SIU-ICUD: Principles and Outcomes of Focal Therapy in Localized Prostate Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors should state the type of report presented, whether it is a systematic review or a narrative summary. This should also be reflected in the manuscript title.

Table two is not clear. It states: “Approach and mechanism of action of main focal therapy modalities.” It depicts the modalities and types but not the mechanisms of action for each.  It also appears to represent Venn diagrams but the reason for the overlap in technologies is not clear.

The authors should add that their statements in line 201-207 are based on expert opinion and that the current level of evidence is low-grade.

The authors should include specialists performing another major type of focal therapy such as brachytherapy and describe the procedure and outcomes.

Author Response

Reviewer 1

Comment 1: The authors should state the type of report presented, whether it is a systematic review or a narrative summary. This should also be reflected in the manuscript title.

Response 1: We thank the reviewer for the comment. We edited the title and the M&M section according to his suggestions.

Title. Principles and Outcomes of Focal Therapy in Localized Prostate Cancer – a Literary Review

Materials and Methods. A non-systematic literature search was performed through PubMed database which focused on the following topics: patient selection, imaging techniques, treatment modalities, cancer control and safety outcomes, integration with other approaches and future perspectives.

Comment 2: Table two is not clear. It states: “Approach and mechanism of action of main focal therapy modalities.” It depicts the modalities and types but not the mechanisms of action for each.  It also appears to represent Venn diagrams but the reason for the overlap in technologies is not clear.

Response 2: We thank the reviewer for the comment and we agree with him. Assuming he/she refers to Figure 1 instead of Table 2, we turned Figure 1 into a Table, as follows:

Table 1. Overview of the main focal therapy techniques, energy sources, mechanisms of action and approaches.

Comment 3: The authors should add that their statements in line 201-207 are based on expert opinion and that the current level of evidence is low-grade.

Response 3: We thank the reviewer for the comment. We added the following sentence at the end of that paragraph (3.5.1. Focal Therapy Success):

“From a broader clinically relevant perspective, success is based on the overall FT strategy, which aims to control csPCa while avoiding or delaying radical and/or systemic treatments. Under this paradigm, neither subsequent focal re-treatments nor surveillance of non-csPCa is considered a failure. This viewpoint raises interesting questions about the interpretation of long-term outcomes – particularly whether progression to radical treatment after 5-10 years should be viewed as a true failure of FT or rather a successful delay of more invasive intervention [25]. Despite these promising concepts, however, FT still requires robust long-term data and comparative studies with standard treatments before it can be widely adopted as a standard of care.”

Comment 4: The authors should include specialists performing another major type of focal therapy such as brachytherapy and describe the procedure and outcomes.

Response 4: We thank the reviewer for this suggestion. We should clarify that this manuscript was commissioned as a summary of the focal therapy chapter from the 3rd WUOF/SIU ICUD Book on Localized Prostate Cancer (https://wuof.org/files/3rd-WUOF-SIU-ICUD-Localized-Prostate-Cancer-FINAL4.pdf). While the Authors' list was predetermined by ICUD nomination, we have expanded the manuscript to include more details on focal brachytherapy.

Line 147-148. “Focal brachytherapy delivers targeted radiation through permanently implanted radioactive seeds to a specific area of the prostate.”

Line 156-158. Treatment delivery varies by modality and approach. The transperineal approach is typical for cryotherapy, IRE and focal brachytherapy and common for FLA, vascular PDT, nanoparticles and microwave ablation.

The new Table 1 includes details on focal brachytherapy, while oncological and functional outcomes of focal brachytherapy were already highlighted in Table 2 and Table 3, respectively.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Compliments to the authors for comprehensively reviewing the principles and outcomes of focal therapy in localized prostate cancer

Excellent manuscript that has covered FT extensively. Reviewing this has been a huge learning experience.

Few aspects could be added

1.     Management of FT failure

2.     Do robotic partial prostatectomy and prostatic artery embolization constitute in the spectrum of focal therapy options?

3.     CHRONOS trial

4.     Role of ADT with FT.

Author Response

Reviewer 2

Comment 1: Compliments to the authors for comprehensively reviewing the principles and outcomes of focal therapy in localized prostate cancer. Excellent manuscript that has covered FT extensively. Reviewing this has been a huge learning experience.

Response 1: We sincerely thank the reviewer for the nice comment.

Comment 2: Few aspects could be added: 1. Management of FT failure

Response 2: We would like to thank the reviewer for this suggestion. We have added a paragraph about the management of FT failure, as follow:

“3.6. Management of Focal Therapy Failure

FT failure requires histological confirmation through prostate biopsy and restaging to exclude metastatic disease. In non-metastatic recurrences, standard management includes salvage radiation therapy (sRT) or salvage radical prostatectomy (sRP), with sRP surgical complexity correlating with the extent of previous ablation [Lebdai et al]. Interestingly, although limited, available evidence suggests that both salvage treatments can achieve oncological and functional outcomes comparable or only marginally inferior to the same treatment in a primary setting [Marra et al].

