September 30, 2009 (Berlin, Germany) — An innovative heat technique, which warms the tissue in and around a tumor to 40 to 43 degrees Celsius (104 to 109.4 degrees Fahrenheit), has been shown to improve outcomes for patients with advanced soft-tissue sarcomas. This technique has previously shown benefits in other localized advanced cancers, including cervical cancer.

The data were presented at a presidential session during the 15th Congress of the European CanCer Organization and the 34th European Society for Medical Oncology Multidisciplinary Congress.

They come from a phase 3 trial of 341 patients with advanced soft-tissue sarcomas, and show that patients who underwent heat treatment prior to chemotherapy were 30% more likely to be alive and cancer free 3 years later than patients who did not undergo heat therapy.

First clear evidence that targeted heat therapy adds to chemotherapy.

However, a significant difference in overall survival was seen only when the researchers considered a majority subgroup of patients who received the full course of heat treatment; it was not seen in the intention-to-treat analysis.

This is the "first clear evidence that targeted heat therapy adds to chemotherapy," said lead investigator Rolf Issels, MD, professor of medical oncology at Klinikum Grosshadern Medical Center at the University of Munich in Germany.

Currently, the technique is used only in academic centers, in several sites throughout Europe, and at Duke University in Durham, North Carolina. The procedure requires specialist equipment, and the targeted heat therapy is guided by magnetic resonance imaging.

"We expect our findings will encourage other researchers to test the approach in other locally advanced cancers," Dr. Issels added, noting that the technique has already shown promise in recurrent breast cancer and locally advanced cervical cancer.

This latest study shows "important results from a large homogenous group of patients, which confirm and are in line with previous results from different tumor types," said Gerald van Rhoon, PhD, from Erasmus University in the Netherlands. "It shows that if you do good heat, you get good results," he told Medscape Oncology, explaining that in the past this field has been hampered by poor technology.

Dr. van Rhoon was not involved in the soft-tissue sarcoma study, but he is a specialist in this field and is secretary of the European Society of Hyperthermic Oncology. He is also one of the authors of a recently published trial showing benefits from targeted heat therapy when added to radiation in the treatment of locally advanced cervical cancer (Int J Radiat Oncol Biol Phys. 2009;73:242-250).

There are several theories as to how targeted heat therapy works, Dr. van Rhoon explained. It increases apoptosis, or programmed cell death, and appears to reduce the repair of sublethal damage to the tumor after chemotherapy or radiation. In addition, it increases blood perfusion of the tumor, which improves chemotherapy access and increases oxygenation, which makes the tumor more sensitive to radiation.

Results in Soft-tissue Sarcoma

The results presented by Dr. Issels at the meeting come from a trial of patients with locally advanced soft-tissue sarcoma that were at high risk for recurrence and spread. More than half of the tumors were located in the abdomen, which carried the worst prognosis; the other tumors were located in the arms and legs.

All patients received chemotherapy (with etoposide, ifosfamide, and adriamycin) before and after surgery and radiation. Half of the patients were randomized to receive the innovative targeted heat therapy before chemotherapy.

The most frequent adverse effect of the heat therapy was mild to moderate discomfort, reported by 45% of the patients; blisters were reported by 17.8% of patients. The most serious adverse effect was severe burns, seen in 1 patient (0.6%). The heat treatment did not increase the toxicity of chemotherapy, the researchers noted.

The targeted heat therapy more than doubled the proportion of patients who responded to chemotherapy. The overall response rate was 28.8% for those treated with heat and 12.7% for those not treated with heat (P = .002).

Median disease-free survival was 32 months for those who had heat therapy, and 18 months for those who did not, an improvement of 30% (P = .011).

In the intention-to-treat population, the difference in overall survival between those who did and didn't receive heat treatment was not significant (79 vs 73 months; P = .43).

However, when the researchers considered only those patients who underwent all the assigned cycles of heat treatment (269 patients; 78.9% of the intention-to-treat population), the difference between those who did and those who did not receive heat became significant (P = .038).

In this analysis, patients who received the full heat treatment "were 42% less likely to experience a recurrence of their cancer at the same site or to die than those who were getting chemotherapy alone, surviving an estimated 120 months before local progression of their disease, compared with an estimated 75 months," Dr. Issels reported. These figures come from an analysis performed nearly 3 years after the start of treatment.

At 2 years, 76% of patients were alive without local progression of their cancer, compared with 61% of patients in the group treated with chemotherapy alone, he added.

When Dr. Issels reported these findings at the meeting, several delegates questioned this secondary analysis. They were concerned that the difference between the 2 treatment groups was not significant in the intention-to-treat population.

Dr. Issels acknowledged the need for caution because the significant overall survival result was seen in a subpopulation of patients; nevertheless, he was enthusiastic about the finding, and emphasized the benefit seen on all the outcome measures.

This strategy has been under development for about 20 years, and "the clear results from this trial show that the field had now matured to the point where we must step up efforts to explore its potential to offer an entirely new way of treating locally advanced disease in several major cancers."

When it works, the impact is large.

Dr. van Rhoon was also enthusiastic, and told Medscape Oncology that this approach holds potential for many different cancer types. "In the Netherlands, about 60% of all cancers have an average 5-year survival with current treatment, but that leaves 40% of cancer patients with a low life expectation. Often, these are locally advanced tumors that would be suitable for targeted heat therapy, which could improve the response to chemotherapy and/or radiotherapy and give the patient a better chance," he explained. "When it works, the impact is large," he added.

The study was funded by the German cancer foundation Deutsche Krebshilfe and the German scientific organization the Helmholtz Association.

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstract 1LBA. Presented September 22, 2009.


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