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The objectives of this study were to compare the effects of two vasodilators, sodium nitroprusside (SNP) and calcitonin gene-related peptide (CGRP) on mean arterial pressure (MAP), heart rate (HR) and temperatures in tumour and surrounding normal tissue during local hyperthermia treatment. Eleven tumour-bearing pet dogs with spontaneous soft tissue sarcomas were given SNP intravenously during local hyperthermia. The drug infusion rate was adjusted to maintain a 20% decrease in MAP. The median (95% CI) increase in the temperature distribution descriptors T 90 and T 50 was 0.2°C (0.0-0.4°C, p = 0.02) and 0.4°C (0.1-0.7°C, p = 0.02), respectively, in tumour. Normal subcutaneous tissue temperatures were mildly increased but remained below the threshold for thermal injury. The effects of CGRP were investigated in six tumour-bearing dogs following a protocol similar to that used for SNP. The median (interquartile (IQ) range) decrease in mean arterial pressure was 19% (15-26%) after CGRP administration and a significant increase was seen in tumour but not normal subcutaneous tissue temperatures. The median (95% CI) increase in the temperature distribution descriptors T 90 and T 50 was 0.5°C (0.1-1.6°C, p = 0.03) and 0.8°C (0.1-1.6°C, p = 0.13), respectively. Administration of SNP or CGRP did not result in local or systemic toxicity in tumour-bearing dogs. However, the magnitude of increase in tumour temperatures was not sufficient to improve the likelihood of increased response rates. Therefore, there is little justification for translation of this approach to human trials using conventional local hyperthermia. [ABSTRACT FROM AUTHOR]

Magnetic Resonance Imaging (MRI) is an attractive method of temperature monitoring in vivo due to its non-invasive nature. The natural extension of this temperature monitoring is to implement temperature control. This work outlines a method of MRI-based thermal modelling for multi-source phased array heating systems that can potentially be employed, in the future, for real time temperature prediction and control. This method is based on Pennes bioheat equation. It employs the superposition of an empirically acquired basis set of temperature distributions that define the heating system's temperature response. MR thermal images based on the proton resonance frequency shift (PRFS) technique are used to acquire this basis set. The feasibility of this approach is tested in phantom using a radiofrequency (RF) heating system. The results show that this method can accurately reproduce measured temperature distributions outside of the basis set. [ABSTRACT FROM AUTHOR]

This paper explores the behaviour of the primary and secondary hot spots in homogeneous and two-dimensional inhomogeneous medium. Circular arrays are considered with a radius of up to five wavelengths. The number of sources and their positions in the array are varied, and the influence of these variations on the primary and secondary hot spots is observed. It is found that the primary hot spot reaches its final shape with the addition of a very small number of sources to the array. An increase in the number of sources results in a reduction of the normalized magnitude of the secondary hot spots, but the size of the normalized primary hot spot remains the same. An upper limit of sources in the array exists after which no further reduction of the secondary hot spots is observed. The finite-difference time-domain method (FDTD) is used to obtain the electric-field distribution in the inhomogeneous medium. A genetic algorithm is then applied to find the optimal positions of the antennae in the array. [ABSTRACT FROM AUTHOR]

