Salvage Reirradiation Options for Locally Recurrent Prostate Cancer: A Systematic Review

Background Reirradiation using brachytherapy (BT) and external beam radiation therapy (EBRT) are salvage strategies with locally radiorecurrent prostate cancer. This systematic review describes the oncologic and toxicity outcomes for salvage BT and EBRT [including Stereotactic Body Radiation Therapy (SBRT)]. Methods An International Prospective Register of Systematic Reviews (PROSPERO) registered (#211875) study was conducted using Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. EMBASE and MEDLINE databases were searched from inception to December 2020. For BT, both low dose rate (LDR) and high dose rate (HDR) BT techniques were included. Two authors independently assessed study quality using the 18-item Modified Delphi technique. Results A total of 39 eligible studies comprising 1967 patients were included (28 BT and 11 SBRT). In 35 studies (90%), the design was single centre and/or retrospective and no randomised prospective studies were found. Twelve BT studies used LDR only, 11 HDR only, 4 LDR or HDR and 1 pulsed-dose rate only. All EBRT studies used SBRT exclusively, four with Cyberknife alone and 7 using both Cyberknife and conventional linear accelerator treatments. Median (range) modified Delphi quality score was 15 (6-18). Median (range) follow-up was 47.5 months (13-108) (BT) and 25.4 months (21-44) (SBRT). For the LDR-BT studies, the median (range) 2-year and 5-year bRFS rates were 71% (48-89.5) and 52.5% (20-79). For the HDR-BT studies, the median (range) 2-year and 5-year bRFS rates were 74% (63-89) and 51% (45-65). For the SBRT studies, the median (range) 2-year bRFS for the SBRT group was 54.9% (40-80). Mean (range) acute and late grade≥3 GU toxicity rates for LDR-BT/HDR-BT/SBRT were 7.4%(0-14)/2%(0-14)/2.7%(0-8.7) and 13.6%(0-30)/7.9%(0-21.3%)/2.7%(0-8%). Mean (range) acute and late grade≥3 GI toxicity rates for LDR-BT/HDR-BT/SBRT were 6.5%(0-19)/0%/0.5%(0-4%) and 6.4%(0-20)/0.1%(0-0.9)/0.2%(0-1.5). One third of studies included Patient Reported Outcome Measures (PROMs). Conclusions Salvage reirradiation of radiorecurrent prostate cancer using HDR-BT or SBRT provides similar biochemical control and acceptable late toxicity. Salvage LDR-BT is associated with higher late GU/GI toxicity. Challenges exist in comparing BT and SBRT from inconsistencies in reporting with missing data, and prospective randomised trials are needed.


INTRODUCTION
Prostate cancer is the most common male cancer accounting for over 1.2 million new cases per year with >350,000 deaths (3.8% of all male cancer deaths) (1). Radiation therapy (RT) is a curative treatment option for localised prostate cancer and can be offered to patients from all risk groups (2). Despite advances in diagnostic imaging, RT delivery techniques and dose-escalated radiation, biochemical progression remains common and occurs in 15-57% of patients with localised disease (3)(4)(5).
Multiple salvage options are available for locally recurrent non-metastatic disease including prostatectomy, reirradiation [with brachytherapy (BT) or external beam radiotherapy (EBRT)] and other focal therapies such as high-intensity focused ultrasound (HIFU) and cryotherapy. However, there is limited evidence to support the effectiveness of salvage therapies with concerns regarding the potential for significant toxicity that may impact the long-term quality of life of patients. Due to uncertainty regarding benefits and risks of harm only 15-20%of patients with locally recurrent prostate cancer undergo salvage therapy according to the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (6).
BT has been preferred for reirradiation as it offers delivery of highly conformal high dose radiation with a steep dose gradient and rapid fall off which minimises dose to surrounding organs at risk (7). Disadvantages of BT include its invasive nature and the need for a specialist multi-disciplinary team not available in all radiation centres. Previously, EBRT techniques have been associated with high rates of severe late toxicities and poor local control (8). Stereotactic body radiation therapy (SBRT) involves delivery of a high dose of external beam radiation to a highly conformal target volume with a steep dose gradient in a small number of fractions and is now under investigation for locally recurrent prostate cancer. Advantages of this approach are that it is non-invasive and has the potential to be delivered in more radiation centres than BT (9).
This systematic review collates the most up-to-date evidence for reirradiation of locally recurrent prostate cancer. Two previous systematic reviews which compared all salvage therapies found higher biochemical control rates for BT and EBRT compared to surgical and other non-surgical local therapies [high intensity focused ultrasound (HIFU) and cryotherapy] along with potentially lower genitourinary (GU) toxicity (10,11). The justification for this systematic review is that the identification of the reirradiation modality that offers optimum prostate cancer control and minimal toxicity is important to enable patients to make informed decisions and potentially improve outcomes in patients with radiorecurrent prostate cancer. In addition, the evidence base for salvage BT and SBRT continues to expand with a number of new publications in the past 1-2 years.

