Prostate cancer (PCa), accounting for 33 % of all male cancers, is the second leading cause of cancer death in men, exceeded only by lung cancer. The disease is histologically evident in as many as 34 % of men during their fifth decade of life and in up to 70 % of men aged 80 years and older. The American Urological Association (AUA)'s Prostate Cancer Clinical Guideline Update Panel (Thompson et al, 2007) stated that standard options for the management of clinically localized PCa include watchful waiting and active surveillance, interstitial prostate brachytherapy, external beam radio-therapy (EBRT), radical prostatectomy, as well as primary hormonal therapy (including androgen deprivation therapy, e.g., bicalutamide). Other treatment modalities entailed cryotherapy, high-intensity focused ultrasound (HIFU), and combinations of treatments (e.g., EBRT and interstitial prostate bracytherapy). While watchful waiting and active surveillance, radiation therapy, and radical prostatectomy remain the current standard for the treatment of PCa, laser-induced thermal therapy (LITT) has recently been explored as a means of treatment of PCa.
Stafford et al (2010) stated that image-guided ablation of tumors is assuming an increasingly important role in many oncology services as a minimally invasive alternative to conventional surgical interventions for patients who are not good candidates for surgery. Laser-induced thermal therapy is a percutaneous tumor-ablation technique that utilizes high-power lasers placed interstitially in the tumor to deliver therapy. Multiple laser fibers can be placed into the treatment volume and, unlike other interstitial heating techniques, can be fired simultaneously to rapidly treat large volumes of tissue. Modern systems utilize small, compact, high-power laser diode systems with actively cooled applicators to help keep tissue from charring during procedures. Additionally, because this approach to thermal therapy is easily made magnetic resonance compatible, the incorporation of magnetic resonance imaging (MRI) for treatment planning, targeting, monitoring, and verification has helped to expand the number of applications in which LITT can be applied safely and effectively. These investigators provided an overview of the clinically used technology and algorithms that provide the foundations for current state-of-the-art MR-guided LITT (MRgLITT), including procedures in the bone, brain, liver, and prostate as examples. In addition to advances in imaging and delivery, such as the incorporation of nanotechnology, next-generation MRgLITT systems are anticipated to incorporate an increasing presence of in silico-based modeling of MRgLITT procedures to provide human-assisted computational tools for planning, MR model-assisted temperature monitoring, thermal-dose assessment, and optimal control.
The Visualase Laser Ablation System (Visualase Inc., Houston, TX) is a minimally invasive laser ablation system for the treatment of epilepsy as well as the destruction of tumors (e.g., bone including spinal metastases, brain, kidney, liver and prostate). It consists of a fiber optic laser; its placement is guided by a surgical navigation system, and confirmed by MRI before treatment. It is designed to destroy tumor and limit injury to surrounding structures. For PCa, the Visualase Laser Ablation System is being studied for the treatment of organ-confined disease (Gleason score of 6 or 7 or below).
In a phase I clinical study, Lindner et al (2009) examined the feasibility and safety of image-guided targeted photothermal focal therapy for localized PCa. A total of 12 patients with biopsy proven low-risk PCa underwent interstitial photothermal ablation of the cancer. The area of interest was confirmed and targeted using MRI. Three-dimensional ultrasound was used to guide a laser to the magnetic resonance to ultrasound fused area of interest. Follow-up was performed with a combination of MRI and prostate biopsy. Validated quality-of-life (QOL) questionnaires were used to assess the effect on voiding symptoms and erectile function, and adverse events were recorded. Interstitial photothermal focal therapy was technically feasible to perform. Of the patients studied, 75 % were discharged home free from catheter the same day with the remainder discharged home the following day. The treatment created an identifiable hypo-vascular defect that coincided with the targeted prostatic lesion. There were no peri-operative complications and minimal morbidity. All patients who were potent before the procedure maintained potency after the procedure. Continence levels were not compromised. Based on multi-core total prostate biopsy at 6 months, 67 % of patients were free of tumor in the targeted area and 50 % were free of disease. The authors concluded that image-guided focal photothermal ablation of low-risk and low-volume PCa is feasible. Early clinical, histological and MRI responses suggested 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. Moreover, they stated that further trials are needed to demonstrate the effectiveness of this treatment concept.
