Long term genitourinary toxicity following curative intent intensity-modulated radiotherapy for prostate cancer: a systematic review and meta-analysis

Background Recent studies have shown that radiation-induced pelvic toxicity often requires urological consultation. However, the 10-year incidence of genitourinary toxicity following intensity-modulated radiotherapy (IMRT) amongst patients with localised prostate cancer remains unclear. Hence, we conducted a systematic review and meta-analysis to determine the incidence of late genitourinary toxicity relying on Radiation Therapy Oncology Group (RTOG) and Common Terminology Criteria for Adverse Events (CTCAE) grade as well as the incidence of specific genitourinary toxicity. Secondary objectives involved quantifing the number of studies reporting 120-month follow-up endpoints, time to event analysis, predictive factors or economic evaluation. Methods Articles published from January 2008 to December 2021 describing prospective studies were systematically searched in MEDLINE, EMBASE and Cochrane (PROSPERO protocol CRD42019133320). Quality assessment was performed by use of the Cochrane Risk of Bias 2 Tool for RCTs and the Newcastle Ottowa Scale for non-RCTs. Meta-analysis was performed on the 60-month incidence of RTOG and CTCAE Grade ≥2 genitourinary toxicity, haematuria, urinary retention and urinary incontinence. Results We screened 4721 studies and six studies met our inclusion criteria. All included studies involved normofractionation, three included a hypofractionation comparator arm and none involved nodal irradiation. The pooled 60-month cumulative incidence of RTOG and CTCAE Grade ≥2 genitourinary toxicity were 17% (95% CI: 5–20%, n = 678) and 33% (95% CI: 27–38%, n = 153), respectively. The pooled 60-month cumulative incidence of Haematuria was 5% (95% CI: −4–14%, n = 48), Urinary incontinence 12% (95% CI: 6–18%, n = 194), Urinary retention 24% (95% CI: 9–40%, n = 10). One study reported time to event analyses, one reported predictive factors, no studies reported economic analysis or 120-month toxicity. There was considerable heterogeneity amongst the studies. Conclusion There are few high-quality studies reporting 60-month toxicity rates after IMRT. Conservative estimates of 60-month toxicity rates are high and there is need for longer follow-up and consistent toxicity reporting standards.


BACKGROUND
Recent studies have shown that patients with radiation-induced pelvic toxicity often present to urology centres for management [1,2]. However, the incidence of genitourinary toxicity 5 to 10 years following intensity-modulated radiotherapy (IMRT), remains unclear [3][4][5][6]. The introduction of IMRT is thought to achieve a reduction in toxicity compared to Three-Dimensional Conformal Radiotherapy (3D-CRT) because of the increased treatment conformality [7,8]. However, earlier review studies, which compared the toxicity associated with IMRT against 3D-CRT were limited by a lack of randomised prospective analyses as well as the inclusion of retrospective studies and shorter minimum follow-up periods, which may have underestimated the incidence of late genitourinary toxicity [7,9,10]. More high-quality studies are required to determine the late genitourinary toxicity rates because of the wide variation in radiotherapy techniques and dose regimes.
In addition, the numerous disparate late toxicity scoring systems makes interpretation of the results difficult due to lack of consistency and accuracy [7][8][9][11][12][13][14][15][16]. The Radiation Therapy Oncology Group (RTOG) is one of the dominant scoring systems reported in the oncology literature, however has undergone numerous iterations to improve its accuracy. Whilst the Common Terminology Criteria for Adverse Event (CTCAE) is promoted as the comprehensive standard for reporting treatment-related adverse events in oncological care, it is often underutilised in trials. Hence the incidence of late genitourinary toxicity following IMRT remains poorly characterised [17][18][19].
The primary aim of this systematic review and meta-analysis was to determine the 60-month incidence of genitourinary toxicity relying on RTOG and CTCAE grade and the incidence of specific genitourinary toxicity, including haematuria, urinary retention and urinary incontinence in patients with localised prostate cancer treated with IMRT without nodal irradiation. Secondary objectives involved quantifying the number of studies reporting 120-month follow-up endpoints, time to genitourinary toxicity event analysis, predictive factors or economic evaluation.

