Transrectal Laser Focal Therapy of Prostate Cancer

  • John F. Feller
  • Bernadette M. Greenwood
  • R. Jason Stafford
Chapter
Part of the Current Clinical Urology book series (CCU)

Abstract

Laser focal therapy (LFT) is an evolving ablative technique for the treatment of prostate cancer. Also referred to as laser interstitial thermal therapy (LITT) or focal laser ablation (FLA), this intervention is based on heating of the prostate with an infrared laser to produce tissue destruction from coagulative necrosis. While earlier work focused on a transperineal approach, this has evolved to a less-invasive, transrectal approach delivered in the outpatient setting. This chapter examines the history, mechanism of action, and technique of transrectal magnetic resonance imaging (MRI)-guided LFT with real-time thermometry. We describe the equipment, procedure, and early safety and feasibility results of a series of patients in a clinical trial.

Keywords

Transrectal Laser focal therapy Laser interstitial thermal therapy Focal laser ablation 

Introduction

The lower-stage migration of screen-detected prostate cancer, evolving understanding of the natural history of disease, and increased utilization of multiparametric magnetic resonance imaging (mpMRI) and targeted biopsies are fueling continued interest in focal ablative therapies for prostate cancer. Laser focal therapy (LFT) delivers thermal energy to a targeted region of the prostate to produce coagulative necrosis and destroy a focus of cancerous cells while sparing nonmalignant prostate tissue and nearby vital structures.

Clinical trial NCT02243033 is an ongoing trial investigating the safety and efficacy and oncologic outcomes of transrectal, MR-guided LFT with near real-time MR thermometry (MRT) in an outpatient setting [1]. This study involves the use of the Visualase Thermal Therapy System (Medtronic, Minneapolis, MN, USA) coupled with the DynaLOC software and DynaTRIM hardware for instrument placement planning and transrectal access. Each of these devices and their respective components are commercially available for use as indicated in US Food and Drug Administration (FDA) 510(k) clearance; however, until 2010 they had not been used in combination; thus, investigation and establishment of a rigorous review in the setting of an institutional review board (IRB)-approved clinical trial were warranted.

Procedures are performed in a closed-loop fashion within the MRI to facilitate the MR temperature imaging feedback for monitoring therapy progress. Laser ablation targeting via transrectal approach was utilized to bring a known, highly researched, and commercialized approach to targeting of MR-visible prostate lesions, thus minimizing uncertainties in this aspect of the investigation. While a simple percutaneous transgluteal approach could be used for placement, this approach could limit access to some lesions and exclude some larger patients due to limitations on the applicator length and requires a higher level of expertise for accurate placement. Transperineal approaches are also being explored in the MR environment using MR-conditional templates and software for guidance; however, there are no commercially available solutions for guidance at this time [2].

History

Preclinically, McNichols et al. originally investigated the use of the Visualase Thermal Therapy System in the prostate in porcine and canine models [3, 4]. The canine prostate most closely resembles the human prostate. A transperineal approach was pioneered by Barqawi et al. at the University of Colorado [5] and further investigated at the Mayo Clinic (NCT01743638) [6], the University of Toronto (NCT00448695) [7], and the University of Chicago (NCT01792024) [8]. Early results of Raz et al., Lindner et al., Woodrum et al., and Wenger et al. [9, 10, 11, 12] demonstrated the safety and feasibility of the transperineal approach to focally ablate prostate cancer in human subjects. McNichols et al. applied laser interstitial thermal therapy in neurologic applications, further demonstrating the precision and control achieved with the MRI-guided, real-time MR-thermal mapping technique [13, 14]. The precision and control demonstrated in the neurologic setting were postulated to be reproducible in the prostate gland.

In 2009 an MRI-guided in-bore biopsy system [15] was FDA cleared for prostate biopsy using DynaLOC computer software (Fig. 25.1) for planning and DynaTRIM MRI-compatible positioning hardware (Fig. 25.2) for device delivery. This novel system was awarded the Medical Design Excellence Award (Gold) 2010 in the radiological and electromechanical devices category [16]. It was hypothesized that the same equipment that was used for planning the trajectory of the biopsy gun could possibly be useful for laser applicator placement and laser energy delivery with a transrectal approach. In 2008, McNichols, Greenwood, and Stafford conducted preclinical experiments with phantoms at MD Anderson Cancer Center. The objective was to simulate workflow for assembly of devices and delivery of treatment in-bore using existing, commercially available instruments and equipment. The components included:
  • Visualase laser fiber

  • Cooling catheter

  • Introducer

  • Trocar

  • Needle guide

Fig. 25.1

DynaLOC module of DynaCAD software for interventional planning of trajectory for prostate biopsy or other intervention. Figure courtesy of Invivo Corporation, Orlando, FL, USA

Fig. 25.2

DynaTRIM hardware for positioning of needle guide prior to insertion of coaxial or applicator. Figure courtesy of Invivo Corporation, Orlando, FL, USA

In 2010, Feller et al. established the first IRB-approved clinical trial for transrectally delivered, MRI-guided laser focal therapy of prostate cancer using real-time MR thermometry in an outpatient setting (NCT 02243033) with the first patient treated in May 2010 [1]. Initially the study was intended for treatment-naïve, organ-confined, low- and intermediate-risk prostate cancer; however, a protocol amendment was approved by the institutional review board for salvage treatment in carefully selected research subjects [1].

