John A. DeFord

Effective Estimation and Computer Control of Minimum Tumour Temperature During Conductive Interstitial Hyperthermia

The goal of heat therapy in the treatment of malignant disease is to raise the temperature of all neoplastic tissue to a cytotoxic temperature for a predetermined period of time. This seemingly simple task has proved difficult in vivo in part because of non-uniform power absorption and in part because of non-homogeneous and time-varying tumour blood flow. We have addressed this difficulty first by utilizing the conceptually simple technique of conductive interstitial hyperthermia, in which the tumour is warmed by multiple, electrically heated catheters, and second by implementing on-line control of minimum tumour temperatures near each catheter, estimated on the basis of the steady-state ratio of catheter power to catheter temperature rise. This report presents an analysis of the accuracy, precision, and stability of the on-line minimum temperature estimation/control technique for 22 patients who received 31 separate courses of conductive interstitial hyperthermia for the treatment of malignant brain tumours, and in whom temperature was monitored independently by 12-16 independent sensors per patient. In all patients the technique was found to accurately and precisely estimate and control the local minimum temperatures. Comparison of measured and estimated temperatures revealed a mean difference of 0.0 +/- 0.4 degrees C for those sensors within 1.0 mm of the expected location for minimum temperatures. This technique therefore offers an attractive method for controlling hyperthermia therapy-even in the presence of time varying local blood flow.

Design and evaluation of closed-loop feedback control of minimum temperatures in human intracranial tumours treated with interstitial hyperthermia

The dynamic nature of blood flow during hyperthermia therapy has made the control of minimum tumour temperature a difficult task. The paper presents initial studies of a novel approach to closed-loop control of local minimum tissue temperatures utilising a newly developed estimation algorithm for use with conductive mated from the power required to maintain each member of an array of electrically heated catheters at a known temperature, in conjunction with a new bioheat equation-based algorithm to predict the ‘droop’ or fractional decline in tissue temperature between heated catheters. A closed loop controller utilises the estimated minimum temperature near each catheter as a feedback parameter, which reflects variations in local blood flow. In response the controller alters delivered power to each catheter to compensate for changes in blood flow. The validity and stability of this estimation/control scheme were tested in computer simulations and in closedloop control of nine patient treatments. The average estimation error from patient data loop control of nine patient treatments. The average estimation error from patient data analysis of 21 sites at which temperature was independently measured (three per patient) was 0·0°C, with a standard deviation of 0·8°C. These results suggest that estimation of local minimum temperature and feedback control of power delivery can be employed effectively during conductive interstitial heat therapy of intracranial tumours in man.

Conductive interstitial hyperthermia in the treatment of intracranial metastatic disease.

SummaryBackgroundIntracranial metastases commonly complicate oncologic care affecting 140,000 patients per year in the United States. Treatment of these tumors is difficult and often unsuccessful. Hyperthermia is a treatment alternative that has shown promise in treating cancer in other areas. Therefore it was employed in an attempt to provide increased tumor control in CNS metastases.MethodsThis Phase I and Phase II clinical trial of interstitial hyperthermia in 13 patients with recurrent or progressive intracranial metastatic disease was undertaken to evaluate complications, delivery of heat and patient outcome.ResultsFeared complications of clinically significant bleeding, increased mass, or infection from the interstitial implant and treatment did not occur. The seizures which occurred in 4 patients were controlled with additional anticonvulsants. Three venous thromboembolic events were treated medically and with percutaneously placed inferior vena cava filters. The KPS of the majority of patients declined slightly with treatment but rebounded to near baseline within several months. CT scans demonstrated decrease or stabilization of tumor volumes in 7 of the 13 patients. In 4 of these patients, regression or stabilization persisted until death from nonCNS disease.ConclusionsInterstitial hyperthermia therapy for intracranial metastases is technically feasible and may provide increased tumor control. In this small series, it did not cause unreasonable complications. This therapy has some positive effect, but requires study of more patients before its role is definitively known. Combining hyperthermia with brachytherapy and/or chemotherapy is being evaluated.The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense.

