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Purpose: To determine if adjuvant interstitial hyperthermia (HT) significantly improves survival of patients with glioblastoma undergoing brachytherapy boost after conventional radiotherapy., Methods and Materials: Adults with newly-diagnosed, focal, supratentorial glioblastoma < or = 5 cm in diameter were registered postoperatively on a Phase II/III randomized trial and treated with partial brain radiotherapy to 59.4 Gy with oral hydroxyurea. Those patients whose tumor was still implantable after teletherapy were randomized to brachytherapy boost (60 Gy at 0.40-0.60 Gy/h) +/- HT for 30 min immediately before and after brachytherapy. Time to progression (TTP) and survival from date of diagnosis were estimated using the Kaplan-Meier method., Results: From 1990 to 1995, 112 eligible patients were entered in the trial. Patient ages ranged from 21-78 years (median, 54 years) and KPS ranged from 70-100 (median, 90). Most commonly due to tumor progression or patient refusal, 33 patients were never randomized. Of the patients, 39 were randomized to brachytherapy ("no heat") and 40 to brachytherapy + HT ("heat"). By intent to treat, TTP and survival were significantly longer for "heat" than "no heat" (p = 0.04 and p = 0.04). For the 33 "no heat" patients and 35 "heat" patients who underwent brachytherapy boost, TTP and survival were significantly longer for "heat" than "no heat" (p = 0.045 and p = 0.02, respectively; median survival 85 weeks vs. 76 weeks; 2-year survival 31% vs. 15%). A multivariate analysis for these 68 patients adjusting for age and KPS showed that improved survival was significantly associated with randomization to "heat" (p = 0.008; hazard ratio 0.51). There were no Grade 5 toxicities, 2 Grade 4 toxicities (1 on each arm), and 7 Grade 3 toxicities (1 on "no heat" and 6 on the "heat" arm)., Conclusion: Adjuvant interstitial brain HT, given before and after brachytherapy boost, after conventional radiotherapy significantly improves survival of patients with focal glioblastoma, with acceptable toxicity.

Purpose: Although thermotolerance may be an important variable in clinical hyperthermia, few means have been described to measure its effect or duration in the clinical setting. This study was undertaken to determine if heat shock protein 70 could be used as an assay to predict the presence of retained thermotolerance in human tumors., Methods and Materials: Tissue samples were obtained from patients undergoing hyperthermia and assayed for heat shock protein 70 synthesis. Eight patients having advanced, persistent, or recurrent malignant tumors had open-ended thermometry catheters placed into the lesion being heated. Through these catheters, tissue samples were obtained using a fine needle aspiration technique. Attempts were made to obtain samples before and after the first three heat treatments. Some samples were labeled immediately with radioactive methionine (35S) at 37 degrees C for 4-8 hr, others were given a test heat dose in vitro and then labeled. Protein synthesis profiles were analyzed by gel electrophoresis and autoradiography., Results: Preliminary results show that it is possible to obtain tissue from hyperthermia patients in a safe and practical manner, that the rate of heat shock protein 70 synthesis can be measured in a variety of tumors, and that the persistence of thermotolerance in the clinical setting can be shown by the inability to reinduce heat shock protein 70 synthesis., Conclusion: The measurement of heat shock protein 70 using the described technique may provide an assay for retained thermotolerance in clinical hyperthermia. Technical difficulties which need to be addressed include obtaining sufficient tissue in all patients, confirming the presence of tumor in the obtained tissue, and obtaining tissue at more frequent intervals to best determine the kinetics of thermotolerance.

