Hypofractionated radiotherapy versus conventional radiotherapy in patients with intermediate- to high-risk localized prostate cancer: a meta-analysis of randomized controlled trials

Prostate cancer (PCa) is one of the most common cancers in the world, especially in North America and Western Europe [1], with over 50% of patients suffering from intermediate- to high-risk localized PCa [2, 3]. On the basis of the results of previous studies, external-beam radiation therapy (EBRT) combined with androgen deprivation therapy (ADT) is a standard treatment for patients with intermediate- to high-risk PCa [4, 5]. Compared with a dose of 75.6 to 79.2Gy for low-risk patients, doses up to 81Gy in form of conventional fractionation schedules have been recommended for patients with intermediate- to high-risk PCa [6‐8]. However, conventionally fractionated dose escalation protracts treatment time, which could possibly increase side effects and yield lower treatment efficacy.

In ideal conditions, radiotherapy dose fractionation schedules should take into account the sensitivity to radiation of the tumor relative to nearby non-tumor tissues. Accumulating evidence shows that the α/β ratio for PCa is low and range from 0.9 to 2.2 Gy [9]. Radiobiological theory suggests that hypofractionated radiation schedules applied in fewer fractions and with larger single doses could increase treatment effects [10]. Further, hypofractionated radiotherapy with single dose≥2.5 Gy per fraction could theoretically maintain high biologically effective doses, while not increasing acute and late adverse events, but efficiently shortening the treatment time. Such outcome would translate into higher treatment capacity and could potentially reduce treatment cost [11].

The results of treatment after hypofractionated radiotherapy have only been reported from several small randomized trials [12, 13]. The efficacy and adverse events of hypofractionated radiotherapy seemed to be comparable with conventional schedules in the treatment of intermediate- to high-risk PCa. However, small sample size trials might have biased results, although no significant effect of publication bias was detected. Lastly, we pooled the relevant outcomes of randomized trials and compared the efficacy and adverse events profile of hypofractionated with those of conventional radiotherapy for intermediate- to high-risk localized PCa.

A large number of clinical studies have suggested that dose escalation is associated with improved biochemical and OS outcomes [26‐29]. A study of the National Cancer Data Base showed that dose escalation resulted in an improvement in OS for patients with intermediate- to high-risk PCa [30]. Kuban et al. [29] published their dose-escalation study of 301 patients with T_1b to T₃ PCa. Clinical failure or freedom from biochemical was superior for patients treated with 78Gy versus 70Gy (78% vs. 59%, p = 0.004), and the patients with initial prostate specific antigen (PSA)>10 ng/ml (intermediate- to high-risk PCa) had a greater benefit (78% vs. 39%, p = 0.001). However, conventionally fractionated dose escalation increased toxicity and overall treatment time. With improved radiotherapy technologies, hypofractionated radiotherapy plays a crucial role in the treatment of intermediate- to high-risk PCa. Several randomized trials have proved that efficacy and adverse events of hypofractionated radiotherapy were similar to conventional radiotherapy in most [13, 20] but not all trials [18]. With aims to provide sufficient evidence for clarifying the discrepancies, the present meta-analysis was designed to compare clinical outcomes and adverse events of hypofractionated radiotherapy with conventional radiotherapy for patients with intermediate- to high-risk PCa with the aim to increase the precision of the comparisons and the estimate of treatment benefit.

Overall survival is the most important result for any cancer therapy because it accounts for secondary mortality causes, the interventions used, and all other mortality causes. Given the indolent nature of the progression of prostate cancer, long-term follow-up is of particular importance to assess differences in overall survival [31]. The median follow-up for the selected studies ranges from 5 to 9 years, and we found that hypofractionated radiotherapy was not superior to conventional radiotherapy. Although hypofractionated radiotherapy did not significantly improve overall survival, it enhanced biological efficacy of delivered radiation dose and reduced overall treatment time, presumably making the treatment more acceptable for patients. Biochemical failure was defined according to the Phoenix definition of nadir PSA plus 2 ng/ml [32]. Although there was no significant difference in avoiding biochemical failure between the two groups, there was still a trend in favor of hypofractionated radiotherapy. The α/β ratio for PCa is 1.5Gy from the included studies. After further analysis, we found that the biologically effective dose (BED) of hypofractionated radiotherapy was slightly higher compared to conventional radiotherapy. This difference may explain why no significant difference in biochemical failure was detected between groups.

Recently, hypofractionated radiotherapy has been introduced as treatment for prostate cancer. Noteworthy, hypofractionated radiotherapy schedules have a large variability in the treatment regimens, and the data on adverse events are sparse. Thus, we pooled the relevant data and found the incidence of acute adverse gastrointestinal event (grade ≥ 2) was higher in the hypofractionated radiotherapy; conversely, for late grade ≥ 2 gastrointestinal adverse events, a significant increase in the conventional radiotherapy was found. Furthermore, grade ≥ 3 acute gastrointestinal adverse events in the two groups was not significantly different, and grade 2 acute gastrointestinal adverse events were acceptable for patients. The BED for acute gastrointestinal effect for hypofractionated radiotherapy was significantly greater compared to conventional radiotherapy in the included trials evaluated for acute gastrointestinal toxicity (p<0.05). This could be expected to contribute to the increased acute toxicity with hypofractionated radiotherapy. The reduction in late adverse event for hypofractionated radiotherapy is consistent with the linear-quadratic model by Catton et al. [25] that would predict a lower biologically equivalent dose for normal tissues with an α/β of 3-5Gy. This finding is further supported by the trial conducted by Dearnaley et al. [33], who reported a lower 5-year incidence of grade ≥ 2 gastrointestinal adverse events for both hypofractionated groups compared to conventional therapy.

Our pooled data showed that Grade ≥ 2 acute and late genitourinary adverse events were not significantly different between the groups. In 2016, another meta-analysis from Cao et al. found similar genitourinary adverse events between hypofractionated and conventional groups [34]. A long-term late adverse event finding from Arcangeli et al. showed that, a relevant impact did not appear with high-dose fractions and; significant differences were only seen for minor (grade 1), late genitourinary adverse events, namely, for macroscopic hematuria [21].

Our meta-analysis was the first designed to compare clinical outcomes and adverse events between hypofractionated radiotherapy and conventional radiotherapy for the treatment of intermediate- to high-risk localized PCa. In terms of efficacy and adverse events, a large number of studies had tested hypofractionated radiotherapy and found that effects were compared to conventional radiotherapy in the treatment of low-risk localized PCa [35‐37]. Published meta-analyses suggest that hypofractionated radiotherapy could result in comparable therapeutic effects for patients suffering from localized prostate cancer without increasing the rate of acute or late adverse events of the gastrointestinal or genitourinary system [38‐41]. Our results are in accordance with these previous findings.

Noteworthy, the current meta-analysis had a number of limitations. First, the patients included in our meta-analysis were all Caucasian ethnicity. Therefore, the conclusions of this study should be treated with caution when applied on other ethnic populations. Second, we failed to analyze the absence of biochemical failure because the reported data was insufficient. Third, the heterogeneity of acute gastrointestinal adverse events was relatively large, which might affect its result.

In summary, meta-analytical data suggest that the efficacy of hypofractionated radiotherapy is comparable to conventional radiotherapy in the treatment of intermediate- to high-risk localized PCa. Although incidences of acute gastrointestinal adverse events were found higher for patients treated with hypofractionated radiotherapy, hypofractionated radiotherapy was safe with overall acceptable adverse event rates. However, due to the limited sample of trials that informed this meta-analysis, these findings should be utilized cautiously when directed in clinical treatment.