In selected patients with localized recurrent disease, a re-do FT may be a feasible option. However, this approach requires careful evaluation of the initial treatment failure and assessment of whether additional FT could maintain cancer control without compromising the timing of definitive salvage treatment in aggressive disease [Marra et al].”

Lebdai S, Villers A, Barret E, Nedelcu C, Bigot P, Azzouzi AR. Feasibility, safety, and efficacy of salvage radical prostatectomy after Tookad® Soluble focal treatment for localized prostate cancer. World J Urol. 2015;33(7):965-971. doi:10.1007/s00345-015-1493-8

Marra G, Valerio M, Emberton M, et al. Salvage Local Treatments After Focal Therapy for Prostate Cancer. Eur Urol Oncol. 2019;2(5):526-538. doi:10.1016/j.euo.2019.03.008

Marra G, Marquis A, Suberville M, Woo H, Govorov A, Hernandez-Porras A, Bhatti K, Turkbey B, Katz AE, Polascik TJ. Surveillance after Focal Therapy - a Comprehensive Review. Prostate Cancer Prostatic Dis. 2024 Oct 4. doi: 10.1038/s41391-024-00905-0. Epub ahead of print. PMID: 39367182.

Comment 3: Few aspects could be added: 2. Do robotic partial prostatectomy and prostatic artery embolization constitute in the spectrum of focal therapy options?

Response 3:  We thank the reviewer for raising this point. We did not include robotic partial prostatectomy and monoliteral PAE among FT techniques because the evidence in this regard is extremely limited: 3 studies with 51 patients for partial robotic prostatectomy [Villers et al., Sood et al., Kaouk et al.] and 1 pilot study with 10 patients for monoliteral PAE [Frandon et al].

Villers A, Puech P, Flamand V, et al. Partial Prostatectomy for Anterior Cancer: Short-term Oncologic and Functional Outcomes. Eur Urol. 2017;72(3):333-342. doi:10.1016/j.eururo.2016.08.057

Sood A, Jeong W, Keeley J, et al. Subtotal surgical therapy for localized prostate cancer: a single-center precision prostatectomy experience in 25 patients, and SEER-registry data analysis. Transl Androl Urol. 2021;10(7):3155-3166. doi:10.21037/tau-20-1476

Kaouk JH, Ferguson EL, Beksac AT, et al. Single-port Robotic Transvesical Partial Prostatectomy for Localized Prostate Cancer: Initial Series and Description of Technique. Eur Urol. 2022;82(5):551-558. doi:10.1016/j.eururo.2022.07.017

Frandon J, Bey E, Hamard A, et al. Early Results of Unilateral Prostatic Artery Embolization as a Focal Therapy in Patients with Prostate Cancer under Active Surveillance: Cancer Prostate Embolisation, a Pilot Study. J Vasc Interv Radiol. 2021;32(2):247-255. doi:10.1016/j.jvir.2020.10.002

Comment 4: Few aspects could be added: 3. CHRONOS trial.

Response 4: We thank the reviewer for this suggestion. We edited the manuscript as follows:

3.8. Future Perspectives and Challenges, line 347-348. “Key priorities include establishing standardized follow-up protocols, defining uniform criteria for treatment success, and generating robust long-term oncological data. In this regard, the results of the ongoing CHRONOS trial, an RCT comparing radical treatment versus FT, are awaited to provide high-level evidence [Reddy et al.].”

Reddy D, Shah TT, Dudderidge T, et al. Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS): A prospective, multi-centre therapeutic phase II parallel Randomised Control Trial. Contemp Clin Trials. 2020;93:105999. doi:10.1016/j.cct.2020.105999

Comment 5: Few aspects could be added: 4. Role of ADT with FT

Response 5: The role of ADT in combination with focal therapy (FT) is an open debate. FT, as a local treatment for organ-confined low- to intermediate-risk disease, should not require the use of systemic therapy. Currently, no evidence supports the adoption of perioperative/neoadjuvant ADT before FT, thus we chose to omit this discussion from our manuscript. However, we added a sentence about the combination of FT with neoadjuvant agents (finasteride, bicalutamide…) which is evaluated within the setting of the CHRONOS-B arm, as follows:

3.7. Integration with Other Treatment Approaches, line 321-323. “Emerging evidence suggests potential benefits in combining FT with systemic treatments, particularly immunotherapy. The local tissue destruction and antigen release during FT may enhance immune responses, potentially affecting both treated and untreated disease sites [48,49]. Early studies combining cryoablation with checkpoint inhibitors have shown promising results in experimental models, though clinical validation remains ongoing [50,51]. Finally, the CHRONOS-B arm of the ongoing CHRONOS trial, comparing FT alone versus FT with neoadjuvant agents such as finasteride or bicalutamide, will provide some evidence about this combination [Reddy et al.].”

