Tumor Biol. (2014) 35:9911–9918 DOI 10.1007/s13277-014-2297-y

RESEARCH ARTICLE

Who benefits from hypofractionated radiation therapy for clinically localized prostate cancer: evidence from meta-analysis Linbin Sun & Shimiao Zhu & Yang Zhao & Hui Zhang & Zhiqun Shang & Ning Jiang & Gang Li & Yuanjie Niu

Received: 8 June 2014 / Accepted: 30 June 2014 / Published online: 6 July 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014

Abstract The aim of this study is to explore the oncological outcomes of hypofractionated radiotherapy for patients with prostate cancer. We systematically searched PubMed, Embase, and the Cochrane Library prior to April 2014 and references of relevant original papers and review articles. Unpublished data from meeting abstracts were supplemented. Studies comparing hypofractionated with conventionally fractionated radiotherapy (CFRT) on oncological outcomes of patients with clinically localized prostate cancer were included. Twelve distinct datasets involving 4,572 participants from 13 papers were eligible for this meta-analysis. The biochemical failure rate (BFR) decreases significantly in the hypofractionated radiotherapy (HFRT) group for approximately 30 % (11–43 %). However, no significantly lower prostate cancer-specific survival and overall survival in HFRT group were observed. In subgroup analyses, HFRT without radiation doses reduction was especially effective in controlling BFR (HR=0.71, 95 % CI 0.53–0.95; P=0.02). Compared to CFRT, HFRT only yield a consistent advantage on BFR in high-risk patients (HR=0.61, 95 % CI 0.46–0.82; P=0.001). Sun L, Zhu S, and Zhao Y contributed equally to this work. Electronic supplementary material The online version of this article (doi:10.1007/s13277-014-2297-y) contains supplementary material, which is available to authorized users. L. Sun : S. Zhu : Z. Shang : N. Jiang : G. Li : Y. Niu (*) Department of Urology, Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, 23 Pingjiang Road, Tianjin, China e-mail: [email protected] Y. Zhao Department of Radiology, Second Hospital of Tianjin Medical Unversity, Tianjin, China H. Zhang Department of Nephrology, Cangzhou Central Hospital, Cangzhou, Hebei, China

Moreover, androgen deprivation therapy (ADT) had no effect on two radiotherapies in controlling BFR. HFRT improves biochemical failure-free survival in patients with clinically localized prostate cancer. Further well-designed trial is needed to confirm our findings. Keywords Prostatic neoplasms . Radiotherapy . Hypofractionation . Outcome . Meta-analysis

Introduction Prostate cancer (PCa) is the most common noncutaneous cancer in men in the Western world, with more than 241,740 new cases and approximately 28,170 PCa-specific deaths estimated in 2012 [1]. After the introduction of prostate-specific antigen (PSA) testing, most PCa patients were diagnosed in early stage. Radical prostatectomy always comes with serious complications without better outcomes [2], therefore, radiotherapy is often recommended to those patients with early stage (localized disease). At present, there is no agreement on the optimal radiation schedule to be used for localized PCa. Conventional radiation schedules ranged from 60 to 70 Gy administered over 6 to 7 weeks [3]. In the past decade, new radiotherapies for PCa treatment have been explored. Several phase III randomized control trials (RCT) and subsequent meta-analysis have shown the benefit of dose escalation, and suggest that high-dose radiotherapy is superior to conventional-dose radiotherapy in preventing biochemical failure in PCa patients regardless of risk status [4–7]. In recent years, there has been a rise of interest in the fraction sensitivity of PCa. Hypofractionated radiotherapy (HFRT) is a new trial to optimize fractions for radiotherapy, which was designed to increase the dose per fraction by delivering an identical or altered total dose simultaneously in a shorter time period [8]. There are several obvious

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advantages for HFRT treatment, including convenience for patients, significantly fewer visits, and lower cost [9]. RCT were also conducted to evaluate the effect of HFRT on oncological outcomes compared with conventionally fractionated radiotherapy (CFRT). Some studies have reported promising result on biochemical failure control [10, 11], while some other studies failed to detect significant benefit of HFRT on its therapeutic effect [3]. A meta-analysis of published data may be reliable to assess whether various fraction makes radiotherapy less effective. The main objective of this metaanalysis was to explore the effect of HFRT on biochemical failure control. Comparisons for overall mortality and diseasespecific mortality were also assessed between the two types of fractionated radiotherapy.

