Focal Ablation of Prostate Cancer: The Concept, Herb Lepor

The spectrum of site(s) and aggressiveness of disease, age at diagnosis and varying treatment priorities between oncological control and functional outcomes are unique characteristics of prostate cancer (PCa). Guideline-approved treatments for PCa include active surveillance (AS), radical prostatectomy (RP), radiation therapy (RT) and whole gland cryoablation. Because of the spectrum of the disease, the selection of treatment must balance oncological control, treatment-related complications, functional outcomes and patient priorities. Approximately 40% of men randomized to AS will progress to radical treatment within 5 years. According to the most recent update of the Scandinavian Prostate Cancer Group Trial 4 with a mean followup of 25 years, 9 and 6 men must undergo RP in order to prevent a single prostate cancer mortality or development of metastasis, respectively. The undertreatment of AS and overtreatment of RP suggest a treatment strategy targeting site(s) of clinically significant prostate cancer (csPCa) may be the preferred management for selected cases of clinically localized PCa.

A barrier to organ sparing management of PCa has been disease multifocality and the inability of transrectal ultrasound and systematic biopsy (SB) to reliably identify site(s) of csPCa. The introduction of multiparametric (mp) magnetic resonance imaging (MRI) and MRI-fusion targeted biopsy (MRFTB) coupled with acceptance of AS for very low and low-risk disease has been the game changer for interest in focal therapy (FT) or partial gland ablation (PGA) of PCa.

Justification of Focal Ablation of PCa

Untreated Gleason Grade Group (GGG) 1 does not represent an oncologic risk: PCa screening and detection should avoid detection of low-risk disease. Therefore, failure to detect or treat out-of-field low-risk disease should not be considered a limitation of FT.

A pre-FA mpMRI reliably identifies the index lesion: The overwhelming majority of PCa managed by RP are multifocal. However, the aggressiveness of PCa is typically defined by a single index tumor characterized by the highest GGG and pathological stage. MRI reliably identifies the index cancer in more than 85%–95% of men undergoing and 93% of men deemed candidates for FA.

MRI/MRFTB/SB rarely misses csPCa in cases for FT: The consensus is that the selection of candidates for FA should include a high quality mpMRI, magnetic resonance targeted biopsy of all MRI PI-RADS™ >2 lesions, and systematic biopsy. Appropriate candidates for FA have csPCa associated with an MRI lesion and contralateral SB showing GGG ≤1 disease. We identified 59 men who fulfilled our selection criteria for FA who underwent RP at our institution. MRI, MRFTB and SB were performed on all candidates prior to RP. The surgical specimens were step sectioned and all cancers were identified and mapped. The presence of any Gleason pattern 4 disease outside a planned ablation template of magnetic resonance lesion +10 mm margin was 23%. The linear length of Gleason pattern 4 was always less than 1 mm. Therefore, only very low volume Gleason pattern 4 would have been untreated. Approximately half of men with low risk disease who are candidates for AS have unrecognized GGG >1.

Ablative energy reliably eradicates in-field csPCa: At our institution 90% of FA are performed for GGG >1 disease and only 2% were found to have csPCa on aggressive reflex biopsy at 6 months. Whether untreated disease within or outside the ablation zone will become life threatening over time requires further investigation.

Quality of life is an important end-point: Several multicenter prospective studies have reported significant quality of life complications following RP and RT with or without androgen deprivation therapy. Haglind reported on functional outcomes one year following more than 2,000 open and robotic RP performed in Swedish high-volume surgical centers. The rates of incontinence defined by using 2 or more pads a day were 20% and 21% following open and robotic RP, respectively. A recent study at the Memorial Sloan Kettering Cancer Center showed that only 30% of men with no baseline erectile dysfunction undergoing bilateral nerve sparing RP had erectile function restored to baseline levels even with the use of post-prostatectomy phosphodiesterase inhibitors. Simply reporting erectile dysfunction ignores climacturia, shortening of the penis or penile curvature, which are issues rarely discussed when counseling men about sexual dysfunction following RP.

Disease recurrence occurs following RP: The 5-year probability of biochemical recurrence following RP for men with biopsy GGG 1, 2, 3, 4 and 5 is approximately 4%, 12%, 37%, 52% and 74%, respectively (Epstein et al).

Prior FA does not preclude whole gland treatment: The majority of disease recurrences following FA are managed by re-ablation. There is emerging evidence that salvage RP and RT can be performed safely without increased complications rates.

Focal Ablation: The Application–Mark Emberton

The ideal candidate for focal therapy is a man with csPCa (GGG ≥2) that is associated with a clearly defined abnormality (lesion) in the prostate. The ideal volume for the lesion would be 0.5 cc. This is typically a lesion of 10 mm or so in diameter. The reason for this is that a margin will need to be applied around the lesion. This margin should be between 5 and 10 mm beyond the visible limits of the tumor as microscopic extension has been described up to 9 mm beyond the radiological limits of the tumor. Larger tumors require greater margins, and these will tend to overlap with key structures such as nerve bundles, urethra or external urethral sphincter. Such a man conforms to a radiological staging of T2a/b N0 M0.

