Regional power deposition for hyperthermia: theoretical approaches and considerations.

Physical analysis of electromagnetic and ultrasonic fields is useful to define systems capable of depositing power in "deep" tumors extending more than a few cm from the skin surface. Several recent analyses of electromagnetic field configurations for treating such tumors are reviewed here. Most electromagnetic systems result in exposure of substantial normal tissue volumes or regions to unfocused power absorption, and safely achieving intratumoral temperature elevation to greater than or equal to 42 degrees relies in part upon higher blood flow rates existing in normal tissue than in tumor. Optimizing therapeutic approaches to deep tumors with devices producing regional power deposition may thus require improved knowledge and control of regional blood flow distributions, along with further development of energy sources appropriate for specific deep sites. Multiple electric dipole sources with separate phase and amplitude control appear to be the most general noninvasive electromagnetic solution at present for deep heating. In specific locations, focused ultrasound is also theoretically capable of producing advantageous power deposition at depth.

Combined interstitial irradiation and localized current field hyperthermia: results and conclusions from clinical studies.

Low-dose-rate continuous irradiation in conjunction with localized current fields has been investigated in Phase I human trials at several institutions since 1977. To date, nearly 100 patients with a variety of malignant lesions (carcinomas, melanomas, sarcomas, lymphomas) in different anatomical locations (skin, head and neck, breast, pelvis, extremities) have been entered into experimental protocols. Different radiation and thermal dose levels have been evaluated. Significant progress in equipment and techniques has been accomplished. A wide range of complete response rates (38 to 83%) and complication rates (7 to 25%) has been reported. Analysis of results showed a good correlation of complete response rates with the radiation dose level and minimum temperature. The most successful regimens included either an "optimal radiation dose" (greater than 6000 rads) or an "effective time-averaged minimum temperature" (44 degrees). Important considerations in the design of clinical trials for Phases II and III are: (a) in regimens with curative aim, a hyperthermic effect may not be achieved in all regional sites of disease, especially in those areas harboring subclinical disease. Radiation dose-fractionation schedules of proven adjuvant efficacy thus must be used; (b) whether the total radiation dose to the site of bulky disease when combined with hyperthermia can be reduced without loss of therapeutic efficacy relative to conventional radiation doses is critically dependent upon minimum temperatures and uniformity of temperature within the tumor; (c) optimized combined therapy is likely to reflect a high level of quality assurance in administering both the interstitial irradiation and the interstitial hyperthermia; (d) the present criteria for evaluation of tumor response (no response, partial response, and complete response) are clinically meaningless. The criterion, "local control" or "failure," should be adopted in future trials in Phases II and III with the curative aim to allow comparison of results with historical or concurrent controls treated with radiation alone.

Pharmacokinetics and toxicity of intraperitoneal cisplatin combined with regional hyperthermia.

Hyperthermia (HT) potentiates in vitro cytotoxicity of cisplatin, providing a rationale for HT enhancement of cisplatin effect in vivo. In this study, regional abdominal HT was combined with intraperitoneal (IP) cisplatin in canines to characterize temperature distributions, as well as pharmacokinetics and toxicity of IP cisplatin with and without HT. Cisplatin (65 mg/m2) in normal saline was administered IP with a two-hour dwell time in ten Beagle dogs. Five of the ten dogs were randomly selected to receive concurrent regional microwave-producing HT at approximately 41.5 degrees C (IP) for a 60-minute period. Systemic temperatures in heated animals ranged from 37 degrees C to 40 degrees C; IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP cisplatin concentrations were ten to 22 times greater than serum levels; the IP drug half-lives were 133 +/- 9 minutes and 68 +/- 15 minutes in heated and unheated dogs, respectively (P less than .001). Total concentrations of serum and urine cisplatin did not differ between the heated and unheated controls. The area under the concentration v time curve for free, ultrafilterable cisplatin in serum in units of percent minutes was 40 +/- 8 in heated and 60 +/- 7 in unheated controls (P = .006). Except for transient nausea and vomiting, no evidence of serious toxicity was observed in serum chemistries or histopathologic sections at 21 days post-treatment. Experiments involving in vitro incubation of cisplatin in normal saline were performed as a function of saline temperature; these showed that the amount of reactive cisplatin metabolites formed increased linearly with temperature by approximately 30% from 38 degrees C to 44 degrees C. This study supports the hypothesis that, with IP temperature elevation, there is an increased rate of generation and retention of reactive metabolites of cisplatin in the peritoneal cavity relative to unheated controls. In spite of these differences in pharmacokinetics, no significant toxicity was encountered. This study provides a model for treatment of IP malignancy such as ovarian carcinoma with IP cisplatin and regional HT.