Methods

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by Fowler et al. [8]: NTD2Gy =Dnew[1+dnew/(α/β)]/[1+2 Gy/ (α/β)]. In this formula, Dnew and dnew are, respectively, the total doses and doses per fraction for a given hypofractionation scheme. The α/β ratio of 1.5 Gy was used for PCa tissue [13]. Two investigators independently conducted the systematic search and extracted relevant data from included studies; all disagreements about eligibility were resolved by a third reviewer. The studies were evaluated using the Therapy/ Prevention arm in level of evidence [14]. Another assessment of the methodological quality of the included studies was conducted in line with the Cochrane handbook [15]. For bias risk assessment, the selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias were assessed in each of the studies. Quality assessments were undertaken independently by at least two authors.

Search strategy and selection criteria Presentation and data analysis This meta-analysis was performed in accordance with the guideline proposed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [12]. Studies were included if they fulfilled the following criteria: (1) The men in these studies were pathologically verified to have adenocarcinoma of the prostate (International Classification of Diseases-10: C61) without evidence of metastasis disease; (2) patients who had undergone previous pelvic radiotherapy, radical prostatectomy, or systematic androgen deprivation therapy (ADT) were excluded; and (3) studies that had data comparing the HFRT with CFRT on oncological outcomes of PCa. The primary sources of the reviewed studies were MEDLINE, EMBASE, Web of Science, and the Cochrane Library through April 2014. The search terms can be found in Table S1. Bibliographies of relevant retrieved studies and recent reviews were also scanned for additional publications. Studies were considered regardless of language limitation. Unpublished trials were supplemented by searching of meeting abstracts in “Red Journal” website from 2010 to 2012. When more than one study with the same population was identified, data on outcomes were extracted according to all available information instead of single study. Data extraction and quality assessment General characteristics of each study were recorded: medical center, year of publication, study design, radiotherapy techniques, sample size, doses per fraction, number of fractions, total doses, normalized total doses at 2.0 Gy/fraction (NTD2Gy), study population (age, percent of patients that received neoadjuvant and/or adjuvant androgen deprivation, and tumor risk group), and follow-up period. To compare the total doses, we calculated NTD2Gy using the formula defined

The primary outcome measures were biochemical failure rate (BFR). Biochemical failure was defined as relapse according to the most recent Phoenix criterion of nadir PSA +2 ng/mL [16]. First, we looked through the overall analyses. Then, subgroup analyses based on radiation dose reduction, risk group, and ADT reception were addressed. Risk levels were distinguished according to the National Comprehensive Cancer Network (NCCN) guidelines [17]. ADT was recognized as neoadjuvant, concomitant, and/or adjuvant modalities. Secondary outcome measures consisted of prostate cancerspecific survival (CSS) and overall survival (OS). For categoric variables, weighted hazard ratio (HR) and their 95 % confidence intervals (95 % CI) were calculated using software according to the significance of heterogeneity. A fixed-effects model was used if there was no evidence of heterogeneity between studies; otherwise, a random-effects model was used for the metaanalysis. Fixed-effects model, using the Mantel–Haenszel method, assumed that studies were sampled from populations with the same effect size, whereas the randomeffects model using the DerSimonian and Laird method considered that studies were taken from populations with different effect sizes. Inter-study heterogeneity was evaluated using the Q test [18]. We also calculated the quantity I2 statistic that represented the percentage of total variation across studies. As a guide, I2 values of 25, 50, and 75 % correspond to low, medium, and high levels of heterogeneity [15]. The RR and 95 % CI were calculated for each trial and presented in a Forrest plot. All analyses were conducted using Review Manage (v. 5.2; The Cochrane Collaboration, Oxford) and STATA software (version 11.0; College Station, TX).