Since focal therapy had become a topic of discussion and was evolving rapidly, an international consensus panel consisting of 15 expert members generated a report in 2014 [17] for the purpose of providing guidance to clinicians on focal therapy of localized disease in clinical practice and trial design from the perspective of experts in the field. Consensus was reached using the RAND/UCLA appropriateness methodology [18]. Topics addressed included patient selection, setting, outcomes measures, and re-treatment. NCT02243033 pre-dated these guidelines (Table 25.1) [1].
Table 25.1

NCT02243033 study parameters [1]

Ages eligible for study

45 years to 90 years

Genders eligible for study

Male

Accepts healthy volunteers

No

Sampling method

Non-probability sample

Inclusion criteria (treatment naïve)

Male, 45 years of age or older

Diagnosis of prostate adenocarcinoma

Clinical stage T1c or T2a

Gleason score of 7 (3+4 or 4+3) or less

Three or fewer TRUS biopsy cores with prostate cancer

PSA density not exceeding 0.375 ng/ml/cc

One, two, or three tumor-suspicious regions identified on multiparametric MRI

Negative radiographic indication of extra-capsular extent

A Karnofsky performance status of at least 70

Estimated survival of 5 years or greater, as determined by treating physician

Tolerance for anesthesia/sedation

Ability to give informed consent

At least 6 weeks since any previous prostate biopsy

MR-guided biopsy confirmation of adenocarcinoma at one or more MRI-visible prostate lesion(s) with Gleason score of 7 (3+4 or 4+3) or less

Inclusion criteria for salvage limb

Previous prostate cancer treatment with biochemical recurrence

MR-guided biopsy confirmation of locally recurrent adenocarcinoma at one or more MRI-visible prostate lesions

Exclusion criteria

Presence of any condition (e.g., metal implant, shrapnel) not compatible with MRI

Severe lower urinary tract symptoms as measured by an International Prostate Symptom Score (IPSS) of 20 or greater

History of other primary non-skin malignancy within previous 3 years

Diabetes

Smoker

TRUS transrectal ultrasound, PSA prostate-specific antigen, MRI magnetic resonance imaging

Evidence has demonstrated that active surveillance can be used judiciously in men with low-risk Gleason score 3+3 low-volume disease [19]. Our study included Gleason score 3+3, 3+4, and 4+3 in the treatment-naïve group and carefully selected men of any Gleason score for the salvage limb [1].

Procedure Planning with MRI Guidance

At our institution, we rely heavily on MRI to detect, localize, biopsy, treat, and follow each focus of prostate cancer. Our multiparametric MRI (mpMRI) protocol consists of T2-weighted axial, sagittal, and coronal imaging, axial diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) imaging. Apparent diffusion coefficient (ADC) maps and histograms are also generated. Scans are acquired with two 8-channel general-purpose “flex” coils (Invivo, Orlando, FL, USA), which operate as a 16-channel phased array on a Philips Achieva XR ramped to 1.5 T (Philips Healthcare, Best, the Netherlands). An important aspect of our MRI-based prostate program is the choice of equipment used for imaging and intervention. Many artifacts, such as motion, susceptibility, and metallic and dielectric signal losses, are linearly worse at higher field strengths, negatively impacting image quality. Additionally, some patients and implants contraindicated for 3 T can still be scanned safely and on label at 1.5 T. Therefore, we use a 1.5 Tesla system for continuity of care for imaging, biopsy, therapy delivery, and follow-up. For therapy it is particularly helpful to use 1.5 T as the thermal maps are gradient echo based and are less influenced by bowel gas, motion, and other artifact-generating problems such as hip arthroplasty at 1.5 T. For our study [1], the same reader interprets each mpMRI, and the same interventional radiologist performs each in-bore MR-guided biopsy. The entire research team, which includes two radiologists, a researcher, and a registered MRI technologist, is present for all laser focal therapy treatments.

The published negative predictive value (NPV) of mpMRI for exclusion of clinically significant prostate cancer is 63–98 % [20, 21]. Using this relatively high negative predictive value, we can target the most aggressive appearing component of even a heterogeneous lesion for biopsy using the inverse linear relationship of apparent diffusion coefficient value and aggressiveness of disease [22, 23, 24, 25]. Assigning a Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) suspicion score [26] to each lesion helps to standardize lesion scoring, description, and follow-up, i.e., observation or biopsy. Figure 25.3 illustrates the workflow for performance of in-bore MRI-guided interventional planning for laser therapy delivery.
Fig. 25.3

DynaLOC user interface displaying sagittal calibration scan (upper left), adjustment coordinates (upper right), and axial planning image (lower left)

With intravenous access established, the patient lays prone on the MRI table with a dual-array 16-channel receive-only phased-array coil placed anteriorly and posteriorly over the pelvis. A transrectal needle guide is inserted in the rectum using viscous lidocaine as lubricant and anesthetic. The needle guide (Fig. 25.4) is mounted to the clamp stand (Fig. 25.5), which can be adjusted anterior-posterior, left-right, and head-foot. The needle guide functions two ways: It is both a receptacle for the biopsy gun or other instrument and also functions as a fiducial marker. When imaged in-plane, it appears as two bright, parallel white lines. Using the localization software, a cursor is placed at the tip of the needle guide on a sagittal T2-weighted image. The patient is scanned in the axial plane and that image is imported. A cursor is placed on the suspicious region, and the software calculates the delta between the needle guide starting position and the anticipated target location. The software displays coordinates to adjust the needle guide position to achieve the desired trajectory.
Fig. 25.4