Interstitial techniques for hyperthermia therapy of cancer continue to evolve in response to requirements for better localization and control over heating of deep seated tissues. Magnetic induction heating of ferromagnetic implants is one of several available techniques for producing interstitial hyperthermia, using thermal conduction to redistribute heat within an array of controlled temperature "hot sources." This report describes seven induction heating coil designs that can be used for producing strong magnetic fields around ferromagnetic seed implants located in different sites in the body. The effect of coil design on the extent and uniformity of the magnetic field is characterized, and appropriate electrostatic shield designs for minimizing electric field coupling to the patient are described. Advantages and disadvantages of each coil type are discussed in terms of the radiated fields, coil efficiency, and ease of use, and appropriate applications are given for each design. This armamentarium of induction coils provides the ability to customize magnetic field distributions for improved coupling of energy into ferromagnetic implant arrays located at any depth or orientation in the body. Proper selection of heating coil configuration should simplify patient setup, improve the safety of patient treatments, and pave the way for future applications of interstitial heating in sites that were previously untreatable.

This report describes the experience in 40 evaluable patients entered into a Radiation Therapy Oncology Group (RTOG) study to evaluate the feasibility of administering 45 degrees C for 15 minutes for superficial malignant lesions: 18 patients (45%) tolerated only 1 heat session at 45 degrees C; 7 (17.5%), 2 sessions; 4 (10%), 3 sessions; and 3 (7.5%) tolerated > or = 4 sessions. The overriding reason for discontinuing at 45 degrees C treatment was pain. Of the 40 evaluable patients, 22 (55%) had complete tumor regression, and 8 (20%) had partial regression. Tumors < or = 3 cm in diameter had significantly better complete tumor response than lesions > 3 cm (85% vs 41%) (p = .02). We conclude that 45 degrees C heating is difficult to use in patients chiefly because of pain; this may be due in part to inadequacy of currently available external hyperthermia equipment. Caution must be exercised in the application of thermal isoeffect heat dose concepts in clinical practice until further trials have been performed and a better understanding of the time-temperature relationship is established.

Purpose: The University of Arizona, University of California at San Francisco, City of Hope Medical Center, and University of Wisconsin participated in a Phase I/II protocol to assess the heating ability and the toxicity of interstitial thermoradiotherapy using ferromagnetic implantation., Methods and Materials: Forty-four patients with advanced primary or recurrent extra-cranial solid malignancies were enrolled in this study. Fourteen gauge catheters were implanted into tumors and, once in the department of Radiation Oncology, loaded with ferromagnetic seeds to deliver a 60 min hyperthermia treatment. Multi-point thermometry was continuously used throughout the heating sessions for all patients, sampling the periphery as well as the core of the tumor. After 192Iridium brachytherapy, 18 patients then had an additional treatment. The mean radiation dose while on protocol was 50.0 Gy, with total doses (including prior radiotherapy) ranging from 20.3-151.8 Gy (median = 88.7 Gy). Response and toxicity were assessed by inspection, palpation, and/or radiologic studies. Forty-one patients were evaluable for response, and there were 55 analyzable hyperthermia treatment sessions., Results: The complete response rate was 61% (25/41). The partial response rate was 31.7% and only 7.3% failed to respond. Median duration of local control has not yet been reached. The mean maximum, minimum, and mean time-averaged temperatures for all in-tissue sensors were 43.7 degrees C, 38.7 degrees C, and 41.0 degrees C, respectively. Tumor size was the only factor significantly correlated with temperatures or with complete response rate; larger tumors attained higher temperatures but smaller tumors had a higher response probability. Nineteen patients (43%) experienced toxicities, however there was only a 7% (3/44) rate of serious complications (Grade 3 or 4). Prior treatment with hyperthermia was the only factor significantly correlated with serious toxicity., Conclusion: These results, a 93% total response with only 7% serious toxicity, are encouraging especially in the context of the patient population treated. Phase II/III studies involving ferromagnetic implantation are warranted.