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Results Literature research and characteristics of studies We identified 606 records, of which 13 reports of 12 comparative trials (6 randomized-controlled trials [3, 10, 11, 19–23], 3 cohort studies [22, 24–26], and 3 retrospective case–control studies [22, 27, 28]) with a total of 4,572 participants (see Fig. S1). Table 1 showed the information extracted from the included studies; median number of participants was 289 (range 162–936) and the median length of follow-up varied from 25 to 90 months, with a median of 60 months. Reports had been published between 2002 and 2012. Three studies were from Italy, three from USA, two from Canada, one from Australia, one from Switzerland, one from Lithuania, and one from Uruguay. Three-dimensional conformal radiotherapy (3D-CRT) were used in control subjects from nine studies and in cases from seven studies; short-course intensitymodulated radiotherapy (IMRT) was used in control subjects from two studies and in cases from four studies; 2D-CRT and stereotactic body radiotherapy (SBRT) were both applied in only one study. Median normalized total dose at 2.0 Gy/fraction (NTD2Gy) was 78 Gy (range 62–88). In terms of potential bias, four studies had adequate randomization and three had adequate allocation concealment (Fig. S2). Two studies were randomized, but no details were provided. The others were not conducted under randomization. Only one study confirmed the success of doubleblinding. We also assessed the level of evidence for included studies. Five of six RCT got 1b level, the remnant one RCT with inadequate follow-up time and unclear following rate were allotted to level of 2b accompanied with three cohort trials, and three case–control trials achieved 3b level. Meta-analysis results There is significantly lower biochemical rate (BFR) in HFRT group (Fig. 1a). The benefits correspond to absolute of 30 % (95 % CI 11–43 %). Heterogeneity is significant among studies (P=0.01, I2 =55 %; Fig. 1a). For CSS, there is only a nonstatistically significant trend in favor of HFRT (HR=0.69, 95 % CI 0.40–1.19; P=0.18; Fig. 1b). In this analysis, no significant heterogeneity among studies is observed (P=0.59, I2 =0 %; Fig. 1b). In addition, patients who received HFRT have no significant better OS compare with CFRT (HR=0.86, 95 % CI 0.67–1.10; P=0.24; Fig. 1c). There is also no significant heterogeneity among studies (P=0.60, I2 =0 %; Fig. 1c). Previous studies have shown that high-dose radiotherapy is superior to conventional-dose radiotherapy in preventing PCa patients from biochemical failure [4–7]. So, the subgroup analysis was stratified by change of radiation doses. HFRT without total doses reduction is especially more effective than CFRT in controlling biochemical failure (HR=0.71, 95 % CI

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0.53–0.95; P=0.02; Fig. 2). In the subgroup analysis for HFRT with total doses reduction, no significant benefit of HFRT in BFR control is observed in all comparisons (HR= 0.90, 95 % CI 0.81–1.00; P=0.05; Fig. 2). Additionally, preexisting heterogeneity between studies disappeared in both subgroup analyses (Fig. 2). In the subgroup analysis stratified by disease risk, no significant better effect of HFRT on BFR control was detected in low-medium risk PCa (HR=0.95, 95 % CI 0.81–1.11; P= 0.53; Fig. 2). In contrary, there was a significant benefit of HFRT on BFR control in high-risk subjects, compared with conventional radiotherapy (HR=0.61, 95 % CI 0.46–0.82; P= 0.001; Fig. 2). Another subgroup analysis was also conducted based on ADT reception status. Significant benefits of HFRT were detected in both subgroup-analyses (for patients that received ADT: HR=0.67, 95 % CI 0.53–0.84, P<0.001; for patients that received no ADT: HR=0.72, 95 % CI 0.60–0.88, P=0.001; Fig. 2). Sensitivity analysis and publication bias To evaluate the reliability of our data, sensitivity analyses for BFR, CSS, and OS were conducted. These analyses excluded all non-RCT and led to results very similar to overall ones and often to a reduction of the heterogeneity (Fig. 3). The funnel plot revealed the expected funnel shape (Fig. 1), thereby showing no significant evidence of publication bias.

