Single‐fraction image‐guided robotic radiosurgery efficiently controls local prostate cancer recurrence after radical prostatectomy

Abstract Purpose To assess the therapeutic potential of single‐fraction robotic stereotactic ablative body radiotherapy (SABR) in patients with locally recurrent prostate cancer (PC) after radical prostatectomy (RP). Materials and methods We included 35 patients with biochemical failure after RP with single‐site local recurrence in the prostate bed diagnosed by PSMA PET/CT. About 20/35 pts had previously received post‐surgical adjuvant radiation therapy. High‐resolution multiparametric magnetic resonance imaging (mpMRI) for exact visualization of tumor tissue was performed at 1.5 (n = 23; Siemens Magnetom Aera) or 3 Tesla (n = 12; Siemens Magnetom VIDA, Siemens Healthineers, Erlangen, Germany). Using the MRI and PET/CT dataset for planning, SABR was carried out after ultrasound‐guided placement of a single gold fiducial marker at the site of tumor recurrence using a CyberKnife M6 unit (Accuray Inc., Sunnyvale, USA). Due to the high diagnostic accuracy of PSMA PET/CT and mpMRI, pre‐SABR biopsy of tumor tissue was not deemed necessary. PSMA PET/CT performed in median 88 days before SABR confirmed the absence of distant metastases. MpMRI was performed at a median of 22 days prior to the intervention. SABR was performed in a single fraction with a dose of 20 (5/35), 21 (27/35) or 22 (3/35) Gy. Follow‐up serum PSA was measured every 3 months thereafter. Results Median patient age was 72 years (57‐80 years) and median time from RP to SABR was 96.8 months (IQR, 69.3‐160.2). Median serum PSA before SABR was 1.38 ng/mL (IQR 0.75‐2.72). At 3 months, median PSA had dropped significantly in 27/35 patients to a median of 0.35 ng/mL (IQR 0.25‐0.68). At 6 months, 30/35 patients showed biochemical response to SABR, while five patients were progressing: three had systemic disease on PSMA PET/CT, while two patients had rising PSA values without a visible correlate on PET/CT. The median follow‐up time was 16 months. Grade 1 genitourinary (GU) toxicity was reported in 3/35 patients (9%) and grade 1 gastrointestinal (GI) toxicity in 2/35 patients (6%), respectively. Conclusion SABR is an efficient new treatment option in the management of single‐site local recurrent PC without the evidence of systemic disease; due to its very low toxicity, it is an alternative to surgical re‐treatment or other focal therapies. It can significantly delay the onset of androgen deprivation therapy (ADT) in biochemical failure after radical prostatectomy.


| INTRODUC TI ON
Radical prostatectomy (RP) is a frequently performed standard-of-care treatment option in the management of patients with prostate cancer, which is the most common malignancy in males throughout the Western hemisphere; its incidence in Germany is more than 57 000 cases per year. 1  Approximately 17-30% of patients develop a detectable serum PSA 5 years after RP; the actual recurrence rate rises with increasing tumor size, resection status, and corresponds to tumor Gleason score at RP. [2][3][4] In men who did not receive adjuvant radiation therapy, salvage radiotherapy is considered the treatment of choice. 5 In patients who already underwent adjuvant radiation therapy or in whom systemic recurrence is suspected, androgen deprivation therapy (ADT) is a commonly used therapeutic option.
Recently, there is growing interest in early local therapy of recurrence in the prostate bed which can be diagnosed at high sensitivity since PSMA PET/CT has been introduced into a clinical routine. 6 Any type of image-guided local ablative treatment delays the onset of ADT and other systemic therapies in the majority of patients; also, local therapy of PCA recurrence might prolong overall survival and improve prognosis. 7 Local therapies like radiation therapy or surgery differ from a systemic approach in terms of side effects and efficacy.
If local recurrence in the prostate bed is diagnosed on clinical examination, ultrasound, or imaging, salvage radiotherapy or surgical excision can be considered as locally ablative treatment options. In most cases, surgical removal of local PC recurrence is technically challenging and associated with significant morbidity. 8,9 Anatomical landmarks are altered in postsurgical patients and precise localization and excision of tumor tissue may be impossible. Standard external beam radiation therapy (EBRT) for local recurrence of prostate cancer after RP is well tolerated but the whole prostate bed is irradiated, potentially leading to higher grades of side effects due to higher doses to the affected organs at risk (OAR).
Stereotactic ablative body radiation (SABR), moreover, is a novel technique to treat small lesions in a single fraction with high ablative doses and very low toxicity 10 ; its patient acceptance is high as the necessary ablative radiation dose can mostly be applied in one single fraction of 20 to 22 Gy. [11][12][13] We sought to assess the efficacy of this new treatment option in patients with single-site local recurrence of PC after RP +/− adjuvant RT. Conclusion: SABR is an efficient new treatment option in the management of singlesite local recurrent PC without the evidence of systemic disease; due to its very low toxicity, it is an alternative to surgical re-treatment or other focal therapies. It can significantly delay the onset of androgen deprivation therapy (ADT) in biochemical failure after radical prostatectomy.

K E Y W O R D S
prostate cancer, prostatectomy, PSA, recurrence, SABR Treatment response and follow-up were assessed by initial serum PSA measurement 3 months after SABR, and every 3 months thereafter. In cases with rising PSA levels a repeated PSMA PET/ CT was performed. Side effects of SABR were recorded at patient visits every 3 months after SABR using a standardized patient questionnaire.
After radical prostatectomy, 20 high-risk patients had undergone adjuvant radiation therapy due to an unfavorable initial clinical tumor stage of pT3a and over and/or positive surgical resection margins.  IPSA levels before surgery, PSA levels before SABR, and PSA nadir after SABR for each patient as well as tumor characteristics at initial treatment are shown in Table 2.
The median follow-up time was 16 months (6-47 months). At the timepoint of censoring of data, all patients were still alive.
Toxicity following SABR was reported at every standard visit interval. Grade 1 genitourinary (GU) toxicity was reported in three patients (9%), thereof one patient developed acute grade 1 GU toxicity in terms of cystitis and two patients late toxicity manifesting as pollakisuria. G1 gastrointestinal (GI) toxicity occurred in two patients (6%). Both reported temporary and intermittent diarrhea at first control interval after SABR. Grade 2 or higher GI toxicity was not reported.

| D ISCUSS I ON
Biochemical recurrence after radical prostatectomy with or without adjuvant radiation therapy occurs commonly in daily clinical practice.
It is well documented that 30-35% of men develop a relapse within 10 years after the initial definitive treatment. 2,14-16 Guidelines recommend salvage RT with a total dose of at least 66 Gy of the prostate bed and pelvic lymph nodes as a first-line treatment option if local recurrence is suspected 17 ; mostly, this treatment option will be employed without prior imaging and its success is solely monitored by the measurements of the PSA value. 5,18,19 If routine follow-up PSA measurements demonstrate BCR of prostate cancer, the focus of recurrence can be exactly localized by means of PSMA PET/CT and mpMRI. 20

| CON CLUS ION
Single-fraction image-guided SABR for recurrent PC after radical prostatectomy is a reliable and safe treatment option in patients with isolated local recurrence in the prostate bed. After the PSMA PET/CT-based localization of tumor tissue, high-resolution MRI allows for exact treatment planning. SABR offers excellent local tumor control and is very well tolerated based on its low toxicity profile.

CO N FLI C T S O F I NTE R E S T
The authors declare that they have no conflict of interest.

E TH I C S A PPROVA L
IRB approval was waived.

O RCI D
A.