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.

Temperature measurement artefacts of thermocouples and fluoroptic probes during laser irradiation at 810 nm.

This study examined the artefact induced in temperature measurements made with thermocouples and Luxtron fluoroptic probes in the presence of infrared radiation. Localized heating was created using a continuous-wave, 810 nm diode laser system emitting 2.0 W from a cylindrical diffusing optical fibre, in air, water and an agar-albumin phantom. The temperature was measured every 1.0 s for 10 to 150 s, with both a thermocouple and a Luxtron fluoroptic probe at distances of 2, 3, 4, 5, 6 and 7 mm from the cylindrical diffusing tip. In all cases, the fluoroptic probe recorded a higher temperature than the thermocouple during laser irradiation. The difference in measured temperatures between the Luxtron probe and the thermocouple ranged from 1.6 degrees C to 18.8 degrees C in air, from 0.3 degrees C to 10.2 degrees C in water, and from 1.4 degrees C to 10.1 degrees C in phantom, depending on the distance of the probe from the laser source. The results suggest that in the presence of laser irradiation, self-heating of the Luxtron probe induces a significant artefact in temperature measurements at distances less than 4 mm from the source fibre. As a result, fluoroptic probes may not be suitable for monitoring tissue temperature for treatments when laser irradiation is present if sensors are located close to the fibre tip (<4 mm).

Helical antenna arrays for interstitial microwave thermal therapy for prostate cancer: tissue phantom testing and simulations for treatment.

Interstitial microwave therapy is an experimental treatment for prostate cancer. The objective of this work was to measure the power deposition (specific absorption rate, SAR) patterns of helical microwave antennae both individually and in array patterns that would be useful for clinical treatment protocols. Commercial helical antenna 3D SAR patterns were measured in muscle equivalent phantoms using a thermographic technique. Two array patterns were tested: a 'square' and a 'crescent' array, both surrounding the urethra. To assess the feasibility of pre-treatment planning, the measured SAR patterns were input to a treatment planning computer simulation program based on a series of trans-rectal ultrasound images from a prostate cancer patient. The simulation solved the Pennes linear bioheat heat transfer equation in prostate tissue, with the aim of achieving a target of 55 degrees C at the prostate periphery while not allowing normal surrounding tissues (bladder, urethra, rectum) to rise above 42 C. These criteria could not be met with the square array but they could be met with the crescent array, provided that the prostate was first dissected away from the rectum. This can be done with a procedure such as 'hydrodissection', where sterile saline is injected to separate the prostate and rectum. The results of these SAR measurements and heat transfer simulations indicate that arrays of helical antennae could be used for safe and effective thermal therapy for prostate cancer.

Ultrasound properties of liver tissue during heating.

The objective of this work was to determine changes in the ultrasound properties of heated tissues, with potential application to monitoring of minimally invasive thermal therapy (MITT). Changes in backscatter coefficients and frequency-dependent attenuation coefficients were measured over the frequency range 2.5 MHz to 5 MHz from heated samples of store-bought fresh bovine liver, which was used as a tissue model. Individual liver samples were heated from 37 degrees C to either 50 degrees C, 55 degrees C, 60 degrees C, 65 degrees C or 70 degrees C by warm water. The backscatter coefficient increased during the first 3 min by a factor of 1.09 and 1.11 before the tissue reached 50 degrees C and 55 degrees C, respectively. A decrease in backscatter coefficient followed at 50 degrees C by a factor of 1.12 below the initial level and, at 55 degrees C, the backscatter coefficient dropped below the initial level by a factor of 1.19. The backscatter coefficient decreased within the first 2 min by a factor of 1.22 before the tissue reached 60 degrees C, then increased gradually to a factor of 1.05 below the initial level. At 65 degrees C and 70 degrees C, the changes in backscatter coefficient were highly variable, which may have been due to production of gas microbubbles in the heated tissues. The ultrasound attenuation coefficient increased by as much as 1.48 dB cm-1 over a 30-min period at 70 degrees C. First-order rate parameters derived from the attenuation results revealed one rate process at 50 degrees C and 55 degrees C and two rate processes at 60 degrees C, 65 degrees C and 70 degrees C. An activation energy of 1.00 x 10(4) cal mol-1 was derived from the second rate constants at 60 degrees C, 65 degrees C and 70 degrees C, which indicates that changes in attenuation may be due to protein denaturation. In conclusion, ultrasound image monitoring of thermal therapy treatment in liver may be feasible; however, the backscatter coefficient changes during heating are small and are of the same order as the variation in these changes from point to point in the tissue.

