James R. Oleson

Randomized trial of hyperthermia and radiation for superficial tumors.

PURPOSE Randomized clinical trials have demonstrated hyperthermia (HT) enhances radiation response. These trials, however, generally lacked rigorous thermal dose prescription and administration. We report the final results of a prospective randomized trial of superficial tumors (</= 3 cm depth) comparing radiotherapy versus HT combined with radiotherapy, using the parameter describing the number of cumulative equivalent minutes at 43 degrees C exceeded by 90% of monitored points within the tumor (CEM 43 degrees C T(90)) as a measure of thermal dose. METHODS This trial was designed to test whether a thermal dose of more than 10 CEM 43 degrees C T(90) results in improved complete response and duration of local control compared with a thermal dose of </= 1 CEM 43 degrees C T(90). Patients received a test dose of HT </= 1 CEM 43 degrees C T(90) and tumors deemed heatable were randomly assigned to additional HT versus no additional HT. HT was given using microwave spiral strip applicators operating at 433 MHz. RESULTS One hundred twenty-two patients were enrolled; 109 (89%) were deemed heatable and were randomly assigned. The complete response rate was 66.1% in the HT arm and 42.3% in the no-HT arm. The odds ratio for complete response was 2.7 (95% CI, 1.2 to 5.8; P = .02). Previously irradiated patients had the greatest incremental gain in complete response: 23.5% in the no-HT arm versus 68.2% in the HT arm. No overall survival benefit was seen. CONCLUSION Adjuvant hyperthermia with a thermal dose more than 10 CEM 43 degrees C T(90) confers a significant local control benefit in patients with superficial tumors receiving radiation therapy.

Sensitivity of hyperthermia trial outcomes to temperature and time: Implications for thermal goals of treatment

PURPOSE In previous work we have found that the cumulative minutes of treatment for which 90% of measured intratumoral temperatures (T90) exceeded 39.5 degrees C was highly associated with complete response of superficial tumors. Similarly, the cumulative time for which 50% of intratumoral temperatures (T50) exceeded 41.5 degrees C was highly associated with the presence of > 80% necrosis in soft tissue sarcomas resected after radiotherapy and hyperthermia. In the present work we have calculated the time for isoeffective treatments with T90 = 43 degrees C and T50 = 43 degrees C, respectively, using published thermal isoeffective dose formulae. The purpose of these calculations was to determine the sensitivity of treatment outcome to variations in thermal isoeffective dose. METHODS AND MATERIALS The basis for the calculations were the thermal parameters and treatment outcomes in three patient populations: 44 patients with moderate or high grade soft tissue sarcoma treated preoperatively with hyperthermia and radiation; 105 patients with superficial tumors treated with hyperthermia and radiation, and 59 patients with deep tumors treated with hyperthermia and radiation. RESULTS The thermal dose values calculated are strongly associated with outcome in multivariate logistic regression analysis. Simple dose-response equations result from the analysis, and we use these equations to assess the sensitivity of outcome upon variations in thermal dose. This information, in turn, allows us to estimate the number of patients required in Phase II and III trials of hyperthermia and radiation therapy. CONCLUSIONS For regimens of 5 to 10 hyperthermia treatments, improvements in median T90 (superficial tumors) and T50 (deep tumors) parameters by 1.2-1.5 degrees C could result in response rates high enough (compared to radiotherapy alone) to justify Phase III trials. A similar improvement in response rates would require an increase in overall duration of treatment by a factor of 3 to 5. This would be difficult to achieve while also avoiding thermal tolerance induction. Achieving these temperature goals may be possible with improvements in hyperthermia technology. Alternatively, there may be ways to increase the sensitivity of cells to temperatures that can be achieved currently, such as pH reduction or chemosensitization.

Observations on the Use of Ferromagnetic Implants for Inducing Hyperthermia

Magnetic induction heating of ferromagnetic implants can be used to produce highly localized hyperthermia in deep seated tumors. We discuss the physical parameters which characterize this method and give illustrations from initial clinical investigations in animals. The physical parameters studied include magnetic field strength, frequency, load size, field uniformity, coil designs, and the heating potential of implant materials and configurations. Calculations consistent with our experimental results predict a maximum heating frequency of the order of 500 kHz for large cross-sectional loads, such as the human abdomen, and 1.9 MHz for smaller loads, such as the human brain. An experlhnental technique is introduced for accurate quantitative evaluation of the heating potentials of ferromagnetic materials in a gelled phantom medium. These data are analyzed in terms of heating efficiency per unit implant length (¿L), which is itself a function of implant length, diameter, annealed state, and orientation with respect to the magnetic field. A spiral sheet coil design is described and recommendations are given for proper E-Field shielding of induction coils for clinical applications. A brief discussion of techniques of implanting the ferromagnetic materials is also given. Finally, several in vivo animal studies are presented to illustrate the use of the technique for treating tumors in pelvis, thorax, oral-pharynx, and brain.