Reddy D, Shah TT, Dudderidge T, et al. Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS): A prospective, multi-centre therapeutic phase II parallel Randomised Control Trial. Contemp Clin Trials. 2020;93:105999. doi:10.1016/j.cct.2020.105999

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript is interesting but some points could be improved

1. The Authors should report if external stereotactic radiotherapy has been used for focal therapy in men with PCa

2. The Authors should report the role of SUVmax PSMA PET/CT in the diagnosis (Pepe P, Pepe L, Tamburo M, Marletta G, Savoca F, Pennisi M, Fraggetta F. 68Ga-PSMA PET/CT and Prostate Cancer Diagnosis: Which SUVmax Value? In Vivo. 2023 May-Jun;37(3):1318-1322) and follow up (Loos G, Buteau JP, Oh J, Van Dyk S, Chang D, Murphy DG, Hofman MS, Williams S, Chander S. PSMA PET/CT patterns of recurrence after mono-brachytherapy in men with low and intermediate prostate cancer and subsequent management. Brachytherapy. 2024 Nov-Dec;23(6):719-726) after therapy in men with PCa

3. The Authors should underline the role of targeted and systematic transperineal prostate biopsy (clinical advantages) as inclusion criteria for men candidate to focal therapy (Pepe P, Pennisi M. Morbidity following transperineal prostate biopsy: Our experience in 8.500 men. Arch Ital Urol Androl. 2022 Jun 29;94(2):155-159)

Author Response

Reviewer 3

The manuscript is interesting but some points could be improved

Comment 1: The Authors should report if external stereotactic radiotherapy has been used for focal therapy in men with PCa

Response 1: We thank the reviewer for the comment. There is evidence reporting the use of external stereotactic radiotherapy devices able to deliver higher radiation doses on a specific target within the prostate with the aim of reducing toxicity [Katz et al]. However, despite with a lower dose, these systems still involve the treatment of benign non-cancerous prostate parenchyma, hampering to consider external stereotactic radiotherapy as a true focal treatment. For this reason, we did not include external stereotactic radiotherapy in our review. Conversely, we included focal brachytherapy among the main energies used for focal therapy for prostate cancer (see responses to Reviewer 1).

Katz A, Formenti SC, Kang J. Predicting Biochemical Disease-Free Survival after Prostate Stereotactic Body Radiotherapy: Risk-Stratification and Patterns of Failure. Front Oncol. 2016;6:168. Published 2016 Jul 8. doi:10.3389/fonc.2016.00168

Comment 2: The Authors should report the role of SUVmax PSMA PET/CT in the diagnosis (Pepe P, Pepe L, Tamburo M, Marletta G, Savoca F, Pennisi M, Fraggetta F. 68Ga-PSMA PET/CT and Prostate Cancer Diagnosis: Which SUVmax Value? In Vivo. 2023 May-Jun;37(3):1318-1322) and follow up (Loos G, Buteau JP, Oh J, Van Dyk S, Chang D, Murphy DG, Hofman MS, Williams S, Chander S. PSMA PET/CT patterns of recurrence after mono-brachytherapy in men with low and intermediate prostate cancer and subsequent management. Brachytherapy. 2024 Nov-Dec;23(6):719-726) after therapy in men with PCa.

Response 2: We thank the reviewer for the comment.

As concerns the first paper, we have edited the manuscript as follows:

3.2. Prostate Cancer Lesion Identification and Localization, line 122-123. “PSMA PET/CT has also shown promise, revealing a sensitivity comparable to mpMRI in a head-to-head comparison, with the SUVmax value potentially correlating with cancer aggressiveness [21, Pepe et al].”

As concerns the second paper, while interesting, it does not specifically highlight the role of PSMA PET/CT scan in post-focal therapy follow-up. In the method section, the authors did not specify the brachytherapy template (focal vs whole gland) and the MRI was adopted only after 2018 despite a study period of 2002-2020. Therefore, we believe that citing this study would not further contribute to highlighting the role of PSMA PET/CT in the post-focal therapy setting.

Comment 3: The Authors should underline the role of targeted and systematic transperineal prostate biopsy (clinical advantages) as inclusion criteria for men candidate to focal therapy (Pepe P, Pennisi M. Morbidity following transperineal prostate biopsy: Our experience in 8.500 men. Arch Ital Urol Androl. 2022 Jun 29;94(2):155-159).

Response 3: We thank the reviewer for the comment and we agree with him. We have added a small paragraph highlighting the role of MRI-targeted and systematic biopsies in the patient selection for focal therapy.

3.2. Prostate Cancer Lesion Identification and Localization, line 126-130. “The optimal biopsy approach to assess focal therapy eligibility combines both MRI-targeted and systematic biopsy. While MRI-targeted biopsy enhances the detection of clinically significant prostate cancer by 20-40%, systematic sampling of the entire gland provides precise information about tumor distribution and helps identify the small cancer foci not seen by the MRI outside the planned treatment area [Kasivisvanathan et al., Ahmed et al.]”

Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med. 2018;378(19):1767-1777. doi:10.1056/NEJMoa1801993

Ahmed HU, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017;389(10071):815-822. doi:10.1016/S0140-6736(16)32401-1

Author Response File: Author Response.pdf