Transrectal needle guide. Figure courtesy of Invivo Corporation, Orlando, FL, USA

Fig. 25.5

Clamp stand allows adjustment of the needle guide in the anterior-posterior. Left-right and head-foot directions to achieve planned trajectory. Figure courtesy of Invivo Corporation, Orlando, FL, USA

When performing laser therapy, the device trajectory is planned, and the device is adjusted to reach the lesion prior to device insertion; however, the z-depth of insertion is adjusted to subtract the pre-calculated throw of the biopsy gun. As of this writing, the software does not accommodate a throw-less introducer, so one must manually subtract the automatically generated recommend throw.

Procedure

Laser energy can be deposited into tissue at a range of power settings, leading to various rates of energy delivery. Higher powers deliver at faster rates and tend to use shorter exposure times. All procedures performed at our institution are conducted using an FDA-cleared 15 W Visualase Thermal Therapy System. This laser system is available in 15 W and 30 W models. While the system is listed by the vendor as MR conditional for use at magnetic field strengths up to 1.5 T at this time, investigators have reported findings at 3.0 T as well [11]. Per the manufacturer, “The catheter and fiber are MR compatible up to 1.5T, however the SMA connector on the proximal end of the LDF is not. Damage to imaging equipment or patients can occur if appropriate precautions are not taken” [27].

The 15 W laser system utilizes a 980 nm diode laser. The system is on a consolidated mobile cart with the laser, a computer, a dual monitor vertical display, and a water pump (Fig. 25.6). The laser is powered by standard AC power, and the thermal mapping software is connected to the MRI scanner via an Ethernet cable.
Fig. 25.6

Visualase Laser Therapy System (Medtronic, Minneapolis, MN, USA)

The laser fiber is housed within a water-cooled applicator. Water cooling is helpful to facilitate use of higher laser powers being generated to create larger foci of coagulation necrosis (1.5–2.0 cm diameter) in a relatively short time (60–150 s) without charring the tissue adjacent to the applicator surface. Charring would result in increased absorption at this interface and an inability to generate a large focus of coagulation necrosis as well as potential damage to the applicator itself. To this end, a room temperature saline bag is hung from an intravenous (IV) pole on the Visualase cart, and tubing is run through a peristaltic pump that is part of the system to deliver normal saline through a cooling catheter to protect the heat-diffusing tip during heating. It is important to check to make sure there is flow and no leaks along the line prior to the start of heating. While the Visualase system uses MR temperature imaging to measure tissue temperature changes, it does not monitor absolute temperature. Therefore, it is important to pay careful attention to when the cooling pump is turned on and off. During real-time monitoring, generally the pump is turned on just prior to laser delivery, and the baseline reference image is set after the pump has started to avoid flow artifacts in the temperature maps and thermal damage images (Figs. 25.7 and 25.8).
Fig. 25.7

Axial thermal map image

Fig. 25.8

Axial irreversible damage estimate image

Additionally, while cooling can assist in returning to baseline prior to the next ablation, the pump should be turned off after an ablation if a new baseline is to be acquired in the subsequent ablation site. Baseline reference images should always be as close to normal body temperature as possible with the Visualase system. This extends to urethral and rectal cooling scenarios as well, when employed.

Table 25.2 lists the tray setup for the procedure.
Table 25.2

Tray setup for laser focal therapy

Urokit: 400 or 600

Laser fiber optic 980 nm diode

Cooling catheter

Titanium stiffener

13G introducer trocar

13G introducer catheter/sheath

Cooling fluid line set

Effluent collection bag

Steri-strips

NaCl: 1000 cc bag (cooling fluid)

TRIM needle guide

HurriCaine (benzocaine) gel or lidocaine gel

22 g titanium Bx needle set

0.5 % Marcaine—nerve block

Alcohol wipes

IV gentamicin 80 mg

IV midazolam (Versed)

IV fentanyl

IV hydromorphone hydrochloride (Dilaudid)

Oxygen/nasal cannula

IV Romazicon (flumazenil)

IV naloxone (Narcan)

IV ondansetron (Zofran)

As part of the IRB-approved single institution clinical trial, the risks, benefits, and alternatives of MR-guided laser focal therapy of the prostate gland are explained to each patient and all questions answered. Both verbal and written informed consent are obtained. Each patient reviews and signs a California Human Subjects Bill of Rights. A formal documentation of the informed consent process is completed by research staff for every subject. Patients are informed that this procedure, regardless of complexity or time, may be associated with unforeseen problems, which may include but are not limited to the following, taken from our informed consent document:
  • Pain and/or discomfort

  • Excessive bleeding from the rectum/anus

  • Hematuria

  • Hematospermia

  • Urinary retention

  • Urinary tract infection or urosepsis

  • Erectile dysfunction

  • Urinary incontinence

  • Numbness of the penis

  • Residual prostate cancer

  • Thermal injury to nearby organs

  • Carbonization of laser applicator

  • Rectal fistula

Regarding rectal fistula, a search of the US FDA MAUDE adverse event report database revealed a single report of an event dated April 17, 2015: Medtronic Navigation, Inc. (Louisville) SYSTEM 002-3100 30 W Thermal Therapy Powered Laser Surgical Instrument, Device Problems: Patient-Device incompatibility [28]. The report, submitted by the manufacturer, contains a manufacturer narrative that explains the nature of the rectourethral fistula experienced by the patient and ascribes the event to previous treatment of the patient with radiation therapy and subsequent weakening of the rectal wall. According to the report, it was hypothesized by the surgeon that this weakening prevented recovery in the way normal, healthy tissue would heal, thus causing the rectourethral fistula. The report also cites two occurrences of erectile dysfunction [28].