RTOG quality assurance guidelines for clinical trials using hyperthermia.

M. W. DEWHIRST, D.V.M., PH.D.,* T. L. PHILLIPS, M.D.,+ T. V. SAMULSKI, PH.D.,+ P. STAUFFER, MSEE,? P. SHRIVASTAVA, PH.D.,+ B. PALIWAL, PH.D.,+ T. PAJAK, PH.D.,+ M. GILLIM, PH.D.,+ M. SAPOZINK, M.D., PH.D.,+ R. MYERSON, M.D., PH.D.,+ F. M. WATERMAN, PH.D.,+ S. A. SAPARETO, PH.D.,+ P. CORRY, PH.D.,+ T. C. CETAS, PH.D.,+ D. B. LEEPER, PH.D.,+ P. FESSENDEN, PH.D.,+ D. KAPP, M.D., PH.D.,+ J. R. OLESON, M.D., PH.D.+ AND B. EMAMI, M.D.*

Relationships among tumor temperature, treatment time, and histopathological outcome using preoperative hyperthermia with radiation in soft tissue sarcomas

The lack of an unambiguous thermal dosimetry continues to impede progress in clinical hyperthermia. In an attempt to define better this dosimetry, a model based on the cumulative minutes during which arbitrary percentages of measured tumor temperature points exceeded an index temperature was tested in patients with soft tissue sarcomas treated with preoperative hyperthermia and conventional radiation therapy. Patients received 5000-5040 cGy at 180-200 cGy per fraction. Hyperthermia was delivered 30-60 minutes after radiation therapy and given for 60 minutes. Patients were randomized between one and two hyperthermia treatments per week for a total of five or 10 treatments, respectively. Lesions were excised 4-6 weeks after completion of hyperthermia/radiation therapy. Successful treatment outcome was considered to be the finding of greater than 80% necrosis of the sarcoma upon histopathologic examination of the resected specimen. Forty-five patients were eligible with thermometry data available in 44 patients. An average of 19 interstitial sites were monitored each treatment per tumor. Sixty percent of tumors had a successful histopathologic outcome. Univariate analysis demonstrated that several descriptors of the temperature distribution were strongly related to treatment outcome; more strongly than nonthermometric factors, such as the number of treatments per week, tumor volume and patient age and more strongly than the commonly used temperature descriptors Tmin and Tmax. Descriptors that incorporated both temperature and time were also superior to the more commonly used descriptors Tmin and Tmax. Multivariate stepwise logistic regression analysis revealed that a descriptor of both the hyperthermia treatment time and the frequency distribution of intratumoral temperatures was the strongest predictor of histopathologic outcome and that the best predictive model combined this time/temperature descriptor and one versus two treatment per week grouping. The more conventional temperature descriptor, minimum measured tumor temperature, did not significantly enhance the predictive power of treatment group. Based on these results, we recommend that descriptors based on both the frequency distribution of intratumoral temperatures and hyperthermia treatment time be tested for relationships with treatment outcome in other clinical data bases. Furthermore, we recommend that temperature descriptors that are less sensitive to catheter placement and tumor boundary identification than Tmin and Tmax (such as T90, T50, and T10) be tested prospectively along with other important thermal variables in Phase II trials in further efforts to define a thermal dosimetry for spatially nonuniform temperature distributions.

Cumulative minutes with T90 greater than tempindex is predictive of response of superficial malignancies to hyperthermia and radiation

PURPOSE To better define thermal parameters related to tumor response in superficial malignancies treated with combined hyperthermia and radiation therapy. METHODS AND MATERIALS Patients were randomized to receive one or two hyperthermia treatments per week with hyperthermia given during each week of irradiation. Hyperthermia was given for 60 min with treatments begun within 1 hr following irradiation. Power was increased to patient tolerance or normal tissue temperature of 43.0 degrees C. Irradiation was generally given 5 times per week with doses prescribed to normal tissue tolerance (generally 24-70 Gy at 1.8-2.5 Gy per fraction). Multipoint thermometry was used with temperatures obtained every 5 min. RESULTS One hundred eleven individual treatment fields containing 1 or more tumor nodules were completely evaluable. The complete and overall response rates were 46% and 80%, respectively. Forty-one percent of all treatment fields (51% of responding lesions) remained controlled at 2 years. Multivariate analysis revealed that the cumulative minutes that the temperature achieved by 90% of the measured tumor sites (T90) was > or = 40.0 degrees C, tumor histology, tumor volume, and radiation dose were significantly associated with complete tumor response. The complete response rate was not significantly affected by the number of hyperthermia treatments given per week. The incidence of clinically significant complications was low. CONCLUSIONS These results support the usefulness of the cumulative minute system in describing time-temperature relationships. The significance of thermal variables with regard to tumor response strongly supports the contention that hyperthermia can be a useful adjunct to irradiation for the local control of cancer.

