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Brachytherapy versus external beam radiotherapy boost for prostate cancer: Systematic review with meta-analysis of randomized trials
Cancer Treatment Reviews 70 (2018) 265–271
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Cancer Treatment Reviews journal homepage: www.elsevier.com/locate/ctrv
Systematic or Meta-analysis Studies
Brachytherapy versus external beam radiotherapy boost for prostate cancer: Systematic review with meta-analysis of randomized trials
T
Daniel Lam Cham Keea, Jocelyn Galb, Alexander T. Falka, Renaud Schiappab, Marie-Eve Chanda, ⁎ Mathieu Gautiera, Jérôme Doyena, Jean-Michel Hannoun-levia, a b
Department of Radiotherapy, Centre Antoine Lacassagne, University of Cote d’Azur, Nice, France Biostatistics Unit, Centre Antoine Lacassagne, University of Cote d’Azur, Nice, France
A B S T R A C T
Background: Brachytherapy boost after external beam radiotherapy for intermediate and high-risk prostate cancer is presented as an attractive technique in numerous retrospective and prospective studies. Currently, three randomized controlled trials comparing brachytherapy versus external beam radiotherapy boost used nonhomogenous irradiation features. Therefore, we analyzed the oncological outcomes by a systematic review with meta-analysis of the randomized controlled trials. Methods: We performed a systematic literature review of MEDLINE and COCHRANE databases up to 30/04/10 and we considered all published randomized controlled trials comparing brachytherapy versus external beam radiotherapy boost for intermediate and high-risk prostate cancer according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The review was assessed using Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool and the identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT). Eight publications from 3 RCTs were selected. Results: There was a significant benefit in 5-year biochemical-progression-free survival in favor of BT versus EBRT boost (HR: 0.49 [95% CI, 0.37–0.66], p < 0.01). There was no difference at 5 years in overall survival (HR: 0.92 [95% CI, 0.64–1.33], p = 0.65), ≥ grade 3 late genito-urinary (RR: 2.19 [95%CI, 0.76–6.30], p = 0.15) and late gastro-intestinal toxicities (RR: 1.85 [95%CI, 1.00–3.41] p = 0.05). Conclusion: This meta-analysis provides further evidence in favor of BT boost for intermediate and high-risk prostate cancer in terms of b-PFS improvement, leading to suggest BT boost as level I and grade A recommendation. However, the risk of grade ≥ 3 late toxicity must be carefully investigated.
Introduction Surgery and radiotherapy are considered as standard treatments in every risk groups of localized prostate cancer. Regarding radiotherapy, it is well established that dose escalation improves biochemical-progression-free survival (b-PFS) and less likely overall survival (OS) [1–3]. From technical point of view, because brachytherapy (BT) achieves
a high conformal dose distribution to the prostate while spearing organs at risk (bladder, urethra, rectum), it is presented as an attractive tool for prostate cancer [4]. BT is proposed either as monotherapy for low and intermediate-risk prostate cancers [5–8] or boost for intermediate- and high-risk prostate cancers [9–11]. Numerous retrospective studies and systematic reviews suggested that BT boost for intermediate- and high-risk prostate cancer could play a key role for b-PFS improvement [12–17]. Currently, three prospective
Abbreviations: A.F, Alexander Falk; ADT, Androgen Deprivation Therapy; AMSTAR, Assessing the Methodological Quality of Systematic Reviews; BED, Biological Effective Dose; b-PFS, Biochemical Progression-Free Survival; BT, Brachytherapy; CI, Confidence Interval; CONSORT, Consolidated Standards of Reporting Trials; D.LCK, Daniel Lam Cham Kee; EBRT, External Beam Radiotherapy; G3, Grade 3; GI, Gastro-intestinal; GU, Genito-urinary; HDR, High-Dose Rate; HR, Hazard ratio; J.D, Jerome Doyen; J.G, Jocelyn Gall; JM.HL, Jean-Michel Hannoun-Levi; LDR, Low-Dose Rate; ME.C, Marie-Eve Chand; NCCN, National Comprehensive Cancer Network; OS, Overall Survival; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analysis; Qol, Quality of Life; R.S, Renaud Schiappa; RCTs, Randomized Controlled Trials; RR, Relative Risk; TOI, Trial Outcome Index ⁎ Corresponding author at: Department of Radiation Therapy, Antoine Lacassagne Cancer Center, University of Cote d’Azur, 33, avenue de Valombrose, 06189 Nice Cedex, France. E-mail address: [email protected] (J.-M. Hannoun-levi). https://doi.org/10.1016/j.ctrv.2018.10.004 Received 12 May 2018; Received in revised form 5 October 2018; Accepted 6 October 2018 0305-7372/ © 2018 Elsevier Ltd. All rights reserved.