METHODS AND MATERIALS
An International Prospective Register of Systematic Reviews registered (#211875) systematic review was conducted.

Study Design
The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines (12).
Studies were identified by searching the Cochrane library, EMBASE and MEDLINE electronic databases from inception to 14 th December 2020.

Data Extraction
Two authors (JZ and FS) independently reviewed the abstracts and assessed the quality of each study using an 18-item Modified Delphi technique, which has been previously validated for case series (13). Discordance between reviewers were resolved following arbitration by a third reviewer (AH).

Data Selection
Eligible studies included patients treated with primary EBRT, BT or combination EBRT/BT and salvage therapy for local recurrence with either EBRT or BT. For BT techniques, studies of high-dose rate brachytherapy (HDR-BT), low-dose rate brachytherapy (LDR-BT) and pulse-dose rate brachytherapy (PDR-BT) were included.
Studies that predominantly included patients who had primary treatment with radical prostatectomy, cryotherapy or HIFU were not included in this review as the focus was to collate and present the most up-to-date evidence concerning reirradiation specifically.
Studies with fewer than 20 patients were excluded, along with editorials, letters, abstracts, case reports, conference proceedings and studies not written in English. Where studies had evaluated the same patient cohort as another publication, only the most recent publication was used for analysis unless distinct treatment outcomes or toxicity were described.

EXTRACTED VARIABLES
Extracted data included the first author and country in which the study took place, study type (prospective or retrospective), single/ multi-centre status, number of patients, primary disease characteristics, primary treatment modalities, interval between original treatment and salvage treatment, patient age at salvage, pre-salvage prostate specific antigen (PSA), diagnostic imaging prior to salvage treatment, histological confirmation of local recurrence and percentage of biopsy-proven recurrences in study cohort, whole-gland salvage treatment versus focal salvage treatment, type of salvage radiotherapy (HDR-BT, LDR-BT, PDR-BT or EBRT), salvage dose fractionation schedule, percent of patients who received androgen deprivation therapy (ADT) with their salvage treatment, duration of follow up post salvage therapy, treatment outcomes [biochemical control (BC), biochemical recurrence free survival (bRFS), metastasis free survival (MFS), relapse free survival (RFS), cancer specific survival (CSS), overall survival (OS)] and grade 1-4 GU and gastrointestinal (GI) toxicity as classified by the Common Terminology Criteria for Adverse Events (CTCAE) (14) or Radiation Therapy Oncology Group (RTOG) score (15). Use of any patient recorded outcome measure (PROM) in the study was also collated including the type of tool used. Median (range) values calculated for all collected variables except toxicity rates where mean (range) used to account for the studies which report no toxicity.