Improved coupling of ultrasound hyperthermia applicators to patients.

Coupling ultrasound (US) hyperthermia (HT) applicators to patients requires an acoustical medium conforming to both applicator and patient that allows for rapid, reproducible set-up for each treatment and prevents drift or misalignment of the applicator during treatments. We describe a technique that uses a commercially available immobilization foam to create a rigid, conforming foam block that kinematically positions the US applicator over the tumor area. The central volume of the foam block is removed and filled with a plastic bag of degassed water or with US gel during treatments. We also describe a technique for positioning surface and interstitial thermometry sensors in alignment with individual elements of a multi-element US applicator. Using these techniques, relative movement between patient and applicator is minimized, correct thermometry sensor location relative to each US element is confirmed, and efficient transmission of the acoustical power into the target volume is assured. These techniques are particularly important when using multi-element applicators with complex temperature-power control algorithms.

Hyperthermia by magnetic induction: II. Clinical experience with concentric electrodes.

Thirty-one patients with visceral or extensive superficial malignant tumors of various histologies and sites have been evaluated for our hyperthermia protocols employing magnetic induction at 13.56 MHz with concentric electrodes associated with a commercially available device. Response data in patients completing combined hyperthermia and radiation treatment was difficult to analyze because of the short survival of these patients with advanced disease. Acute toxicity, however, was limited to 2/31 patients with minor skin blistering from excessive superficial heating. In this report we focus on clinical thermometric results. In 6/31 (19%) of patients, portions of the tumor achieved greater than or equal to 42.5 degrees C. In 3/31 (10%), nearly all the tumor achieved greater than or equal to 42.5 degrees C. Those tumors successfully heated to greater than or equal to 42.5 degrees C throughout were relatively superficial. In 22/31 (71%), temperature greater than or equal to 42.5 degrees C were not achieved at any measured site. Maximum applied power levels were limited by development of painful superficial hot spots in 21/31 (68%), by diffuse discomfort or systemic intolerance in 9/31 (29%), by maximum power output from the generator in 1/31, or by other factors in 2/31 patients. Some patients had both local and systemic discomfort that limited power levels. Based upon analysis of the thermometric results, we discuss the anatomic sites and tumor depths for which this technique is most applicable.

Uniform regional heating of the lower trunk: numerical evaluation of tumor temperature distributions.

The temperature distributions in deep seated tumors resulting from uniform heating of the abdominal and pelvic regions of the trunk are predicted from a one dimensional numerical solution of the bio-heat transfer equation. The effect of tumor size and location are investigated for two tumor perfusion models: uniform perfusion and a concentric annulus perfusion model. Tumor temperature distributions are considered acceptable if the range of temperatures in the tumor lie between 42 degrees C and 60 degrees C. This range of tumor temperatures is defined as Tave +/- 2 sigma where sigma is the population standard deviation of tumor temperatures from the average computed at the nodal points in the finite difference array. To simulate practical clinical restrictions, muscle and fat temperatures are not allowed to exceed 44 degrees C, significant portions of the viscera are not allowed to exceed 42 degrees C, and the total absorbed power required to maintain steady state cannot exceed two kilowatts. Over 100 possible cases are presented in a compact form. From this study it appears that heating systems with power deposition patterns approximately uniform are promising for heating deep-seated tumors. Small, detectable tumors (approximately 2 cm in size) are adequately heated for a wider range of conditions than are larger tumors. Excessively high temperatures in deep-seated, normal tissue could be a significant limitation for this technique.

Analysis of prognostic variables in hyperthermia treatment of 161 patients.

