If I asked you what was John Grisham’s most important book, which would you pick? The Firm? The Client? According to him, it’s a thin book you’ve never heard of. It’s called The Tumor: A Non-Legal Thriller.
When I received the free book many years ago, I was bemused. The paperback was far from thrilling. It was advocacy in the guise of a “what if?” story, a tale of the multiverse, if you will. In one scenario, a character named Paul is diagnosed with an advanced brain tumour. He undergoes surgery, followed by chemotherapy and radiotherapy, but the tumour recurs and he passes away in a bedridden state of confusion and deterioration as the cancer assails his brain. But in a different scenario, ultrasounds transform this fatal condition into a chronic one.
Grisham’s message is that we are on the cusp of a cancer revolution. We can use sounds to treat cancer, and we need to invest money to bring this game-changing technology to the clinic as soon as possible.
Can ultrasounds be therapeutic? Our first inkling that it might be the case was a real fish-out-of-water story.
The ultrasound panacea
We can hear sounds up to a frequency of about 20 kilohertz. Above this threshold, we call them ultrasounds and we can’t perceive them anymore. But that doesn’t mean they do not have an effect on living things.
During the First World War, ultrasounds were first being used to help submarines navigate as part of a system which would acquire the name SONAR—SOund NAvigation Ranging. The first of these was the brainchild of a Canadian, Reginald Fessenden, and was built in 1914. It could detect an iceberg underwater from two miles away (a little over three kilometers).
Its adoption in medicine came about from a serendipitous observation: when the sonar was used, dead fish would be spotted. French physicist Paul Langevin, who studied under Pierre Curie (of radioactivity fame), would replicate this finding in water tanks using high-intensity ultrasounds, and people who would dip their hand in the ultrasound-carrying water of his tank would report pain in their extremity. Ultrasound wasn’t just useful to measure distances through echolocation, as bats naturally did and submarines were now equipped to do.
It had biological effects.
Soon, ultrasounds were being used to treat patients with rheumatoid arthritis and to destroy parts of the brain in people with Parkinsonism, and in a predictable display of “cart-before-the-horse-itis,” ultrasounds were heralded as a cure-all. Come one, come all! Whether you have ulcers, asthma, hemorrhoids, or chest pain, the almighty ultrasounds can cure what ails you. Hype eventually died down, and ultrasounds began to be studied as diagnostic tools, which would lead to their use in visualizing internal organs and, of course, fetuses.
The exuberance the medical community felt toward therapeutic ultrasound in the 1940s is now slowly coming back, supported by actual scientific evidence. I don’t think John Grisham’s promotion of ultrasounds in his book is folly. These sound waves are showing a lot of promise.
Bubbles of destruction
For the ultrasounds to have a precise effect on a small part of the body, like a tumour in the prostate, they have to be focused. Grisham compares this to sunlight passing through a magnifying glass, which focuses the light rays to burn a hole in a leaf.
Like a blender has different modes of action, from stirring to crushing ice, focused ultrasounds can be tweaked in a few ways to have different effects on the body. Low-intensity focused ultrasounds can transmit heat to a tumour inside the body that will either cause stress or, if the treatment lasts long enough, hyperthermia, where the overall temperature rises above normal. Alternatively, these low-intensity sound waves can create mechanical stimulation. Think of a train rattling its tracks causing a nearby building to shake.
But it’s when the intensity is kicked up to high that we start to get some truly potent effects. High-intensity ultrasounds can destroy biological tissue in one of two ways, depending on how they are emitted. By heating up the tissue, they cause it to die. By a mechanical process known as histotripsy, they break cells down to their building blocks. I am reminded of videos of houses being obliterated by the blast of an atomic bomb. If your cancer is that house, you can stop worrying and love the ultrasound bomb.
Histotripsy, which loosely translates as “tissue friction,” relies on tiny bubbles to blast our cells. The ultrasounds, when the correct setting is used, will trigger the formation of microbubbles in the tissue. These microbubbles will swing back and forth and eventually collapse. This creates significant levels of mechanical stress on the tissue, which disrupts it and turns it into sludge. Through histotripsy, focused ultrasounds can transform an organized and functioning cancerous tumour into dead, ground-up gloop, which the body can then reabsorb.