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considered. Data were extracted from the trial results and not from the individual patient data collection due to lack of availability. Any differences in extracted data were resolved via within-pair consensus. If a consensus could not be reached within study pairs, the entire group was consulted to achieve consensus on the most accurate results. Extracted data included details on study design, inclusion and exclusion criteria, randomization, participant demographic and oncologic characteristics, interventions, measured outcomes and results (number of events, hazard ratios (HR), relative risks (RR), 95% confidence interval (CIs), and p values).
randomized controlled trials (RCTs) compared for intermediate- and high-risk prostate cancer, BT boost versus external beam radiotherapy (EBRT) boost [18–20]. However, partly due to the randomization period, all of them used different BT techniques, different total doses and dose per fraction delivered to prostate, different radiotherapy fields and different androgen deprivation therapy duration. All these parameters could influence oncological outcomes and toxicity profiles. In order to provide an objective synthesis of the overall oncological outcome, we performed a systematic review with meta-analysis of these 3 RCTs concerning BT boost for intermediate- and high-risk prostate cancer
Statistical analysis
Methods and materials
Meta-analysis was performed using R 3.2.2 software on Windows® and metafor R package. Heterogeneity between studies was measured by visual inspection of plots and the I2 statistic [22]: a higher I2 value indicates higher heterogeneity. Both random-effects models and fixedeffects models were used for calculation in forest plots. If heterogeneity was measured, random-effects models were preferred. Otherwise fixedeffects models were used. For time to event data, HR and 95% CI obtained directly from studies were used to compare results, using the inverse variance technique. For dichotomous data, Mantel-Haenszel method was used and expressed as risk ratio with 95% CI. In both cases, p < 0.05 was considered significant.
Search strategy A systematic literature review was performed up to 30 April 2018 using search engines (MEDLINE via PubMed and COCHRANE databases) and we considered all published RCTs comparing BT versus EBRT boost for intermediate- and high-risk prostate cancer. Searches were carried out with the terms “brachytherapy” AND “prostate cancer” AND “randomised/randomized”. Inclusion criteria, study eligibility, and data extraction The Preferred Reporting Items for Systematic Reviews and Metaanalysis (PRISMA) criteria were used for article selection (Fig. 1), which were performed independently by three investigators (D.LCK, J.G and JM.HL). Furthermore, the study was also reviewed using Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool evaluation as suggested recently by Weed [21]. Only full text articles published in English language with RCTs comparing BT versus EBRT boost for intermediate- and high-risk prostate cancer (defined by NCCN: National Comprehensive Cancer Network risk stratification) were
Assessment of risk of bias and trial quality Identified reports were reviewed according to Consolidated Standards of Reporting Trials (CONSORT) [23] and the risk of bias in individual studies was assessed using a tool recommended by metaanalysis guidelines that evaluate aspects of RCT design and execution [24,25]. The general quality of this review article was done using AMSTAR tool evaluation [26,27].
Fig. 1. PRISMA flow diagram detailing the search strategy and identification of studies used in data synthesis. RCTs: Randomized controlled trials; INTERMEDIATE AND HIGH-RISK PROSTATE CANCER: Intermediate and High-risk prostate cancer; BT: Brachytherapy. 266
Median follow-up (years) Number of patients Age (mean/median) PSA (mean/median) PSA < 10 PSA:10–20 PSA > 20 Gleason scores (mean/median) ≤6 7 ≥8 Clinical stages ≤T2 ≥T3 Risk groups Low Intermediate High ADT duration (months) 0 6 12 36 Irradiation techniques Boost techniques Irradiation doses Total BED (αβ: 3) Total BED (αβ: 1.5) Oncological outcome @ 5 years b-PFS OS MFS Overall death PC specific death Metastatic disease Toxicity ≥ G3 Acute GU Acute GI Late GU Late GI
Table 1 Patient & treatment features.