From 1977-1982, 161 patients were treated using hyperthermia as an adjuvant in Phase I trials. Microwave applicators (MW), capacitively coupled plates (RF plates), interstitial localized current fields (LCF), and magnetic induction heating (MI) techniques were used together with radiation in 135 patients, with chemotherapy in 10 patients, and alone in 16 patients. Tumor volume response categories were no response (NR, less than 50% decrease); partial response (PR, 50% less than or equal to volume decrease less than 100%); and complete response (CR, complete disappearance). The CR rates and total response rates (CR + PR) were 38/160 (24%) and 90/160 (56%), respectively. There were highly significant differences among techniques in CR vs PR + NR (p = .001), and in CR + PR vs NR (p less than .0005). Response did not vary significantly with histologic category. Overall toxicity was 16%, and did not vary significantly with technique (p = .193). In the patient group treated with hyperthermia and radiation, multivariate analysis revealed that a set of three variables had prognostic importance for CR: technique (p = .011), radiation dose (p = .019), and tumor volume (p = .001, negatively correlated). A good correlation also existed between CR and the minimum tumor temperature averaged over all treatments, TMIN (p less than .0005). Temperature variables themselves were correlated with tumor volume. Minimum T correlated negatively with volume (p = .017) and TMAX correlated positively with volume (p = .026). In fewer than 50% of patients could minimum T greater than 40.7 degrees C be achieved. Our conclusions are: TMIN, tumor volume, radiation dose, and heating technique have prognostic value for initial response; variation in CR vs technique reflects variation in tumor volume treated and in minimum temperature achieved with these techniques; and acute toxicity of treatment is infrequent, but serious toxicity is possible with the interstitial technique.

Magnetic induction heating of tissue: numerical evaluation of tumor temperature distributions.

A one dimensional (radial) numerical model based on the bioheat transfer equation has been developed and applied to the abdomen and pelvis heated by a concentric magnetic induction electrode. This model consists of four normal tissue regions: viscera, muscle, fat and skin. Each region is assigned thermal properties characteristic of that region and power deposition values consistent with those for this mode of heating. Tumors of 2, 4 and 7 cm thicknesses are positioned in five different radial locations ranging from the central axis to the skin surface. Two blood perfusion models of the tumor are considered: the uniformly perfused model and an annular model. Tumor temperature distributions are considered acceptable if the average tumor temperature plus and minus two standard deviations lie between 42 degrees C and 60 degrees C. To stimulate practical clinical restrictions, muscle and fat temperatures are not allowed to exceed 44 degrees C, significant portions of the viscera (except for a 1 cm thick band) are not allowed to exceed 42 degrees C, and the total absorbed power required to maintain steady state cannot exceed one kilowatt. Over 100 possible cases are presented in a compact form. A conclusion drawn from this study is that with few exceptions, only small tumors in the muscle annulus are heated adequately with this modality. Large tumors will have significant unheated portions if the specified limitations are not exceeded. While this heating modality can raise the necrotic core of a tumor to high temperatures, it cannot adequately heat well perfused regions of a deep seated tumor. These conclusions are borne out clinically and are discussed in a companion paper.

Transperineal templates for brachytherapy treatment of pelvic malignancies--a comparison of standard and customized templates.

A technique is described for the design and construction of customized templates for transperineal implants and interstitial hyperthermia of pelvic malignancies. The design of the template and the distribution of the transperineal Iridium-192 seed ribbons are based on prior optimization of the dose distribution. The target volume is defined by means of pelvic examination and pertinent radiographic studies including a CT. The pelvic CT study is obtained with a plastic obturator in the rectum or the vagina. The obturator is used as a reference structure for aligning the target contour from each image plane to form a composite 2-dimensional contour of maximum tumor extent in a plane perpendicular to the obturator. Dose distributions are calculated to determine the placement of the Iridium-192 seed ribbons in the template. Laparoscopic guidance is used for actual placement of brachytherapy source needles together with a rectal or vaginal obturator to stabilize the template and to assure that the needle placement conforms with the planned geometry. Dose distributions for 10 consecutive patients calculated for customized templates as well as for five commercially available standard templates show that the customized templates are superior to standard templates in that the planned dose distribution matches the configuration of the target volume and is more uniform than with standard templates.