Raz et al (2010) reported the findings of 2 patients with low-risk PCa who were treated with outpatient in-bore MRI-guided focal laser ablation (FLA). 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 de-vascularization of the target. No adverse events were noted. The authors stated that MRI-guided FLA of low-risk PCa is feasible and may offer a good balance between cancer control and side effects; refinement of this outpatient procedure may result in an inexpensive, minimally invasive alternative to current active therapies. Moreover, they noted that further trials will be necessary to define the safety and oncologic efficacy of this therapy, but these early findings are promising.
Eggener et al (2010) reviewed the rationale, patient selection criteria, diagnostic imaging, biopsy schemes, and treatment modalities available for the focal therapy of localized PCa. A National Center for Biotechnology Information PubMed search (http://www.pubmed.gov/) was performed from 1995 to 2009 using medical subject headings "focal therapy" or "ablative" and "prostate cancer". Additional articles were extracted based on recommendations from an expert panel of authors. Focal therapy of the prostate in patients with low-risk cancer characteristics is a proposed treatment approach in development that aims to eradicate all known foci of cancer while minimizing damage to adjacent structures necessary for the preservation of urinary, sexual, and bowel function. Conceptually, focal therapy has the potential to minimize treatment-related toxicity without compromising cancer-specific outcome. Limitations include the inability to stage or grade the cancer(s) accurately, suboptimal imaging capabilities, uncertainty regarding the natural history of untreated cancer foci, challenges with post-treatment monitoring, and the lack of QOL data compared with alternative treatment strategies. Early clinical experiences with modest follow-up evaluating a variety of modalities are encouraging but hampered by study design limitations and small sample sizes. The authors concluded that prostate focal therapy is a promising and emerging treatment strategy for men with a low-risk of cancer progression or metastasis. They stated that evaluation in formal prospective clinical trials is essential before this new strategy is accepted in clinical practice. Adequate trials must include appropriate end points, whether absence of cancer on biopsy or reduction in progression of cancer, along with assessments of safety and longitudinal alterations in QOL.
Nguyen and Jones (2011) evaluated the rationale, effectiveness, and morbidity of various methods of achieving focal prostatic ablation. These investigators performed a literature review of focal therapy in prostate cancer with an emphasis on more established methods (e.g., cryotherapy and HIFU). The authors concluded that focal ablative methods allow targeted destruction of prostatic tissue while limiting the morbidity associated with whole-gland therapy. Local cancer control after focal therapy appears promising but does not approach that of established whole-gland therapies. Until it is feasible to identify patients reliably with truly focal disease and predict their natural history, focal therapy cannot be considered to be the definitive therapy for localized PCa.
Colin et al (2012) noted that current challenges and innovations in PCa management concern the development of focal therapies that allow the treatment of only the cancer areas sparing the rest of the gland to minimize the potential morbidity. Among these techniques, FLA appears as a potential candidate to reach the goal of focusing energy delivery on the identified targets. These investigators performed an up-to-date review of this new therapeutic modality. Relevant literature was identified using Medline database with no language restrictions (entries: focal therapy, laser interstitial thermotherapy, prostate cancer, FLA) and by cross-referencing from previously identified studies. Precision, real-time monitoring, MRI compatibility, and low-cost of integrated system were principal advantages of FLA. Feasibility and safety of this technique have been reported in phase I studies. Focal laser ablation might eventually prove to be a middle ground between active surveillance and radical treatment. The authors concluded that FLA may have found a role in the management of PCa. However, they stated that further trials are needed to demonstrate the oncologic effectiveness in the long-term.
Bozzini et al (2013) reviewed the literature to concentrate on the practical aspects of focal therapy for PCa with the following key words: photodynamic therapy (PDT), high-intensity focused ultrasound, cryotherapy, focal laser ablation, electroporation, radiofrequency, external beam radiation, organ-sparing approach, focal therapy, prostate cancer, and then by cross-referencing from previously identified studies. Prostatic tumor ablation can be achieved with different energies: freezing effect for cryotherapy, thermal effect using focalized ultrasound for HIFU, and using thermal effect of light for FLA and activation of a photo-sensitizer by light for PDT, among others. Radiofrequency and microwave therapy have been tested in this field and demonstrated their usefulness. Electroporation is currently being developed on pre-clinical models. External beam radiation with microboost on neoplastic foci is under evaluation. High-intensity focused ultrasound and cryotherapy require the use of sophisticated and expensive machines and, consequently, the procedure is expensive. Laser techniques seem to be less onerous, with the added advantage of size. The authors concluded that several energy modalities are being developed to achieve the trifecta of continence, potency, and oncologic efficiency. Those techniques come with low-morbidity but clinical experience is limited regarding to oncologic outcome. Comparison of the different focal approaches is complex owing to important heterogeneity of the trials. In the future, it seems likely that each technique will have its own selective indications.