Blood perfusion measurements in human tumours: Evaluation of laser Doppler methods

Laser Doppler flowmetry is a simple method of determining, directly and continuously, tissue blood flow. However, its applicability to monitoring tumour blood flow interstitially during hyperthermia treatments is still being evaluated. The purposes of this study were to physically characterize the measurement probes, to evaluate potential sources of artifact with the interstitial use of the probes during hyperthermia treatment, and to obtain measurements in human tumours during hyperthermia sessions. The accuracy of the method in quantifying blood flow, velocity and volume during hyperthermia was found to be unaffected by heating the measurement probe to 42-46 degrees C or by exposing it to various intensities of 915 MHz microwave fields (10-40 W), or 1 MHz ultrasound fields. Catheter insertion methods were developed to place the flow probes interstitially in tumours. Tissue damage was confined to a distance of no greater than 0.12 mm away from the catheter tract, and physical evidence of vascular disruption was within a distance of 0.05 mm as measured in a rat tumour model. This degree of damage/disruption is unlikely to affect LDF measurements which represent blood flow averaged over a 1.0-1.5 mm radius from the probe tip. Concurrently, the device was used to monitor tumour blood flow parameters interstitially in human subjects during hyperthermia treatments given in combination with conventional radiotherapy. Blood-flow data from multiple sites of measurement showed marked heterogeneity within individual tumours (up to 55-fold differences) and between different tumours (greater than 100-fold differences). Measurements made by translating the probe along a tumour radius, beginning at the tumour core and advancing to the tumour edge, were consistent with a two-component tumour perfusion model (shell and core). Data are presented from one patient illustrating a persistent change in perfusion distribution during the hyperthermia treatment course, which occurred concomitantly with increases in thermal data. These results suggest that the technique might be of value in monitoring change in flow between treatments. Responses during hyperthermia treatment sessions were also investigated. Four temporal patterns of flow were observed, ranging from a steady increase in flow to a plateau level to a steady drop in flow during heating. These patterns were not well correlated with average temperature recorded at the site of flow measurement. Further study is needed to determine if this LDF technique is to be useful for evaluation of heat transfer by blood perfusion.

Improved palliation of cerebral metastases in epithelial ovarian cancer using a combined modality approach including radiation therapy, chemotherapy, and surgery.

PURPOSE Recent reports suggest an increasing incidence of CNS metastases in patients with ovarian cancer. We reviewed our experience in the management of brain metastases from ovarian carcinoma and merged our results with those of several other series reported in the literature to determine prognostic factors and the role of chemotherapy, radiation therapy, and surgery. PATIENTS AND METHODS From 1977 to 1990, 15 of 795 patients who were treated for epithelial ovarian cancer at Duke University developed brain metastases. Fourteen of the patients were treated for their brain metastases; this included radiation therapy (RT; four), surgery and RT (one), RT and systemic chemotherapy (six), and all three treatment modalities (three). A meta-analysis was performed that combined the data from the current series with those of several recent clinical series that reviewed patients with brain metastases from ovarian carcinoma (67 patients total) to elucidate the impact of treatment and extent of disease on survival. RESULTS In the current series, median survival (MS) after the diagnosis of brain metastases was 9 months. For the combined series, MS was 5 months. Thirteen patients who were treated with whole-brain RT and systemic chemotherapy (MS, 7 months), 10 patients who were treated with RT and surgery (MS, 10 months), and nine patients who were treated with all three modalities (MS, 16.5 months) had significantly longer survival than 19 patients who were treated with RT alone (MS, 3 months) (P = .05, P = .01, and P < .001, respectively). In a multivariate analysis, the only variable that provided prognostic information was treatment, namely the addition of systemic chemotherapy or surgery to RT for the treatment of brain metastases. CONCLUSION Multimodal treatment of patients with brain metastases from ovarian cancer can result in significant palliation.