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 Fisher's 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.

Automated temperature scanning for hyperthermia treatment monitoring.

Ideal descriptors of hyperthermia treatments will most likely depend on complete target temperature distributions. Although these distributions can be modeled numerically, the accuracy of models is limited by the sparseness of temperatures measured in vivo. Thus, the strategy of monitoring temperatures may play a key role in improving hyperthermia therapy. Scanning temperatures by manual translations of thermometers was found to be excessively time consuming. Consequently an automated system was developed consisting of linear actuators, outriggers, guide tubes, thermometry catheters, personal computer, and dedicated hardware and software. During treatments, scan patterns were created with algorithms using temperatures measured preceding each thermometer translation. Measurement position had a noteworthy influence on thermal dose estimated by current models. Relative to manual scanning, automated scanning increased measurement efficiency, reduced probe position uncertainty, reduced operator time, and provided improved data for modeling bioheat transfer and thermal dose.

Tandem tip fracture: a rare complication of intracavitary therapy of cervix cancer and how to avoid its occurrence.

A case is described in which the distal tip of a tandem fractured off in a patient's uterus during an intracavitary application of a tandem and ovoids. Potential contributing factors are evaluated. Methods to prevent and detect structural defects in tandems before they become clinically manifest are discussed.

Phase I/II study of external radio frequency phased array hyperthermia and external beam radiotherapy in the treatment of prostate cancer: technique and results of intraprostatic temperature measurements.

As part of an ongoing Phase I/II study at Duke University Medical Center investigating the toxicity and efficacy of external beam radiotherapy plus hyperthermia for deep-seated, locally advanced or recurrent solid tumors, 12 patients with prostate malignancies (adenocarcinoma--11, leiomyosarcoma--1) were treated with radiotherapy plus hyperthermia. Hyperthermia was given after radiotherapy using a Radio Frequency Phase/Amplitude Control Sigma 60 annular phased array device. All patients had simultaneous temperature measurements made in the rectal lumen and within the prostate during at least one hyperthermia session. Intraprostate thermometers were placed via a unique method described herein using both computerized tomography scan and a rigid sigmoidoscope for guidance. We were able to achieve the desired tumor temperature of > or = 42.5 degrees C in only 1/28 (3.5%) of hyperthermia treatments. Subjective symptoms of pain and/or pressure limited power deposition in 79% of hyperthermia treatments. Higher temperatures were achieved in the distal rectum than in the prostate in all treatments, although the differences were not statistically significant. This temperature differential could not be compensated by using phase and amplitude steering. Rectal temperatures adjacent to the prostate were predictive of prostate temperatures. We conclude that using this regional heating technique we were unable to demonstrate an ability to get an advantageous temperature differential between the prostate and normal tissue. This technique is not useful as an adjuvant to radiation therapy for prostate cancer. The usefulness of other regional heating techniques and devices should be explored.

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.

Interstitial thermoradiotherapy: thermal dosimetry and clinical results.

From August 1977 to August 1986, 72 patients with advanced primary or recurrent cancers were treated using interstitial thermoradiotherapy. Sites treated included the pelvis in 49 patients, the head and neck in 15, and other sites in six. Median tumor volume was 52 cm3, and all but nine patients had received prior irradiation. In 69 patients, hollow stainless steel catheters were implanted and used as electrodes with a 0.5 MHz radiofrequency (RF) generator, whereas in three patients, standard plastic Henschke tubes were used with a commercially available interstitial microwave (MW) system operating at 915 MHz. Most patients were heated intraoperatively for 30 minutes, aiming for a minimum measured intratumoral temperature (Tmin) of 42 degrees C. The implant was occasionally preceded by external irradiation, and after hyperthermia, the catheters were afterloaded with 192Ir for brachytherapy. Tmin exceeded 42 degrees, 42.5 degrees, 43 degrees, and 44 degrees in 25, 16, 12, and 3, respectively, of 70 patients with temperature data available, and the probability of successful heating was independent of tumor volume or site. Twenty-five of 69 (36%) evaluable patients achieved a complete response (CR). Probability of CR demonstrated a significant univariate dependence upon Tmin, radiation dose, site treated, and tumor volume, but multivariate analysis showed only three significant predictor variables: tumor volume, radiation dose, and Tmin. The probability of a CR ranged from 95% for patients with small tumors receiving high doses of radiation and adequate heat, to 5% for patients with large tumors receiving low radiation doses and less than adequate heat. Of 25 patients with CR, 10 relapsed; median response duration was less than 18 months, depended marginally upon disease site, and was independent of Tmin, radiation dose, and tumor volume. Seventeen patients sustained a complication, of which nine were severe enough to require hospitalization or surgery. All severe complications occurred in patients with pelvic tumors. The probability of a complication of any severity had a significant univariate association with maximum intratumoral temperature (Tmax) and tumor size. We conclude that interstitial thermoradiotherapy offers the promise of heating large tumors in locations where externally applied hyperthermia has not been successful.

