Targeted Microwave Focal Therapy
Condition: Prostate Cancer Stage I
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Focal therapy (FT) for prostate cancer (PCa) is an interesting therapeutic option for
      localized disease with a favorable low- to intermediate-risk profile. The aim of this
      approach is to offer a personalized and less aggressive treatment as compared to radical
      treatments such as radical prostatectomy (RP) or primary radiation therapy, reducing
      functional morbidity while maintaining oncologic efficiency.

      FT is based on the treatment of a part of the prostate, containing the index lesion. The
      index lesion is identified as a single visible lesion up to 12 mm at multiparametric MRI
      (mpMRI), which is biopsied with a fusion biopsy obtaining a Gleason score inferior or equal
      to 3+4. These features allow a focal treatment aimed to ablate the area containing the tumor.
      In case of a concomitant presence of 1 or 2 cores of Gleason score 3+3 found at systematic
      biopsy and invisible to mpMRI, a strategy of surveillance will be adopted, focusing the
      treatment only on the index lesion (only in patients older than 70 years old). Different
      sources of energy have been used to date for focal therapy. Among these, has emerged a very
      low loss (VLL) microwave ablation system, called TATO3®, specifically developed to work with
      the fusion biopsy platform Koelis Trinity® that allows an accurate 3D reconstruction of the
      prostate, with the goal to offer a targeted treatment after a targeted biopsy. Aim of this
      experimental trial is to evaluate the efficacy of the Trinity®-guided TATO3® treatment in the
      ablation of the index lesion, together with the safety of the procedure and the short-term
      oncologic outcomes.
    

Detailed description: 
      Focal therapy (FT) for prostate cancer (PCa) is an interesting therapeutic option for
      localized disease with a favorable low- to intermediate-risk profile. The aim of this
      approach is to offer a personalized and less aggressive treatment as compared to radical
      treatments such as radical prostatectomy (RP) or primary radiation therapy, reducing
      functional morbidity while maintaining oncologic efficiency.

      FT is based on the treatment of a part of the prostate, containing the index lesion. Over 90%
      of PCa are multifocal, and unilateral disease is estimated to be present in only 20-40% of
      patients. Despite the multifocal nature of PCa, many affected men have just a single
      substantial lesion, which is called index lesion. Ohori et al determined that up to 80% of
      PCa volume arises through the index lesion. Clinically, vast evidence indicates that the
      index lesion features predict the behavior of the disease. Indeed, risk stratification of the
      index lesion predicts PCa outcomes, irrespectively from the presence of unilateral or
      bilateral disease, and most metastatic PCa arise from the cell clone of the index lesion. FT
      relies on the concept that residual PCa in the untreated area does not compromise long-term
      disease control, given that it falls into the criteria of active surveillance. The success of
      focal therapy strongly depends on the ability to detect the foci of PCa through
      multiparametric magnetic resonance imaging (mpMRI), which has gained a paramount role in PCa
      diagnosis. Clinically significant prostatic lesions have features detectable at mpMRI and can
      be targeted with fusion biopsies, which combine the data coming from mpMRI and transrectal
      ultrasound (TRUS) imaging. Data from PROMIS trial demonstrated MRI sensitivity of 93% for
      clinically significant cancer, and a meta-analysis by Moldovan et al showed a negative
      predictive value of mpMRI of 88.1%. A European consensus meeting suggested that mpMRI in
      combination of a systematic sampling achieves a negative predictive value of 90-95%. Bearing
      in mind the limitations of the mpMRI, however, to-date systematic biopsies are mandatory, to
      ensure the most accurate sampling possible, and any FT performed should consider a reasonable
      security margin.