Discussion Summary and results in relation to other studies This meta-analysis with comprehensive search showed that altered fractionated radiotherapy could improve the effectiveness of radiotherapy in clinically localized PCa, compared to conventional radiotherapy, with a small but significant benefit in biochemical failure control. Better BFR control was mainly observed in the HFRT group without decreased total doses, and corresponded to an absolute benefit of 31 %. However, there was no significant difference in the mortality rate between the groups receiving HFRT and CFRT. The absence of significant differences in the CSS between the two fractionated schedules may reflect a lack of statistical power in detecting these changes in a short follow-up period (5-year follow-up is not long enough to assess mortality for localized PCa). For OS, less significant difference between the two fractionated schedules may be caused by non-prostate cancer-specific deaths. Well-designed prospective comparative studies with long-term follow-up are awaited to confirm/support our findings.

3b C-C

1.9 3

1.8 2.4 2 2.625 1.8/2 4 2 2.75 2 3.62

2 3.1 2 3/4.5 2 3/3.15 2 2.5 2 2.7

D/F (Gy)

42 20

42 30 33 20 37/40 14 32 20 39 15

40 20 37 17 38–40 20 39 28 38 26

NO. of fractions

3D-CRT IMRT

IMRT IMRT 3D-CRT 3D-CRT 3D-CRT SBRT 2D-CRT 2D-CRT 3D-CRT 3D-CRT

3D-CRT 3D-CRT 3D-CRT 3D-CRT 3D-CRT 3D-CRT 3D-CRT IMRT IMRT IMRT

Radiation technique

77.5 77.1

71.3 80.2 66 61.9 68–80 88 64 67 78 79

80 81.5 74 81 76–80 77.1/82.8 78 80 76 84.4

NTD2Gy (Gy)a

263 87

102 102 470 466 403 71 109 108 80 82

85 83 44 47 160 114 561 792 152 151

Cases

71 (45–84) 70 (50–82)

72 (66–75) 74 (68–77)

NA NA 70.3 (53–84) 70 (53–84) NA NA 64 (44–83)

75 (54–83) 75 (61–82) 65 (50–78) 63 (53–75) 68 (50–80) 70 (54–78) NA NA NA NA

Ageb

0 0

20 (20) 20 (20) 0 0 178 (44) 0 0 0 80 (100) 82 (100)

85 (100) 83 (100) 0 0 49 (31) 40 (35) 372 (66) 482 (61) NA NA

ADT (%)c

60/151/12 27/58/2

113/278/79 113/265/88 57/189/157 21/30/20 34/63/12 26/57/25 0/80/0 0/82/0

59/143/2

0/0/85 0/0/83 NA NA 70/81/9 41/52/21 75/253/340 257/408/217 NA NA

Risk group Low/medium/high

84 (2–109) 78 (12–101)

58 (55–59) 45 (39–51)

60 (?) 60 (?) 90 (3–138)

55 (4–113) 58 (4–113) 68 (54–100)

70 (?) 70 (?) ≥12 ≥12 63 (36–92) 66 (24–95) ≥60 ≥60 60 (?) 60 (?)

Follow-up (month)b

c

b

a

Patients (percent) received neoadjuvant and/or adjuvant androgen deprivation

Medium/mean (range)

Assuming α/β=1.5

LOE level of evidence, RCT randomized-controlled trail, C-C case–control study, D/F dose/fraction, 3D-CRT three-dimensional conformal radiotherapy, IMRT short-course intensity-modulated radiotherapy, SBRT stereotactic body radiotherapy, NTD2Gy normalized total dose at 2.0 Gy/fraction

Toronto-PMH [28]

Italy-L'Aquila [27]

Australia-RAH [22, 23]

Switzerland-Geneva [22]

Canada-multic [3, 22]

Houston-Anderson [21]

Philadelphia-FCCC [11]

Cleveland-CCF [22, 26]

Uruguay-Italiano [24, 25]

1b RCT 1b RCT 3b C-C 1b RCT 3b C-C

1b, RCT 2b RCT 2b Cohort 2b Cohort 1b RCT

Italy-RENCI [10, 19]

Lithuania-Vilnius [20]

LOE, design

Dataset [ref.]

