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Erschienen in: memo - Magazine of European Medical Oncology 4/2023

Open Access 10.11.2023 | short review

Focal therapy in intermediate- and high-risk prostate cancer

verfasst von: Nicolai A. Huebner, Stephan Korn, Pawel Rajwa, Shahrokh F. Shariat

Erschienen in: memo - Magazine of European Medical Oncology | Ausgabe 4/2023

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Summary

Focal therapy is a treatment option for clinically localized prostate cancer, finding increased use in recent years. It is generally associated with very good functional outcome regarding pad-free continence and preservation of erections. Oncologic outcomes are controversial, especially depending on the ideal endpoint. Both the presence of clinically significant prostate cancer (csPCA) on biopsy and the absence of any whole-gland or systemic treatment as “failure-free survival” (FFS) have been used. While salvage whole-gland and systemic therapy is rare, a substantial number of patients will have csPCA on follow-up biopsies after focal therapy, either in-field or out of field. Generally, patients selected for focal therapy are considered intermediate-risk, although some patients with high-risk features have been included into focal therapy studies. With the data currently available focal therapy presents a good treatment option for patients with feasible intermediate-risk prostate cancer, interested in functional outcome, after proper counseling on the higher recurrence rate, and the need for surveillance biopsies during follow-up.
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Introduction

While prostate cancer (PCA) is a very heterogenous disease, local therapy has been rather one -sided for many years. With recent advances in diagnostic imaging using multiparametric magnetic resonance imaging (mpMRI) [1, 2], high resolution Ultrasound [3] as well as additional methods of grading using genomic biomarkers [4], focal therapy has become a subject of increased interest.
Historically the sources of energy currently used for focal therapy have been used in the case of salvage therapy after prior radiation, such as heat with High-intensity focused ultrasound (HIFU) [5] and freezing with cryotherapy [6] or electric current in irreversible electroporation (IRE). In many cases therapy was applied to the entire prostate and was often associated with poor functional outcome [7].
Attempts at focal therapy have really become more successful with the introduction of mpMRI of the prostate. Although it remains an experimental therapy within international guidelines [8] the number of academic centers offering a form of focal therapy, and the available high-quality data is constantly growing. The recommended patient selection for focal therapy, however, remains mostly based on expert opinion at this time.
Also, the ideal endpoints for focal therapy are not uniform. One endpoint for focal therapy frequently used is failure-free survival, meaning absence of radical or systemic treatment. This endpoint generally allows for second courses of focal therapy, as well as positive biopsies after focal therapy [9, 10]. Another more careful oncologic endpoint is the presence of clinically significant PCA (csPCA) or any PCA at biopsy, in most cases measured at 12 or 24 months [11].

Indication of focal therapy in intermediate-risk PCA

Intermediate risk prostate cancer is the most common indication for focal therapy. Most consensus statements of international groups regarding this topic recommend including patients with ISUP 2 or 3 PCA and a PSA below 15. Minimal amounts of ISUP 1 on the contralateral side is not seen as a contraindication [12, 13]. Most of the current data on focal therapy is collected within this patient cohort.
One of the few comparative studies in the field was published by Shah et al. Using propensity matching they compared 246 focal therapy patients to 246 radical prostatectomy patients [14]. Their primary endpoint was FFS, which was described earlier for focal therapy and was also adapted for RP patients meaning need for salvage whole gland or systemic treatment. Untreated biochemical recurrence after RP was not considered failure, and patients receiving adjuvant radiation therapy (RT) were excluded. There was no significant difference for FFS between RP and focal therapy at 3.5 and 8 years (86% vs 91%, 82% vs 86% and 79% vs 83%). The authors concluded that oncological outcomes were similar between therapies in this collective. However, a major point of critique remains the different nature of failure due to the different nature of therapy, even though “failure” is certainly a very relevant endpoint for patients. Another study by Scheltema et al. compared 50 patients after IRE to 50 patients after RP in a matched-pair analysis with the main endpoint of functional outcomes [15]. They found that IRE was superior in pad-free continence as well as erections sufficient for intercourse at 12 months, however significantly more patients had oncological failure in the IRE group. Overall, 29% of patients with IRE had biopsy proven csPCA at 12 months and 8% (4) fulfilled the previously mentioned definition of FFA (whole gland or systemic therapy). None of the patients in the RP group had recurred using the definition of PSA > 0.2 ng/ml.
A prospective multicenter study on MRI-guided HIFU cohort of 101 intermediate risk PCA patients has been published by Ehdaie et al. [11] with the primary endpoint of absence of csPCA in the target confirmed by biopsy after 24 months. In this study the HIFU procedure was carried out within an MRI-scanner under real-time MRI heat monitoring of the prostate, allowing for the best possible control of energy application. Of 89 patients who underwent biopsy at 24-months, 88% had no csPCA within the target area, however this number was reduced to 60% when considering the entire prostate, as out-of-field recurrence was a common event. Treatment related side-effects were very rare, and also functional outcome was excellent with 100% of patients with continence at baseline showing pad-free continence at 24-months. There were very mild changes in erections, with a mean difference in IIEF‑5 scores at 24 months was −0.16.
Similarly, Wysock et al. [16] reported a prospective cohort of patients undergoing primary focal cryotherapy and biopsy at 6 months. Within their cohort of 83 patients only 5 showed cancer on biopsy at 6 months, and only one had csPCA. The same group of authors also reported 24 months functional outcomes after focal cryotherapy showing preserved potency in 70% of patients [17]. An older retrospective analysis of the international COLD-registry from 2012 did show that in patients undergoing focal cryotherapy pad-free continence was 98.4% and maintenance of spontaneous erections was 58.1% suggesting improvement also in functional outcomes for cryotherapy [18].
The largest single retrospective analysis describes a cohort of 1379 men treated with focal therapy using transrectal HIFU over 15 years [10] They showed a 7-year FFS of 68% and 65% for intermediate- and high-risk cancers. Clavien-Dindo > 2 adverse events occurred in 0.5% (7/1379) patients. The metastasis-free (MFS), and overall survival (OS) within 7 years was 100% and 97%. Functional outcome was not specifically reported in this study.