Range
267
(10) (6) (4) (2)
3 2 7 2
(6) (4) (14) (4)
36 (71) 48 (94) 41 (80) 34 (67) 9 (17) 10 (20)
21 49 38 41 12 15
5 3 2 1
51 (49) 0 0 0 RC2D prostate LDR 192Ir 40 Gy/20f + 35 Gy (48 h) 125 175
53 (51) 0 0 0 RC2D prostate RC2D prostate 66 Gy/33f 110 154
(39) (92) (72) (77) (24) (28)
0 (0) 21 (41) 30 (59)
0 (0) 21 (40) 32 (60)
14 51 (49) 66 19 15 (30) 17 (33) 19 (37) 6.7 19 (37) 23 (45) 9 (18) 31 (61) 20 (39)
4–9
49–74 1.2–93
8.8–20
32 (60) 21 (40)
14 53 (51) 65 20.2 23 (43) 12 (23) 18 (34) 6.8 18 (34) 28 (53) 7 (13) 4–9
57–74 3.4–71
8.8–20
NA 16 (15) 32 (30) 6 (6)
65 (61) 94 (89) NA 19 (42) NA NA
26 (25) 28 (26) 0 (0) 52 (49) RC3D prostate RC3D prostate 55 Gy/20f 105 156
7 (7) 43 (40) 56 (53)
82 (77) 24 (23)
36 (34) 43 (41) 18 (17) NA 48 (45) 40 (38) 18 (17)
7.1 106 (49) 70 47–80
0.75–12.25
Range
EBRT (%)
BT (%)
EBRT (%)
Range
Hoskin et al. [19,29,31]
Sathya et al. [18,28]
NA 8 (7) 34 (31) 8 (7)
83 (75) 97 (88) NA 26 (58) NA NA
25 (23) 30 (27) 0 (0) 55 (50) RC3D prostate HDR 192Ir 35,75 Gy/13f + 2 × 8.5 Gy 134 214
2 (2) 48 (44) 60 (54)
76 (69) 34 (31)
35 (32) 45 (41) 30 (27) NA 46 (42) 44 (40) 20 (18)
7.1 110 (51) 70
BT (%)
47–80
0.67–12
Range
1 (1) 0 (0) 11 (6) 6 (3)
166 (85) 170 (88) 92.6 51 (26) 11 (6) 18 (9)
0 (0) 0 (0) 195 (1 0 0) 0 (0) RC3D pelvis RC3D prostate 78 Gy/39f 130 182
0 (0) 64 (33) 131 (67)
137 (70) 58 (30)
6.5 195 (52) 69 11 91 (47) 66 (34) 38 (19) NA 11 (5) 109 (56) 75 (38)
EBRT (%)
79.3–90.5 82.4–92.4 88.6–96.6
45–86 2.7–39.1
Range
ASCENDE-RT [20,21,30]
5 (3) 0 (0) 39 (21) 17 (9)
169 (90) 174 (92) 94.1 31 (17) 6 (3) 14 (7)
0 (0) 0 (0) 188 (1 0 0) 0 (0) RC3D pelvis 125I 46 Gy/23f + 115 Gy 192 222
0 (0) 54 (29) 134 (71)
135 (72) 53 (28)
6.5 188 (48) 67 10.8 89 (47) 63 (33) 38 (20) NA 10 (5) 97 (52) 81 (43)
BT (%)
84.8–94.5 88.2–96.6 90.5–97.7
50–85 2.4–40
Range
D.L.C. Kee et al.
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Evidence synthesis
Biochemical progression-free survival (b-PFS) In the forest plot, the b-PFS data were homogeneous (I2 = 0%) (Fig. 2). There was a significant benefit at 5 years of BT boost vs. EBRT boost with HR: 0.49 (95% CI, 0.37–0.66, p < 0.01). For ASCENDE-RT trial, the 7- and 9-year b-PFS were 86%, 83% for BT vs. 75% and 62% for EBRT respectively. For Hoskin et al., the b-PFS at 7- and 10-year were 66% and 46% for BT vs. 48% and 39% for EBRT respectively. For Sathya et al., the b-PFS at 10.6- and 14-year were 67% and 53% for BT vs. 38% and 30% for EBRT respectively.
After applying inclusion criteria and considering only articles comparing BT versus EBRT boost after initial EBRT for intermediateand high-risk prostate cancer (BT monotherapy and BT as first treatment were excluded), 8 articles from 3 RCTs were identified. Only common data at 5 years were shown on forest plots: b-PFS, OS, ≥ grade 3 (G3) late genito-urinary (GU) and gastro-intestinal (GI) toxicities, using hazard ratio (HR) for b-PFS and OS and relative risk (RR) statistical analysis for GU and GI toxicities. Specific data provided by each article were reported independently, notably b-PFS and OS at the last follow-up of each study and quality of life scores.
Overall survival (OS) In the forest plot, the OS data were homogeneous (I2 = 0%) (Fig. 3). There was no difference at 5 years in OS with HR: 0.92 (95% CI, 0.64 to 1.33, p = 0.65). For ASCENDE-RT trial, the 7- and 9-year OS were 86%, 78% for BT vs. 82% and 74% for EBRT respectively. For Hoskin et al., the OS at 7and 10-year were 81% and 67% for BT vs. 88% and 79% for EBRT respectively. For Sathya et al., the OS at 10.6- and 14-year were 80% and 33% for BT vs. 87% and 23% for EBRT respectively.
