With the headline, “Rare Cancer Treatments, Cleared by F.D.A. but Not Subject to Scrutiny,” a recent article in The New York Times reported that several medical centers were treating patients with cancer using a hyperthermia system that had received a Humanitarian Use Device approval from the U.S. Food and Drug Administration (FDA).¹ The device “is indicated for use in conjunction with radiation therapy for the treatment of cervical cancer patients who are ineligible for chemotherapy,” according to the FDA.²

A Humanitarian Use Device approval means that “there are limited clinical data that suggest benefit from device use and these data show that the probable benefit to health outweighs the risk of injury or illness from its use,” the FDA pointed out in its approval letter.³ That letter also outlines criteria for a registry study to provide additional evidence of the probable benefit and safety.

Research Problems

Medical centers that have been using the hyperthermia system have found it difficult to provide additional research data, mainly due to lack of finances and difficulty accruing patients, Mark W. Dewhirst, DVM, PhD, said in an interview with The ASCO Post. Dr. Dewhirst is Professor of Radiation Oncology and Director of the Radiation Oncology Program at Duke University Comprehensive Cancer Center in Durham, North Carolina. He served as director of a clinical program grant to study the use of hyperthermia in the treatment of cancer.

The company that manufactures the system receiving the Humanitarian Use Device approval, the BSD-2000, as well as other hyperthermia devices is BSD Medical of Salt Lake City. “It is very small and has never been able to finance any large-scale trial on its own,” Dr. Dewhirst said. “It is just not economically feasible at all.” In addition, it has been difficult to accrue adequate numbers of patients who have advanced cervical cancer and are unable to receive chemotherapy.

These difficulties in obtaining data, along with recent revisions in the study protocol to include patients with other types of cancer (not just those with the approved indication of cervical cancer in patients ineligible for chemotherapy) can give rise to concerns about adequate scrutiny. There are, however, controlled, randomized studies, most of them positive, Dr. Dewhirst noted, on the use of hyperthermia for cervical and other forms of cancer. In addition, hyperthermia for superficial cancers “is approved and reimbursable by Medicare,” he said.

Minimal Injury to Normal Tissues

Research has shown that hyperthermia—defined as exposing body tissue to temperatures up to 113°F—“can damage and kill cancer cells, usually with minimal injury to normal tissues,” and “may shrink tumors,” according to the National Cancer Institute (NCI).⁴ Usually used in combination with radiation or chemotherapy, hyperthermia can be applied locally to small areas such as tumors, regionally to large areas such as a body cavity, organ, or limb, or to the whole body to treat metastatic cancer.

The NCI Fact Sheet on hyperthermia points out that many but not all of the clinical trials of hyperthermia in combination with radiation and/or chemotherapy, have shown a significant reduction in tumor size. “However, not all of these studies have shown increased survival in patients receiving the combined treatments.”

Approved and Reimbursable

Hyperthermia “is approved and reimbursable, but only for a very limited indication, and that indication is for superficial cancers,” Dr. Dewhirst explained. “The most common use of hyperthermia that can be reimbursed is for chest wall recurrences in breast cancer, which typically appear as a rash, or sometimes as little nodules on the chest wall; sometimes these wrap around the back or up on the arms. That is treatable with a combination of hyperthermia and radiation and is reimbursable by Medicare.” Several centers in the United States currently use hyperthermia to treat superficial cancers, “and they are busy all the time,” Dr. Dewhirst commented.

Superficial melanomas could also be treated with hyperthermia, he noted. But aside from these superficial cancers, “there is no other indication that is approved for the use of hyperthermia in the United States,” he stated.

“There is a more extreme version of hyperthermia called thermal ablation,” Dr. Dewhirst added. That involves heating a tumor “to a very high temperature for a short period of time, essentially to coagulate the tissue,” he said, and “is reimbursable for liver metastases” and some other indications, he added.

Cervical Cancer Trials

A study in the Netherlands that used three different systems to deliver hyperthermia, including the BSD-2000, found that “hyperthermia in addition to radiation may be especially useful in locally advanced cervical tumours.”⁵ The Dutch study involved 358 patients with bladder, cervical, or rectal cancer, randomly assigned to radiotherapy or radiotherapy plus hyperthermia.

“The effect in cancer of the cervix was quite remarkable,” Dr. Dewhirst commented. For patients with cervical cancer, 3-year overall survival was 27% after radiotherapy alone vs 51% after radiotherapy plus hyperthermia. “That trial actually formed the basis for the approval of hyperthermia in the Netherlands for the treatment of locally advanced cervical cancer,” Dr. Dewhirst said.

“But during the time when that trial was being run in the Netherlands, several trials in the United States were testing chemoradiation in patients with cervical cancer, and those trials ended up being positive,” Dr. Dewhirst said. “By the time the results of the hyperthermia trial came out, chemoradiation was the standard of care in the U.S.” That lessened the impact of the hyperthermia trial, according to Dr. Dewhirst, because it was not perceived as comparing radiotherapy plus hyperthermia to the standard of care.

“So we decided to run a phase III trial with chemoradiation plus or minus heat,” Dr. Dewhirst explained. The trial initially involved Duke and Northwestern University, and then expanded to involve several European centers in an attempt to get a sufficient number of patients. “We had the trial open for about 3 or 4 years,” he said, “but our accrual rate was just too slow and we had to close it. So unfortunately there has never been a trial that has compared the standard of care with or without heat.”