Conscious sedation is performed during the laser focal therapy procedure utilizing intravenously administered Versed (midazolam) and intravenously administered fentanyl. Prophylactic antibiotic therapy is also administered including 500 mg of orally administered ciprofloxacin twice a day the day before, the day of, and for 3 days following the laser focal therapy as well as intravenously administered gentamicin 80 mg given at the time of the laser focal therapy.

The patient is positioned prone in a 1.5 T Philips Achieva XR MR System (Best, the Netherlands). MR guidance for laser placement within the prostate is performed using the Invivo DynaTRIM hardware and DynaLOC software (Invivo, Orlando, FL, USA). An endorectal needle guide is placed in the rectum coated with benzocaine or lidocaine gel for topical anesthesia. Following calibration scanning, a periprostatic nerve block is performed bilaterally utilizing MR guidance and a 22-gauge MR-compatible titanium needle; 10 cc of 0.5 % Marcaine is injected into the periprostatic fat at the junction between the prostate gland and the seminal vesicle bilaterally—an anatomic feature referred to as the “Mt. Everest sign” (Fig. 25.9).
Fig. 25.9

Axial 2D bFFE image with the “Mt. Everest” peak of fat between the seminal vesicle, prostate, and rectum (arrow)

This technique of nerve block, referred to in the urologic literature as the “Mt. Everest technique,” is usually performed for transrectal prostate biopsies under ultrasound guidance [29, 30]. While the “Mt. Everest technique” performed under MRI guidance has not yet been described in the literature, we have found the procedure easily performed and an important component of pain management in addition to conscious sedation during the laser focal therapy (Figs. 25.10, 25.11, 25.12, and 25.13).
Fig. 25.10

Axial 2D bFFE image confirming the position of the 22 g needle in the apex of the “Mt Everest” peak of fat (arrow)

Fig. 25.11

Axial STIR image showing the normal perirectal fat and seminal vesicles before the bilateral periprostatic nerve block injections

Fig. 25.12

Axial STIR image after bilateral periprostatic nerve block injections showing the bilateral infiltration of the fat in the rectoprostatic angles (arrows)

Fig. 25.13

Axial STIR image more inferiorly after bilateral periprostatic nerve block injections showing the bilateral infiltration of the fat in the rectoprostatic angles (arrows)

The MR-visible index lesion is localized utilizing T2-weighted fast spin echo (FSE) imaging and diffusion-weighted imaging (DWI) with an apparent diffusion coefficient (ADC) map calculated. The laser fiber and cooling catheter are made of nonmetallic materials but are visible on MRI, making it superior to other energy sources for imaging while the device is in place. In particular, metal-based applicators create susceptibility artifacts, which are problematic for both MR temperature imaging as well as the echo-planar imaging sequence utilized for DWI lesion localization. While attempting to localize, these artifacts are most pronounced on DWI, often obscuring the tumor and much of the gland due to magnetic field inhomogeneity, susceptibility, and distortion. This problem is not encountered with the Visualase laser, which is imageable in vivo.

Le Nobin et al. examined the performance of mpMRI compared to whole-mount histology and noted underestimation of lesion volume with mpMRI [31]. This has led to the pursuit of a 1 cm margin around the MR-visible lesion as a goal of treatment planning.

The target is localized using the DynaLOC software designed to be used with the DynaTRIM hardware localization system. Following this, a 150 mm 13-gauge MR-conditional coaxial needle system is then inserted into the prostate gland through the endorectal needle guide into the target tumor. A confirmation scan of the needle position is obtained and adjustments made if needed. The needle trocar is then removed from the catheter sheath. A water-cooled laser applicator rated for a 15 W 980 nm laser source (Visualase Urokit 400) is introduced through the catheter sheath into the tumor using a titanium MR-conditional stiffener. For small tumors or those located in the apex near the external urethral sphincter, the smaller laser applicator with a 1 cm heat-diffusing tip (Visualase Urokit 400) is utilized. For larger tumors located elsewhere in the prostate gland, the larger laser applicator with a 1.5 cm heat-diffusing tip (Visualase Urokit 600) is utilized.

The placement of the tip of the laser applicator is verified via acquisition of a two-dimensional fast steady-state acquisition (2D bFFE) in the axial and sagittal planes. The stiffener in the cooling catheter is then replaced with the laser fiber.