High risk PCA

Data regarding primary focal therapy in high-risk PCA patients is scarce as it is not recommended [8, 12, 13]. Some data that exists is within larger prospective cohort studies such as the previously mentioned trial by Reddy et al. [10]. They described their cohort of 1379 patients who had undergone focal HIFU within a time of 15 years. Among those were 28% considered high risk PCA according to the D’Amico risk criteria [19]. Within their Data there is no difference in FFS between intermediate- and high-risk patients at 7 years (68% vs. 65%). However only 1.2% of patients included had ISUP Grade ≥ 4 cancer. The rest of the patients were considered high-risk due to PSA levels or local tumor stage ≥ T2c.
This shows that risk classification according to the D’Amico criteria clearly is not ideal when discussing focal therapy. However, the question remains which criteria should be used, as clinical tumor stage of T2c suggestive of bilateral disease might in fact be a contraindication in the eyes of many for focal therapy, whereas an mpMRI showing possible extracapsular extension might not necessarily be one. Similarly, an absolute cut-off value for PSA such as 20 ng/ml is certainly not ideal, and PSA Density (PSAD) might be a better way to define inclusion criteria. As of yet there is very little data regarding PSAD in focal therapy. It has been described in a small cohort of 25 patients by Hoquetis et al. [20] and was associated with a higher likelihood of cancer outside the treated area if above 0.1. However, this was calculated after treatment, where prostate Volume can vary significantly, and inflammation might be present depending on the timeframe. There is no dedicated study published for focal therapy in high-risk patients.

Conclusion

Focal therapy is a treatment option for intermediate-risk prostate cancer, being used increasingly in many academic centers. Adverse events are rare and functional outcomes slightly vary depending on the energy source yet are very good in almost all cases. Oncologic outcomes vary depending on the endpoints used as well as the study. In the case of FFS the outcomes have been shown to be comparable to radical prostatectomy in a select patient cohort. As diagnostic methods improve, the more recent data is encouraging, to offer focal therapy as a treatment option for intermediate-risk patients interested in their functional outcome, however the ideal patient selection is still unclear and extreme caution is advised for patients with high-risk disease. At follow-up biopsy, csPCA is present in many patients which they should be counseled on prior to therapy. Focal therapy currently remains an experimental treatment approach.

Conflict of interest

N.A. Huebner,S. Korn,P. Rajwa and S.F. Shariat declare that they have no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by/​4.​0/​.

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Literatur
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Zurück zum Zitat D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969–74. CrossRefPubMed D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969–74. CrossRefPubMed
Metadaten
Titel
Focal therapy in intermediate- and high-risk prostate cancer
verfasst von
Nicolai A. Huebner
Stephan Korn
Pawel Rajwa
Shahrokh F. Shariat
Publikationsdatum
10.11.2023
Verlag
Springer Vienna
Erschienen in
memo - Magazine of European Medical Oncology / Ausgabe 4/2023
Print ISSN: 1865-5041
Elektronische ISSN: 1865-5076
DOI
https://doi.org/10.1007/s12254-023-00932-y

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