We prospectively evaluated whether delivering a thermal dose of ≥10 cumulative equivalent minutes at 43°C to >90% of the tumour sites monitored (CEM43° T[sub 90]) would produce a pathologic complete response (pCR) in ≥ 75% of high-grade soft tissue sarcomas treated pre-operatively with thermoradiotherapy. The impact of thermal dose on local failure (LF), distant metastasis (DM), and toxicity was also assessed. Thirty-five patients ≥ 18 years old with grade 2 or 3 soft tissue sarcomas accessible for invasive thermometry were enrolled on the protocol. All patients received megavoltage external beam radiotherapy (RT) in daily fractions of 1.8-2.0Gy, five times a week, to a median total dose of 50Gy and an initial hyperthermia treatment (HT) of 1h duration utilizing the BSD 2000 with Sigma 60 or MAPA applicators at frequencies of 60-140MHz. Further HT was given for patients with CEM43° T[sub 90] > 0.5 after initial HT ('heatable' patients), twice a week to a maximum of 10 HT or CEM43° T[sub 90] > 100. Of the 35 patients entered, 30 had heatable tumours, one of which was inevaluable for pCR or LF as the patient died of DM prior to surgery, leaving 29 evaluable patients. Of these 29 patients, 15 (52%) had a pCR (95% CI: 37-73%), significantly less than the projected rate of ≥75% (p = 0.02). Of the 25 heatable tumours that achieved CEM43° T[sub 90] ≥10, 14 (56% ) had a pCR (95% CI: 39-78%) significantly less than the projected rate (p = 0.06). Three of the 29 patients (10% ) with heatable tumours had a LF, versus 1/5 unheatable tumours (p = 0.48). Fourteen of the 30 patients (47%) with heatable tumours developed DM, versus 2/5 unheatable tumours (p = 1.00). Ten of the 30 patients (33%) with heatable tumours developed treatment-induced toxicity. Thus, no correlation of thermal dose with histologic response was observed. Prospective control of CEM43° T[sub 90] failed to achieve the projected pCR rate following pre-operative thermoradiotherapy for high-grade soft tissue sarcomas, despite excellent local control. Possible explanations for this outcome are discussed. [ABSTRACT FROM AUTHOR]

The optimization of power deposition for electromagnetic (EM) thermal therapy is investigated. Several goal or objective functions are examined using a generalized mathematical formulation. These include maximization of: (1) target power absorption, (2) the ratio of target to non-target power absorption, (3) target power absorption weighted by the ratio of target to non-target power absorption, and (4) target power absorption subject to the constraint that the non-target high power volume ('hot spot' volume) is below a chosen level. The merit of these functions was retrospectively tested using an anatomic data base containing 38 cancer patients that were clinically heated with EM phased arrays. CT and/or MRI image data were used to define relevant anatomic geometries and tissue properties for finite element numerical models. Power optimization is achieved by variation of seven available control parameters (four amplitudes and three phases) for these clinical array devices. The results indicate that site dependent improvements in target power absorption can be achieved using these goal functions relative to a configuration that utilizes equal phase and amplitude for the sources. The relative merit among these various functions favours an optimization strategy that maximizes the target power absorption weighted by the ratio of target power to non-target power absorption. [ABSTRACT FROM AUTHOR]

Presents a study that examines the activity of weekly cisplatin and hyperthermia with concurrent radiation therapy in advance cervical carcinoma. Effect of the addition of chemotherapy to standard radiation therapy on the risk of due death to cervical carcinoma; Strategy that has been shown to improve results of radiation therapy alone; Criteria for eligible patients in the single-institution clinical trial.

The success of hyperthermia treatments is dependent on thermal dose distribution. However, the three-dimensional temperature distribution remains largely unknown. Without this knowledge, the relationship between thermal dose and outcome is noisy, and therapy cannot be optimized. Accurate computations of thermal distribution can contribute to an optimized therapy. The hyperthermia modeling group in the Department of Radiotherapy, University Medical Center Utrecht devised a Discrete Vasculature [Kotte et al., Phys. Med. Biol. 41, 865-884 (1996)] model that accounts for the presence of vessel trees in the computational domain. The vessel tree geometry is tracked using magnetic resonance (MR) angiograms to a minimum diameter between 0.6 and 1 mm. However, smaller vessels (0.2-0.6 mm) are known to account for significant heat transfer. The hyperthermia group at Duke University Medical Center has proposed using perfusion maps derived from dynamic-enhanced magnetic resonance imaging to account for the tissue perfusion heterogeneity [Craciunescu et al., Int. J. Hyperthermia 17, 221-239 (2001)]. In addition, techniques for noninvasive temperature measurements have been devised to measure temperatures in vivo [Samulski et al., Int. J. Hypertherminal, 819-829 (1992)]. In this work, a patient with high-grade sarcoma has been retrospectively modeled to determine the temperature distribution achieved during a hyperthermia treatment. Available for this model were MR depicted geometry, angiograms, perfusion maps, as necessary for accurate thermal modeling, as well as MR thermometry data for validation purposes. The vasculature assembly through modifiable potential program [Van Leeuwen et al., IEEE Trans. Biomed. Eng. 45, 596-604 (1998)] was used in order to incorporate the traceable large vessels. Temperature simulations were made using different approaches to describe perfusion. The simulated cases were the bioheat equation with constant perfusion rates per tissue type, perfusion maps alone, tracked vessel tree and perfusion maps, and generated vessel tree. The results were compared with MR thermometry data for a single patient data set, concluding that a combination between large traceable vessels and perfusion map yields the best results for this particular patient. The technique has to be repeated on several patients, first with the same type of malignancy, and after that, on patients having malignancies at other different sites.

