Description:
Hyperthermia can be administered using local and whole body techniques. Local hyperthermia entails elevating the temperature of superficial or subcutaneous tumors while sparing surrounding normal tissue, using either external or interstitial modalities. Whole body hyperthermia requires the patient to be placed under either general anesthesia or deep sedation. The patient's body temperature is increased to 108° F by packing the patient in heated (hot water) blankets. The elevated body temperature is maintained for a period of four hours, while the essential body functions are closely monitored. Approximately one hour is required for a "cooling off" period, after which the patient is constantly observed for a minimum of 12 hours. This modality has been variously termed "systemic thermotherapy" or "whole body hyperthermia."

Policy:
MEDICALLY NECESSARY:

• Local hyperthermia therapy when used in combination with radiation therapy for the treatment of patients with primary or metastatic cutaneous or subcutaneous superficial tumors (e.g., superficial recurrent melanoma, chest wall recurrence of breast cancer and cervical lymph node metastases from head and neck cancer)

INVESTIGATIONAL:

• Local hyperthermia, using either external or interstitial modalities, in conjunction with radiation therapy for all other uses not identified as medically necessary
• Regional deep tissue hyperthermia in the treatment of malignancies
• Whole body hyperthermia therapy
• Hyperthermic melphalan perfusion in stage I, IIIB and IIIAB extremity melanoma, as well as hyperthermia in conjunction with any other chemotherapy

Policy Guidelines:
The best results with hyperthermia in conjunction with radiation therapy are seen in lesions measuring 3 cm or less in diameter. In addition, patients with widespread metastatic disease are not likely to benefit from local hyperthermia.

Hyperthermia is typically administered every 72 hours (i.e., twice a week) for a total of 10 to 12 treatments. This treatment schedule is based on thermobiologic principles; specifically, thermotolerance develops more than eight to10 hours after treatment and subsides over the next 60 to 100 hours.

Rationale:
The use of hyperthermia as an adjunct to radiation or chemotherapy of superficial tumors has been an area of active investigation for the past 20 years, in part due to improvements in instrumentation and temperature-monitoring technique, as well as an increasing understanding of the biology of hyperthermia. One of the first randomized trials of hyperthermia was reported by Overgaard, who randomized 71 patients with superficial melanoma to receive either radiation therapy or combined radiation and hyperthermia. The combined treatment group reported a 46 percent complete response rate compared to 28 percent in the radiation-only group.¹ In 1991, Perez and colleagues reported on the results of a study that randomized 236 patients with superficial tumors measuring less than 5 cm in thickness to receive either radiation alone, or radiation in conjunction with hyperthermia.² The major endpoints for the study were the initial tumor response, its continuous control and treatment delivery. The overall complete response rate was not different between the two groups (30 – 32 percent). However, when the treatment comparisons were made by the size of the lesion in the patients with lesions < 3 cm in diameter, the difference in local control was significantly better for patients assigned to the combined treatment group (52 percent vs. 39 percent). In 1996, the International Collaborative Hyperthermia Group reported on the outcomes of a trial that focused on hyperthermia treatment of superficial breast cancer.³ A total of 306 patients with advanced primary or recurrent breast cancer were randomized to receive either radiation therapy alone or combined radiation and hyperthermia therapy. The primary endpoint of the trial was complete local control; 59 percent of those in the combined treatment group achieved complete local response compared to 41 percent in the radiation therapy alone group. Similar to the findings of Perez, results were improved in patients with smaller lesions, as indicated by diameter or depth.

Other studies have reported conflicting results. For example, Emami and colleagues reported negative results in a study that randomized 173 patients with persistent or recurrent superficial tumors to receive either interstitial radiation therapy alone or radiation combined with hyperthermia. In this study, the hyperthermia was administered interstitially, primarily as a technique to provide more uniform heat to the target lesion. There was no difference between the complete response rates in the two groups.⁴ The Radiation Trials Oncology Group (RTOG) has published guidelines outlining quality control criteria for adequate hyperthermia treatment.⁵ When the investigators compared these criteria to their data, they found that only one patient met the criteria for adequate hyperthermia sessions. The issue of quality assurance and reproducible parameters for delivering hyperthermia has been identified as an obstacle by other authors, as well.^2,6 Identification of the optimal parameters for hyperthermia has also been researched. The majority of the clinical trials describe eight to 12 hyperthermia regimens delivered twice weekly, or every 72 hours. These schedules recognize the phenomenon of thermotolerance, a transient resistance to subsequent heat treatment.

There are inadequate data to permit scientific conclusions regarding the use of whole body hyperthermia as an adjunct to either radiation or chemotherapy, and inadequate data regarding the use of local hyperthermia in conjunction with chemotherapy alone. A literature search of the MEDLINE database targeted at clinical articles published between 1995 and 2001 found citations describing technical feasibility studies and a few phase I and II studies, but there were no controlled studies reporting on patient outcomes.^7.8.9 There were no studies identified that focused on the use of local hyperthermia with chemotherapy alone.

References

1. Overgaard J, Gonzalez Gonzalez D, Hulshof MC et al. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology. Lancet 1995;345(8949):540-3.
2. Perez CA, Pajak T, Emami B et al. Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group. Am J Clin Oncol 1991;14(2):133-41.
3. Vernon CC, Hand JW, Field SB et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys 1996;35(4):731-44.
4. Emami B, Scott C, Perez CA et al. Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the Radiation Therapy Group. Int J Radiat Oncol Biol Phys 1996:34(5):1097-04.
5. Emami B, Stauffer P, Dewhirst M et al. RTOG quality assurance guidelines for interstitial hyperthermia. Int J Radiat Oncol Biol Phys 1991;20(5):1117-24.
6. Sherar M, Liu FF, Pintilie M et al. Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: data from a phase III trial. Int J Radiat Oncol Biol Phys 1997;39(2):371-80.
7. Robins HI, Rushing D, Kutz M et al. Phase I clinical trial of melphalan and 41.8 degrees C whole-body hyperthermia in cancer patients. J Clin Oncol 1997;15(1):158-64.
8. Mittal BB, Zimmer MA, Sathiaseelan V et al. Phase I/II trial of combined 131I anti-CEA monoclonal antibody and hyperthermia in patients with advanced colorectal adenocarcinoma. Cancer 1996;78(9):1861-70.
9. Wiedemann GJ, Robins HI, Gutsche S et al. Ifosfamide, carboplatin and etoposide (ICE) combined with 41.8 degrees C whole body hyperthermia in patients with refractory sarcoma. Eur J Cancer 1996;32A(5):888-92.
10. Kouloulias V, Plataniotis G, Kouvaris J, et al. Chemoradiotherapy combined with intracavitary hyperthermia for anal cancer: Feasibility and long-term results from a phase II randomized trial. Am J Clin Oncol. 2005;28(1):91-99.
11. ones EL, Oleson JR, Prosnitz LR, et al. Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol. 2005;23(13):3079-3085.
12. Issels RD, Schlemmer M, Lindner LH. The role of hyperthermia in combined treatment in the management of soft tissue sarcoma. Curr Oncol Rep. 2006;8(4):305-309.

Coding Section

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This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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