Evidence acquisition
Selection criteria. Accepted articles were considered eligible for inclusion if they met the following criteria: (1)  Study eligibility. The included articles from the literature search were reviewed in three consecutive phases. One researcher (RD) screened titles and abstracts for the first pass. The second pass involved a two-author (RD, AB) review of the full texts. Finally, the reference lists of the selected articles and those of previous systematic reviews were reviewed to identify other possible studies that could be included. The coding for inclusion and exclusion criteria were applied and recorded for each stage.
Discrepancies were resolved with the assistance of a senior reviewer (MO'C).
Data extraction and analysis. Data extraction was independently performed by two authors (RD and AB) according to a preformed standardised template generated using Covidence (Veritas Health Innovation, Melbourne, Australia), an online tool for systematic reviews. We tabulated the study characteristics (author, year, country, baseline sample size, endpoint sample size, median follow-up, setting, design), patient demographics and cancer metrics (age, PSA, tumour score and grade, hormone use status, radiotherapy (fractions and dose) and secondary outcomes (60month incidence of haematuria, urinary incontinence and urinary retention; whether the studies reported 120-month outcomes, time to event, predictive or economic analysis).
Meta-analysis was performed on the 60-month rates of RTOG or CTCAE late ≥2 genitourinary toxicity, haematuria, urinary retention and urinary incontinence using R-studio (Boston, MA 2020). A random effects model (DerSimonian-Laird method) was selected for the studies reporting genitourinary toxicity, because of the evidence of the heterogeneity in demographic and treatment characteristics amongst the studies. The Q-test and the I 2 statistic method were performed to measure statistical heterogeneity across studies. The Chi-square test with Yates correction was used in the subgroup analysis of hypofractionation and normofractionation. Where appropriate, funnel plots were constructed to assess publication bias.
Quality assessment. The Cochrane Risk of Bias 2 tool was used for quality assessment for randomised controlled trials. The Newcastle Ottowa Scoring system was used to evaluate the risk of bias for non-RCT studies. The Newcastle Ottowa Scoring scores were adapted for graphical presentation by the following conversion: 2 stars = low risk, 1 star = unclear risk, 0 stars = high risk. Risk of bias analysis was performed using robvis (McGuinness, LA 2019), an online extension of an R-studio package [21].
Patient demographics. There was a combined total of 5840 prostate cancer patients treated with curative intent IMRT amongst the included studies. Patient demographic characteristics from the selected studies, including age, tumour stage and grade, prostate-specific antigen, hormonal status, diabetes, and cardiovascular history are summarised in Table 2. The median (range) of sample sizes at baseline was 626 (41-3216). There was a total of 2244 (38% of the baseline population) patients included at the 60month follow-up endpoint, with sample size attrition rates ranging from 7 to 83% between studies (Table 3). Baseline IPSS was not reported in the included studies.
Risk of bias assessment. Weighted summary bar plots of the studies assessing the incidence rate of late genitourinary toxicity revealed an overall high risk of bias for all studies based on the Cochrane Risk of Bias 2 Tool. A large proportion of the bias was due to the lack of blinding of participants and outcome assessors (Fig. 4). For each analysis, there were less than ten included studies, reducing the usefulness of funnel plot presentations to assess publication bias. Gy Greys, # Fractions SIB simultaneous integrated boost, SEQ Sequential boost, HYPO Hypofractionation, NFRT normofractionation, IGRT Image-guided radiotherapy, CIMRT Conventional fractionated intensity-modulated radiation therapy, CIMRT conventional fractionation intensity-modulated radiation therapy. a IMRT was encouraged, although 3D-CRT was permitted in this study provided that all protocol-mandated normal tissue dose constraints were met [27].