Interpretation of data The characteristics of the 703 patients are shown in Table 1 and were generally homogeneous for age and NCCN risk groups apart from a few low-risk patients in Hoskin et al. study (< 10%). In each study, association of ADT with radiotherapy and ADT duration time were different: no ADT (Sathya and Hoskin et al.), 6 months and 36 months (Hoskin et al.), and 12 months (ASCENDE-RT trial). The EBRT technique used was 3D conformal apart from Sathy et al. who used 2D technique. The radiotherapy field was mainly prostate while ASCENDERT trial had pelvic field. BT technique used was also different: Sathya et al. [18,28] used low-dose rate (LDR) temporary iridium implant for 48 h delivering 35 Gy; Hoskin et al. [19,29] used high-dose rate (HDR) temporary iridium BT delivering 8.5 Gy × 2 in 24 h; ASCENDE-RT trial [20] used LDR BT with permanent iodine seeds delivering 115 Gy. In order to accurately compare the doses delivered by BT vs. EBRT boost techniques, the cumulative biological effective dose (BED) to the prostate was calculated using the following formula: for BT:
≥G3 late genito-urinary (GU) toxicity In the forest plot, there was detectable heterogeneity between trials for data concerning ≥ G3 late GU toxicity (I2 = 84%) (Fig. 4). There was no significant difference with RR: 2.19 [95%CI, 0.76 to 6.30], p = 0.15. ≥G3 late gastro-intestinal (GI) toxicity In the forest plot, the ≥ G3 late GI toxicity data were homogeneous (I2 = 0%) (Fig. 5). There was no significant difference with RR: 1.85 [95%CI, 1.00 to 3.41] p = 0.05. Quality of life (QoL) Only 2 RCTs investigated the QoL [30,31] and the authors did not use the same questionnaires: ASCENDE-RT used “SF36v2” while Hoskin et al. used “version 3 of FACT-P, FACT-G and FACT-P Trial Outcome Index (TOI) measurements”. Sexual function declines from baseline on both studies. Decline in physical and urinary functions in the BT group was observed in ASCENDE-RT trial but not in Hoskin et al. trial.
BED = d+ g{d2/(α / β )} g = {2/(µT)2}{µT − 1 + e(−µT)}; µ = 0.693/T1/2; T1/2 = 0.5 ; T = total treatment time for EBRT:
Quality assessment and risk of bias
BED = nd(1 + d/(a/b)) Identified reports were reviewed according to CONSORT checklist detailed in Table 2 (supplementary data) whereas risk of bias assessment was presented and detailed in Fig. 6 (supplementary data). Three main sources of biases include: (1) lack of accessibility to full trial protocol for the three RCTs; (2) unblinded design; (3) Sathya et al. trial stopped prematurely and the decision to terminate a trial early can bias results in favor of BT in terms of toxicity. The evaluation of this study
n = number of fractions, d = dose per fraction. α/β was 1.5 for prostate cancer and 3 for organs at risks. Consequently, the BED for prostate cancer (α/β = 1.5) in BT arm vs. EBRT arm were respectively 175 Gy vs 154 Gy for Sathya et al., 215 Gy vs 156 Gy for Hoskin et al., and 222 Gy vs 182 Gy in ASCENDE-RT trial (Table 1).
Fig. 2. Forest plots of 5-year biochemical progression free survival for brachytherapy boost versus external beam boost in intermediate and high-risk prostate cancer. 268
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Fig. 3. Forest plots of 5-year overall survival for brachytherapy boost versus external beam boost in intermediate and high-risk prostate cancer.
