Background Prostate cancer (PCa) is the most diagnosed malignancy in men worldwide, and the management of localized disease has evolved significantly in recent years.
Focal therapy (FT) has emerged as a promising alternative to selectively treat areas of localized clinically significant (cs) PCa while preserving healthy prostatic tissue and minimizing the potential for treatment-related side effects of radical therapies such as prostatectomy and radiation.
The most updated definition for FT meant to describe guided ablation of an image defined, biopsy confirmed, cancerous lesion with a safety margin surrounding the targeted lesion and differentiates this technique with other forms of regional ablative therapies grouped as partial gland ablation (PGA) techniques.
To our knowledge, there is lack of a globally accepted guidelines for procedural planning, technical considerations and patient follow up and the published evidence shows variability in criteria for patient selection, optimal energy source and follow up strategies.
European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogential Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) and AUA-American Society for Radiation Oncology (ASTRO)- Society of Urologic Oncology (SUO) guidelines, state FT to be conducted in the setting of a clinical trial using predefined criteria and is not considered as standard of care as yet.
NCCN guideline also do not recommend FT as a routine primary therapy for localised PCa given the lack of long-term data comparing outcomes to radiotherapy (RT) or radical prostatectomy (RP).
Despite these recommendations, several consensus statements, mostly based on expert opinions have been published to address the need for standardization in FT definitions, patient selection and follow up; Detailed description of these consensus is beyond the scope of the current exhibit.
MR guided focal therapy As mentioned before, FT is a rapidly growing minimally invasive treatment with the aim of personalizing therapeutic options for men with PCa, reducing the rate of side effects related to radical treatments, such as incontinence and erectile dysfunction.
There are several technologies that can deliver energy to destroy cancer cells as part of a FT strategy, among which US-guided FT has been the most extensively studied.
However, since multiparametric (mp) MRI has become the main modality for the detection and follow-up of man with csPCa, and is considered the standard of care, more recent studies have been focused on MRI-guided FT, showing promising results.
MRI-guided FT main advantages over other techniques include: 1) Localization of the lesion in 3 planes allowing a better definition of the lesion margins and planning of the ablation volumes, and 2) the possibility of real time thermal monitoring, permitting intraprocedural optimization of ablation temperatures and treatment margins.
These advantages translate into promising results with lower rates of adverse events and shorter hospital stay.
However, MRI-guided FT represents a highly skilled method which requires specific training and expertise its use may be restricted to academic centers with expertise on the technique.
Additionally, the equipment used (specific devices for therapy and anesthesia) must be MR-compatible, which implies additional costs.
Patient selection and technical principles FT may be considered for patients with low-grade or intermediate-grade PCa and localized disease; About 15 to 30% of PCa are unifocal and/or unilateral, which makes them suitable for FT.
This treatment modality is based on the 'index lesion theory' and therefore seeks to treat the largest tumoral focus typically harboring the highest Gleason score, which determines the natural course of disease and patient's prognosis.
Absolute contraindications for MRI-guided ablation include general MRI contraindications, and relative contraindications encompass large prostatic volume, presence of cysts or calcifications, and presence of radiotherapy seeds.
MR thermography MR thermography consists of a noninvasive temperature mapping, used in thermal ablation therapies i.e., Focal Laser Ablation (FLA), High intensity Focused Ultrasound (HIFU), transurethral ultrasound ablation (TULSA), allowing real-time monitoring of the temperature in the area being treated (Figure 1).
This optimizes tumoral control preventing injury of the surrounding healthy tissues.
There are several methods to measure temperature-related changes on MRI, of which the proton resonance frequency (PRF) shift of water protons is the most frequently used, and the one we are going to focus on this exhibit.
Other methods include T1 and T2 relaxation time of water protons, proton density, magnetization transfer, and diffusion coefficient.
PRF MR thermometry is based on the fact that water hydrogen bonds will disrupt at elevated temperatures, which ultimately results in decreased chemical shift and therefore, decreased resonance frequency for water protons.