Use of nitroprusside to increase tissue temperature during local hyperthermia in normal and tumor-bearing dogs.

The present study investigates the effects of nitroprusside, a potent vasodilating agent, on tissue temperature during local hyperthermia in five normal and five tumor-bearing dogs. Caudal thigh muscles were heated in normal dogs and muscle temperatures were recorded during hyperthermia. Tumor-bearing dogs received two hyperthermia treatments during a course of radiation therapy. Temperatures were recorded in tumor and surrounding normal tissues. Mean arterial pressure was decreased by approximately 40-45% during nitroprusside infusion and was associated with a compensatory increase in heart rate and increases in tissue temperature. In normal dogs, muscle temperatures increased an average of 1.7 degrees C with nitroprusside administration. When nitroprusside was administered at the beginning of local hyperthermia to induce step-down heating, approximately 48% of the measured positions in caudal thigh muscle achieved a temperature greater than or equal to 43 degrees C, sufficient to induce step-down heating, during the hyperthermia episode. In tumor-bearing dogs, there was a significant increase in tumor and normal tissue temperatures during nitroprusside administration. Estimated T90 and T50 descriptors increased by 0.9 degrees C and 1.6 degrees C, respectively, for tumor tissue and by 0.4 degrees C and 1.2 degrees C, respectively, for normal tissue. Despite the increase in normal tissue temperatures no toxicity was observed in these dogs. Nitroprusside may be a useful agent for manipulation of tumor temperatures during the entire hyperthermia treatment or for a short time period at the initiation of treatment to induce step-down heating.

Tumor temperature distributions predict hyperthermia effect.

Review of clinical hyperthermia (HT) trial results shows that there previously has not been a robust model relating efficacy of HT treatments to characteristics of the temperature distribution. Lack of a model has been an impediment in Phase II trials; these trials must include defining the prescription for HT treatment, optimizing the schedule of HT treatments, and defining quality assurance procedures. We propose a model that is based upon noting that the majority of a tumor volume is contained in the outermost "shell" of a solid tumor, across which shell the radial temperature distribution is assumed to be linear. Any linear distribution can be defined by coordinates of a point and a slope, and we choose the temperature at the radiographically defined edge of a tumor and the slope (dT/dr) across the outer shell as these determinants of the linear radial temperature distribution. A discriminant analysis of success or failure of treatment can then be based upon these two descriptors (Tedge, dT/dr). We have tested this model using data from patients with soft tissue sarcoma (Stage IIB or greater) that have entered an ongoing prospective trial of conventional preoperative radiotherapy (5000 cGy/25 Fx/5 wk) together with HT, the latter randomized to be given once or twice weekly during the 5 week course. Wide local excision of the primary tumor is done 1 month after completion of radiotherapy, and the extent of histologic change in the resected specimen is scored. Our model has an 86% predictive value for lack of complete or nearly complete necrosis in the resected specimen according to whether the time-averaged Tedge and slope during each HT treatment satisfy the equation Tedge + 1.2 (slope in degree C/cm) less than or equal to 40.6 degrees C in all but one treatment at most. Conversely, in 85% of cases with complete or nearly complete tumor necrosis, temperature distributions satisfied Tedge + 1.2 (slope in degree C/cm) greater than 40.6 degrees C during at least one HT treatment. Requiring greater than or equal to one third of treatments of a patient to satisfy the preceeding discriminant equation resulted in 80% of patients being correctly classified as a responder or nonresponder, with only one false positive prediction (patient incorrectly classified as a responder). The model can reveal systematic changes in the edge temperature distribution during the treatment course that are consistent with tumor perfusion changes inferred and measured by independent means.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Intraperitoneal cisplatin and regional hyperthermia for ovarian carcinoma.

