Freezing Desmoid Tumors Halts Progression, May Cure?

Liam Davenport

October 22, 2019

BARCELONA, Spain — For patients with a rare form of connective tissue tumor whose condition progresses after medical treatment, total necrosis of their tumor could occur if they are treated with cryoablation, say French researchers.

In fact, the technique could "cure some patients who had progressive disease," said principle investigator Jean-Emmanuel Kurtz, MD, PhD, Service d'Oncologie Médicale, Hôpitaux Universitaires de Strasbourg, France.

Cryoablation, which is performed under general anesthesia, involves inserting probes into the tumor, which then deliver argon gas at temperatures as low as –40 °C.

Over several freezing and thawing cycles, tumor cells die off, and the tumor turns into a necrotic mass with the consistency of Jell-O, Kurtz explained. This mass is then resorbed into the body. For some patients, no tumor remains.

His team has used the technique experimentally in patients with desmoid tumors for some years now, and "some of these patients are free of tumor, even large tumors, even 6 or 7 years later," he said.

They reported results of the first prospective trial of this technique in patients with desmoid tumors here at the European Society for Medical Oncology Congress 2019. Their study received funding from the French National Cancer Institute.

Cryoablation halted disease progression in almost 90% of cases and led to marked improvements in pain scores and quality of life, he said.

The procedure is "safe, and we think it should be offered to progressing patients in sarcoma centers," he commented.

He emphasized that the technique should only be offered by "an expert medical oncologist and interventional radiologist doublet," owing to the risk for nontumor tissue damage.

The results show that cryoablation "offers another nonmedical option for the management of progressive desmoid tumors" that "can be applied in masses for which an open surgical procedure would have severe complications," commented invited discussant Ioannis P. Boukovinas, MD, PhD, PharmD, from Bioclinic Thessaloniki, Greece.

Boukovinas noted, however, that the study had several weaknesses, including the lack of a control arm. In addition, the prior medical treatments "were of known limited activity," and the follow-up period, which was only 1 year, was too short.

"Terrible Disability"

Desmoid tumors, which originate from musculoaponeurotic structures, have "an unpredictable behavior," and they can grow to be large and disfiguring, Kurtz commented. Some patients experience "terrible disability, deteriorating quality of life, and, hopefully rarely, death."

In the past, desmoid tumors have been removed surgically, but this surgery too can be disfiguring, and sometimes, depending on the location of the tumor, surgery is not possible.

In Europe, current guidelines recommend watchful waiting after diagnosis, Kurtz noted.

For patients who experience progression, medical treatment includes nonsteroidal anti-inflammatory drugs, tamoxifen, and low-dose chemotherapy, generally in the form of a combination of methotrexate and vinblastine.

"In those whose tumors progress after these first-line options, we have new treatments," he said. These include the targeted agents sorafenib (Nexavar, Bayer/Onyx Pharmaceuticals) and pazopanib (Votrient, Novartis).

Although these drugs as well as radiotherapy are options, Kurtz noted that "the care of progressing desmoid tumors still represents an unmet need."

The first reports of the use of cryoablation for the treatment of desmoid tumors emerged 9 years ago. His own team's experience began about that time. One patient had "a huge desmoid near the backbone"; for that patient, treatment with cryoablation yielded results that were "so astounding that we decided there was definitely something to this," Kurtz told Medscape Medical News.

He continued to discuss the idea in the intervening years with Afshin Gangi, MD, PhD, a leading interventional radiologist at Hôpitaux Universitaires de Strasbourg.

After Kurtz took charge of the sarcoma tumor board at their institution, the idea of conducting a phase 2 trial took off.

First Prospective Trial

The CRYODESMO-01 study was conducted in 50 patients who had desmoid tumors that were progressing after at least two lines of "adequate medical therapy" and were either unresectable or would require "mutilating" surgery, as judged by a tumor board.

The tumor had to be measurable using modified RECIST criteria on gadolinium contrast–enhanced MRI and deemed accessible for cryoablation, with 90% of tumor destruction achievable in one procedure.

Cryoablation was performed over two 10-minute freezing cycles. The cycles were separated by a passive 10-minute thawing period. Ice flow volume was constantly monitored on MRI.

Patients were subsequently hospitalized for 2 days, after which they were discharged. Clinical and MRI assessments were planned to occur at regular intervals during the next year.