The real-time biplane MR temperature imaging series (MR thermometry) is prescribed from the steady-state series and then transferred during acquisition real-time to the Visualase computer and is converted into temperature maps based upon the phase data from the fast gradient echo acquisition. The in-plane resolution of the MR thermometry is approximately 2.6 mm2 with a 4 mm slice thickness acquired every 5–7 s. The temperature map is biplane, facilitating control and safety in the axial and sagittal planes contemporaneously. The heat-diffusing laser applicator tip location and laser output and functionality are verified prior to therapy using a test dose of 4.5 W (30 % power on the 15 W system) monitored with MR thermometry. This is usually enough applied power to visualize the focus of heating on the Visualase system and compare to the anticipated location, but not enough power to cause thermal damage regardless of the exposure time; i.e., the temperature remains below 43 °C. With this information overlaid on the anatomical images, safety cursors can be programmed into the Visualase system. Generally, at least one high-temperature safety cursor is placed adjacent to the laser applicator and set to terminate power delivery if the estimated temperature on the MR temperature image exceeds 90 °C. Low-temperature safety cursors can be used to control the maximum temperature delivered to nearby, heat-sensitive critical structures such as the rectal wall or external urethral sphincter. Lastly, safety cursors may be used to monitor the return of the tissue temperature within the treatment volume, such as temperatures achieved in the peri-ablational zone surrounding the visible irreversible damage estimate on the Visualase system.

Important temperature limits for monitoring thermal therapy with MR thermometry are summarized in Table 25.3 (Visualase) [32].
Table 25.3

Temperature limits for monitoring thermal therapy with MR thermometry

>100 °C: Vaporization of intra- and extracellular water. Rupture of cell membranes

60–100 °C: Instant denaturation of proteins and cellular components. Tissue coagulation

44–59 °C: Time-dependent thermal damage. Thermal denaturation of critical enzymes, cell death

~43 °C: Critical temperature below which thermal damage does not occur regardless of exposure time

When the decision is made by the surgeon to deliver treatment, the patient is reminded to remain still during the therapy so temperature images do not suffer from motion-related artifacts. A 15 W laser operating at 980 nm is used to deliver therapy using 80–90 % of the maximum available power (12–13.5 W) with exposure times of 120–150 s. While 30 W lasers are available, applied power >15 W has not been found to be necessary to achieve the prescribed coagulation necrosis dimensions desired in the prostate. In our experience, the applied power range used provides a good tradeoff between the rate of coagulation necrosis formation and the ability to respond to and control the coagulation necrosis volume and location.

The laser applicator is inspected following each thermal ablation cycle whenever the applicator is removed to place in a new treatment location. Any charring or carbonization of the laser applicator should result in discontinued use because fiber damage increases rapidly with continued use. Materials become susceptible to failure with repeated treatments and heating. To prevent carbonization damage to the laser applicator, it is important to:
  • Respect the heating-cooling cycle of no more than a 150-s treatment time at 80–90 % (12–13.5 W) followed by cooling below 40 °C between treatments.

  • Make sure the cooling catheter water pump is functioning during treatments.

  • Withdraw the laser fiber within the cooling catheter, avoiding too many treatments in one location.

  • Clean the laser cooling catheter tip with alcohol wipes each time it is removed.

The 150 mm 13-gauge MR-compatible coaxial system is placed into the prostate gland through the rectum strategically to minimize the number of rectal wall punctures required for adequate coverage of the tumor by the laser focal therapy. The laser applicator and coaxial needle system are removed from the endorectal needle guide upon confirmation of total tumor ablation with a 1 cm margin as measured by the Arrhenius damage integral (aka irreversible damage estimate) displayed by the Visualase system.

Immediately following therapy, a standard intravenous dose of gadolinium-based contrast agent is delivered, and 2D axial and sagittal T1-weighted gradient-recalled imaging is performed utilizing water excitation for fat suppression. These perfusion-weighted images are assessed providing a means for ablation zone/coagulation necrosis measurement and evaluation of evidence of periprostatic necrosis. They are also assessed for evidence of coagulation necrosis involving the rectal wall, neurovascular bundles, or external urethral sphincter.

After the endorectal needle guide is removed, the patient must demonstrate ability to void before leaving the outpatient facility. If the patient cannot void, a 14 Fr or 16 Fr coude urinary catheter is inserted and subsequently removed after his 48-h follow-up mpMRI. Rarely a suprapubic urinary catheter may be required. The patient is provided with post-procedure instructions and precautions, copies of informed consent document and California Human Subjects Bill of Rights, and a follow-up appointment schedule. The patient is instructed to return at 48 h for a diagnostic post-laser focal therapy multiparametric MRI of the prostate gland and an ultrasound of the urinary bladder pre- and post-void to exclude any significant post-void residual volume within the urinary bladder.

