Revisiting patient selection and treatment planning in the VIOLETTE trial of targeted microwave ablation

We read with great interest the prospective multicentre VIOLETTE trial (ClinicalTrials.gov identifier: NCT04582656) evaluating targeted microwave ablation for localised intermediate‐risk prostate cancer [1].

The authors should be commended for conducting one of the first European multicentre phase II studies exploring this emerging focal therapy (FT) modality. However, several aspects related to patient selection, treatment planning, and outcome interpretation warrant further discussion.

First, the inclusion criteria are notably restrictive and differ from most contemporary FT series and systematic reviews [2]. Only patients with a single MRI‐visible lesion ≤15 mm, International Society of Urological Pathology (ISUP) Grade Group (GG) 2, and no higher‐grade disease on systematic biopsies were included. While this may enhance internal validity, it significantly limits generalisability.

Moreover, the inclusion of patients with favourable ISUP GG 2 disease, as well as those up to the age of 80 years, raises questions regarding the clinical justification for intervention rather than active surveillance, or even observation in selected cases.

Second, methodological aspects of treatment planning remain insufficiently detailed. The number of ablations (median of three ablations per patient) and margin selection (median 4 mm) were left to operator discretion, without clear standardisation or supporting references. In addition, the rationale guiding the number of ablations performed is not specified—whether this reflects complete volumetric coverage of the target lesion or the use of overlapping applications (‘double‐tap’ strategy) remains unclear and limits reproducibility.

In relation to treatment margins, this is particularly relevant given that multiparametric MRI is known to systematically underestimate tumour size, especially in Prostate Imaging‐Reporting and Data System (PI‐RADS) 3–4 lesions, which comprised the vast majority of this cohort. Consequently, a 3–6 mm margin may be insufficient to ensure complete tumour coverage and could plausibly contribute to the observed in‐field failure rate [3].

Third, early oncological outcomes raise concerns regarding both baseline disease underestimation and the timing of post‐treatment assessment. Clinically significant cancer was already detected as early as 6 months in a subset of patients, including both in‐field and out‐of‐field disease, with out‐of‐field disease observed in ~12% of patients at 12 months. Given the short interval, these findings are more likely attributable to baseline disease misclassification rather than true biological progression.

In addition, the use of early biopsy at 6 months may influence the interpretation of oncological outcomes, as tissue remodelling and delayed treatment effects following FT may not yet be complete. Consistent with this, the radiotherapy literature has shown that biopsy timing can significantly impact outcome interpretation [4]. These factors underscore the need for careful interpretation of early oncological results [2].

Finally, heterogeneity in procedural approach (transrectal vs transperineal), absence of operator experience data, and lack of multivariable analysis further complicates interpretation of the results. While the reported 81% in‐field control rate at 12 months is encouraging, it should be interpreted in the context of these limitations.

Overall, the VIOLETTE trial represents an important step in the development of microwave‐based FT [1]. However, greater standardisation of patient selection, treatment planning, and procedural methodology—along with improved pre‐treatment disease characterisation—will be essential to optimise oncological outcomes and improve reproducibility across centres.

Disclosure of Interests

We confirm that there are no conflicts of interest related to this work.