It has been shown that the perfusion of blood in tumor tissue can be approximated using the relative perfusion index determined from dynamic contrast-enhanced magnetic resonance imaging (DE-MRI) of the tumor blood pool. Also, it was concluded in a previous report that the blood perfusion in a two-dimensional (2-D) tumor vessel network has a fractal structure and that the evolution of the perfusion front can be characterized using invasion percolation. In this paper, the three-dimensional (3-D) tumor perfusion is reconstructed from the 2-D slices using the method of fractal interpolation functions (FIF), i.e., the piecewise self-affine fractal interpolation model (PSAFIM) and the piecewise hidden variable fractal interpolation model (PHVFIM). The fractal models are compared to classical interpolation techniques (linear, spline, polynomial) by means of determining the 2-D fractal dimension of the reconstructed slices. Using FIFs instead of classical interpolation techniques better conserves the fractal-like structure of the perfusion data. Among the two FIF methods, PHVFIM conserves the 3-D fractality better due to the cross correlation that exists between the data in the 2-D slices and the data along the reconstructed direction. The 3-D structures resulting from PHVFIM have a fractal dimension within 3%-5% of the one reported in literature for 3-D percolation. It is, thus, concluded that the reconstructed 3-D perfusion has a percolation-like scaling. As the perfusion term from bio-heat equation is possibly better described by reconstruction via fractal interpolation, a more suitable computation of the temperature field induced during hyperthermia treatments is expected.

A conformal ultrasound phased array prototype with 96 elements was recently calibrated for electronic steering and focusing in a water tank. The procedure for calibrating the shape of this 2D therapy array consists of two steps. First, a least squares triangulation algorithm determines the element coordinates from a 21 x 21 grid of time delays. The triangulation algorithm also requires temperature measurements to compensate for variations in the speed of sound. Second, a Rayleigh-Sommerfeld formulation of the acoustic radiation integral is aligned to a second grid of measured pressure amplitudes in a least squares sense. This shape calibration procedure, which is applicable to a wide variety of ultrasound phased arrays, was tested on a square array panel consisting of 7- x 7-mm elements operating at 617 kHz. The simulated fields generated by an array of 96 equivalent elements are consistent with the measured data, even in the fine structure away from the primary focus and sidelobes. These two calibration steps are sufficient for the simulation model to predict successfully the pressure field generated by this conformal ultrasound phased array prototype.

Background: Nitric oxide synthase (NOS) inhibitors have been investigated as potential cytotoxic agents to treat tumors lacking p53 function. Furthermore, their ability to reduce tumor blood flow can be combined with drugs that are specifically designed to kill cells that are hypoxic or to improve temperatures during local heat (hyperthermia) treatment of tumors. This paper reports the unexpected development of acute pancreatitis in two tumor-bearing pet dogs that were treated with the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) during administration of local hyperthermia., Methods: Prior to the use of L-NAME in tumor-bearing dogs, purpose-bred beagles were studied. Following induction of inhalation anesthesia, local hyperthermia was applied to either normal thigh muscle (beagles) or tumors (tumor-bearing dogs). Once a thermal steady state was achieved, L-NAME was administered and temperature monitoring continued. Animals were observed after treatment for evidence of toxicity., Results: The beagles tolerated the treatment well, with no side effects noted either clinically or by routine CBC or blood chemistry analyses. In contrast, the first two tumor-bearing dogs accrued onto the phase I study developed acute pancreatitis in the immediate post-treatment period which necessitated hospitalization and intensive care. The trial was stopped. Both dogs had intercurrent risk factors which predisposed them to development of pancreatitis, although neither had a history of symptoms of pancreatitis at the time the hyperthermia + L-NAME treatment was given., Conclusions: We conclude that caution should be exercised when considering NOS inhibition for cancer treatment. Careful evaluation of history and health status as well as recognition of potential risk factors may be key in avoiding potentially fatal complications. This study demonstrates the value of performing potentially harmful treatments in tumor-bearing dogs prior to introduction into the human clinic.