      For a successful treatment, patient selection is essential. Currently, the ideal candidates
      for FT should be patients harboring intermediate-risk PCa with favorable features and a
      limited component of Gleason score pattern 4. A 2015 consensus meeting stated that providing
      FT to patients with low-risk prostate cancer would represent overtreatment in men suitable
      for active surveillance. Furthermore, candidates for FT must have a life expectancy of more
      than 5 years and a WHO performance status of 0 or 1. In the last years, FT has solidly
      evolved from low-risk to intermediate-risk disease: since the first FT trials, more than 2700
      patients have been treated, and this approach is now at the level of exploration of
      indications, quality control measures, and reproducibility in larger trials. In 2017, a
      randomized controlled trial (RCT) has shown the potential benefits of FT versus active
      surveillance in low-risk PCa in terms of cancer progression, secondary treatments, and
      negative biopsies at 2-yrs follow-up. In intermediate-risk PCa, another RCT of partial
      prostate ablation versus RP has completed the feasibility phase: the main study is set up,
      with the goal to prove the benefit of FT versus RP in terms of PCa mortality. In line with
      the recommendations of the 2015 consensus meeting, the investigators believe that suitable
      candidates for FT are those with a single small focus of Gleason score 7 (3+4) PCa, with
      possible limited adjunctive presence of clinically insignificant foci of Gleason score 6
      (3+3) invisible to mpMRI. When speaking of FT for PCa, several energy modalities have been
      developed, including high-frequency ultrasound (HIFU), cryotherapy, laser interstitial
      thermotherapy, photodynamic therapy, irreversible electroporation, brachytherapy, and
      radiofrequency ablation. To date, studies were able to prove the feasibility, low morbidity
      profile, and satisfying short- and medium-term oncologic results of FT, mainly based on
      imaging and rebiopsy. Nevertheless, according to the last European Association of Urology
      (EAU) guidelines, FT is still considered experimental, to be offered within a clinical trial.
      Recently, among energy modalities has emerged also a very low loss (VLL) microwave ablation
      system, called TATO3®, specifically developed to work with the fusion biopsy platform Koelis
      Trinity® that allows an accurate 3D reconstruction of the prostate, with the goal to offer a
      targeted treatment after a targeted biopsy. Aim of this experimental trial is to evaluate the
      efficacy of the Trinity®-guided TATO3® treatment in the ablation of the index lesion,
      together with the safety of the procedure and the short-term oncologic outcomes.

      Since the 1980s, microwaves have been widely used for the treatment of Benign Prostatic
      Hyperplasia (BPH). Low intensity energy is applied to the entire organ to reduce the volume
      of the gland. Several studies have shown the safety of microwaves propagation through the
      prostate with transurethral, transperineal and transrectal accesses, while variable results
      have been achieved in terms of prostate volume reduction.

      The treatment of PCa by microwaves requires the use of higher energy as compared to BPH
      treatment, in order to irreversibly denature tumor cells. A phase I/II clinical has been led
      since 1998 to investigate the safety and efficacy of transperineal microwave therapy for
      recurrent PCa following external beam radiation therapy. A preliminary result on 25 patients
      has shown a very low complication rate following the treatment, and good oncological results.
      Six months after the treatment, 64% of the biopsy result were negative. On the last update of
      2004 with 41 patients enrolled, no serious complications were observed as a result of the
      procedure and, although mild continence problems were encountered, these were generally
      temporary.

      TATO3® VLL microwave ablation system represents the last evolution in the field of microwave
      treatment for PCa. Following dry lab testing, it has been experimented in the animal setting
      on dogs. More recently, it has been used at Hôpital Cochin, Paris in the setting of clinical
      study, where preliminary results on 10 patients with low risk PCa showed an excellent safety
      profile of targeted focal microwave treatment for the ablation of index tumor. Final results
      are awaited this summer. Another study is ongoing in at Erasme Hospital, Brussels, treating
      patients already scheduled for radical prostatectomy, with the aim of examining the extension
      of the treated area and confirming the absence of cancerous cells. To-date, the treatment is
      well tolerated and efficacious.

      Since 2015, the investigators have acquired a significant expertise in the field of prostate
      fusion biopsies, achieving outstanding cancer detection rates and improving the risk
      stratification of newly diagnosed PCa. This expertise has been gained using different
      platforms in commerce, from the Koelis Urostation® to the most recent Koelis Trinity®, and
      the investigators have reported the outcomes of these fusion biopsies on a multicentric
      series of more than 2.000 patients, the largest series of fusion biopsies ever published in
      the literature. The natural step forward would be the implementation of the Koelis bioptic
      platform with the possibility of delivering a focal treatment to the foci of PCa, which can
      be achieved with TATO3® microwave ablation system, minimizing side effects while maintaining
      cancer control.
    

Intervention name(s): Katty focal therapy
Intervention type(s): Device
Intervention description(s): Microwave ablation with TATO3 generator (Katty system) under guidance of ultrasound/mpMRI fusion image device Trinity
Intervention model: Single Group Assignment
Intervention model description: Targeted microwave ablation
Masking: None (Open Label)
Primary purpose: Treatment