Table 1 The characteristics of trails included for meta-analysis

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Fig. 1 Pooled effects of reducing BFR (a), CSS (b), and OS (c) of HFRT compared with CFRT. Data are expressed as weighted risk ratios (95 % confidence interval)

In head and neck squamous cell carcinomas, better clinical outcomes were found only in the altered fractionated schedules with increased total doses [29]. In addition, across a range

Fig. 2 Subgroup-analysis for BFR in patients with HFRT versus CFRT stratified by totaldose reduction status, risk group, and status of ADT. Data are expressed as pooled RR (95 % confidence interval)

of total radiotherapy doses from 64 to 79.2 Gy in previous meta-analysis, BFR control in men with localized prostate cancer, according to regression analysis, was associated with

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Fig. 3 Sensitivity analyses of the primary and subgroup outcomes. NA not applicable

radiation dose [4]. Both the results above confirmed our data that significant benefit of HFRT can only be found when total radiation doses remain unchanged. We then tried to define the characteristics, with which patients can benefit from altered fraction size. For patients with high-risk disease, the magnitude of the benefit on BFR control in HFRT arm was significantly higher than those with low-medium risk. The little advantage of HFRT on BFR control in low-medium risk PCa might suggest that both kinds of radiotherapies (HFRT and CFRT) were effective in controlling BFR. Moreover, we failed to observe significant difference in patients receiving CFRT and HFRT when the concomitant ADT was arranged. This might indicate a weak influence of ADT on radiotherapy. Results in the context of existing knowledge Using hypofractionated schedules, relatively greater doses delivered per fraction would theoretically produce more toxicity while offering increased therapeutic benefit in tumor control. However, well-designed RCT conducted by Arcangeli et al. suggested that the hypofractionation regimen only lead to a slight and nonsignificant increase in tolerable and temporary acute toxicity, while the severity and frequency of late complications was equivalent between the two treatment groups [30]. The preliminary results of a resent phase III-RCT confirmed that HFRT was well tolerated as conventionally fractionated treatment at 2 years [31]. We also conducted a meta-analysis based on all available published evidences to assess the good tolerance of HFRT, and an equal safety between the two groups was reconfirmed (unpublished). The α/β ratio for most cancers is believed to be as high as 10 Gy, but for prostate cancer values approximate

1.5 Gy have been suggested, which is smaller than the roughly 3 Gy reported for the late reactions of most normal tissues [13, 31–33]. As a result, patients with head and neck squamous cell carcinoma, as well as lung cancer, can significantly benefit from hyperfractionated radiotherapy [29, 34], while PCa patients can benefit from hypofractionated regimens. Strengths and limitations Heterogeneity was detected in overall analysis assessing BFR. But, it was removed in subgroup and sensitivity analyses. Little heterogeneity may indicate that the included patients effectively maintained the most important inherent nature of population in radiotherapy and that largely improved the predictability and reliability of our metaanalysis. Moreover, the stability of the meta-analysis was verified by sensitivity analyses, which pooled risk ratios by omitting non-RCTs, and funnel plots were shown to test the potential publication bias. In addition, our analysis cumulated the data from all studies that passed our predefined criteria; therefore, we are confident of the validity of our findings. However, we have to acknowledge some inherent limitations of the studies included in our meta-analysis that cannot be ignored when interpreting our data. There was methodological heterogeneity, as there were different types, doses and planning target margin of radiation among included studies. Data from RCT have shown that treatment technique [35], doses [4, 36], and planning target margin [36] can all affect the outcomes of prostate cancer radiotherapy. Therefore, more meaningful assessment of the biological effects of altered fractionation schedules can be made only by controlling for these factors.

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Conclusions This meta-analysis showed that HFRT was better than CFRT with regard to BFR. However, there was no significantly lower CSS and OS in the group of HFRT, though obvious trends preferring HFRT were observed. In subgroup analyses, HFRT yield advantages in biochemical outcomes only when the total doses of radiation remains unchanged. Benefits of hypofractionated schedules on biochemical failure control could be detected in high-risk patients. Receiving ADT or not had no significant effect on the difference between the two fractionated schedules. Further well-designed research is needed to explore the optimal radiotherapy schedule of modified fraction, including planning target margin, treatment delivery techniques, and doses. Oncological outcomes of much longer follow-up period are also crucial. Acknowledgment The work was supported by the National Basic Research Program of China (grant no. 2012CB518304) and the International S&T Cooperation Program of China (ISTCP) (grant no. S2012GR0142). Conflict of interest None.

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