Failure of local tumor control still poses a problem for radiotherapy and translates into reduced survival. Combining radiation with chemotherapy or other newer modalities has shown promising results. Immunological approaches to tumor therapy have found renewed interest due to improved insight into mechanisms involved in the immune response to tumors. In this paper, we studied tumor growth delay after various combination regimens of locally injected adenovirus constitutively expressing IL12 and B7.1 (AdIL12/B7.1) and fractionated radiotherapy in two nonimmunogenic murine tumor models, 4T1 and B16.F10. Effects of radiation and virus infection on surface antigen expression in these tumor lines were assessed. Mechanisms of action of AdIL12/B7.1 were studied by conducting additional experiments with and without depletion of NK-cells and/or T-cells, and by cytotoxic T-lymphocyte assays, and immunohistochemical evaluation of tumor blood vessels. Both B7.1 and IL12 were effectively expressed in both irradiated and unirradiated 4T1 and B16.F10 tumor cells but did not add significantly to radiation-induced cell killing in vitro. However, local tumor infection by AdIL12/B7.1 after irradiation significantly increases the effectiveness of radiotherapy when applied after completion of radiotherapy. The mechanism appears to be complicated, involving a host of factors that included the ability of IL12 to activate T-cells and NK-cells and to inhibit angiogenesis and the ability of radiation to induce apoptosis or necrosis among tumor cells. These data support the combination of radiotherapy with adenovirus-mediated immunotherapy and suggest that the concept of adding genetic immunotherapy after radiotherapy in a combined regimen merits further study.

Two numerical techniques are used to calculate the effect of large vessel counter-current flow on hyperthermic temperature distributions. One is based on the Navier-Stokes equation for steady-state flow, and the second employs a convective-type boundary condition at the interface of the vessel walls. Steady-state temperature fields were calculated for two energy absorption rate distributions (ARD) in a cylindrical tissue model having two pairs of counter-current vessels (one pair with equal diameter vessels and another pair with unequal diameters). The first assumed a uniform ARD throughout cylinder; the second ARD was calculated for a tissue cylinder inside an existing four antenna Radiofrequency (RF) array. A tissue equivalent phantom was constructed to verify the numerical calculations. Temperatures induced with the RF array were measured using a noninvasive magnetic resonance imaging technique based on the chemical shift of water. Temperatures calculated using the two numerical techniques are in good agreement with the measured data. The results show: 1) the convective-type boundary condition technique reduces computation time by a factor of ten when compared to the fully conjugated method with little quantitative difference (approximately 0.3 degree C) in the numerical accuracy and 2) the use of noninvasive magnetic resonance imaging (thermal imaging) to quantitatively access the temperature perturbations near large vessels is feasible using the chemical shift technique.

Purpose: The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia., Methods and Materials: Tumor pO2 was measured using an Eppendorf polarographic device, pHe using interstitial electrodes, and blood flow using contrast-enhanced magnetic resonance imaging (MRI)., Results: There was an overall improvement in tumor oxygenation observed as an increase in median pO2 and decrease in hypoxic fraction (% of pO2 measurements <5 mm Hg) at 24-h post hyperthermia. These changes were most pronounced when the median temperature (T50) during hyperthermia treatment was less than 44 degrees C. Tumors with T50 > 44 degrees C were characterized by a decrease in median PO2 and an increase in hypoxic fraction. Similar thermal dose-related changes were observed in tumor perfusion. Perfusion was significantly higher after hyperthermia. Increases in perfusion were most evident in tumors with T50 < 44 degrees C. With T50 > 44 degrees C, there was no change in perfusion after hyperthermia. On average, pHe values declined in all animals after hyperthermia, with the greatest reduction seen for larger T50 values., Conclusion: This study suggests that hyperthermia has biphasic effects on tumor physiologic parameters. Lower temperatures tend to favor improved perfusion and oxygenation, whereas higher temperatures are more likely to cause vascular damage, thus leading to greater hypoxia. While it has long been recognized that such effects occur in rodent tumors, this is the first report to tie such changes to temperatures achieved during hyperthermia in the clinical setting. Furthermore, it suggests that the thermal threshold for vascular damage is higher in spontaneous tumors than in more rapidly growing rodent tumors.

