An MRI/PET PSMA-based phase I–II study of salvage high-dose-rate brachytherapy after surgery and radiotherapy

Abstract

Local failure is the main pattern of failure in patients with prostate cancer undergoing radical prostatectomy (RP) [1] as well as in patients who receive salvage external beam radiation therapy (EBRT) combined with short-term (6-month) androgen deprivation therapy (ADT) [2] after RP failure. Hence, there is a substantial percentage of patients with prostate cancer who will experience a second local relapse after RP and salvage EBRT with very limited local treatment options. Current guidelines and expert consensus recommendations support patient monitoring or initiation of ADT if maximal pelvic therapy has been given.

The advent of novel imaging techniques, such as ⁶⁸Ga PSMA-PET, has yielded detection rates of 50% of areas with pathological metabolism in patients with PSA values < 0.5 ng/mL [3]. This paradigm shift has led many radiation oncologists to revisit reirradiation as a reasonable alternative to the use of ADT.

Focal reirradiation with brachytherapy has been mainly used as salvage therapy after EBRT failure when the prostate gland is intact [4]. Although brachytherapy has a unique dosimetric profile that makes it specially suited for small prostatic recurrences that can be approached via the transperineal route, its use in the post-prostatectomy setting is limited [4] and technically challenging.

Seven patients with a median follow-up of 7.6 years who fulfilled the eligibility criteria were enrolled in this investigator-initiated trial (NCT06982469: Prostate HDR Salvage post RP). Eligibility criteria included: (i) increasing PSA level after RP and salvage EBRT of at least 65 Gy and radiological evidence of isolated prostatic bed relapse (IPBR) visible on ⁶⁸Ga PSMA-PET and multiparametric MRI; (ii) IPBR potentially implantable transperineally with TRUS guidance; (iii) absence of intraluminal infiltration of the vesico-urethral anastomosis, external urinary sphincter, rectum or bladder; (iv) patient written informed consent to participate in the institutional review board-approved study (University of Navarre IRB code 2020.212); and (v) life expectancy > 5 years. Examples of the typical second salvage locations, as determined by multiparametric MRI and PSMA-PET, with the final dosimetric result are shown in Fig. 1.

Fig. 1

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Graphical description of typical locations of isolated prostate bed relapses characterised using multiparametric MRI, ⁶⁸Ga PSMA-PET along with the resultant dosimetry of high-dose-rate brachytherapy. *Contours: clinical tumour volume (green), gross tumour volume (red), bladder (yellow), rectum (cyan); prescription isodose of 100% (yellow, thin) and 150% (red, thin). Red dots: catheters. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; T2w, T2-weighted.

The implant procedure was performed in a similar way to standard prostate brachytherapy [5] including: (i) TRUS-guided tru-cut biopsy of the recurrent lesion and identification of the gross tumour volume (GTV) with fiducial markers; (ii) use of real-time MRI-TRUS fusion; (iii) insertion of one needle into the GTV with surrounding needles at a distance of 5.0–7.5 mm distance, avoiding placement in normal organs (organs at risk [OARs]); (iv) plain X-ray films with dummy wires in the operating room in the supine position before transportation to avoid inadvertent downward shift of the catheters during treatment; (v) intra-operative MRI for verification and dosimetry; and (vi) plain X-ray films with dummy wires before each treatment for verification.

The GTV was contoured in the intra-operative MRI using radiologist guidance as well as the ⁶⁸Ga PSMA-PET imaging as a reference. The clinical target volume (CTV) was defined as the GTV with a symmetrical margin of 5 mm, with OAR avoidance. The Planning Treatment Volume was considered to be equal to the CTV. OARs included the external urinary sphincter, vesico-urethral anastomosis, rectum, bladder and sigmoid/small bowel if appropriate. A dose of 27.0 Gy in two daily fractions of 13.5 Gy each was prescribed to the minimum dose received by 90% of the CTV (CTVD₉₀) provided that the OAR constraints had been met. Rectum 2cm³, external urinary sphincter contralateral dose received by 50% of the volume (V₅₀) and vesico-urethral anastomosis contralateral V₅₀ were limited to 6.7 Gy, 3.0 Gy and 3.5 Gy, respectively. No further treatments, such as external irradiation or ADT, were given.

Toxicities were graded according to the Radiation Therapy Oncology Group morbidity score criteria. Biochemical failure was defined as any PSA increase of 0.2 ng/mL above nadir. Biochemical relapse-free survival was calculated using the Kaplan–Meier method from the date of brachytherapy to the last follow-up visit.

The median (range) patient age at second salvage was 67 (63–74) years, with a median (range) PSA of 1.41 (0.3–5.9) ng/mL and a median PSA doubling time of 10.3 months. The interval between first and second salvage ranged from 45.5 to 136.0 months. IPBR was not biopsied prior to salvage therapy; however, it was biopsied at the time of brachytherapy and was positive in only three out of seven patients, probably due to small tumour size and poor TRUS visualisation. Four IPBRs were peri-anastomotic and three occurred in seminal vesicle remnant locations.

One patient experienced grade 3 dysuria aggravated by repetitive infections that led to severe incontinence and required an artificial sphincter. Finally, three patients developed early biochemical failure 3–4 months after brachytherapy that resulted in two local failures in the same IPBR area and one oligometastatic failure. The other four patients remain disease-free with a 5-year biochemical relapse-free survival of 58.5%.

In this setting, ADT is the ‘gold standard’, as per the National Comprehensive Cancer Network guidelines among others [6]. This option remains a palliative treatment which significantly impacts patient quality of life. Hence, local salvage can be reasonably offered to patients with good performance status and who have a life expectancy > 5 years, thereby avoiding or delaying the commencement of ADT.

The available literature in this clinical setting is very limited and is mainly based on stereotactic body radiation therapy (SBRT) [7], with the exception of two brachytherapy reports in which patients treated for second salvage were not reported separately [4, 8]. A recent multicentre SBRT retrospective series [7] included 117 patients who were treated with different second salvage regimens ranging from 20 Gy/5 Rx to 36 Gy/6 Rx. The median progression-free survival was 23.5 months with a 3-year progression-free survival below 30% and a 3-year cumulative incidence of grade ≥2 late genitourinary or gastrointestinal toxicity of 18%.

In our study, four out of seven patients remain controlled at a maximum follow-up of 55.6 months, with a 4.5-year biochemical relapse-free survival of 57.1%. These results compare favourably with the SBRT study referenced above [7] because the majority of the risk factors were similar in the two series.

Dose intensity was the only factor that substantially differed between series. In the SBRT reference study [7], patients received biologically effective doses (α/β = 2) ranging from 60 to 158 Gy₂, with the majority of patients receiving more than 120 Gy₂. In the present high-dose-rate reirradiation study, the biologically effective dose of the CTVD₉₀ was 198 Gy₂, rising to 419 Gy₂ in the GTVD₉₀ due to the inherent dose increment in the centre of the implant. Dose escalation might emerge as a plausible explanation for the observed results.