Regarding urinary function, BT could increase ≥ G3 late GU toxicity [37] even though this result was not confirmed in this meta-analysis. It should be noted that the result was heterogeneous leading to consider the random-effects model which did not show any difference between BT vs. EBRT. We also considered toxicity after 18 months as late toxicity for Sathya et al. study, using RR, meaning that we estimated the worst-case scenario in terms of toxicity risk. Meanwhile, ≥ G3 late GU toxicity could also be inherent to the BT technique (permanent vs. temporary implants). Better dose optimization using other BT techniques like HDR [11,38,39] and technological advances for definition and sparing critical structures can help decrease the urinary toxicity [10]. The analysis of ≥ G3 late GI toxicity results showed a trend favoring EBRT arm (but p = 0.05 and CI includes 1). However, the same calculation based on RR used for GU toxicity evaluation was also applied for GI toxicity. Consequently, the latter was probably over-estimated. The irradiation fields used in the 3 RCTs were also different (pelvic vs. prostatic irradiation only) and within Hoskin et al. trial, both pelvic and prostate fields could be used. This is an important confounding factor for late GI toxicity. The actual use of intensity modulated radiation therapy can help reduce this toxicity and ensure safer dose escalation without altering tumor control [20]. For QoL analysis, the difference in urinary function favoring EBRT was not clinically significant at last follow-up compared to baseline mean scores. Indeed, ≥ G3 GU toxicity occurring after BT boost was largely episodic in nature [30]. Sexual and physical decline may be mainly due to ADT. Indeed, the latter could be considered as a confounding factor due to different ADT duration between the 3 RCTs and within Hoskin et al. trial itself. Regarding bias risk, 2 RCTs [18,19] had selection, attribution and reporting bias. In the 3 RCTs, performance and detection bias were not applicable as blinding between BT vs. EBRT is technically not feasible (Fig. 6 – supplementary data). However, both b-PFS and OS are objective criteria that are homogeneous and have similar trend in both random-effects and fixed-effects models in this meta-analysis.
using AMSTAR tool showed a high-quality review. Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.ctrv.2018.10.004. Discussion In this meta-analysis, we confirmed the results of the individual RCTs that BT boost results in a significant benefit in b-PFS. Using CONSORT criteria, 2 RCTs [18,19] have major bias and concluded that the generalizability of their findings could not be proposed as the control EBRT arm was not the standard of care treatment (doses delivered in EBRT arm were too low). However, ASCENDE-RT trial showed that even with escalated EBRT, BT boost gives better benefit in terms of b-PFS. Another confounding factor for b-PFS analysis is the use of androgen deprivation therapy (ADT) and its optimal duration. In these 3 RCTs, the b-PFS was significantly better in every BT technique used (low or high-dose rate and permanent or temporary implants) independently of the duration of ADT. This can be due to higher BED delivered by BT (12–38%) compared to EBRT (Table 1) and/or inherent to the BT technique delivering a non-homogeneous dose escalation within the isodose prescription (“simultaneous integrated boost” to tumor index) [32]. Another criticism to these RCTs was that the gain was only on b-PFS and not in OS. It should be noted that none of these studies were designed to assess OS as a primary end point. However, ASCENDE-RT trial [20] showed that the improved b-PFS gained using BT was correlated with improved metastatic-free survival (MFS) as demonstrated by both Spratt et al. and Kishan et al. in large retrospective series [33,34]. With a hazard ratio of 0.49 in favor of BT boost at 5 years and still highly significant afterwards, it can be hypothesized that the b-PFS gain could lead to a significantly better OS rate if RCTs were correctly powered with a longer follow-up. This improvement in overall survival for BT boost has been recently published in 3 large retrospective by Johnson et al., Kishan et al. and Ennis et al [16,35,36].
Fig. 4. Forest plots of 5-year rates of late genito-urinary ≥ G3 toxicity for brachytherapy boost versus external beam boost in intermediate and high-risk prostate cancer. 269
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Fig. 5. Forest plots of 5-year rates of late gastro-intestinal ≥ G3 toxicity for brachytherapy boost versus external beam boost in intermediate and high-risk prostate cancer.
Meanwhile, toxicity results interpretation (using RR), should be analyzed with caution as there were clinical (EBRT dose and fields, technique and dose of BT), methodological (grading of toxicities) and statistical (time of report and statistical method used) heterogeneities. Even if there were only 3 RCTs, a systematic review of the nonrandomized studies on the interest of BT boost in intermediate- and high-risk prostate cancer was not performed as it has been already extensively published (with or without matched pair comparison with EBRT). In all of those reviews, BT boost was shown to significantly improve bio-chemical control whatever BT doses and techniques used. Furthermore, in terms of evidence-based medicine, the rules to consider level I evidence and subsequent grade A recommendations vary between different countries’ guidelines. Indeed, in France, UK and Australia a meta-analysis of RCTs is warranted while it is not necessary in North-America [40–43].