High-frequency ultrasound properties of multicellular spheroids during heating.

High-frequency ultrasound monitoring is a possible method for real-time imaging of thermal therapy in tissues at microscopic resolution. The objective of this work was to measure changes in the ultrasound properties of V79 spheroids (grown from Chinese Hamster lung fibroblasts) exposed to heating. Spheroids are clonal aggregates of cells that provide a useful model for investigating the ultrasound properties of cells in the absence of connective tissue. Relative echo signal power and attenuation coefficients were measured over the frequency range 30 MHz to 70 MHz, from spheroids heated from 37 degrees C to 50 degrees C or 60 degrees C. Echo signal power from the viable rim decreased during the first 5 min by a factor of 1.08 before the spheroid reached 50 degrees C. For the next 25 min, echo signal power rose to a factor of 1.27 above the initial level, after which it remained relatively constant over the remainder of the 50 degrees C heating period. At 60 degrees C, echo signal from the viable rim remained relatively constant, although it appeared to have possibly decreased slightly over the duration of the heating period. Echo signal power from the necrotic core fell to a factor of 1.4 and 1.54 below the initial level at 50 degrees C and 60 degrees C, respectively. First-order chemical rate analysis applied to the echo signal power results in the viable rim at 50 degrees C revealed a rate constant for the 5-15-min heating interval. Interpretation of the echo signal power results in terms of histological stains indicates that the rise in echo signal power at 50 degrees C was due to a loss of cell cohesion, and the possible drop in echo signal power at 60 degrees C was due to spheroid coagulation. Attenuation coefficients decreased by up to 1.54 dB mm-1 over a 30-min period at 60 degrees C. The appearance of a real-time ultrasound image of lesion formation in cells is discussed.

Ultrasound imaging of thermal therapy in in vitro liver.

The objective of this work was to image liver tissue heated to temperatures below the vaporization threshold as a function of time, to test the feasibility of real-time ultrasound monitoring to control lesion size during minimally invasive thermal therapy (MITT). Two experiments were devised. In one experiment, a thermal gradient was established in a rectangular volume of tissue to correlate changes in ultrasound image echogenicity (B-mode image brightness) with tissue temperature. In the other, a thermal lesion was produced in a rectangular volume of tissue by an interstitial microwave antenna, and the progression of the lesion was monitored by ultrasound. In both experiments, the echogenicity of the tissue increased slightly for tissue temperatures up to 40 degrees C, but became lower than that of unheated tissue for temperatures above 40 degrees C. In the second experiment, images of the lesion were compared with a photograph of the lesion taken after the experiment was complete. The final lesion was composed of two concentric regions--an inner region of heavily coagulated tissue and an outer region of less-damaged tissue. These two damaged regions indicated that increased ultrasound attenuation was largely responsible for the decreased echogenicity observed in the ultrasound images, and the increase in echogenicity of tissue heated to temperatures up to 40 degrees C is thought to be due to decreased ultrasound attenuation at these temperatures.

Vascular targeted photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent prostate cancer following definitive radiation therapy: assessment of safety and treatment response.