Mechanism of Action

As previously stated, laser energy can be deposited into tissue at various rates based on the power level used. Here we describe our technique. All procedures performed at our institution utilize a 15 W laser system incorporating a 980 nm interstitial diode laser inside a cooling catheter (Fig. 25.14).
Fig. 25.14

Cooling catheter system (CCS) for protection of laser-diffusing fiber (LDF) during thermal ablation (Medtronic, Minneapolis, MN, USA)

The near real-time (5–7 s per update) MR thermometry acquired by the MRI and displayed on the Visualase utilizes the water proton resonance frequency (PRF) shift thermometry technique [33]. By looking at changes in the phase of a gradient-recalled echo sequence to estimate temperature-dependent frequency shifts, this technique provides a quantitative estimate of temperature change versus an initial reference image. The technique has been well characterized and is used in other FDA-cleared technology for thermal ablation, such as MRI-guided focused ultrasound (ExAblate 2100 l Insightec, Haifa, Israel). The temperature sensitivity coefficient (α[alpha]) for the PRF is approximately −0.01 ppm/°C in soft tissue and varies relatively little in different tissues, whether treated or untreated. A fairly rigorous technical review versus competing techniques can be found in Rieke et al. [34]. Briefly, the temperature dependence of the water resonance is due to temperature-dependent hydrogen bond lengths, which allow the protons to spend more or less time in close proximity to their parent oxygen, resulting in an approximately linear temperature-dependent change in the chemical shift (σ[sigma]). The chemical shift is usually given in parts per million with respect to the Larmor frequency (γ[gamma]B0), where γ(gamma) is the proton gyromagnetic ratio and B0 is the field strength. Knowing this, the phase change measured between two gradient-recalled echo images relates to the temperature change (Δ[Delta]T) as
$$ \begin{array}{l}\varDelta \left(\mathrm{Delta}\right)\phi (phi)=-2\pi (pi)\cdotp \gamma \left(\mathrm{gamma}\right){B}_0\\ {}\kern10.5em \cdotp TE\cdotp \alpha \left(\mathrm{alpha}\right)\varDelta \left(\mathrm{Delta}\right) T,\end{array} $$

where TE is the sequence echo time. From this relation, the temperature can be estimated.

It should be noted that since lipid tissue is covalently bonded, it has no temperature-dependent changes. Therefore, lipids should be suppressed or avoided to avoid errors unless more advanced techniques are employed. Also, all changes in the local magnetic field captured by this phase change are expected to come from temperature only during the measurement period. Changes from non-temperature-dependent sources, such as due to motion, particularly near susceptibility interfaces, or drift in the field over long periods of time, result in errors in the temperature measurement and should be considered if present in data.

Damage to tissue from rapid, high-temperature heating can be modeled as an Arrhenius rate process, whereby the damage (Ω[Omega]) is cumulative over the course of the exposure. This can be expressed as an integral over time (in seconds) as
$$ \varOmega = A\cdot \underset{0}{\overset{t}{{\displaystyle \int }}}\ {e}^{-{E}_a/ RT\left(\tau \right)} d\tau, $$

where A is a frequency factor (3.1 × 1098 s−1), Ea (6.25 × 105 J/mol) is the activation energy, R is the universal gas constant, and T(τ[tau]) is the absolute temperature in degree Kelvin as a function of time [35, 36]. The Visualase system uses the estimated temperature from the MR temperature images to calculate this integral discretely on a voxel-by-voxel basis to provide an estimate of damage (Ω[Omega] ≥1) [37].

During a patient treatment, an initial nontherapeutic dose is administered for acquisition of baseline images (body temperature T0 = 37.2 °C). Once the laser-diffusing fiber (LDF) is localized in multiple planes and placement in the desired tissue is confirmed, the energy is increased, and cycles of energy are administered for 120–150 s at 80–90 % energy at 15 W until coagulation necrosis is achieved. On the Visualase platform, the colorized thermal map, temperature graph, and calculated irreversible damage estimate (orange color overlay on the anatomic image) are depicted on the user interface during treatment (Fig. 25.15).
Fig. 25.15

Visualase user interface for planning and monitoring thermal dose

Low-temperature control points are placed adjacent to sensitive structures such as the rectal wall, external urethral sphincter, and neurovascular bundles in order to avoid undesired tissue damage. Should the temperature exceed a preset threshold, the laser aborts automatically to protect the designated regions. Careful consideration must be given to the factors influencing energy delivery and lesion size including:

  • Core fiber size (Urokit 400 vs. Urokit 600)—for small lesion or those near sensitive structures, a smaller fiber with more cycles of ablation may be preferred over the larger fiber to minimize risk of undesired damage.

  • Duration and amplitude of energy—by increasing or decreasing laser energy power or exposure time.

  • Cooling rate—thermal damage can be controlled by adjusting the flow rate of saline in the cooling catheter. If urethral or rectal cooling is used, this can also reduce the rate and extent of therapeutic thermal damage.

  • Location of rectal wall punctures and therapy trajectory—strategic planning of tumor ablation will minimize number of rectal wall punctures and ensure contiguous volume ablation/coagulation necrosis to the desired 1 cm margin around the MRI-visible lesion.

During planning it is imperative to note the location of the rectal wall, external urethral sphincter, and neurovascular bundles and to assess their relationship and proximity to the target lesion in multiple planes. It may be desirable to plan multiple, low-energy, long-duration treatments in tissue close to sensitive structures to avoid unintended irreversible damage to those tissues. Another strategy is to increase the saline flow rate through the cooling catheter.

To reiterate, our institution uses a 15 W rather than 30 W laser system for the following reasons:
  • The tumors requiring ablation can be in close proximity to anatomic structures that warrant careful monitoring and repeated cooling for an acceptable safety profile.

  • Power greater than 12–13.5 W for greater than 150 s increases the risk of carbonization of the laser applicator.

  • Power of 12–13.5 W for up to 150 s combined with multiple treatment sites can create adequate volumes of coagulation necrosis in a reasonable procedure time.

