov radiation often visible in photographs of cooling ponds containing radioactive material. Specialist high sensitivity imaging systems can visualise this faint glow during surgical procedures, thus allowing the surgeon to visualise any residual cancerous tissue. This technique requires the patient to be given a radioactive tracer and also exposes the surgical team to radiation but is a potentially useful tool in reducing the need for repeat surgery to remove cancerous tissue missed during earlier procedures.

Proton beam therapy

Proton beam therapy

Radiotherapy is a well-established cancer therapy. X-ray radiation is delivered to the tumour, and as the tumour cells are dividing rapidly their DNA is highly susceptible to damage which stops the cell dividing. But radiation also damages healthy cells, causing unwanted side effects, and proton beam therapy can help reduce this collateral damage.

Proton therapy systems are very large and as each costs ~$100m only a handful of proton facilities are currently in operation around the world (recently London, New York and Manchester have all announced plans to install proton therapy facilities). To understand what’s so good about proton therapy, it’s helpful to first recap how normal radiotherapy works. Imagine a basketball court containing thousands of empty beer glasses – these represent the normal cells in your body, while the centre circle contains flower vases, representing cancer cells. Using a machine gun, placed on the ground at the edge of the court, we now try to smash the vases; the bullets represent x-rays and some beer glasses are inevitably hit by bullets travelling towards the vases and by bullets on their way out of the centre circle. It’s a good idea to move around the edge of the court as we shoot, otherwise we’ll create a path of badly broken glasses in our line of fire. By regularly moving, the unwanted beer glass breakages are spread out over the whole court, while the total number of beer glass breakages remains the same. Exactly the same principle is applied to radiotherapy; the dose is directed towards a tumour from varying angles around the body, minimising the damage to any particular area of skin or tissue since x-rays are powerful enough to go through the body, frequently hitting healthy cells on the way in or out.

In proton beam therapy, a stream of protons is used rather than x-rays. Protons, the positively charged particles in the middle of atoms, are fired from a particle accelerator the size of a small house located within a dedicated nuclear physics facility. The benefit of protons over x-rays is that operators can specify the energy at which they are fired, with the result that the protons penetrate to a specific depth in the body and no further. To use our basketball court analogy, it’s like using a slingshot to shoot pebbles at the glass vases. Each pebble starts travelling at high speed but doesn’t have enough energy to go beyond the vases in the middle. As each pebble ricochets off glasses or vases it gradually slows down so that by the time it reaches the centre circle it’s going so slowly that it crashes into more and more vases until it eventually stops. Therefore, when protons are fired into the body, the majority of damage is done at the specific depth of the tumour; some damage is done to the cells in front of the tumour but most of the energy is deposited within the tumour and nothing behind the tumour is harmed. This is particularly beneficial when a tumour is located close to a critical structure such as the spinal cord or within the brain.

Proton therapy does have some drawbacks (in addition to the cost and size of the facility). In particular, very complex treatment planning is required for each patient in order to get the maximum benefit and as yet the clinical benefits of proton therapy over normal radiotherapy haven’t been conclusively proven in multiple clinical studies.

 
Conclusions

Despite the development of some very sophisticated technologies, which Bond’s Q would be proud of, it’s evident that finding and killing cancer cells inside a person, without causing too much collateral damage, is extremely tricky. Unfortunately, there’s no silver bullet (or golden gun for that matter).

Differentiating the good guys from the bad will always be taxing in a battle where the antagonists don’t wear colour coordinated jumpsuits. It will always be a challenge for the doctor to know which cells to let live and which to let die (sorry, couldn’t resist that). And finally, it’s worth considering the astronomical number of cells involved in this battle. Ernst Stavro Blofeld, one of Bond’s greatest nemesis, even at the peak of his career, could rarely muster more than a hundred armed henchman, yet a modest sized solid tumour can contain several billion cells – more cells than there are human beings on Earth. It’s a big task but the battle against cancer is slowly and surely being won.

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