In an attempt to improve local control and survival over those achieved with brain implant alone, a Phase I/II study of interstitial thermoradiotherapy was undertaken for recurrent malignant gliomas and recurrent solitary brain metastases. Between June 1987 and September 1990, 49 tumors in 48 patients were treated with thermoradiotherapy, including 26 glioblastoma multiforme (GM), 16 anaplastic astrocytomas (AA), 4 adenocarcinomas, and 3 melanomas. Patient age ranged from 18 to 71 years and Karnofsky Performance Status from 40 to 90. Stereotactically implanted catheters were used for both hyperthermia and brachytherapy. Hyperthermia was administered immediately before and after brachytherapy, heating as much of the tumor as possible to 42.5 degrees C for 30 min using helical coil microwave antennas. High-activity iodine-125 sources delivered tumor doses of 32.6 to 63.3 Gy. Complications included reversible neurologic changes in 13 patients, 9 seizures, 4 infections, 1 deep venous thrombosis with pulmonary embolus, and 1 scalp burn. Eighteen patients underwent reoperation for tumor and/or necrosis. Follow-up ranged from 9 to 166+ weeks. The median follow-up for living patients with GM and AA was 37 weeks and 92 weeks, respectively. Actuarial median survival was 47 weeks for patients with GM. For patients with AA, actuarial survival was 65% at 18 months and median survival has not yet been reached. Multivariate analysis showed a strong correlation between freedom from local tumor progression and "T90" temperature or minimum tumor temperature. Interstitial brain thermoradiotherapy is now being evaluated in a randomized Phase II trial for previously untreated GM.

There is a convincing biological rationale for combining hyperthermia with radiation. Clinical data suggests that adjuvant hyperthermia improves the efficacy of radiation therapy when adequate hyperthermia is delivered. A major stumbling block is the technical difficulty of delivering adequate hyperthermia to all but small, superficial tumors or interstitially implanted tumors. Efforts are being made toward improving hyperthermia technology and treatment techniques. Only after adequate equipment becomes more widely available and quality assurance mechanisms are in place can the true role of hyperthermia be defined.

Between June 1987 and June 1989, 29 recurrent malignant gliomas or recurrent solitary brain metastases in 28 patients were treated in a Phase I study of interstitial irradiation and hyperthermia. Patient age ranged from 18 to 65 years, and the Karnofsky Performance Status scores ranged from 40 to 90%. There were 13 glioblastomas, 10 anaplastic astrocytomas, 3 melanomas, and 3 adenocarcinomas. Catheters were implanted stereotactically after computed tomography-based preplanning. Hyperthermia was administered before and after brachytherapy, using one to six 2450- or 915-MHz helical coil microwave antennas and one to three multisensor fiberoptic thermometry probes. The goal was to heat as much of the tumor as possible to 42.5 degrees C for 30 minutes. Within 30 minutes after the first hyperthermia treatment, implant catheters were afterloaded with high-activity iodine-125 seeds delivering tumor doses of 32.6 to 61.0 Gy. Most patients had no sensation of heating. Complications included seizures in 5 patients, reversible neurological changes in 9 patients, a scalp burn in 1, and infections in 3. Of 28 evaluable 2-month follow-up scans, 11 showed definite improvement in the radiological appearance of the tumor, 4 were slightly improved, 7 were stable, and 6 showed tumor progression. Ten patients underwent reoperation for persistent tumor and/or necrosis. Eleven of 28 patients are alive 40 to 97 weeks after treatment. Thirteen patients died of a brain tumor, 2 died of extracranial melanoma metastases, 1 died of new brain melanoma metastases, and 1 died of a pulmonary embolus. The median survival was 55 weeks overall. Median survival has not yet been reached for the anaplastic astrocytoma subgroup. We conclude that interstitial brain hyperthermia using helical coil microwave antennas is technically feasible. The level of toxicity is acceptable, and the computed tomographic response rate is encouraging.