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Conclusion This meta-analysis of RCTs provides further evidence in favor of BT boost for intermediate- and high-risk prostate cancer, leading to unanimously suggest BT boost as level I and grade A recommendation for b-PFS improvement, while the risk of increased toxicity needs to be further investigated. Assuming this new level of evidence, health authorities and insurance companies should be prepared while care providers should be properly trained so as to offer this boost technique to future prostate cancer patients [44,45]. References [1] Dearnaley DP, Sydes MR, Graham JD, Aird EG, Bottomley D, Cowan RA, et al. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007;8:475–87. [2] Peeters STH, Heemsbergen WD, Koper PCM, van Putten WLJ, Slot A, Dielwart MFH, et al. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol Off J Am Soc Clin Oncol 2006;24:1990–6. [3] Zietman AL, DeSilvio ML, Slater JD, Rossi CJ, Miller DW, Adams JA, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA 2005;294:1233–9. [4] Yan K. Recent developments in radiotherapy. N Engl J Med 2017;377:2200. [5] Brachman DG, Thomas T, Hilbe J, Beyer DC. Failure-free survival following brachytherapy alone or external beam irradiation alone for T1–2 prostate tumors in 2222 patients: results from a single practice. Int J Radiat Oncol Biol Phys 2000;48:111–7. [6] D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969–74. [7] Tselis N, Hoskin P, Baltas D, Strnad V, Zamboglou N, Rödel C, et al. High dose rate brachytherapy as monotherapy for localised prostate cancer: review of the current status. Clin Oncol R Coll Radiol G B 2017;29:401–11. [8] Goy BW, Soper MS, Burchette RJ, Chang TC, Cosmatos HA. Ten year treatment outcomes of radical prostatectomy vs external beam radiation therapy vs. brachytherapy for 1,503 patients with intermediate risk prostate cancer. 47–47 J Clin Oncol2018:36. https://doi.org/10.1200/JCO.2018.36.6_suppl.47.
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JCO.2017.75.9134. [37] Rodda S, Tyldesley S, Morris WJ, Keyes M, Halperin R, Pai H, et al. ASCENDE-RT: an analysis of treatment-related morbidity for a randomized trial comparing a lowdose-rate brachytherapy boost with a dose-escalated external beam boost for highand intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;98:286–95. [38] Major T, Polgár C, Jorgo K, Stelczer G, Ágoston P. Dosimetric comparison between treatment plans of patients treated with low-dose-rate vs. high-dose-rate interstitial prostate brachytherapy as monotherapy: Initial findings of a randomized clinical trial. Brachytherapy 2017;16:608–15. [39] Wang Y, Sankreacha R, Al-Hebshi A, Loblaw A, Morton G. Comparative study of dosimetry between high-dose-rate and permanent prostate implant brachytherapies in patients with prostate adenocarcinoma. Brachytherapy 2006;5:251–5. [40] OCEBM Levels of Evidence. CEBM 2016. http://www.cebm.net/blog/2016/05/01/ ocebm-levels-of-evidence/ [accessed December 28, 2017]. [41] Council NH and MR. How to review the evidence: systematic identification and review of the scientific literature | National Health and Medical Research Council 2009. https://www.nhmrc.gov.au/guidelines-publications/cp65 [accessed December 28, 2017]. [42] Grade Definitions - US Preventive Services Task Force n.d. https://www. uspreventiveservicestaskforce.org/Page/Name/grade-definitions [accessed December 28, 2017]. [43] Haute Autorité de Santé - Niveau de preuve et gradation des recommandations de bonne pratique - État des lieux n.d. https://www.has-sante.fr/portail/jcms/c_ 1600564/fr/niveau-de-preuve-et-gradation-des-recommandations-de-bonnepratique-etat-des-lieux [accessed December 28, 2017]. [44] Hannoun-Levi J-M, Hannoun A. Brachytherapy boost for prostate cancer: a potential conflict of disinterest. Brachytherapy 2017;16:1081–2. [45] Orio PF, Nguyen PL, Buzurovic I, Cail DW, Chen Y-W. The decreased use of brachytherapy boost for intermediate and high-risk prostate cancer despite evidence supporting its effectiveness. Brachytherapy 2016;15:701–6.
