Adding regional hyperthermia to neoadjuvant chemotherapy produced significantly higher progression-free and disease-free survival rates in patients who had undergone macroscopically complete resection of high-risk, nonextremity soft tissue sarcomas in a phase III trial, according to a study that was presented at the meeting in Barcelona.
At 2 years post treatment, the progression-free survival rate was 70% and the disease-free survival rate was 56% in patients who were treated with regional hyperthermia plus neoadjuvant chemotherapy, according to a subgroup analysis of patients with nonextremity disease. Corresponding rates for neoadjuvant chemotherapy alone were 54% and 39% in this population.
Hyperthermia’s advantage held at 5 years, with rates of 54% for progression-free survival vs. 43% in the control group, and 35% vs. 24% for disease-free survival, Dr. Rolf D. Issels reported at the biennial meeting of the European Society for Therapeutic Radiation and Oncology (ESTRO 29).
“The rationale for using regional hyperthermia is to make tumors more sensitive to chemotherapeutic agents and radiotherapy,” Dr. Issels of the Klinikum Grosshadern at the Ludwig-Maximilians University of Munich said in an interview.
“Besides sensitization to other treatment modalities, hyperthermia also kills tumors in a temperature range between 40° and 43° C [104°-109.4° F], and we know from preclinical and early clinical data that it seems to activate the immune system by delivering stress or danger signals,” he explained.
The main findings of the ESHO/EORTC–Soft Tissue and Bone Sarcoma Group (STBSG) 62962 trial were published recently in the Lancet (2010;11:561-70). Of the 341 recruited patients (median age, 51-52 years), more than half had nonextremity tumors that were predominantly located in the abdomen, pelvis, or trunk, which led to the question of whether macroscopically complete surgical resection in these patients could potentially abrogate the beneficial effects of regional hyperthermia that was observed in the trial.
The new data that Dr. Issels presented at the meeting involved only those patients with nonextremity sarcomas who had macroscopically complete surgical resection. In total, 73 patients with R0/1 resection received neoadjuvant chemotherapy alone, and 76 had received neoadjuvant chemotherapy together with regional hyperthermia.
Neoadjuvant chemotherapy consisted of etoposide, ifosfamide, and doxorubicin (Adriamycin) – a regimen abbreviated as EIA – and was given for four cycles with or without additional regional hyperthermia before definitive surgery and postoperative radiotherapy. This was followed by four more cycles of postinduction chemotherapy with or without regional hyperthermia, according to randomization. Regional hyperthermia was delivered via the BSD-2000/3D Hyperthermia System, in which the patient lies down inside the deep-heating device while receiving intravenous chemotherapy.
The primary end point was local progression-free survival, which remained significantly improved by the addition of regional hyperthermia to EIA chemotherapy, compared with EIA chemotherapy alone. The hazard ratio for local progression free-survival was 0.60, favoring the use of regional hyperthermia and EIA over EIA chemotherapy alone (log rank P = .034). Median local progression-free survival was not reached with regional hyperthermia; it was 30 months with chemotherapy alone.
The hazard ratio for disease-free survival (0.65; log rank P = .031) also favored the use of regional hyperthermia and EIA. Median disease-free survival was 32 months with the intervention vs. 17 months in the control group.
The clinical implications of the research are clear, said Dr. Issels: The combination of regional hyperthermia with neoadjuvant chemotherapy can improve outcomes in patients with high-risk sarcoma. “Unfortunately, we only have a few centers in the world to perform regional hyperthermia together with chemotherapy,” he noted, urging other centers that refer patients to consider the approach used at his institution.
Together with earlier preclinical work, the completed phase III trial provides not only proof of concept, but also proof of efficacy, Dr. Issels added.
“We are going to transfer the knowledge to advanced pancreatic cancer,” he said. “We have an open study to deliver gemcitabine plus cisplatin as second-line therapy combined with regional hyperthermia in locally advanced or metastatic pancreatic cancer.”
Dr. Issels and associates are also looking at the use of thermosensitive liposomes containing chemotherapeutic agents in early preclinical studies.
Disclosures: The study was funded by Deutsche Krebshilfe, the Helmholtz Association of German Research Centres (HDF), the European Organisation for Research and Treatment of Cancer (EORTC), the European Society for Hyperthermic Oncology (ESHO), and the U.S. National Institutes of Health. Dr. Issels has received research and educational grants from Amgen, Baxter, BSD Medical, and PharmaMar, together with honoraria and consulting fees from GSK and MedTherm.