The software creates maps in gradient-recalled echo (GRE) sequence, where the relative phase shift can be determined by calculating the difference between the maps during heating and preheating.
Methods available for focal therapy There are several methods available to perform MRI-guided FT, and the most frequently used include the following: • Focal laser ablation (FLA): Also known as laser interstitial thermos-therapy (LITT) or interstitial photothermal therapy, this method is based on ablation trough hyperthermia which in the end, leads to coagulation necrosis.
Once the location of the index lesion is confirmed with MR images, the laser fibers are positioned into the targeted depth (Figure 2).
Procedure can be performed with a transperineally, transrectal or trans gluteal approach.
The ablation is carried out with minimum temperatures of 60°C for 1-2 minutes with MR thermography monitoring.
The number of ablations varies according to the volume of the lesion, and this will also determine the total time of the procedure.
Note is made that ablation of lesions in the vicinity of the urethra may require the use of a suprapubic urinary catheter to allow for continuous irrigation of the urethra during the procedure.
Once the ablation is completed, devascularization of the index lesion is confirmed with dynamic contrast enhanced (DCE) images, measuring the non perfused volume (NPV) (Figure 3).
FLA can be performed on an outpatient setting, with sedation and/or regional anesthesia alone, which are the main advantages.
Regardless of whether more than one ablation is required, it is usually a short procedure with prompt recovery.
In addition to being a safe technique with low complication rates.
Studies with a follow-up of 1 year have shown good outcomes in oncological and functional terms (continence and potency). • High intensity focused ultrasound (HIFU): This technique is also based on the ablation trough hyperthermia.
It uses a specific transrectal device/probe capable of generating high frequency ultrasound waves to a target area, causing heating through raised temperatures of 60-95°C in a few seconds, leading to coagulation necrosis.
Once the device is positioned, MR images are acquired, and the index lesion is contoured.
The software generates the specific treatment plan including the required energy level and number of sonifications, which are performed at intervals to minimize heat accumulation and damage to surrounding tissues.
The transducer includes a cooling system that circulates water continuously to prevent heating of the nearby tissues such as the rectal mucosa.
The procedure also uses thermal maps to allow the control of heating within the treated area (Figure 4) with overall low rate complications/morbidity.
It can be performed under general or spinal anesthesia.
When considering this technique, it is important to consider that, because the penetration of ultrasound waves is limited, the success rates may be decreased in patients with large prostate volumes, anteriorly located lesions, and when multiple calcifications are present.
Recent studies have shown that HIFU represents a feasible option with a low rate of complications, acceptable survival, and oncological outcomes at 5-year follow-up. • Cryoablation: Traditionally this technique has been used for treatment of the whole gland, but currently it is also part of the FT strategies.
Cryoablation is based on fast tissue freezing induced with temperatures below -40°C followed by slow thawing, producing irreversible cell damage and apoptosis.
Several cryo-needles are inserted into the prostate through the transperineally route under MR-guidance and once in position, several freeze-thaw cycles are induced to gradually ablate the targeted tissue.
Although real-time temperature mapping is not possible, the growing ablation zone or "ice ball", can be monitored with serial mpMRI images to allow for anatomical control of the treated area.
It is vitally important to place urethral and rectal warming catheters before the procedure to protect the adjacent tissues.
This is performed under general anesthesia and recovery times are slightly longer than with other therapies. • Transurethral ultrasound ablation (TULSA): This is a novel ablation technique with similar principles to HIFU, but with an alternative approach via transurethral.
It uses a transurethral heating applicator that generates focused energy into the prostatic tissue reaching temperatures of around 55°C, to produce thermal coagulation necrosis; Unlike HIFU, the ultrasound beam is delivered continuously.
An endorectal cooling device is also utilized to prevent rectal tissue damage, and real time temperature mapping with MR thermography is possible.
This procedure can be performed in an outpatient setting, under spinal or general anesthesia.
Its main advantage is that it allows for focal, partial (half gland) or complete gland treatment, with reported high success rates.