PURPOSE: To review the theoretical basis and results of a Phase I study of concurrent intraperitoneal cisplatin and hyperthermia in the treatment of ovarian carcinoma. METHODS AND MATERIALS: Previously treated patients with epithelial ovarian carcinoma received intraperitoneal instillation of cisplatin and 60 minutes of regional hyperthermia, with a goal temperature of 41.5 degrees C. Cisplatin dose started at 20 mg/m2 with escalation to the maximally tolerated dose. Six such cycles given every 3 weeks were planned. Pharmacokinetic studies with and without hyperthermia were performed. RESULTS: Fifteen patients receiving 17 courses of treatment were evaluable. The maximally tolerated dose of cisplatin was between 80 and 120 mg/m2. The dose limiting toxicity was nephrotoxicity in all but one course. The median intraperitoneal temperature was 40.7 degrees C; the majority of treatments in which the goal temperature was not reached had power limited by patient discomfort. No major toxicities attributable to hyperthermia were noted. Pharmacokinetic studies noted no significant differences between treatments with vs. without hyperthermia, with intraperitoneal to plasma area under the curve ratios being 30-35. Ten patients had a decline in their CA-125 count during treatment, although in only two patients did this response persist beyond their course of treatment. CONCLUSION: Intraperitoneal cisplatin and regional hyperthermia can be performed with reasonable toxicity. The maximally tolerated dose of 80-120 mg/m2 in pretreated patients (which is similar to those reported with cisplatin alone) and median intraperitoneal temperatures of 40.7 degrees C, however, are felt to be too low to be efficacious in a significant percentage of women with bulky recurrent disease. Further study using intravenous thiosulfate and controlled analgesia is being performed.

Therapy monitoring in human and canine soft tissue sarcomas using magnetic resonance imaging and spectroscopy.

PURPOSE: The goals of this study were to determine whether magnetic resonance parameters (a) can identify early during therapy those patients most likely to respond to hyperthermia and radiotherapy, (b) can provide prior to or early during therapy information about the temperature distributions which can be obtained in patients receiving hyperthermia, and (c) can provide an understanding of the effects of hyperthermia on tumor metabolic status. METHODS AND MATERIALS: Twenty-one human patients and 10 canine patients with soft tissue sarcomas treated with preoperative hyperthermia and radiation had a series of magnetic resonance imaging and phosphorous spectroscopy studies done. To address the goals for both the human and canine populations, changes in mean T2 relaxation times, pH, and various phosphometabolite ratios from the pretreatment (Study 1) to the post first hyperthermia study (Study 2) were correlated with treatment outcome; pretreatment magnetic resonance parameters and changes in magnetic resonance parameters (Study 2-Study 1) were compared with various cumulative thermal descriptors; and thermal descriptors of the first hyperthermia were compared with changes in magnetic resonance phosphometabolite ratios. RESULTS: A decrease in adenosine triphosphate/phosphomonoester from study 1 to study 2 is associated with a greater chance of > or = 95% necrosis in surgical resected tumors from human patients, but no significant relationships were observed between changes in tumor pH or phosphometabolite ratios and time to local failure in dogs. Pretreatment magnetic resonance parameters correlated with various thermal dose descriptors in canines but not in humans. Change in adenosine triphosphate/inorganic phosphate and phosphomonoester signal to noise ratio correlated with cumulative thermal descriptors in dogs and humans, respectively. In dogs only, increases in thermal dose resulted in decreases in high energy phosphometabolites. CONCLUSION: Changes in magnetic resonance parameters early during therapy may be predictive of treatment outcome. Pretreatment and changes in magnetic resonance parameters appear to predict how well a tumor will be heated during hyperthermia. Magnetic resonance spectroscopy also appears to be a useful tool to study the effects of various thermal doses on tumor metabolic status.