REGIONAL HYPERTHERMIA FOR ADVANCED TUMORS: A CLINICAL STUDY OF 353 PATIENTS

A Phase I study using deep regional hyperthermia (HT) with an annular phased array was conducted in 14 U.S. medical centers from 1980 through 1986. There were 353 patients whose average age was 57 years. All patients had advanced recurrent or persistent tumors. Prior frequently complex, multimodality anti-cancer therapy was received by 71% of the patients. Gastrointestinal adenocarcinoma was present in 146 (41%) patients, genitourinary tumors in 86 (24%), soft tissue sarcomas in 46 (13%), malignant melanoma in 21 (6%) and 15% had other tumors. The sites treated included: pelvis 55%, abdomen 21%, liver 14%, thorax 6%, and other sites 3%. All patients received deep regional HT with an average frequency of 55 MHz. A total of 1412 HT treatments was administered to these 353 patients with an aim to increase the temperature in the volume of interest to greater than 42 degrees C for greater than or equal to 30 minutes. Thermal dose (TD in equivalent minutes at 42.5 degrees C) was less than 50 in 104 (29%), greater than or equal to 50 less than 100 in 30 (11%), greater than or equal to 100 in 26 (7%), and greater than 200 in 34 (10%). The remaining 150 (42%) patients had TD = 0. In addition to HT, 260 (74%) received radiotherapy (RT). RT was given at 180 or 200 cGy daily with an average total dose of 33.4 Gy. A total of 42 (12%) patients were given chemotherapy (CT) with HT, and 15 (4%) CT + HT + RT/HT alone was given to 47 (13%) patients. Complete response (CR) was obtained in 35 (10%) and partial response (PR) in 59 (17%) patients. CR was 12% in patients who received RT, vs 2% in those who did not receive it, p = 0.003. Radiation dose was an important factor influencing response, p less than 0.001. Thermal dose was not an important parameter influencing tumor response. A duration of CR ranged from 4 to 73 weeks with an average duration of 31 weeks and the median duration of 28 weeks. The overall 2-year survival was 13% with the median survival of 42 weeks. Patients with CR and PR had a 2 year survival of 41%, and a median survival of 71 weeks. This compared with 8% 2-year survival and 24 weeks median survival in patients who did not have CR or PR, p less than 0.001. Of the patients presenting with significant pain, 62% had complete or partial pain relief.(ABSTRACT TRUNCATED AT 400 WORDS)

Preoperative hyperthermia and radiation for soft tissue sarcomas: Advantage of two vs one hyperthermia treatments per week☆

As part of an ongoing Phase II trial at Duke University Medical Center (DUMC), patients with Stage IIB-IVA soft tissue sarcomas (STS) potentially amenable to wide local excision were treated with preoperative hyperthermia (HT) plus radiation therapy (RT), with HT randomized to one versus two treatments per week, stratified with respect to tumor volume. 17 patients were treated and analyzed. HT was given 30-60 minutes after RT, with heating maintained for 1 hour after 42.0 degrees C was reached. In patients treated with 2 HT per week, treatments were separated by 48 hrs. Concurrent RT was given with 180-200 cGy fractions, five treatments per week, to a nominal tumor dose of 5000-5040 cGy. Surgical extirpation was performed 4 weeks after completion of HT/RT. Treatment effect was evaluated by histopathologic examination of the resected lesions, according to a previously reported system. The mean number of HT given in the 1 and 2/wk groups was 4.4 and 7.3, respectively (p less than 0.01). Tmax for the 1 and 2 HT/wk groups was 42.4 +/- 2.1 degrees C and 43.5 +/- 1.8 degrees C, and T min was 38.1 +/- 0.8 degrees C and 38.6 +/- 0.5 degrees C, respectively. The increase in T min from first to last treatment was 0.5 +/- 1.2 degrees C and 1.0 +/- 0.8 degrees C, respectively. The T min from the best treatment was 39.1 +/- 1.2 degrees C and 40.0 +/- 1.0 degrees C, and the Tmax from the best treatment was 44.5 +/- 3.4 degrees C and 45.4 +/- 2.5 degrees C for the 1 and 2 HT/wk groups, respectively. There were no statistically significant differences between the 2 treatment groups for any of the above temperature parameters. Severe histopathologic changes were found in 71% (12 of 17) of the lesions. T min and Tmax and highest T min and Tmax were between 0.4-1.1 degrees C higher in patients with severe changes (p = NS). All 9 patients in the 2 HT/wk group had extensive changes, versus only 3 of the 8 patients in the 1 HT/wk group. This difference was highly statistically significant (p = 0.009, two-tailed Fishers exact test). These findings suggest an advantage to twice weekly, as opposed to weekly, HT in the setting of this study. Whether there is a corresponding therapeutic gain, or whether these results can be extrapolated to other settings requires further investigational efforts. It is recommended that treatment parameters, particularly temperature parameters, continue to be examined in Phase II trials.