Adding Heat to Chemotherapy Improves Some Results in Sarcoma

Zosia Chustecka

May 19, 2010

May 19, 2010 — Patients with high-risk soft-tissue sarcoma who were treated with regional hyperthermia and chemotherapy had better outcomes than those treated with chemotherapy alone in a phase 3 trial reported online April 28 in the Lancet Oncology.

However, the improvements were seen most impressively in locoregional control and were not found in the highly important distant failure rate, an outside expert commented.

Results from this trial were presented last year at the joint meeting of the European CanCer Organization (ECCO) and the European Society for Medical Oncology (ESMO), as reported by Medscape Oncology.

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

These are "important results" for the technique of regional hyperthermia, which "confirm and are in line with previous results from different tumor types," said Gerald van Rhoon, PhD, from Erasmus University in the Netherlands. He said that previous studies were hampered by poor technology, but this study shows that "when you do good heat, you get good results."

Dr. van Rhoon was not involved in the current study, but has used this local hyperthermia technique and was one of the authors on a paper reporting benefits from targeted heat therapy added to radiation in the treatment of locally advanced cervical cancer (Int J Radiat Oncol Biol Phys. 2009;73;242-250).

Ready for Use in Sarcoma Patients?

"This randomized trial provides the first evidence that regional hyperthermia added to preoperative and postoperative chemotherapy is clinically more effective than chemotherapy alone in a specific population of patients with high-risk soft-tissue sarcoma," Dr. Issels and colleagues conclude in their paper.

This therapeutic strategy offers a new treatment option.

"This therapeutic strategy offers a new treatment option, and can be integrated into the multimodal treatment approach for these patients," they add. Indeed, the researchers have already added regional hyperthermia to their routine clinical practice.

However, before accepting this approach as a new standard of care for local soft-tissue control, there needs to be further examination of the toxicity and morbidity associated with regional hyperthermia, cautioned Raphael Pollock, MD, PhD, a sarcoma specialist at the University of Texas M.D. Anderson Cancer Center in Houston.

Approached by Medscape Oncology for comment, Dr. Pollock said: "This is an interesting report that suggests that the addition of hyperthermia as an adjunctive treatment enhances the impact of systemic chemotherapy on control of stage III soft-tissue sarcoma."

"The effect appears to be of benefit in the context of local disease control," he added.

However, he pointed out that "distant failure, the lethal event in most extremity sarcomas, did not appear to be affected by the addition of hyperthermia."

"This seeming dichotomy might be taken as evidence that metastasis is a relatively early event in soft-tissue sarcoma, one that is not particularly affected by enhanced hyperthermia-mediated local control, as it appears to occur later as a 'downstream' event," he explained.

Dr. Pollock noted that he would like to see details about toxicity, in particular whether or not the consequences of regional hyperthermia used in this manner include increased wound complication rates, delays in return of extremity function, and increased incidence of peripheral neuropathies.

"Were the local morbidity of hyperthermia plus chemotherapy to be indistinguishable from that of chemotherapy alone, an even more exuberant expression of enthusiasm for this approach would appear to be in order," he said.

Innovative Technique

Regional hyperthermia is an innovative technique that has, to date, been used only at a few academic centers across Europe, and at Duke University in Durham, North Carolina (which was involved in the current study). It requires specialist equipment; the targeted heat therapy is guided by magnetic resonance imaging to warm up tissue in the tumor and surrounding area.

For this study, Dr. Issels and colleagues used the BSD-2000 Hyperthermia System (manufactured by BSD Medical Corporation, Salt Lake City, Utah). They aimed for tumor temperatures of 42 °C for 60 minutes on days 1 and 4 of each chemotherapy cycle, during both induction and postinduction.

"The rationale for using regional hyperthermia is that heat kills cells by direct thermal toxicity, increases drug efficacy, and induces tumoricidal immune responses," the researchers explain.

Trial Design

The trial involved 341 patients with high-risk soft-tissue sarcoma, of whom 169 were assigned to receive heat therapy in addition to chemotherapy; the remainder received chemotherapy alone.

All patients received the same chemotherapy (etoposide, ifosfamide, and doxorubicin), which was administered in cycles every 3 weeks.

Nearly all of the patients (90.6%) underwent surgery. Most had definitive tumor resection after induction chemotherapy, and a few patients (<10%) underwent amputation. The median interval between induction therapy and surgery was 5.9 weeks.

Many of these patients also received radiotherapy (61% to 63%), at a mean interval of 6.3 weeks after surgery.

The proportion of patients who underwent surgery and radiotherapy was similar in the 2 treatment groups.

However, more patients in the hyperthermia group completed the full postinduction chemotherapy (52.7% vs 41.3%). In addition, they completed more cycles of chemotherapy (median, 8 vs 5).

Results in Detail

The primary end point of the trial was local progression-free survival. This was significantly better (P = .003) in the hyperthermia group than in the chemotherapy-alone group, with an absolute difference of 15% at 2 years (76% vs 61%).

Secondary end points were also significantly better in the hyperthermia group. Disease-free survival was nearly double that of chemotherapy alone (32 vs 18 months; = .011), and the treatment response rate was more than double (28.8% vs 12.7%; P = .002).

In addition, in a prespecified per-protocol analysis of patients who completed treatment, there was significantly better overall survival in the hyperthermia group (P = .038).

However, this secondary analysis was questioned by some researchers when it was reported at the ESMO/ECCO meeting, because survival is usually reported in an intent-to-treat analysis, and in this trial there was no overall survival benefit when the results of all patients (not just those who completed treatment) were considered (74 vs 79 deaths; P = .43).

Dr. Issels and colleagues explain that the improvement seen in both local progression-free survival and disease-free survival in the hyperthermia group was "predominantly attributable to the regional hyperthermia-related prevention of local progression, since the number of deaths were similar in both treatment groups."

However, there is an additional risk for toxicity. In this trial, the addition of hyperthermia significantly increased the risk for leukopenia, probably because the heating field covered part of the bone marrow, particularly in patients with large abdominal or pelvic tumors, the researchers note. Leukopenia was reported in 77.6% of the hyperthermia group and in 63.5% of the chemotherapy-alone group (P = .005).

The authors describe the toxicity seen in this trial as "moderate," and emphasize that the benefit they saw was in patients with high-risk soft-tissue sarcoma.

"Whether a similar benefit will be seen in lower-risk patients, and whether the safety profile will be the same — and hence the trade-off between benefit and harm worthwhile — remains to be established," they add.

Dr. Issels and 2 coauthors report receiving consulting fees from Medtherm Corp. His other coauthors have disclosed no relevant financial relationships.

Lancet Oncol. Published online April 28, 2010. Abstract

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