Purpose: To explore the use of a novel program of preoperative radiation and hyperthermia in the management of high-grade soft tissue sarcomas (STS)., Methods and Materials: Eligible patients were adults over 18 with Grade 2 or 3 STS, surgically resectable without a local excision prior to referral to Duke University Medical Center and without distant metastases. Patients were staged generally with CT and/or MR imaging. The diagnosis was established with fine needle aspiration or incisional biopsy. Patients were then treated with 5000 to 5040 cGy, 180-200 cGy per fraction. Chemotherapy was usually not employed. Generally two hyperthermia treatments per week were given with a planned thermal dose of 10-100 CEM 43 degrees T90. Invasive thermometry and thermal mapping were done in all patients. Surgical resection was planned 4-6 weeks after the completion of radiation and hyperthermia., Results: Ninety-seven patients were treated on study between 1984 and 1996. Follow-up ranged from 12 to 155 months (median 32). All tumors were high-grade in nature, 44 greater than 10 cm in size (maximum tumor diameter), 43 5-10 cm in size, 10 less than 5 cm. Seventy-eight of the 97 tumors were located in an extremity. Of the 97 patients, 48 remain alive and continually free of disease following initial therapy. Of the remaining 49 patients, 44 have relapsed (34 dead, 10 living with disease), 3 have died secondary to complications of therapy, and 2 have died of unrelated causes. Ten-year actuarial overall survival, cause-specific survival, and relapse-free survival are 50, 47, and 47% respectively. The predominant pattern of failure has been distant metastases with only 2 patients developing local failure alone. Ten-year actuarial local control for extremity tumors is 94%, 63% for the 19 patients with tumors at sites other than the extremity. Of the 78 patients with extremity lesions, 63 have had limb preservation and remain locally controlled. Overall 38 patients experienced 57 major complications. There were 3 deaths, one due to adriamycin cardiomyopathy and two secondary to wound infections. Four patients required amputation secondary to postoperative wound healing problems. Complications directly attributable to hyperthermia occurred in 15 patients with 11 instances of second- or third-degree burns and two instances of subcutaneous fat necrosis. The hyperthermia complications were generally not severe and either healed readily or were excised at the time of surgical resection of the primary tumor., Conclusions: For these aggressive high-grade soft tissue sarcomas, this treatment program of preoperative thermoradiotherapy provided excellent local regional control for extremity lesions (95%) and satisfactory local regional control (63%) of nonextremity sarcomas, but did not appear to influence the rate of distant metastases or survival. Complications were frequent but apart from the direct thermal burns, not too different from those reported for preoperative radiotherapy alone. More effective adjuvant systemic therapy is necessary to impact favorably on survival.

Hyperthermia temperature optimization involves arriving at a temperature distribution which minimizes a stated goal function, the goal function having a biological basis in maximizing tumor cell kill while not exceeding normal tissue toxicity. This involves the computationally intensive process of multiple evaluations of the temperature goal function, requiring repeated evaluations of the power deposition and its corresponding temperature distribution. Two computational schemes are proposed to expedite the temperature optimization process: (1) temperature distribution evaluation by superpositioning precomputed distributions, and (2) using representative tissue groups (rather than every point in the domain) to evaluate the goal function. The application of these schemes is illustrated with a typical optimization problem, as applied to symmetric and asymmetric, heterogeneous models. Application of these schemes reduced the optimization time on a DEC Alpha 1000 4/266 (Alpha is a registered trademark of Digital Equipment Corporation.) from several h to min, with little difference in results. The computational schemes, though demonstrated in the context of electromagnetic hyperthermia, are generally applicable to other forms of nonionizing radiation employed in hyperthermia therapy.

The adverse prognostic impact of tumor hypoxia has been demonstrated in human malignancy. We report the effects of radiotherapy and hyperthermia (HT) on soft tissue sarcoma oxygenation and the relationship between treatment-induced changes in oxygenation and clinical treatment outcome. Patients receiving preoperative radiotherapy and HT underwent tumor oxygenation measurement pretreatment after the start of radiation/pre-HT and one day after the first HT treatment. The magnitude of improvement in tumor oxygenation after the first HT fraction relative to pretreatment baseline was positively correlated with the amount of necrosis seen in the resection specimen. Patients with <90% resection specimen necrosis experienced longer disease-free survival than those with > or = 90% necrosis. Increasing levels of tumor hypoxia were also correlated with diminished metabolic status as measured by P-31 magnetic resonance spectroscopy.