Computer-aided design and evaluation of novel catheters for conductive interstitial hyperthermia

Conductive interstitial heating is a modality in which heating elements are implanted directly into the treated tissue. One implementation of such therapy employs electrically heated catheters that are implanted in staggered, parallel rows. To explore strategies for maximising the uniformity of tissue temperature distributions achieved with heated catheters, a two-dimensional computer model with cylindrical co-ordinates was used to evaluate radially and longitudinally the temperature distributions produced by a typical interior catheter surrounded by other similar catheters. Insights from the computer model led to new designs for catheters containing multiple heating elements that produced more uniform thermal distributions, eliminating previous ‘cold spots’ within the treatment volume located near the ends of the catheter. The new catheter designs also include compartments for the optional placement of radioactive seeds for simultaneous thermoradiotherapy.

Conductive, Interstitial Hyperthermia: A New Modality for Treatment of Intracranial Tumors

Malignant brain tumors comprise a devastating class of diseases with an overall dismal prognosis. The incidence of primary malignant gliomas, the most common category of primary intracranial tumors, is 12,000 to 15,000 patients per year in the United States.1,2 Metastatic brain tumors are reported in an additional 100,000 patients per year.3,4 Whereas the survival of patients with metastatic intracranial tumors is often determined by widespread systemic disease, in primary intracranial malignancies local recurrence represents the major source of failure. Despite aggressive cytoreductive surgery, radiation therapy, and chemotherapy, the clinical outcome is generally grim. Salcman (1980) in a review of 1561 glioblastoma cases treated with maximal resection, with or without the addition of radiation or radiation plus chemotherapy, found a two-year survival of 10%.5 Walker (1978) in a study of 222 patients with anaplastic gliomas found 1% survival at 24 months with surgery and radiation therapy, and 5% survival at 24 months with surgery, BCNU and radiation.6 Multiple combinations of modalities and different approaches have been explored quite extensively by many investigators. Even studies resorting to extreme approaches using high doses of radiation and chemotherapy have yielded only limited benefits to a minority of the population at risk.4,5,7–12 As expected, these cases have been accompanied by significant side effects and complications.13,14 Regrettably, anticipated refinements in standard therapies are not expected to appreciably improve the prognosis for patients with malignant gliomas.9,15,16

Evidence of changes in regional blood perfusion in human intracranial tumours during conductive interstitial hyperthermia

Human intracranial tumours were treated using local heat therapy produced by surgically implanted catheters containing local resistive heating elements. Changes in local tumor blood flow were assessed indirectly from an algorithm based on the bioheat transfer equation. The algorithm used the ratio of catheter power to catheter temperature rise to estimate regional blood perfusion. Local heat therapy produced consistent reductions in local apparent perfusion. Changes in apparent regional perfusion occurred in intriguing patterns that gave clues to possible vascular events of therapeutic significance.

Droop: a rapidly computable descriptor of local minimum tissue temperature during conductive interstitial hyperthermia

Although the goal of local hyperthermia therapy for cancer is to elevate the temperature of a tumour to cytotoxic levels, without the presence of ‘cold spots’, varying blood flow has made the achievement of consistent, therapeutic temperature distributions extraordinarily difficult. The paper presents a novel approach to estimating local minimum tumour temperatures during conductive interstitial hyperthermia which facilitates identification and elimination of cold spots. Conductive interstitial hyperthermia is modelled mathematically for a parallel array of implanted, electrically heated catheters which warms the treated tissue by thermal conduction and blood perfusion. Computer simulations employing the bioheat transfer equation reveal a predictive relationship between implanted catheter temperature, catheter power, implantation geometry and local minimum tumour temperature. Formulation of this relationship in terms of a parameter named ‘droop’ allows estimation of local minimum intratumoural temperatures from individual catheter temperature and power. Computer simulations are also performed to determine the sensitivity of the droop-based estimator to variations in properties of the tissue and catheters. Generally, variations in geometry or thermal properties of about 10 per cent cause estimation errors of less than 1°C in magnitude. These results suggest that online estimates of thermal ‘droop’ may provide a practical route to more consistent control of intratumoural minimum temperature during conductive interstitial heat therapy.

Interstitial hyperthermia using electrically heated catheters

A description is given of a hyperthermia method that uses resistively heated interstitial catheters and conductive heat transfer for treatment of malignant brain tumors. As opposed to radiant heat sources such as ultrasound or microwave radiation, this system utilizes simple direct conversion of electrical energy to heat via resistive elements placed in implantable catheters. Heat transfer occurs via conduction and blood convection. Preliminary results indicate that tissue thermal profiles surrounding the catheters are predictable, given a fixed geometry, and feasible for hyperthermia treatment of tumors.<<ETX>>