  • Manufacturer maximum thresholds in indications for use are achievable with either system.

Case Study

Prior to each therapy, a tumor board is convened to review each case. This discussion includes review of the subject’s clinical history, inclusion/exclusion criteria, and prior multiparametric MRI. Magnetic resonance-guided biopsy pathology is reviewed and correlated to imaging findings.

Presented as a case example is a 70-year-old patient with a serum PSA = 5.4 ng/mL and no history of a TRUS biopsy who underwent mpMRI of the prostate gland. Axial T2-weighted (T2 W) fast spin echo image (Fig. 25.16), apparent diffusion coefficient (ADC) map image (Fig. 25.17), high b-value (b = 1400) diffusion-weighted imaging (DWI) (Fig. 25.18), and dynamic contrast-enhanced (DCE) image (Fig. 25.19) demonstrate the tumor-suspicious region, PI-RADS 5, in the right transition zone anteriorly to the right of midline at the mid-gland level. MR-guided in-bore biopsy of this lesion demonstrated adenocarcinoma Gleason score 3+4 confined to the prostate gland. The patient underwent transrectal MR-guided laser focal therapy in an outpatient setting. Figure 25.20 demonstrates an axial gradient-recalled echo (GRE) image of the laser applicator in place. Figure 25.21 is a sagittal gradient-recalled echo (GRE) image of the applicator tip in position. The thermal map image (Fig. 25.22) demonstrates heating of the intended target area and temperature map. Anatomic imaging is used to guide placement of the laser applicator, and the user can monitor therapy delivery from irreversible damage estimate images (Fig. 25.23). The tumor was treated successfully with no complication as evidenced by 48-h posttreatment contrast-enhanced images (Fig. 25.24) and perfusion map (Fig. 25.25) images documenting non-enhancing coagulation necrosis completely replacing the mpMRI abnormalities associated with the focus of prostate cancer.
Fig. 25.16

Axial T2 FSE

Fig. 25.17

Axial apparent diffusion coefficient (ADC) map image

Fig. 25.18

Axial high b-value diffusion-weighted image (DWI)

Fig. 25.19

Axial dynamic contrast-enhanced (DCE) image

Fig. 25.20

Axialgradient-recalled echo (GRE) image of laser in place

Fig. 25.21

Sagittal gradient-recalled echo (GRE) image of laser in place

Fig. 25.22

Thermal map axial image

Fig. 25.23

Irreversible damage estimate axial image

Fig. 25.24

Axial DCE image 48 h posttreatment

Fig. 25.25

Axial perfusion map 48 h posttreatment

Preliminary Results

The technique for performing transrectally delivered, MRI-guided laser focal therapy has evolved into an outpatient procedure that can be safely performed in 1.5–4 h depending upon the size, shape, and geometry of the tumor(s). As of this writing, 87 prostate cancer foci have been treated with transrectal MRI-guided laser focal therapy in 62 men in our current IRB-approved Phase I clinical trial [1]. Outcome measures for the ongoing Phase I clinical trial are listed below:

Primary Outcome Measures:
  • Safety. Time Frame: 1 year posttreatment reported as number of subjects reporting serious adverse events

Secondary Outcome Measures:
  • Efficacy of treatment. Time Frame: 1 year posttreatment reported as MR-guided biopsy results of treated area and PSA

Other Outcome Measures:
  • Damage estimate volume measurement. Time Frame: 24–96 h reported as measurement (in cc) of Visualase estimates of thermal damage compared to acute post contrast MR images

  • Approach efficacy. Time Frame: 24–96 h reported as number of patients reporting inability to tolerate the procedure

  • Quality of life. Time Frame: 1 year posttreatment reported as patient responses to International Prostate Symptom Score (IPSS), Sexual Health Inventory for Men (SHIM), and Patient Health Questionnaire (PHQ)-9 surveys

In the current Phase I clinical trial, no statistically significant change in IPSS or SHIM scores has been documented [1]. Mean PSA levels in our treatment-naïve cohort decreased 35 %, while the salvage population mean PSA decreased 47 %. Although no patient experienced a serious adverse event, one treatment resulted in carbonization of the laser applicator associated with a retained cooling catheter tip, which the patient spontaneously expelled while voiding without sequelae. During the 6 years since the clinical trial began, no patient has developed metastatic prostate cancer and no mortality from prostate cancer has occurred. Fifteen patients have successfully undergone repeat laser focal therapy for marginal recurrence of prostate cancer, and five patients have successfully undergone subsequent whole-gland therapy for incidence prostate cancer.

Discussion

In our Phase I clinical trial experience as of this writing, transrectally delivered, MRI-guided laser focal therapy of prostate cancer is safe and feasible for both treatment-naïve and salvage patients in an outpatient setting on a 1.5 Tesla MRI system [1]. This study has also documented that patients who have undergone transrectal MRI-guided laser focal therapy remain re-treatment viable, with either additional laser focal therapy or whole-gland therapy.

Conspicuously absent from the transrectal, outpatient approach to the MRI-guided laser focal therapy procedure are the following: (1) general anesthesia, (2) hospitalization, (3) anesthesiologist, (4) 3 Tesla MRI system, (5) endorectal MRI coil, and (6) MR spectroscopy. The addition of the newly modified “Mt. Everest” technique utilizing MRI guidance for the periprostatic nerve block, in particular, has favorably affected the anesthesia requirements and patient tolerance for this outpatient procedure.

