Technique for PDAC may help increase effects of chemotherapy
Effort adds ultrasound, microbubbles to deliver drugs more effectively
Combining chemotherapy with focused ultrasound and microbubbles is safe and helps deliver chemotherapy drugs more effectively to tumors in people with inoperable pancreatic ductal adenocarcinoma (PDAC), a fast-growing and difficult form of pancreatic cancer to treat.
Focused ultrasound is noninvasive and uses sound waves to target areas inside the body, which, when paired with tiny gas-filled bubbles, can temporarily open blood vessels in tumors.
While there was a tendency for this approach to increase survival time, it failed to reach statistical significance. The study, “Treatment of inoperable pancreatic adenocarcinoma with focused ultrasound and microbubbles in patients receiving chemotherapy,” which reports the results of a small Phase 1 clinical trial (NCT04146441),was published in WFUMB Ultrasound Open.
Pancreatic cancers like PDAC are difficult to detect early because symptoms often don’t appear until the disease is advanced. As a result, most people are diagnosed at a stage where the potential curative treatment of surgery is no longer an option.
PDAC is often treated with chemotherapy to manage symptoms and slow the growth of cancer cells. In some cases, chemotherapy can shrink the tumor enough to make surgery possible, offering a chance at more effective treatment.
There are several approved chemotherapy options for pancreatic cancer, including gemcitabine with nab-paclitaxel and Folfirinox, a combination of four drugs. Folfirinox is often the first-line treatment for advanced PDAC and it can be effective, but only about a third of patients see significant tumor shrinkage, while others may see only disease stabilization.
The trouble with PDAC
PDAC tumors have very few blood vessels and are surrounded by a thick, tough tissue made up of support cells, fibers, and immune cells. This dense tissue raises the pressure inside the tumor, squeezing blood vessels and making it hard for oxygen and cancer-fighting drugs to reach the tumor. Many treatments that have tried to break down or change this tough tissue haven’t worked in clinical trials, creating a need for better treatment strategies for PDAC, according to researchers.
Sonochemotherapy is intended to increase the efficacy of chemotherapy and combines chemotherapy, focused ultrasound, and microbubbles to increase the ability of the pancreas or other tissues to absorb medications. In animal models of pancreatic cancer, the treatment significantly increased the efficacy of chemotherapy. Microbubbles are often used in medical imaging to improve visibility. When exposed to low-intensity ultrasound, they start to gently vibrate, which can temporarily make cell and blood vessel walls more open, helping medications enter tissues and work more effectively.
“The aim of this clinical trial was to investigate whether [focused ultrasound] and [microbubbles] could improve the effect of chemotherapy in patients with inoperable pancreatic ductal adenocarcinoma … and to investigate safety and feasibility,” wrote the researchers, who recruited 19 people with inoperable PDAC who were receiving chemotherapy.
For those on Folfirinox, the drugs were given in a set order, with several medications infused on day one, followed by a slow infusion over the next few days. Focused ultrasound and microbubble treatment was applied shortly after the quick injection on day one, before the longer infusion started.
For those receiving nab-paclitaxel and gemcitabine, chemotherapy was given weekly on days one, eight and 15, with a break on the fourth week before the next cycle. Focused ultrasound and microbubbles were administered right after chemotherapy on those same days.
A work in progress
Half the participants received treatment with focused ultrasound and microbubbles, while the remainder formed a control group. Participants in the treatment and control groups had similar mean ages (66 and 69, respectively), but a greater proportion of the treatment group was female. “The included patient group had advanced disease, with considerable variation in treatment course and outcomes,” the researchers said.
Eleven participants were treated with Folfirinox; the remainder received gemcitabine-nab-paclitaxel. The side effects varied greatly between participants, but included nausea and tiredness, which are usual with chemotherapy, and none seemed to be caused by the ultrasound and microbubble treatment.
The participants in the sonochemotherapy group had a slightly lower number of hospitalized days than the standard chemotherapy group.
Changes in tumor size varied from person to person, with no significant differences between the groups. No participants in either group were eligible for tumor removal after two months of treatment. Greater reductions in tumor size correlated to shorter delays in chemotherapy delivery only in the sonochemotherapy treatment group.
The ultrasound and microbubbles tended to slightly increase the median survival time, from 9.8 months to 11.7 months, but this difference wasn’t statistically significant.
The study’s design meant the researchers weren’t able to determine if sonochemotherapy changed disease progression. “A prolonged treatment period, measuring time to progression as an endpoint, may have given valuable information,” they wrote.
Another potential limitation was the relatively small number of participants and the variability in their treatment timelines.
Based on the trend toward larger changes in tumor size with shorter chemotherapy delays, the team suggested that optimizing the timeline could lead to better outcomes. “Reducing the time between chemotherapy and injection of [microbubbles] and [forced ultrasound] and optimization of ultrasound parameters may improve the treatment effect,” they wrote.
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