Despite the promising results of ongoing recent studies on this technique, more definitive results from large, prospective clinical trials are needed.
Imaging Findings and Follow up.
Imaging follow-up post FT should be performed with mpMRI, in accordance with the available expert consensus.
Although there is no definitive established protocol in terms of timing, initial studies have proposed follow up at 6 and 12 months.
To date, consensus has not been reached as to whether further surveillance imaging is mandatory in patients without additional clinical suspicion (i.e., rise in PSA or abnormal digital rectal examination), or in young patients with genetic predisposition and available evidence advocate to follow local practices and protocols.
Immediately after treatment it is expected to find edema and architectural distortion in the treated area and adjacent tissues, including mottling of periprostatic fat and heterogeneous signal on T1WI and T2WI, representing hemorrhage secondary to coagulative necrosis (Figure 5).
The ablation zone will manifest on DCE images as a non-enhancing focal defect surrounded by peripheral enhancement, which can persist for up to 1 month.
Complete or near-complete resolution of the abnormal enhancement, edematous and hemorrhagic changes is expected between 3-6 months.
Typical findings after this period, and thereafter include atrophic and retractile changes at the level of the ablation site, representing scarring and fibrosis (Figure 6).
These changes will demonstrate decreased signal intensity in both T1WI and T2WI, and low signal intensity on diffusion weighted images (DWI) (T2-blackout-effect).
Additionally, cystic changes/retention cysts may develop on follow up, as well as the presence of urethral diverticula, specially after treating lesions in the vicinity of the urethra.
Regardless of the type of therapy, findings suggestive of treatment failure and/or recurrent disease, include early contrast enhancement in the treated lesion, and the combination of hyperintense signal on high B value DWI and hypointense signal on the apparent diffusion coefficient (ADC) map, configuring diffusion restriction.
Multiparametric assessment for residual/recurrent disease after FT To date, there is no consensus for therapy response assessment and follow-up after FT, and the PI-RADS and PI-RR international systems are not designed for these purposes.
However, initial efforts have been made in order to standardize the assessment of focal therapy for PCa and therefore, reduce interobserver variability and optimize communication with clinicians.
Giganti et al, recently proposed an initial scoring system for follow-up with mpMRI, based on their institutional experience called "Prostate Imaging after Focal Ablation (PI-FAB)".
A detailed description of the system is beyond the scope of the current review but in general, it consists of a 3-point scale defined by findings in 3 sequences: DCE, DWI and T2WI, being DCE the dominant sequence, almost irrespective of the appearance on DWI and T2W sequences.
Other authors have acknowledge that while DCE is an extremely important sequence to assess residual/recurrent disease, DWI has also a pivotal role, particularly in the transition zone where BPH nodules may also show early enhancement (Figure 7).
Furthermore, PI-RADS and PI-RR international consensus-based guidelines, use a 5-point scoring system, making desirable to adopt a 5-point scale system for assessment of residual/recurrent after FT, providing radiologists with a familiar framework and facilitating a more reproducible score assignment.
Radiologist familiarization with the appearance of fibrotic changes after treatment including focal dark T2WI signal associated with volume loss, no restricted diffusion and reduced/delayed enhancement after contrast administration (Figure 8) will increase confidence in the assessment of recurrent disease which should demonstrate opposed features.
Overall, the presence of an intermediate to hypointense T2WI focal lesion in combination with diffusion restriction (increased cellularity) and early enhancement (neovascularization) is highly concerning for recurrent disease (Figure 9).
However, there are other lesions in the spectrum demonstrating not marked restricted diffusion and no early enhancement (Figure 10) or isoenhancement to the adjacent prostatic parenchyma with restricted diffusion which are equivocal for recurrent disease.
The non-treated areas of the prostate should continue the regular assessment as per PI-RADS v2.1 recommendations for detection of de novo disease.
Consideration of reporting post-ablation fibrosis involvement of adjacent structures, in particular the rectum should be strongly considered, as this is valued knowledge for the surgeons and radiation oncologists in deciding salvage therapy strategies.