Bladder and Sarcoma Studies

The Duke clinical program grant to study the use of hyperthermia in the treatment of cancer is no longer being funded by the National Institutes of Health, Dr. Dewhirst reported, “but we are continuing to publish papers,” he said. A paper currently in the review process concerns the use of hyperthermia to treat non–muscle-invasive bladder cancer. “So it is the more superficial type,” Dr. Dewhirst noted, “and that particular disease is problematic because it recurs a lot. We did a trial combining mitomycin, which is a standard for first-line failures, in combination with hyperthermia.” The BSD-2000 was used to beam in radiofrequency waves from outside the body,” Dr. Dewhirst explained. “It fits around the pelvis like at CT scanner and is used to heat the bladder from the outside.”

The phase I trial involved about 18 patients with bladder cancer, including “a few patients with long-term disease-free intervals. These are patients who had many recurrences before we got to them,” Dr. Dewhirst reported. An anecdotal observation emerging from the trial was palliative improvement. The first patient enrolled was a woman close to 90 years old who initially couldn’t travel the 1½ hours from home to Duke without stopping three or four times to urinate. “By the time she went through this course of therapy and had a very nice response, she was able to sleep through the night,” Dr. Dewhirst said. “And she is not the only one. We had several patients who experienced a big improvement in their quality of life.”

The impetus for that trial came from a phase III trial in Italy that randomly assigned 83 patients with recurrent bladder cancer to mitomycin intravesically with or without hyperthermia.⁶ Recurrence-free survival at 2 years was 35% in patients receiving chemotherapy alone vs 80% in the chemotherapy-plus-hyperthermia group. “People have been intrigued by that study, but it was underpowered,” said Dr. Dewhirst.

A study conducted at nine centers in Europe and North America randomly assigned 341 patients with localized, high-risk soft-tissue sarcoma to neoadjuvant chemotherapy alone or with regional hyperthermia. Patients receiving the combination therapy had significantly better local progression-free and disease-free survival.⁷ “That’s a phase III trial, and that one was properly powered,” Dr. Dewhirst stated.

Thermally Sensitive Liposomes

“We were very interested in combining hyperthermia with nanotechnology,” Dr. Dewhirst said. “The idea of having a thermally sensitive drug delivery mechanism hearkens back to the 1970s,” Dr. Dewhirst noted, “the concept being that you could make a liposome that would be thermally sensitive and would melt at a certain temperature and releases its contents. You could then use hyperthermia to deliver the dose of drug wherever you wanted it to go. We developed a thermally sensitive liposome that was more practical clinically and had a very rapid release mechanism.”

Dr. Dewhirst also holds an appointment at the School of Veterinary Medicine at North Carolina State University and has been involved in animal studies of hyperthermia. In preclinical animal studies, “we showed with doxorubicin-containing liposome that you could deliver 20 to 30 times more drug to a tumor that way than you can with free drug. We took a tumor in mice that is completely unresponsive to doxorubicin. When we put the same dose of drug in the liposome, and it cured them. We found the same general effect in a variety of different tumors,” he said.

The product has been licensed to a company and remains an active project. “They are still thinking about the next steps to take,” he noted.

“We were particularly interested in using it for locally advanced breast cancer because a lot of women in that situation are inoperable. The idea was to use it to downstage them so that they could then have surgery,” he said, but those studies could not go forward after funding was not renewed for the clinical program grant to study the use of hyperthermia in the treatment of cancer.

Promises and Proof

“There is a tremendous amount of promise in hyperthermia as well as proof. There have been around 15 randomized phase III trials, and 13 of those were positive,” Dr. Dewhirst pointed out. “A variety of different tumors have been looked at, including glioblastomas, sarcomas, cervical, bladder, rectal, and esophageal cancers, and breast cancer—particularly chest wall disease. There have been a wide range of studies, and for the most part, they have been positive.”

While the clinical program to study hyperthermia has been closed at Duke “and is probably not going to reemerge as a major area at Duke again, that doesn’t mean I am not enthusiastic about hyperthermia,” Dr. Dewhirst said. “I am the Editor-in-Chief of the International Journal of Hyperthermia, and I’m still very much a proponent of the strategy. I am doing everything I can to help other people get programs started. ■

Disclosure: Dr. Dewhirst reported no potential conflicts of interest.

References

1. Meier B: Rare cancer treatments, cleared by F.D.A. but not subject to scrutiny. New York Times, December 3, 2013.

2. U.S. Food and Drug Administration: Medical Devices: BSD-2000 Hyperthermia System – H090002. Last updated September 6, 2013. Available at www.fda.gov. Accessed December 20, 2013.

3. U.S. Food and Drug Administration: BSD-2000 Hyperthermia System – H090002 Approval letter. November 18, 2011. Available at www.fda.gov. Accessed December 20, 2013.

4. National Cancer Institute: Hyperthermia in cancer treatment. NCI fact sheet. Reviewed August 31, 2011. Available at www.cancer.gov. Accessed December 20, 2013.

5. van der Zee J, Gonzalez DG, van Rhoon GC, et al: Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: A prospective, randomised, multicenter trial. Lancet 355:1119-1125, 2010.

6. Colombo R, Da Pozzo LF, Salonia A, et al: Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol 21:4270-4276, 2003.

7. Issels RD, Lindner LH, Verweij J, et al: Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: A randomised phase 3 multicentre study. Lancet Oncol 11:561-570, 2010.