By significantly reducing healthcare resources including staffing necessary to perform focal therapy for the treatment of prostate cancer, the cost-effectiveness and access compare favorably to other focal therapy strategies.

There are some additional advantages of laser energy over other energy sources for focal therapy of prostate cancer. First, laser therapy has the most precise temporal and spatial localizing control. Second, the transition zone between coagulation necrosis and viable tissue from laser thermal therapy measures 0.5–2.5 mm, producing a discrete, focused area of ablation. [4] Third, the biplane real-time feedback of MR thermometry and safety controls ensures the favorable safety profile of laser focal therapy. Several other energy sources are not MRI compatible, or the device cannot function with real-time MR thermometry because of susceptibility artifact or magnetic field inhomogeneity. Both the MR thermometrygradient echo sequence (GRE) and the diffusion-weighted imaging (DWI) are exquisitely sensitive to susceptibility and magnetic field inhomogeneity issues. Transrectal high-intensity focused ultrasound (HIFU) is limited to small glands (<40 cc), and many energy sources are used to perform hemiablation or “regional” ablation as opposed to true focal therapy.

Performing the procedure transrectally, using MRI guidance in-bore eliminates the misregistration errors that can be associated with procedures done using MRI-ultrasound fusion strategies outside of the MRI system “in office.” The authors’ experience also suggests a “continuity of imaging modality” advantage to using the same MR imaging technology to perform the diagnostic multiparametric MRI (pre- and post-laser focal therapy), the interventional MRI-guided in-bore biopsy, and the therapeutic MRI-guided laser focal therapy.

Currently, there is a paucity of peer-reviewed published outcomes for the transrectal approach to this procedure, which warrants further investigation and comparison to other approaches (e.g., transperineal) and other energy sources. In 2014 Lee et al. described their experience with successful in-bore, MR-guided laser ablation of prostate lesions [38]. They reported low morbidity and indicated that patients remained re-treatment viable post-procedure. Also in 2014, Lepor et al. demonstrated short-term oncologic control of biopsy-proven prostate cancer with minimal adverse events in a cohort of 25 men [39].

In our study the men who have undergone this treatment can be divided into two groups: treatment-naïve and salvage therapy. Treatment-naïve men can be further subdivided by Gleason score 3+3, 3+4, and 4+3. The salvage group can be divided into categories by primary treatment modality. Treatment-naïve men with low-risk, low-volume Gleason score 3+3 cancer can be followed with active surveillance. Clinically localized, larger-volume Gleason score 3+3 and Gleason score 3+4 and 4+3 cancers can be safely treated with transrectal laser focal therapy in an outpatient setting. It is our goal to study these men for the next two decades to better understand oncologic control and quality of life.

Most Phase I focal therapy studies have closed and moved to Phase II. Upon closure of our Phase I study, we will progress to a Phase II clinical trial and incorporate genomic assays in an effort study the role of genomic pathways for risk stratification of men to active surveillance, focal treatment, or whole-gland therapy. Local control of disease following laser focal therapy will be monitored with 6-month posttreatment MR-guided in-bore biopsy.

In 2014, the International Laser Network was founded to share best practices and methodology for laser focal therapy among early adopters. The primary goal was to ensure patient safety. Other goals included harmonization of data collection intervals and patient-reported outcomes measures (PROMs). Ultimately an IRB-approved, Phase II, multicenter 20-year outcome study will be initiated to establish the efficacy of laser focal therapy. The intent is not to replace active surveillance in men with low-risk, low-volume disease. In our experience, laser focal therapy should be reserved for men with significant, clinically localized disease, except in the salvage setting. Assuming adequate cancer control can be documented, the vision of focal therapy research includes the possibility of converting low- and intermediate- risk, organ-confined, clinically significant prostate cancer into a chronic illness that is managed with an appropriate combination of active surveillance and outpatient laser focal therapy pro re nata (p.r.n.).

Conclusion

MR-guided, transrectal LFT has proven to be a precise, safe, and oncologically efficacious technique for the treatment of localized prostate cancer in Phase I trials.

Our technique compares favorably with other ablative therapies and is performed in a streamlined fashion to reduce patient discomfort and healthcare costs.

As the technology matures through clinical trials and focal therapy in the treatment of prostate cancer continues to expand, we believe this technique will become firmly established as a first-line therapy.

Notes

Acknowledgments

The authors gratefully acknowledge the skill and expertise of our interventional radiologist, Stuart T. May, MD and our MRI technologist, Wes Jones, RT. We also acknowledge the early work of Roger J. McNichols, PhD, who saw the potential of light and harnessed it. Without him much of our work would have been impossible. We dedicate this chapter to him. BMG, JFF, and RJS.

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • John F. Feller
    • 1
  • Bernadette M. Greenwood
    • 2
  • R. Jason Stafford
    • 3
  1. 1.Desert Medical ImagingIndian WellsUSA
  2. 2.Clinical Services, Desert Medical ImagingIndian WellsUSA
  3. 3.Department of Imaging PhysicsThe University of Texas MD Anderson Cancer CenterHoustonUSA

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