Sean R.H. Davidson

Image Guided Photothermal Focal Therapy for Localized Prostate Cancer: Phase I Trial

PURPOSE We ascertained the feasibility and safety of image guided targeted photothermal focal therapy for localized prostate cancer. MATERIALS AND METHODS Twelve patients with biopsy proven low risk prostate cancer underwent interstitial photothermal ablation of the cancer. The area of interest was confirmed and targeted using magnetic resonance imaging. Three-dimensional ultrasound was used to guide a laser to the magnetic resonance to ultrasound fused area of interest. Target ablation was monitored using thermal sensors and real-time Definity contrast enhanced ultrasound. Followup was performed with a combination of magnetic resonance imaging and prostate biopsy. Validated quality of life questionnaires were used to assess the effect on voiding symptoms and erectile function, and adverse events were solicited and recorded. RESULTS Interstitial photothermal focal therapy was technically feasible to perform. Of the patients 75% were discharged home free from catheter the same day with the remainder discharged home the following day. The treatment created an identifiable hypovascular defect which coincided with the targeted prostatic lesion. There were no perioperative complications and minimal morbidity. All patients who were potent before the procedure maintained potency after the procedure. Continence levels were not compromised. Based on multicore total prostate biopsy at 6 months 67% of patients were free of tumor in the targeted area and 50% were free of disease. CONCLUSIONS Image guided focal photothermal ablation of low risk and low volume prostate cancer is feasible. Early clinical, histological and magnetic resonance imaging responses suggest that the targeted region can be ablated with minimal adverse effects. It may represent an alternate treatment approach to observation or delayed standard therapy in carefully selected patients. Further trials are required to demonstrate the effectiveness of this treatment concept.

Drilling in Bone: Modeling Heat Generation and Temperature Distribution

Thermo-mechanical equations were developed from machining theory to predict heat generation due to drilling and were coupled with a heat transfer FEM simulation to predict the temperature rise and thermal injury in bone during a drilling operation. The rotational speed, feed rate, drill geometry and bone material properties were varied in a parametric analysis to determine the importance of each on temperature rise and therefore on thermal damage. It was found that drill speed, feed rate and drill diameter had the most significant thermal impact while changes in drill helix angle, point angle and bone thermal properties had relatively little effect.

Vascular-targeted photodynamic therapy (padoporfin, WST09) for recurrent prostate cancer after failure of external beam radiotherapy: a study of escalating light doses

To report on the efficacy of TOOKAD® (WST 09; NegmaLerads, Magny‐Les‐Hameaux, France) vascular‐targeted photodynamic therapy (VTP) as a method of whole‐prostate ablation in patients with recurrent localized prostate cancer after the failure of external beam radiotherapy (EBRT).

Real-time magnetic resonance imaging-guided focal laser therapy in patients with low-risk prostate cancer.

Two patients with low-risk prostate cancer (PCa) were treated with outpatient in-bore magnetic resonance imaging (MRI)-guided focal laser ablation. The tumor was identified on MRI. A laser fiber was delivered via a catheter inserted through a perineal template and guided to the target with MRI. The tissue temperature was monitored during laser ablation by MRI thermometry. Accumulated thermal damage was calculated in real time. Immediate post-treatment contrast-enhanced MRI confirmed devascularization of the target. No adverse events were noted. MRI-guided focal laser therapy of low-risk PCa is feasible and may offer a good balance between cancer control and side effects.

Focal Laser Ablation for Prostate Cancer Followed by Radical Prostatectomy: Validation of Focal Therapy and Imaging Accuracy

An increased incidence of low-risk prostate cancer (PCa) has led investigators to develop focal therapy as a management option for PCa. We evaluated the effects of focal laser ablation (FLA) on PCa tissue and the accuracy of magnetic resonance imaging (MRI) in determining ablated lesion volume by comparing the whole-mount histology and MRI in four patients that underwent FLA followed by radical prostatectomy. Ablated areas were characterized by homogeneous coagulation necrosis. The MRI-calculated ablated volume correlated well with histopathology. We found that FLA creates confluent ablation with no evidence of viable cells in treated regions. Postablation MRI is able to determine the ablation accurately.

Measurement of thermal conductivity of bovine cortical bone

The thermal conductivity of cortical bone was characterized experimentally. Specimens were taken from the mid-diaphysis of bovine femora, and the rate of heat transfer was measured in three orthogonal directions. The conductivity was found to be 0.58+/-0.018 W/mK in the longitudinal direction, 0.53+/-0.030 W/mK in the circumferential direction, and 0.54+/-0.020 W/mK in the radial direction. Because the directional differences are small, it is concluded that bovine cortical bone can be treated as thermally isotropic.

Treatment planning and dose analysis for interstitial photodynamic therapy of prostate cancer.