DISCUSSION
Our systematic literature review of prospective studies reporting long-term urologic complications after radiation therapy treatment for prostate cancer included five articles in a meta-analysis, with a pooled RTOG ≥ 2 incidence of 17% (95% CI: 5-20%). Additionally, the single study included that assessed late CTCAE grade ≥2 genitourinary toxicity reported a 33% incidence (95% CI: 27-38%). These two metrics correlate well, with a reported 10% under-estimation of toxicity as measured by RTOG compared with CTCAE [28]. Our meta-analysis revealed a strong effect size with broad confidence intervals and considerable heterogeneity amongst studies Fig. 5. Overall, the toxicity rates reported likely remain a conservative estimate given under reporting and bias due to lack of blinding in those assessing the outcomes.
This study reports a 5% (95% CI: −4 to 14%) pooled incidence rate estimate of haematuria at 60 months post-IMRT, which is consistent with rates reported elsewhere in the literature [29][30][31]. The incidence of radiation cystitis remains controversial, with reported estimates ranging from 2.6 to 12.1% amongst mostly low-level evidence studies including retrospective series and conference abstracts, which often lack documentation of toxicity diagnosis and reporting of validated toxicity scoring systems [29,30,32]. The current study reports 12% (95% CI: 6-18%) and 24% (95% CI: 9-40%) pooled 60-month rate estimates of urinary incontinence and urinary retention, respectively. Unfortunately, the rate of urinary retention was only reported in one of the included studies, which had a very small sample size (n = 41 at baseline, n = 7 at 5 years post treatment and n = 10 with urinary retention) and is likely overestimated [23]. The need for long-term follow-up of lower urinary tract symptoms was highlighted by the recent meta-analysis by Awad et al. [33] which found that an increase in median follow-up time after prostate EBRT led to a significantly increased risk of developing urethral strictures (OR 0.005, 95% CI 0.0002-0.01, p = 0.041). The predictive factors of radiation-induced genitourinary complications remain unclear. Currently, the literature consists of observational studies of radiotherapy complications but lacks review studies grouping the data. The cost associated with radiation therapy-related complications also remains poorly described, despite the growing number of global economic comparative evaluations of treatments for localised prostate cancer [19,34,35]. Furthermore, the cumulative incidence of treatment-related genitourinary at 120 months was unable to be determined due to lack of reporting in the included trials and may be higher and more severe, given the progressive fibrosis that can develop in patients with radiotherapy-related toxicity [29]. Other recent meta-analyses have also shown no statistically significant differences in late genitourinary toxicity amongst men with prostate cancer treated with hypofractionated radiotherapy compared with conventional radiotherapy [11,36].
The current study has several limitations, including a small number of included studies, high heterogeneity between studies and predominant use of the RTOG system, which may miss complications. The meta-analysis was dominated by the inclusion of 3216 (69%) patients from the CHHip trial [26], with the main dose fractionation schedule of 74Gy/37#, which is now outdated. Furthermore, radiotherapy in the CHHiP trial was not routinely delivered with image-guidance and involved larger margins than typically expected [26]. Similarly, most of the included studies use generous margins with unclear standards for IGRT [22][23][24]27]. In addition, the PROFIT trial by Catton et al. included an unreported proportion of patients treated with 3D-CRT who met the protocolmandated normal tissue dose constraints [27]. Some relevant trials may have been excluded as they did not meet the inclusion criteria [37][38][39]. However, the vast majority of these studies were low-level single institution retrospective studies, which are likely to underestimate toxicity given the reliance on physician reported rather than patient reported outcomes. Furthermore, the included studies involved contemporary radiotherapy techniques, and were all prospective and mainly RCTs, with standardised outcome measurements.
This study reports the incidence of complications but does not differentiate toxicity grades or compare to alternative treatment pathways (e.g. radical prostatectomy), as the data was not provided in the included studies. Furthermore, this study does Fig. 2 Forrest plots of studies included in the meta-analysis demonstrating the 60-month incidence of RTOG and CTCAE ≥ 2 toxicity, haematuria, urinary incontinence and retention. Fig. 3 Forrest plots of studies included in the meta-analysis comparing the 60-month incidence of RTOG amongst patients treated with hypofractionation and normofractionation intensity-modulated radiotherapy. not evaluate the long-term toxicity associated with adjuvant or salvage radiotherapy, which exposes larger portions of adjacent normal tissue to radiotherapy, and which is likely also underreported. This study does not include an exhaustive assessment of genitourinary toxicity and omits quality of life outcomes which may be equally important [40][41][42][43][44]. Whilst the pooled incidence rate is likely an underestimate in aggregate, it may also be an overestimate for patients with a small prostate and low baseline IPSS and those treated with IGRT. While we report a correlation between radiotherapy treatment and the development of symptoms such as haematuria, urinary incontinence and retention over 60 months this association may not be causal. There is a need for a prospective population-level dataset with central registration for patients with confirmed late radiation cystitis, urinary tract strictures and necrotic bladder neck contractures to allow for baseline assessment and formal standardisation.

CONCLUSIONS
The current study presents the first consolidated literature review and meta-analysis on long-term genitourinary outcomes in patients with prostate cancer treated with primary IMRT. The 60month incidence of genitourinary toxicity following IMRT provided in the current study exceeds traditional expectations and is likely a conservative estimate. Furthermore, the paucity of high-quality studies reporting late toxicity is concerning. Future studies of radiotherapy techniques should involve longer follow-up and improved toxicity reporting standards.