Treatment Details
A summary of patient, disease and treatment characteristics at the time of primary treatment and salvage treatments for BT and EBRT studies is shown in Tables 2-5 respectively. Salvage treatment characteristics for BT and EBRT are shown in Tables 6, 7 respectively.
All EBRT studies (n=11) used an SBRT technique with a total of 483 patients treated. Of these studies (9, 45-54), 9 were retrospective and 2 were prospective (46,47). Two were multicentre and 9 were single centre. Four studies used Cyberknife delivery only and 7 studies included patients treated with Cyberknife or conventional linear accelerator SBRT techniques. Four studies used whole gland salvage only, 4 focal salvage only, 2 included both whole gland and focal treatments and one did not specify. Of the 11 studies, 8 were published between 2019 and 2020. The median total radiation dose prescribed was 34 Gy (range 34-38 Gy), over a median of 5 fractions (range 3-7). The median overall treatment time was 6 days (range 3-14 days).

TOXICITY
A summary of clinician reported acute and late GU and GI toxicity data for each study is presented in Table 8 (BT) and Table 9 (SBRT).
Symptoms of erectile dysfunction were specifically reported by nine BT studies (32%) and one SBRT study (9%).
Thirteen studies (33.3%) (12 BT and one SBRT study) included PROMs, with the most common assessment tool used being the international prostate symptom score (IPSS).