The choice of energy is less important. It must be able to reach the most distant margins of the treatment plan and not be limited by any anatomical impediment. Calcium in the prostate gland will interfere with sound propagation. A fixed hip deformity might limit the placement of needles via the perineum for the purposes of administering cryotherapy or electroporation.

A total of 85% of men will need only 1 treatment over a 5–10 year period. Around 10% of men will require a second treatment during that time. Around 1 in 20 men will need to transition to whole gland treatment, which will be in the form of either surgery or radiotherapy. Good functional outcomes can be achieved with salvage therapy.

Urinary incontinence is unusual (around 1/100 from centers of excellence); 90% of men will preserve erections sufficient for penetration (assuming good erections prior to treatment), 30% of men will require medication to improve erectile quality. Ejaculatory volume will be diminished and around 40% will lose it completely (dry orgasm).

Focal Therapy: The Limitations–Peter Carroll

The fields of genomic profiling and molecular imaging have had a profound positive impact on our ability to effectively and more precisely treat prostate cancer, and the options for the therapy are plentiful. The appeal of focal therapy is that a cancer thought to be confined to one area of the prostate is treated effectively, and this results in less morbidity compared to whole gland treatment. Treatment can be repeated, and patients who fail are generally good candidates for whole gland treatment. There are several different energy sources, and there is no clearly superior approach. The key to success is precise targeting facilitated by reliable imaging and careful case selection.

The majority of patients are not candidates for focal therapy. Most patients treated with focal therapy have lower-risk cancers. Those with “intermediate risk” disease most often have “favorable” intermediate risk features. Many of these patients may be candidates for active surveillance. Those “high risk” patients treated with focal therapy are often defined by higher grade alone. Most patients treated with focal therapy have undergone very rigorous selection, usually including advanced imaging and very extended biopsy. However, followup is often less stringent, very often relying only on “for cause biopsy” (that is, not all patients who undergo focal therapy are followed with biopsy).

The benefit of focal therapy needs to be proven with well done, prospective trials and/or registries. It should not be recommended as a replacement for active surveillance in those eligible for this option. Doing so would erode our credibility at a time when the field of urology has been credited with reducing overtreatment, a strong argument used to recommend against PCa early detection.

Patients presenting with clinically localized disease most at risk for future metastases and prostate cancer-specific mortality are those with much higher volume and grade disease, and are ill-suited for focal therapy. The battle for PCa survival will be won or lost in such patients.

Focal therapy is incremental, not transformative. Radical prostatectomy will remain the most common and perhaps the most impactful therapy for those in most need of treatment

Focal Therapy: Not Ready for Prime Time—Andre Abreu

RP has many advantages. It is not limited by multifocality, location, or cancer volume. It permits detailed histological information and lymph node dissection.

Prostate specific antigen (PSA) failure is easily defined. However, despite many improvements in surgical techniques and technologies, RP is associated with high morbidity (incontinence and erectile dysfunction). Can we do better?

Concept: One of the most pertinent concerns is that 80% of PCa is multifocal. FT, therefore, relies on the concept of ablation of the “index cancer” (the dangerous cancer focus that drives the disease) accompanied by active surveillance of the untreated prostate tissue. Caution is necessary because PCa metastases may originate from a secondary smaller focus. Additionally, “index cancer” is not clearly defined.

Patient selection: The current paradigm for FT relies on MRI of the prostate followed by SB and targeted biopsy (TB) of MRI suspicious lesions. MRI has several limitations, including: 1) high interobserver variability, 2) underestimation of the size of suspicious lesions and 3) poor assessment of extra-prostatic extension. MRI may miss secondary clinically significant foci. TBs are subject to errors, including operator inexperience, incorrect imaging fusion, prostate shift, movement and needle displacement. Patients with a “clinically significant lesion and a negative standard biopsy” can harbor significant cancer in the contralateral “clear” lobe. Patient selection for FT should be based on multiple parameters. However, there are no nomograms or biomarkers to date validated for focal therapy. The limits of focal therapy with respect to grade, extent of disease on biopsy and T stage are unknown.

Delivering FT: Medially located cancers may not be suitable for FT because of proximity to the urethra, with urethral sparing resulting in incomplete treatment. The same applies to apical cancers. Factors such as calcifications, heat sinks, prostate movement and swelling, and the lack of real-time treatment feedback of many ablation modalities may lead to FT failure. Surgeons’ learning curves are additional concerns. The assessment of the slope of the learning curve outside established centers of excellence is still pending. Focal therapy is defined broadly, from lesion plus margin to hemi-gland or 3/4 ablation.

Followup: Followup after FT is challenging. There is no consensus on the interpretation of PSA kinetics and biochemical failure definition after FT. MRI post-FT is challenging. There are no standardized protocols for MRI acquisition and interpretation. The deformation of the prostate post-FT may increase errors of biopsy image-fusion. Artifactual treatment effects confound histologic evaluation.

Outcomes: There is a lack of long-term followup and comparison to standard treatments. The long-term impact of focal therapy on oncologic outcome is still uncertain. Many patients reported on in FT cohorts would be candidates for AS. Is a negative SB (or absence of csPCa) a clinically meaningful outcome? Freedom from RT seems to be clinically meaningful. Salvage RT may have a greater effect on quality of life than primary radical therapy.

Until we have the results of prospective trials addressing these critical issues, FT should be explored with caution.