In a review on “Focal therapy in the management of prostate cancer”, Nomura and Mimata (2012) noted that a widespread screening with prostate-specific antigen has led increased diagnosis of localized PCa along with a reduction in the proportion of advanced-stage disease at diagnosis. Over the past decade, interest in focal therapy as a less morbid option for the treatment of localized low-risk PCa has recently been renewed due to downward stage migration. Focal therapy stands midway between active surveillance and radical treatments, combining minimal morbidity with cancer control. Several techniques of focal therapy have potential for isolated ablation of a tumor focus with sparing of uninvolved surround tissue demonstrating excellent short-term cancer control and a favorable patient's QOL. However, to date, tissue ablation has mostly used for near-whole prostate gland ablation without taking advantage of accompanying the technological capabilities. The available ablative technologies include cryotherapy, HIFU, and vascular-targeted photodynamic therapy. Despite the interest in focal therapy, this technology has not yet been a well-established procedure nor provided sufficient data, because of the lack of randomized trial comparing the efficacy and morbidity of the standard treatment options. Interestingly, FLA is not mentioned as an emerging approach for the treatment of localized PCa.
An UpToDate review on “Initial approach to low-risk clinically localized prostate cancer” (Klein, 2012) states that “The role of ablation with cryotherapy or HIFU as an alternative to radical prostatectomy or RT [radiation therapy] remains uncertain. Potential advantages in men with localized disease include the ability to destroy cancer cells using a relatively noninvasive procedure. As such, these procedures are associated with minimal blood loss and pain. There is also a more rapid post-treatment convalescence. Whether the long-term outcomes are equivalent to those with definitive surgery or RT is uncertain however. Additional experience and longer follow-up are required to compare the rate of disease control and side effects profiles with other treatment modalities”. This review and another UpToDate review entitled “Cryotherapy and other ablative techniques for the initial treatment of prostate cancer” (Pisters and Spiess, 2012) do not mention the use of FLA.
The National Comprehensive Cancer Network's clinical practice guideline on "Prostate cancer" (Version 1.2013) does not mention the use of focal laser ablation as a therapeutic option. Furthermore, there is a National Cancer Institute-sponsored phase II clinical trial on “MR Image Guided Therapy in Prostate Cancer” that is still recruiting participants (March 2012). Its objective is to examine the safety and effectiveness of treating PCa with laser therapy guided by MRI. http://clinicaltrials.gov/show/NCT01377753.
Wenger et al (2014) stated that focal laser ablation (FLA) is an emerging treatment paradigm for prostate cancer that aims to successfully eradicate disease while also reducing the risk of side-effects compared with whole-gland therapies. Pre-clinical and phase I clinical trials for low-risk prostate cancer have shown that FLA produces accurate, predictable, and reproducible ablation zones with negligible injury to the surrounding tissues. Because FLA is magnetic resonance compatible, the procedure can be monitored with real-time feedback to optimize targeted treatment of cancerous foci and minimize quality-of-life side-effects. The authors concluded that FLA is a well-tolerated and feasible therapy for low-risk prostate cancer, and the oncologic effectiveness of this treatment modality is currently under investigation in phase II clinical trials at several institutions.
A review by Sankineni, et al. (2014) summarized the evidence for MRI-guided focused laser ablation for prostate cancer. The article indicated that the feasibility has been demonstrated in a canine model and a cadaveric model (citing Stafford, et al., 2010; Woodrum, et al., 2010), followed by case reports (citing Raz, et al., 2010) and two phase I studies, citing a study by Oto, et al., 2013 and an abstract by Lindner, et al., 2013. The author stated that the most concerning finding of the latter Phase I study by Linder, et al. was that 26% of the MRI-guided FLA treated patients showed a positive biopsy at the four-month follow-up in a site other than the ablated region. Sankineni, et al. (2014) concluded: “While these results are pointing in the right direction, it is important that larger, long term trials validate these findings.”
In summary, there is currently insufficient evidence to support the use of focal laser ablation for the treatment of prostate cancer. The oncologic efficacy of MRI-guided FLA is currently being evaluated in ongoing phase II clinical trials (Wenger, et al., 2014).