With the development of new photosensitizers that are activated by light at longer wavelengths, interstitial photodynamic therapy (PDT) is emerging as a feasible alternative for the treatment of larger volumes of tissue. Described here is the application of PDT treatment planning software developed by our group to ensure complete coverage of larger, geometrically complex target volumes such as the prostate. In a phase II clinical trial of TOOKAD vascular targeted photodynamic therapy (VTP) for prostate cancer in patients who failed prior radiotherapy, the software was used to generate patient-specific treatment prescriptions for the number of treatment fibres, their lengths, their positions and the energy each delivered. The core of the software is a finite element solution to the light diffusion equation. Validation against in vivo light measurements indicated that the software could predict the location of an iso-fluence contour to within approximately +/-2 mm. The same software was used to reconstruct the treatments that were actually delivered, thereby providing an analysis of the threshold light dose required for TOOKAD-VTP of the post-irradiated prostate. The threshold light dose for VTP-induced prostate damage, as measured one week post-treatment using contrast-enhanced MRI, was found to be highly heterogeneous, both within and between patients. The minimum light dose received by 90% of the prostate, D(90), was determined from each patients dose-volume histogram and compared to six-month sextant biopsy results. No patient with a D(90) less than 23 J cm(-2) had complete biopsy response, while 8/13 (62%) of patients with a D(90) greater than 23 J cm(-2) had negative biopsies at six months. The doses received by the urethra and the rectal wall were also investigated.

INTERSTITIAL MICROWAVE THERMAL THERAPY FOR PROSTATE CANCER: METHOD OF TREATMENT AND RESULTS OF A PHASE I/II TRIAL

PURPOSE Interstitial microwave thermal therapy is experimental treatment for prostate cancer with the goal of curing disease, while causing fewer complications than standard treatment options. We present a method for delivering interstitial microwave thermal therapy using microwave radiating helical antennae inserted percutaneously under transrectal ultrasound guidance. We report the results of a trial of this method in 25 patients in whom primary external beam radiation therapy had previously failed. This patient group currently has limited curative options that are associated with a high complication rate. However, these recurrent tumors often remain localized to the prostate, and so they may be amenable to localized therapy. MATERIALS AND METHODS Patients with proved prostatic adenocarcinoma were candidates for treatment when prostate specific antigen (PSA) was 15 ng./ml. or less and prostate volume was 50 cc. or less. Followup included PSA measurement, digital rectal examination, urinalysis, and documentation of adverse events at 4, 8, 12 and 24 weeks. Sextant biopsy was performed at week 24. The procedure involved the insertion of 5 antennae percutaneously through a modified brachytherapy template. The antenna arrangement was determined based on computer simulated predictions of temperature throughout the prostate. The prostate was dissected away from the rectum by an injection of sterile saline to provide a thermal barrier that protected the rectum from thermal damage. Temperatures were monitored using interstitial mapping thermistor probes that were also inserted through the template. A minimum peripheral target temperature of 55C but less than 70C was maintained for 15 to 20 minutes, while the urethra, rectum and hydrodissection space remained below 42C. The urethra and rectum were actively cooled in addition to hydrodissection. RESULTS Peripheral target temperatures of 55C were achieved. The urethra and rectum remained at a safe temperature. The procedure, including setup and treatment, required approximately 2.5 hours of operating room time. At 24 weeks the PSA nadir was 0.5 ng./ml. or less in 52% of patients and 0.51 to 4 ng./ml. was achieved in an additional 40%. The negative biopsy rate at 24 weeks was 64%, assuming that 3 patients lost to followup would have had positive results. No major complications were observed and in most cases minor complications resolved within 3 months. CONCLUSIONS Interstitial microwave thermal therapy for prostate cancer was developed to heat the prostate safely to a cytotoxic temperature. Experience with 25 patients in whom external beam radiation therapy for prostate cancer had failed indicates that the treatment is safe. Although our series indicates that this therapy may be effective, further studies and longer followup are required in larger patient groups to confirm the potential role of this therapy as an option for recurrent and primary prostate cancer.

Measurement of the thermal conductivity of polyacrylamide tissue-equivalent material

The purpose of this work was to measure the thermal conductivity of polyacrylamide (PAG) and compare it with previously reported values. Polyacrylamide phantoms play an important role in the development of hyperthermia and high-temperature thermal therapies based on electromagnetic (EM) radiation by providing a material that mimics the electrical and thermal properties of human tissue. The thermal properties of PAG have, up until now, not been thoroughly investigated and at least two significantly different values have been published. In this study, the thermal conductivity of polyacrylamide was measured from the steady state temperature drop across samples exposed to a known heat flux. The measured conductivity was 0.56 - 0.047 W m m 1 °C m 1 . To validate the correct set of thermal properties for polyacrylamide, simple heating experiments were performed in a PAG phantom and then simulated using a finite element numerical model that incorporated the measured thermal conductivity along with literature values for specific heat and density. Temperature predictions from the model agreed with average temperatures measured in the phantom to within 1 SD of the measured temperatures.

Interstitial Microwave Thermal Therapy for Prostate Cancer

Thermal therapy is used to kill tumors by heating them to temperatures >50 degrees C for an extended period of time. Cell death results from thermal coagulation. The energy sources available for this approach include radiofrequency electrodes, microwave antennas, laser fiberoptics, and ultrasound transducers. Each of these modalities has the potential to be delivered in a minimally invasive manner, and many theoretical and experimental investigations of these devices have been performed. This review describes current knowledge of interstitial microwave thermal therapy for prostate cancer. Examples are given from an ongoing trial in patients who have recurrent or persistent disease following radiation therapy. Future directions for pretreatment planning and real-time monitoring and control are discussed. These techniques have the potential to optimize treatments on a patient-specific basis and will be instrumental in planned future trials of this therapy as first line for prostate cancer.