This all sounds wonderful, but focused ultrasounds are not perfect. There are issues with them that may get resolved as the technology is refined. If you try to burn a single hole in a leaf using a magnifying glass, and the wind moves the leaf by an inch, you will have two holes; likewise, focused ultrasounds are sensitive to patient movements and treatment time can last several hours. The monitoring of the treatment is usually done with a magnetic resonance imaging scanner, a bulky and very expensive piece of machinery. Then there are reports of severe full skin burns, undesired tissue injury, and pain, although these appear to be quite rare.
They are also often claimed to be non-invasive, but the devil is in the details. From my reading of the ultrasound literature, the implied definition of “non-invasive” seems to be that there is no need for the doctor to “invade” the tumour itself. But clearly, the patient with prostate cancer who is told the ultrasound probe must get closer to the prostate by being inserted into the rectum (or, in some cases, the urethra) will do a double take when the word “non-invasive” is bandied about.
That being said, focused ultrasounds do have clear benefits, especially compared to the workhorses of cancer interventions: surgery, chemotherapy, and radiotherapy. As a recent Canadian review of the topic points out, it usually causes little pain and leaves no scar. Infection risk, anesthesia requirements, and costs are lower than with surgery, and some patients, because of their age or other medical conditions, are not great candidates for surgical interventions. There is no exposure to ionizing radiation, a type of radiation which is useful in radiotherapy but is not harmless and thus requires care and monitoring. The technique is also very precise, limiting damage to the surrounding area.
But in breaking the cancer mass down to its components, ultrasounds can also theoretically uncloak a tumour that had remained invisible to the immune system. Cancers can create a microenvironment around them that shields them from immune cells that would otherwise sound the alarm. “Nothing to see here,” the microenvironment calmy pronounces, “move along!” When that environment is disrupted by ultrasounds and fragments of the tumour are loosened, the immune system may now be able to see what had been hidden, sweep in, and take care of the remnants. That’s an enticing idea, and one mostly backed up by studies in mice, but this alleged bonus feature of focused ultrasound therapy remains inconsistent and not fully understood.
Another possible benefit of focused ultrasounds: giving doctors access to the brain. The blood-brain barrier is a property of the blood vessels supplying the brain with oxygen and nutrients. It stops potentially harmful things from getting unloaded out of the blood and into the brain. This useful feature also makes it hard for medicines to reach the brain. Ultrasounds, it seems, can temporarily open up this barrier, which would allow doctors to deliver useful drugs to the central nervous system.
While focused ultrasounds are brimming with possibilities, they need to be shown to be safe and effective before they can be widely deployed. Research is being done on using therapeutic ultrasounds for 126 conditions. Some of these applications will pan out; others will not. Randomized clinical trials are being run not just for cancers like brain tumours and bone metastases, but also for Alzheimer’s disease, Parkinson’s, and major depression. Back in 2004, the Food and Drug Administration in the United States approved a specific ultrasound platform to treat uterine fibroids, which are benign tumours found in the genital tract and affecting roughly one in four women. More approvals have been granted since, such as its use in controlling pain in people with bone metastases.
We have come a long way from observing that submarine sonars were killing fish to fine-tuning our use of ultrasounds to shear or heat up uncontrolled clumps of cells, and there is still much ground to cover before we can declare ultrasounds “a revolution.” In Grisham’s book, Paul undergoes ultrasound therapy for his brain cancer. “There are no complications, and he is discharged home Friday afternoon,” Grisham writes. “He feels fine.”
Here's hoping we are getting a glimpse of the near future.
Take-home message:
- It was discovered that ultrasounds could have an effect on living things when dead fish were spotted after a submarine had used its sonar
- As a medical treatment, focused ultrasounds have two mechanisms of action, depending on the setting: they can heat up living tissue (like a cancerous tumour) or they can create tiny bubbles within it that will oscillate and break the tissue apart
- High-intensity focused ultrasounds show a lot of promise at treating many conditions, although most of these applications are still being tested and have not been approved for clinical use