In line with the typical patient profile, 78% of the fifty patients included in the study were female; the median age was 37 years. The most common tumor sites were the limbs (36%), trunk (30%), and abdominal wall (30%).

Notably, the tumors were large. The median largest diameter was 89 mm (range, 21 – 245 mm), and the median tumor volume was 111 cm3 (range, 0.59 – 1067 cm3).

The study met its primary endpoint; at 12 months, the vast majority of patients had not experienced disease progression, Kurtz told the meeting.

Using the modified RECIST criteria, the team found that 85.7% of patients had no disease progression; 28.57% showed a complete response; 26.19% had a partial response; 30.95% had stable disease; and 14.29% experienced progression.

Treatment efficacy was assessed via MRI contrast uptake. The results showed that the tumor was necrotic in the treatment zone in 84.09% of patients at 12 months; 15.91% showed some form of ongoing disease or recurrence.

Between month 1 and month 12, MRI contrast update imagery showed that there was an increase in cryolesion size. Kurtz noted that the information provided by this assessment method was "more accurate in defining success vs failure" for cryoablation than the RECIST criteria.

The most common adverse effects were pain, peripheral nerve impairment, edema, musculoskeletal impairment, rhabdomyolysis, and skin burns. Kurtz pointed out that 79% of adverse effects were "as expected" and that they were mild to moderate in nature.

There were 24 grade 3/4 adverse effects in 15 patients, including seven cases of rhabdomyolysis.

The majority of severe adverse effects occurred during the cryoablation of large tumors, and most patients had a "favorable outcome over time," Kurtz said.

Assessments with the Brief Pain Inventory revealed a decrease in pain intensity during follow-up, with a concomitant reduction in analgesic intake and an increase in activities of daily living, such as walking, work, and sleep, as well as mood.

This was reflected in improvements in quality-of-life scores. The dimensions of usual activities and anxiety/depression improved steadily during the course of follow-up from month 1 or 2.

Randomized Trial Now Planned

The team is now planning a randomized trial, CRYODESMO-02, which they hope to start in the first quarter of 2020. Funding was obtained from the French National Cancer Institute.

This trial will explore cryoablation as a first-line treatment for desmoid tumors and will compare it with chemotherapy with methotrexate and vinblastine or nonsteroidal anti-inflammatory drugs. Patients who experience disease progression will cross over to the other treatment arm.

Where Does Cryoablation Fit In?

At present, there is "no clear recommendation" for cryoablation in the treatment algorithm for desmoid tumors, Kurtz told Medscape Medical News.

He emphasized that it is clearly "feasible in patients who have failed on prior medical treatment" and stated that he and his colleagues "do not recommend cryoablation before standard medical treatment has been tried." Kurtz added that he sees many patients who say that they have been diagnosed with a desmoid and that they want to undergo cryoablation as initial therapy, "but the answer is 'no.' "

However, he noted that if the results from CRYODESMO-02 are positive, it would put cryoablation as a first-line treatment "on the table, because we will hopefully show that cryoablation is superior to any medical treatment."

In his discussion, Boukovinas wondered about the reliability of using MRI to assess tumor necrosis in the absence of a biopsy.

Kurtz commented to Medscape Medical News that the slow resorption of the necrotic tumor means that at 12 months, a lump may still be felt or "you can see something" on CT imaging, "but it's not viable, it's just slowly getting smaller."

However, on MRI, contrast uptake allows clinicians to view "tiny little spots in which you can find some contrast product, if there is some parts of the tumor that are still viable."

Their recommendation is therefore "to perform cryoablation under MRI, because you can have a real-time assessment of the ice flow," Kurtz continued. "Afterwards, MRI follow-up is fine, because you can make subtraction images, and the center of the tumor which has been treated is absolutely dark and there is no product uptake in there ― this dark zone is free of any viable cells."

As for the management of toxicities, Kurtz urged that all procedures be performed at "expert centers" by a "highly skilled" interventional radiologist working in tandem with a medical oncologist, not least because of the risk for collateral damage to neighboring tissues during freezing.

"The last thing we want to see is some radiologist just buying the machine and starting on his own to treat desmoids," he said. "It may really kill the procedure if we have side effects due to those untrained and inconsequent radiologists, but so far we haven't had this."

European Society for Medical Oncology (ESMO) 2019 Annual Meeting: Abstract 1668O, presented September 30, 2019.

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