of a randomized trial comparing iridium implant plus external beam radiation therapy with external beam radiation therapy alone in node-negative locally advanced cancer of the prostate. Int J Radiat Oncol Biol Phys 2017;99:90–3. Hoskin PJ, Motohashi K, Bownes P, Bryant L, Ostler P. High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: initial results of a randomised phase three trial. Radiother Oncol 2007;84:114–20. Rodda S, Morris WJ, Hamm J, Duncan G. ASCENDE-RT: an analysis of health-related quality of life for a randomized trial comparing low-dose-rate brachytherapy boost with dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;98:581–9. Hoskin PJ, Rojas AM, Ostler PJ, Hughes R, Lowe GJ, Bryant L. Quality of life after radical radiotherapy for prostate cancer: longitudinal study from a randomised trial of external beam radiotherapy alone or in combination with high dose rate brachytherapy. Clin Oncol R Coll Radiol G B 2013;25:321–7. Hannoun-Levi J-M, Chand-Fouche M-E, Dejean C, Courdi A. Dose gradient impact on equivalent dose at 2 Gy for high dose rate interstitial brachytherapy. J Contemp Brachytherapy 2012;4:14–20. Kishan AU, Shaikh T, Wang P-C, Reiter RE, Said J, Raghavan G, et al. Clinical outcomes for patients with Gleason score 9–10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: a multi-institutional comparative analysis. Eur Urol 2017;71:766–73. Spratt DE, Zumsteg ZS, Ghadjar P, Kollmeier MA, Pei X, Cohen G, et al. Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer. BJU Int 2014;114:360–7. Kishan AU, Cook RR, Ciezki JP, Ross AE, Pomerantz MM, Nguyen PL, et al. Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason score 9–10 prostate cancer. JAMA 2018;319:896–905. Ennis RD, Hu L, Ryemon SN, Lin J, Brachytherapy-Based Mazumdar M. Radiotherapy and radical prostatectomy are associated with similar survival in high-risk localized prostate cancer. J Clin Oncol 2018. https://doi.org/10.1200/
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Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevier.com/locate/ctrv
Systematic or Meta-analysis Studies
Brachytherapy versus external beam radiotherapy boost for prostate cancer: Systematic review with meta-analysis of randomized trials
T
Daniel Lam Cham Keea, Jocelyn Galb, Alexander T. Falka, Renaud Schiappab, Marie-Eve Chanda, ⁎ Mathieu Gautiera, Jérôme Doyena, Jean-Michel Hannoun-levia, a b
Department of Radiotherapy, Centre Antoine Lacassagne, University of Cote d’Azur, Nice, France Biostatistics Unit, Centre Antoine Lacassagne, University of Cote d’Azur, Nice, France
A B S T R A C T
Background: Brachytherapy boost after external beam radiotherapy for intermediate and high-risk prostate cancer is presented as an attractive technique in numerous retrospective and prospective studies. Currently, three randomized controlled trials comparing brachytherapy versus external beam radiotherapy boost used nonhomogenous irradiation features. Therefore, we analyzed the oncological outcomes by a systematic review with meta-analysis of the randomized controlled trials. Methods: We performed a systematic literature review of MEDLINE and COCHRANE databases up to 30/04/10 and we considered all published randomized controlled trials comparing brachytherapy versus external beam radiotherapy boost for intermediate and high-risk prostate cancer according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The review was assessed using Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool and the identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT). Eight publications from 3 RCTs were selected. Results: There was a significant benefit in 5-year biochemical-progression-free survival in favor of BT versus EBRT boost (HR: 0.49 [95% CI, 0.37–0.66], p < 0.01). There was no difference at 5 years in overall survival (HR: 0.92 [95% CI, 0.64–1.33], p = 0.65), ≥ grade 3 late genito-urinary (RR: 2.19 [95%CI, 0.76–6.30], p = 0.15) and late gastro-intestinal toxicities (RR: 1.85 [95%CI, 1.00–3.41] p = 0.05). Conclusion: This meta-analysis provides further evidence in favor of BT boost for intermediate and high-risk prostate cancer in terms of b-PFS improvement, leading to suggest BT boost as level I and grade A recommendation. However, the risk of grade ≥ 3 late toxicity must be carefully investigated.
Introduction Surgery and radiotherapy are considered as standard treatments in every risk groups of localized prostate cancer. Regarding radiotherapy, it is well established that dose escalation improves biochemical-progression-free survival (b-PFS) and less likely overall survival (OS) [1–3]. From technical point of view, because brachytherapy (BT) achieves
a high conformal dose distribution to the prostate while spearing organs at risk (bladder, urethra, rectum), it is presented as an attractive tool for prostate cancer [4]. BT is proposed either as monotherapy for low and intermediate-risk prostate cancers [5–8] or boost for intermediate- and high-risk prostate cancers [9–11]. Numerous retrospective studies and systematic reviews suggested that BT boost for intermediate- and high-risk prostate cancer could play a key role for b-PFS improvement [12–17]. Currently, three prospective
Abbreviations: A.F, Alexander Falk; ADT, Androgen Deprivation Therapy; AMSTAR, Assessing the Methodological Quality of Systematic Reviews; BED, Biological Effective Dose; b-PFS, Biochemical Progression-Free Survival; BT, Brachytherapy; CI, Confidence Interval; CONSORT, Consolidated Standards of Reporting Trials; D.LCK, Daniel Lam Cham Kee; EBRT, External Beam Radiotherapy; G3, Grade 3; GI, Gastro-intestinal; GU, Genito-urinary; HDR, High-Dose Rate; HR, Hazard ratio; J.D, Jerome Doyen; J.G, Jocelyn Gall; JM.HL, Jean-Michel Hannoun-Levi; LDR, Low-Dose Rate; ME.C, Marie-Eve Chand; NCCN, National Comprehensive Cancer Network; OS, Overall Survival; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analysis; Qol, Quality of Life; R.S, Renaud Schiappa; RCTs, Randomized Controlled Trials; RR, Relative Risk; TOI, Trial Outcome Index ⁎ Corresponding author at: Department of Radiation Therapy, Antoine Lacassagne Cancer Center, University of Cote d’Azur, 33, avenue de Valombrose, 06189 Nice Cedex, France. E-mail address: [email protected] (J.-M. Hannoun-levi). https://doi.org/10.1016/j.ctrv.2018.10.004 Received 12 May 2018; Received in revised form 5 October 2018; Accepted 6 October 2018 0305-7372/ © 2018 Elsevier Ltd. All rights reserved.
