Special report: Surgery without the scalpel

August 30, 2013
by Brendon Nafziger, DOTmed News Associate Editor
By far, until recently at least, the biggest cancer focus of HIFU has been on prostate cancer. While the FDA has not approved any prostate cancer-treating HIFU device in the United States, treatments are available in other countries, and the controversy around centers trying to lure patients to places like Cancun for HIFU therapy has even made it into the mainstream media — The New York Times, for instance, covered the kerfuffle in 2008.

But some of the newer devices are relying on MR, and not ultrasound, for guidance, which means they might give better soft tissue delineation and more accurate site temperature readings and thus potentially better results, according to Thomas Andreae, with Philips Healthcare’s MRC Therapy Business Development unit in Helsinki, Finland.

Also, new studies suggest HIFU offers a promising kind of prostate cancer treatment called focal therapy. In this, instead of removing or ablating the whole prostate, as is usually done, only the tumors are destroyed, in what its backers describe as a prostate “lumpectomy.”

“Theoretically, the less tissue that you would treat, the fewer side effects you would experience,” Dr. Jonathan Coleman, a urologic surgeon at Memorial Sloan-Kettering Cancer Center in New York, tells DOTmed News.

Early results suggest that might indeed be the case. A study led by University College London physician Dr. Hashim Ahmed and published last year in The Lancet found that 95 percent of the 41 men treated by focal HIFU prostate therapy were cancer-free one year following the treatment. In the study, which used MR to map the tumor (but not to guide treatment in real-time), side effects were also minimal, with most patients retaining urinary continence and erectile function.

“Men who undergo traditional treatment have a 50 percent chance of achieving the so-called trifecta status – the ‘perfect outcome’ with no urine leak, good erections and cancer control at 12 months after surgery or radiotherapy,” a UCL press release claimed. “In this study, the researchers showed that after focal therapy men have a nine in 10 chance of achieving the trifecta outcome at 12 months.”

However, the study, as promising as it might seem, still has a problem – the results are too short-term.

“We don’t have long-term outcomes yet to be able to tell us what the durability of these treatments might be,” Dr. Coleman says.

The problem is that even in men with aggressive forms of prostate cancer, outcomes such as overall survival and disease-free survival can take at least five years to be determined,
Coleman explains, and sometimes up to 10 years.

“It’s one of those very tricky disease processes, and in many cases can take a long time to play out,” Coleman says.

A further difficulty is that if doctors decide to take a “watch and wait” approach with men with intermediate or low-risk disease, they often find that 25 to 35 percent of the men will not have cancer on a repeat biopsy.

However, more data should be coming soon. At Memorial Sloan-Kettering, they’ve run two prospective clinical trials using HIFU as a focal therapy to treat prostate tumors. The studies have been finished, and Coleman says they’re just analyzing the data, and expect to publish results before the end of the year.

Inside job
But those aren’t the only prostate possibilities. Coleman says Sloan-Kettering will also likely investigate another protocol for HIFU in so-called salvage prostate treatments, a sort of back-up therapy for cancer patients who were not cured by radiation therapy.

Another potential approach to HIFU treatments of prostate cancer is to change the location of the therapy altogether. At his lab in Sunnybrook University in Toronto, Dr. Rajiv Chopra, now an associate professor of radiology at UT Southwestern Medical Center in Dallas, is working on a system to apply HIFU from a new angle.

For HIFU, Chopra says there are two practical choices for treatment in order to reach the prostate: you can insert the transducers through the urethra, or through the rectum. Most prostate HIFU treatments now take place through the rectum, he says. But one problem with this method is time.

“If you had to pick one big challenge in the field, it’s how to speed up the treatment,” he says.

Although it only takes a few seconds to heat the tissue, doctors have to wait for blood to remove the heat and for surrounding tissue to cool down, or they risk cooking the intervening muscle and organs. As a result, treatments can last three or four hours. But with the transurethral approach, it could be faster. Here, the transducer tipped catheters are threaded up the urethra, so the heat can be applied directly to the gland.

“So therapies are 20 minutes, 30 minutes,” Chopra says.

Chopra’s team in Toronto has developed a custom-made, transurethral MR-guided HIFU, which is now working off a Philips MRI and modified Sonalleve software. Previously, the team had been using a GE magnet; the basis for the first human feasibility study published in Radiology last year, but made the switch in 2011.

Chopra says they’re still in the early days, and the study using the new Philips software only began in 2012. So far, only five patients have been treated using the modified Sonalleve software, for a study that will likely be published in 2014. In this study, the prostate will be ablated, but then removed following the procedure to examine histological evidence that the cancers were all destroyed.

“There’s no benefits to the patient; we’re looking histologically as to how accurate the technology is,” he says.

Interestingly, Chopra envisions the product as a single-use medical device, with the probe discarded after each use. As for the probe, it would carry eight transducers, each about 5-millimeters long, laid out in a line.