DISCUSSION
This systematic review evaluated the most up-to-date evidence for salvage BT and SBRT and found that both treatment options provide good biochemical control with acceptable late GU/GI toxicity. However there is considerable heterogeneity between  studies for numbers of patients, risk groups of included patients, evaluated treatments, reported endpoints, duration of follow up and methods of toxicity assessment (clinician-assessed versus PROMs). The quality of studies was low and meta-analysis was therefore not conducted due to the significant bias associated with these uncontrolled studies. This highlights the need for further high quality prospective and randomised studies to measure the efficacy and toxicity associated with salvage irradiation. Consensus national and international recommendations for reirradiation are limited. The European Association of Urology (EAU) guidelines recommend salvage reirradiation using BT or SBRT for locally recurrent prostate cancer should only be undertaken in a clinical trial setting (55). American Society for Radiation Oncology (ASTRO) and National Comprehensive Cancer Network (NCCN) clinical practice guidelines does not comment on the use of reirradiation for prostate cancer however both the European Society of Radiation Oncology (ESTRO) and American Society of Brachytherapy (ABS) recommendations on prostate HDR-BT highlight the accumulating evidence for salvage HDR-BT in local recurrence as showing great promise (56)(57)(58).
There has been increasing interest in the use of salvage therapies for locally recurrent prostate cancer after primary radiation, although concerns have been raised regarding the potential for severe late toxicity (59). Both BT and SBRT, show durable outcomes in terms of biochemical control with reasonable reported toxicities in the majority of reviewed studies. However, inconsistencies in reporting and missing data preclude accurate comparison between these studies, which are mainly composed of case series. Longer term efficacy data and duration of follow up was available for more BT studies than SBRT but, at short term follow-up, the clinician-reported toxicity following salvage SBRT appear to be infrequent (60).
Two previous meta-analyses which compared salvage therapies in recurrent prostate cancer have been conducted, which included radical prostatectomy, cryotherapy and HIFU in addition to BT and EBRT (10,61). The meta-analysis by Valle et al. (61) reported that recurrence free survival and toxicity rates were best for salvage radiotherapeutic modalities compared to other salvage treatments, and BT appeared to offer the best balance between toxicity and efficacy. For example, the estimated recurrence free survival at 2 years for BT was 77-79% compared to 52-72% for cryotherapy, HIFU and salvage radical prostatectomy. In addition, lower grade 3 or higher GU toxicity was observed (5-10% versus 20% for BT compared with other salvage therapies) (61). The quality of the evidence was not assessed and sub-group and sensitivity analyses to explore potential impact of clinical heterogeneity were also not specified in this meta-analysis (61). In addition, it was unclear how many studies were excluded from the meta-analysis due to incompatible definitions, outcome measures and follow-up periods. Interestingly, the 2-year bRFS of SBRT (54.9%) appeared to be lower than both LDR-and HDR-BT (71% and 74% respectively). A formal comparison between these modalities is limited by confounding factors, although these data raise an interesting question as to whether salvage SBRT could be inferior to BT in terms of biochemical control. Comparing the SBRT studies to BT remains challenging in view of the heterogeneous populations and shorter follow-up available for SBRT with only one study providing 5-yr bRFS data (although in this study, comparable to outcomes from salvage BT were reported) (47). No prospective randomised studies exist which compare BT and SBRT as salvage therapies for locally recurrent prostate cancer and this is ultimately what is required.
There may be dosimetric advantages with the use of BT compared with SBRT. A previous planning study in the primary disease setting concluded that HDR-BT was able to achieve higher intraprostatic doses and greater sparing of the rectum than SBRT (62). It is possible that developments in SBRT planning and delivery might lead to improved outcomes. For example, the superior soft tissue visualisation and functional imaging capabilities of MR guided SBRT might permit better delineation of tumour, greater accuracy of treatment delivery and offer opportunities for dose escalation (63). Whether this would translate into a clinical benefit at this point remains uncertain. There remains considerable interest in salvage SBRT as evidenced by the fact that 8 of 11 SBRT studies were published in the last two years.
Based on the studies evaluated in this review, salvage LDR-BT appeared to have the potential for higher grade 3+ toxicity compared to HDR-BT (19,24). In a study which used PROMs, LDR-BT had a higher peak change in IPSS in the early postimplant period and a higher peak urinary symptom flare at 12 months compared with HDR-BT, although the majority of these scores returned to baseline 2-3 years post-treatment (40). There have been no prospective studies comparing these techniques in the reirradiation setting. In the primary treatment setting however prospective and randomised studies have shown HDR-BT to have better quality of life scores compared to LDR-BT in the acute post-treatment phase, particularly in the urinary health domain, which suggests that HDR was better tolerated (64,65). Similarly, evidence from registries and randomised trials of LDR/EBRT combination therapy and HDR/EBRT combination therapy in the primary disease setting suggest that LDR/EBRT might be associated with higher incidence of significant late GU toxicity although no direct comparison has been performed between the two treatments (66)(67)(68).