PURPOSE: Tookad is a novel intravascular photosensitizer. When activated by 763 nm light, it destroys tumors by damaging their blood supply. It then clears rapidly from the circulatory system. To our knowledge we report the first application of Tookad vascular targeted photodynamic therapy in humans. We assessed the safety, pharmacokinetics and preliminary treatment response as a salvage procedure after external beam radiation therapy. MATERIALS AND METHODS: Patients received escalating drug doses of 0.1 to 2 mg/kg at a fixed light dose of 100 J/cm or escalated light doses of 230 and 360 J/cm at the 2 mg/kg dose. Four optical fibers were placed transperineally in the prostate, including 2 for light delivery and 2 for light dosimetry. Treatment response was assessed primarily by hypovascular lesion formation on contrast enhanced magnetic resonance imaging and transrectal ultrasound guided biopsies targeting areas of lesion formation and secondarily by serum prostate specific antigen changes. RESULTS: Tookad vascular targeted photodynamic therapy was technically feasible. The plasma drug concentration was negligible by 2 hours after infusion. In the drug escalation arm 3 of 6 patients responded, as seen on magnetic resonance imaging, including 1 at 1 mg/kg and 2 at 2 mg/kg. The light dose escalation demonstrated an increasing volume of effect with 2 of 3 patients in the first light escalation cohort responding and all 6 responding at the highest light dose with lesions encompassing up to 70% of the peripheral zone. There were no serious adverse events, and continence and potency were maintained. CONCLUSIONS: Tookad vascular targeted photodynamic therapy salvage therapy is safe and well tolerated. Lesion formation is strongly drug and light dose dependent. Early histological and magnetic resonance imaging responses highlight the clinical potential of Tookad vascular targeted photodynamic therapy to manage post-external beam radiation therapy recurrence.

Interstitial microwave thermal therapy and its application to the treatment of recurrent prostate cancer.

Interstitial microwave thermal therapy may be an effective alternative to surgery for the treatment of some solid tumours. Arrays of helical antennae can produce complex heating patterns which when combined with active cooling of normal tissue structures can provide conformal heating for thermal coagulation of tumours. The development of a clinical protocol involving phantom and animal model studies, treatment planning, tissue property measurement and methods for on-line treatment monitoring is reviewed. The technology developed has been applied to the problem of recurrent prostate cancer following failed radiation treatment where available curative options are associated with high normal tissue morbidity. The purpose was to develop a treatment option for this group of patients with a very low side-effect profile that would not preclude further treatment if the disease progressed. Results of a Phase I/II trial demonstrate safety, promising efficacy and a low complication rate. As the technology for delivering this treatment matures, larger multi-institutional trials should be considered.

Development of a radiofrequency based thermal therapy technique in an in vivo porcine model for the treatment of small renal masses.

PURPOSE: Incidentally detected small renal tumors appear to grow slowly and be localized to the kidney. Minimally invasive therapies are being investigated as alternatives to standard surgical techniques. Radiofrequency ablation has been reported for the treatment of small renal cell carcinomas. We developed a radiofrequency technique and established its efficacy and safety in a large animal model. METHODS AND METHODS: A total of 22 lesions were created in normal kidneys of 7 pigs. Radiofrequency energy was administered during open exposure of the kidneys or percutaneously under ultrasound guidance. Lesion development was monitored with gray-scale and power Doppler ultrasound. To avoid heating surrounding tissues new hydro-dissection and gas-dissection techniques were developed. Lesion sizes and characteristics were assessed by ultrasound and pathological examination. RESULTS: No complications were observed due to probe insertion and removal. Perirenal structures were thermally damaged before the development and application of the dissection techniques. Lesion size was accurately predicted by gray-scale ultrasound on day 7. Loss of perfusion in the ablated volume was confirmed by power Doppler ultrasound. Lesions were wedge-shaped, presumably due to the effects of heating on segmental blood flow distribution. Pathological examination revealed changes consistent with thermal injury and ischemic type infarction. CONCLUSIONS: Radiofrequency thermal therapy is an effective and efficient method for ablating normal renal tissue in the pig. It may be applied percutaneously under ultrasound guidance with minimal complications provided that vital adjacent structures are protected from thermal damage. Further studies are required in humans before adopting this technique as definitive treatment for small renal cell carcinoma.

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.