Chopra says he’s not alone. A 25-employee start-up, Profound Medical, which launched in 2008, licensed similar technology, and is also starting human trials in Canada using a Siemens MR platform.

Whether the prostate therapies pan out, MR-HIFU could also find a use as a secondary, adjunct therapy, according to Chopra. That is, for hyperthermia.

It’s been known for decades that poorly oxygenated cancers respond worse to radiation therapy. Yet by heating up the tissue, blood flow and oxygenation can be improved, thus boosting radiation therapy’s cancer-killing abilities. While hyperthermia adjunct techniques have been tried before and have failed, that’s largely because the body’s homeostatic mechanisms make it hard to keep the body at a constant high temperature using an external source, Chopra says. But MR-guided HIFU has an advantage: better thermometry. MR is able to accurately quantify the temperature in tissue, based in part on how water molecules react to heat, so an MR-guided treatment, by constantly monitoring and then modulating heat, could potentially make hyperthermia work. But, as with other technologies mentioned here, this is also in the very early stages.

“We’re just going to see some human studies start in the next few years,” Chopra predicts.

Surgery without the scalpel
HIFU relies on heat, but ultrasound causes non-thermal biological effects, too. It can also create microbubbles in tissue, a process known as cavitation. Generally, diagnostic ultrasound manufacturers work to create as little cavitation as possible. But almost a decade ago, researchers at the University of Michigan wondered what would happen if they turned the cavitation up to a high degree. The therapeutic potential of the resulting technology, which they call histotripsy (from “histo,” cell and “tripsy,” breakdown), is being explored in a Michigan spinoff, called HistoSonics.

The technique, developed by Drs. Charles Cain, Brian Fowlkes, Tim Hall, Zhen Xu and William Roberts, all from the University of Michigan, was originally investigated for use in in utero treatments on babies with heart defects. But the company is now at work on commercializing a device to treat benign prostate hyperplasia (BPH), otherwise known as an enlarged prostate. In this, non-cancerous prostate growth makes urination difficult.

To treat it, HistoSonics envisions using its device to send high intensity ultrasound into the excess prostate tissue to, in effect, shave it away. To do this, the therapeutic ultrasound is placed at the perineum, between the rectum and scrotum, and the energy is focused through the skin at a target in the prostate. The cavitation then essentially liquefies the tissue, letting doctors perform noninvasive ‘surgeries’ using the ultrasound energy as a scalpel.

“It liberally homogenizes soft tissue to an a cellular slurry,” Tom Davison with HistoSonics explains. “Because it’s non-thermal, the margins are very precise — it heals rapidly, with much less inflammation compared to thermal modalities.”

The homogenized slurry would then be reabsorbed by the tissue or excreted by urination. In BPH, that means patients could basically urinate out the sludge that was their excess prostate tissue. Studies on dogs have shown the healing is rapid, Davison says, usually occurring within 30 days.

“We believe compared to what’s out there for the treatment of BPH, that this technology is game-changing,” he says. “The urologists are going to like a modality that does essentially the same operation you do with a TERP — which removes the tissue by literally resecting with electrosurgery or lasers.”

Transurethral resection of the prostate, or TERP, is a procedure in which an instrument is threaded through the urethra and then removes, often by laser, the part of the prostate that blocks urine. TERP has about an 18 percent complication rate, Davison says.

So far, the company has raised $11 million in Series A financing from several venture capital groups. Davison says this amount takes them through product development and validation and into the pilot studies — the company has just filed an investigational device exemption with the FDA to begin a clinical trial, which it hopes to launch in a month or two. HistoSonics also has approval from Health Canada to do some studies in our neighbor to the north.
“We are currently, actively engaged in putting together Series B financing,” Davison says. He says they currently have a “couple million” left and they’re hoping to raise $12 to $15 million to take them through clinical trials and into the marketplace.

Right now, HistoSonics only has nine full-time employees. “We’re pretty lean and mean,” Davison says.

“I’ve been a serial entrepreneur for 25 years, and I’ve started a lot of companies, and to be able to accomplish what we have with (nine) people and $11 million is pretty amazing.”

Still, the clinical evidence will have to come in before clinicians will jump on board.

“That’s generally a treatment modality that hasn’t been used in clinical trials as yet. It’ll be interesting to see what the side effect profile looks like with those treatments,” Sloan-Kettering’s Dr. Coleman says. He also says modalities like HistoSonics’ are generally being researched for the treatment of benign disease, possibly because the jury’s out on whether they can be used for cancer, as they might not have the full “tissue-destructive” effects of HIFU.

“The problem that we struggle with in the treatment of any cancer is you’ve got to kill every single cancer cell or make sure those cancer cells will die after treatment,” Dr. Coleman explains, because even if a “small number survive they can proliferate and grow.”

Click here to read part one