Based on the available data, grade 3 or higher GU and GI toxicity with SBRT was rare, although follow-up beyond 2 years is limited (9,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54). SBRT has the potential to limit the risk of severe late GU/GI toxicity compared with less conformal EBRT techniques (69). Careful patient selection remains vital, especially for those at greater risk of excess toxicity following salvage therapy. In a recent observational series of salvage SBRT, grade 3+ GU toxicity was disproportionately observed in patients treated with BT or radical prostatectomy plus salvage RT in the primary disease setting (47). Furthermore, the use of focal salvage techniques with BT and SBRT appear to have lower toxicity rates and comparable bRFS rates however this is limited to a number of uncontrolled, single-arm case series (16,34,36,38,46,51,53,54).
Appropriate patient selection for salvage RT treatments is vital. The European Society for Radiotherapy and Oncology Advisory Committee on Radiation Oncology Practice (ESTRO ACROP) recently conducted a Delphi consensus of expert opinion on patient selection criteria for salvage RT (70). Selection criteria with high levels of agreement (>80%) included Eastern Cooperative Oncology Group performance status of 0-1, satisfactory urinary flow with a known IPSS prior to salvage and use of PET-CT to exclude metastatic disease and MRI to define the target. Agreement was reached that concomitant ADT with salvage RT was unnecessary and that previous ADT use was not a contraindication to salvage RT. It was also recommended that the primary RT dose should be taken into account when considering salvage SBRT. In terms of time duration between primary RT and salvage RT, although consensus was not achieved a minimum interval of 2 years reached major agreement (defined as 65-80% agreement).
The impact on quality of life has not been well assessed in the salvage radiotherapy setting with only a third of studies in this systematic review including PROMs. Only one of 11 SBRT (9.1%) studies included PROMs. Without this information, it is likely that reported rates of toxicity are underestimated (71). Assessment of residual toxicity following primary treatment using validated PROM instruments such as Expanded Prostate Cancer Index (EPIC) could be an important tool for identification of patients at risk of significant toxicity from salvage therapies. Integration of longitudinal PROM assessment into clinical trials is important to ascertain the time-dependent nature of toxicity onset/resolution after treatment (71,72).
The role of ADT with salvage BT/EBRT remains unclear and no consensus could be reached during a previous Delphi consensus (73). The use of ADT with salvage radiation therapy in the evaluated studies was highly variable (8-100%) and reporting of ADT duration was incomplete (16,32,36,41,74). Several BT studies did not report ADT usage or did not use neoadjuvant ADT (24,25,33). Salvage therapies may delay the need for ADT, with up to 69% patients remaining free of ADT at 5 years following salvage SBRT (47). Some authors view salvage BT/SBRT as ADT sparing, which might have the potential to improve quality of life (75).
A recent study found that only 15% of relapses following salvage BT were solely in the prostate (36), suggesting most are likely to be systemic failure therefore accurate and consistent whole body imaging staging is imperative. The optimal combination of re-staging imaging following biochemical failure after primary treatment, and the most clinically relevant PSA level at which to trigger such imaging, remains uncertain (76). Despite the poor accuracy of CT and isotope bone scintigraphy, 21% of studies in this systematic review used these modalities for restaging and patient selection. It is possible that some patients in these studies could have had undiagnosed metastatic disease, and this could be responsible for some subsequent biochemical failures (75,77). Less than half of studies used mpMRI and PET-CT for re-staging prior to salvage therapy. mpMRI has the potential to be particularly useful for detecting local recurrence following previous prostate radiotherapy, although studies evaluating its accuracy are limited (78). The use of novel imaging modalities such as Gallium-68 [ 68 Ga] or Fluorine-18 [ 18 F] labelled PSMA PET-CT, may allow detection of local recurrence at lower PSA levels. While this could lead to a change in management for patients identified with recurrent disease, it was only used in 10% of the studies in this systematic review (79). 68 Ga-PSMA PET-CT has been shown to demonstrate recurrences at prostate-specific antigen (PSA) levels below the Phoenix definition of biochemical failure and it allows for both local staging and exclusion of distant metastatic disease in patients with biochemical failure (80). The recent proPSMA randomised study reported that PSMA PET-CT had a greater accuracy compared to conventional imaging with CT and bone scan in the primary setting (92% vs 65%) (81). PSMA PET-CT also has superior performance characteristics for the detection of distant metastasis in the setting of biochemical failure compared to other PET tracers (82). Nevertheless, the clinical significance of detecting and treating small volume local recurrence at low PSA levels remains uncertain and may risk additional toxicity. Prospective randomised trials comparing BT and SBRT for salvage treatment of locally recurrent prostate cancer are required to determine the efficacy/toxicity of these interventions

LIMITATIONS
The overall quality of evaluated evidence was low. A metaanalysis was not conducted to quantitatively compare the studies as the majority of these were non-comparative retrospective case series with differences in baseline patient demographics, primary and/or salvage treatments, reported endpoints reported and use of ADT. This limits the conclusions that can be drawn about the effectiveness/toxicity of salvage BT/SBRT. High-quality data from prospective trials are still needed to validate the toxicity and long-term clinical outcomes associated with the salvage treatment of recurrent prostate cancer using BT or EBRT, following previous RT.

CONCLUSIONS
Salvage reirradiation of radiorecurrent prostate cancer using HDR-BT or SBRT provides similar biochemical control and acceptable late toxicity. Salvage LDR-BT is associated with higher late GU/GI toxicity. Challenges exist in comparing BT and SBRT from the current literature due to inconsistencies in reporting and missing data. Prospective randomised trials comparing BT and SBRT and assessing PROMs as well as cancer control outcomes in this setting are needed.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.