Radiation has provided excellent local control rates in choroidal melanoma, but significant impairment in visual acuity has occurred in 30-60% of patients due in part to the development of radiation vasculopathy in the fovea and optic disc. Hyperthermia has been shown to have a synergistic effect when added to radiation therapy in human malignancies. The use of hyperthermia in ocular melanoma may allow a reduction in the total radiation dose necessary to achieve local control. A 2450-MHz microwave plaque applicator with integral surface cooling was used to deliver hyperthermia treatments to rabbit eyes containing choroidal melanomas. Extensive thermal mapping was done in acute eyes. In 18 survival animals, a single 23-G needle thermocouple probe with three sensors was inserted into the tumor. Target temperatures of 41.0-46.0 degrees C were maintained for 1 hour. All tumor-bearing eyes were followed for 1 month after treatment, or until tumor growth was noted, with serial ultrasound measurements and visual examinations. A 92% response rate was obtained in tumors treated at temperatures greater than 43.0 degrees C for 1 hour with no significant toxicity. Heat alone has significant tumoricidal properties in this animal model.

A helical coil 2450-MHz microwave antenna was used to induce interstitial hyperthermia in normal dog brain. The HCS-10(1)/11 antenna consisted of a miniature semirigid coaxial cable around which a fine wire coil with 10 turns per 1-cm length was wound. A single antenna and two or three temperature probes were implanted stereotactically, and the temperature distributions surrounding the antenna were measured and compared to those induced using a dipole antenna. The helical coil antenna produced well-localized temperature distributions at depths that were symmetrical around the coil and that extended to the antenna tip. There was minimal variation of the heating patterns with insertion depth using the HCS-10(1)/11 antenna and no excessive heating of extracerebral tissues. In contrast, 2450-MHz dipole antennas induced temperatures of 43 to 46 degrees C at the brain surface and extracerebral tissues (skull, muscle, and scalp), with a relatively uniform but lower temperature in the targeted brain volume. One week after hyperthermia treatment, the thermal lesions induced by the helical coil antenna were visualized using computed tomography. The heating patterns correlated well with the location of the heat lesions and were reproducible among animals. The results indicated that the helical coil antenna could be used to induce localized hyperthermia at specific depths in normal brain without inducing unacceptable heating of the brain surface or extracerebral tissues. Consequently, this antenna seems to be suitable for studying the response of normal brain after a heat insult and may be effective in the application of interstitial microwave brain hyperthermia for malignant brain tumors.

A dual frequency microwave system was constructed for interstitial heating of brain tissue. Single-junction dipole antennas were tested in a phantom model and in normal dog brain to determine how variations in physical factors affected temperature distributions. Non-survival studies were performed at both 915 and 2450 MHz to determine heating patterns that could be achieved within normal brain using this system. Chronic survival studies were performed using a single dipole antenna inserted laterally into one hemisphere of brain and driven at 2450 MHz. Temperatures of 43 or 44 degrees C for 30 min at a reference point 0.5 cm from the antenna junction were used to induce a thermal lesion of approximately 1 cm diameter in the right cerebral hemisphere of dogs. Neurologic and physical changes in dogs were monitored daily for up to 16 weeks after induction of cerebral lesions. The extent and development of thermal lesions was monitored with weekly computed tomographic (CT) examinations and, after death, at histopathologic examination. Results of the phantom studies showed that the longitudinal heating pattern was bell-shaped at both frequencies used and that there was some variation in heating length that depended on insertion depth. Acute studies in dog brain showed that 915 MHz antennas implanted less than 6.5 cm deep produced erratic heating patterns that usually included excessive heating of the surface of the brain. Conversely, 2 cm-long antennas driven at 2450 MHz gave reproducible temperature distributions both longitudinally along and radially away from the antenna. The steepest gradients--about 1 degree C/mm--occurred in the radial direction away from the antenna junction. A single 30 min heat treatment produced a large focal lesion that consisted of central coagulation necrosis surrounded by a sharply demarcated hypervascular zone. Edematous changes were minimal and were observed only during the first week after treatment. As assessed by serial CT scans, thermal lesions reached a maximum size by the first week after treatment and were essentially resolved by 16 weeks after treatment.