The temperature sensitivity of the chemical shift of water (approximately 0.01 ppm/degree C) provides a potential method to monitor temperature changes in vivo or in vitro through the changes in phase of a gradient-echo magnetic resonance (MR) image. This relation was studied at 1.5 T in gel materials and in vivo in canine brain and muscle tissue, heated with a radio frequency (rf) annular phased array hyperthermia antenna. The rf fields associated with heating (130 MHz) and imaging (64 MHz) were decoupled using bandpass filters providing isolation in excess of 100 dB, thus allowing simultaneous imaging and rf heating without deterioration of the MR image signal-to-noise ratio. In a gel, temperature sensitivity of the MR image phase was observed to be (4.41 +/- 0.02) phase degrees/degree C for Te = 20 ms, which allowed temperature changes of 0.22 degree C to be resolved for a 50-mm3 region in less than 10 s of data acquisition. In vivo, for Te = 20 ms, the temperature sensitivity was (3.2 +/- 0.1) phase degrees/degree C for brain tissue, (3.1 +/- 0.1) phase degrees/degree C for muscle, and (3.0 +/- 0.2) phase degrees/degree C for a muscle tumor (sarcoma), allowing temperature changes of 0.6 degree C to be resolved in a 16-mm3 volume in less than 10 s of data acquisition. We conclude that, while the technique is very sensitive to magnetic field inhomogeneity, stability, and subject motion, it appears to be useful for in vivo temperature change measurement.

In the treatment of soft tissue sarcomas, hyperthermia has been demonstrated to enhance tumor necrosis from radiation therapy. The current study reports the clinical course of patients treated with this neoadjuvant therapy regimen. Forty-four patients with deep, undisturbed, nonmetastatic, high grade soft tissue sarcomas completed a neoadjuvant treatment protocol with combined hyperthermia and radiation therapy followed by wide surgical resection. Negative surgical margins were obtained in 40 patients. There was one local recurrence, thus yielding a local control rate of 97.5%. All other failures were either through regional lymphatic spread or pulmonary metastasis. As a group, the patients at 36 months had a 72% overall and a 58% disease-free survival. The most common pathologic diagnosis was malignant fibrous histiocytoma (MFH), which demonstrated a 36-month survival of 52% vs. 82% for others (P = 0.02). Tumor size was not prognostically significant for disease free or overall survival (P = 0.13). Those patients with surgical margins < 1 cm had a significantly lower disease-free survival and overall survival in a multivariate analysis (P = 0.02 and P = 0.006, respectively). Overall survival did not correlate with either the number of hyperthermia treatments received or the amount of tumor necrosis. Although this neoadjuvant protocol results in excellent local control rates, overall survival rates are comparable to adjuvant therapy employing radiation alone.

Numerical modeling methods and hyperthermia treatment temperature measurements have been used together to reconstruct steady-state tumor temperature distributions. However, model errors will exist which may in turn produce errors in the reconstructed temperature distributions. A series of computer experiments was conducted to study the sensitivity of reconstructed two-dimensional temperature distributions to perfusion distribution modeling errors. Temperature distributions were simulated using a finite element approximation of Pennes' bioheat transfer equation. Relevant variables such as tumor shape, perfusion distribution, and power deposition were modeled. An optimization method and the temperatures "measured" from the simulated temperature distributions were used to reconstruct the tumor temperature distribution. Using this procedure, the sensitivity of the reconstructed tumor temperature distribution to model-related errors, such as the perfusion function, was studied. It was found that: 1) if the problem is conduction dominated, large errors in the perfusion distribution produce only small errors in the reconstructed temperature distribution (maximum error < 1.0 degrees C), and 2) when the actual perfusion distribution contains a small random variation (+/- 15%) which is neglected by the model, the reconstructed temperature distribution will be in good agreement with the actual temperature distribution (maximum error < or = 0.3 degrees.

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.