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considered. Data were extracted from the trial results and not from the individual patient data collection due to lack of availability. Any differences in extracted data were resolved via within-pair consensus. If a consensus could not be reached within study pairs, the entire group was consulted to achieve consensus on the most accurate results. Extracted data included details on study design, inclusion and exclusion criteria, randomization, participant demographic and oncologic characteristics, interventions, measured outcomes and results (number of events, hazard ratios (HR), relative risks (RR), 95% confidence interval (CIs), and p values).
randomized controlled trials (RCTs) compared for intermediate- and high-risk prostate cancer, BT boost versus external beam radiotherapy (EBRT) boost [18–20]. However, partly due to the randomization period, all of them used different BT techniques, different total doses and dose per fraction delivered to prostate, different radiotherapy fields and different androgen deprivation therapy duration. All these parameters could influence oncological outcomes and toxicity profiles. In order to provide an objective synthesis of the overall oncological outcome, we performed a systematic review with meta-analysis of these 3 RCTs concerning BT boost for intermediate- and high-risk prostate cancer
Statistical analysis
Methods and materials
Meta-analysis was performed using R 3.2.2 software on Windows® and metafor R package. Heterogeneity between studies was measured by visual inspection of plots and the I2 statistic [22]: a higher I2 value indicates higher heterogeneity. Both random-effects models and fixedeffects models were used for calculation in forest plots. If heterogeneity was measured, random-effects models were preferred. Otherwise fixedeffects models were used. For time to event data, HR and 95% CI obtained directly from studies were used to compare results, using the inverse variance technique. For dichotomous data, Mantel-Haenszel method was used and expressed as risk ratio with 95% CI. In both cases, p < 0.05 was considered significant.
Search strategy A systematic literature review was performed up to 30 April 2018 using search engines (MEDLINE via PubMed and COCHRANE databases) and we considered all published RCTs comparing BT versus EBRT boost for intermediate- and high-risk prostate cancer. Searches were carried out with the terms “brachytherapy” AND “prostate cancer” AND “randomised/randomized”. Inclusion criteria, study eligibility, and data extraction The Preferred Reporting Items for Systematic Reviews and Metaanalysis (PRISMA) criteria were used for article selection (Fig. 1), which were performed independently by three investigators (D.LCK, J.G and JM.HL). Furthermore, the study was also reviewed using Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool evaluation as suggested recently by Weed [21]. Only full text articles published in English language with RCTs comparing BT versus EBRT boost for intermediate- and high-risk prostate cancer (defined by NCCN: National Comprehensive Cancer Network risk stratification) were
Assessment of risk of bias and trial quality Identified reports were reviewed according to Consolidated Standards of Reporting Trials (CONSORT) [23] and the risk of bias in individual studies was assessed using a tool recommended by metaanalysis guidelines that evaluate aspects of RCT design and execution [24,25]. The general quality of this review article was done using AMSTAR tool evaluation [26,27].
Fig. 1. PRISMA flow diagram detailing the search strategy and identification of studies used in data synthesis. RCTs: Randomized controlled trials; INTERMEDIATE AND HIGH-RISK PROSTATE CANCER: Intermediate and High-risk prostate cancer; BT: Brachytherapy. 266
Median follow-up (years) Number of patients Age (mean/median) PSA (mean/median) PSA < 10 PSA:10–20 PSA > 20 Gleason scores (mean/median) ≤6 7 ≥8 Clinical stages ≤T2 ≥T3 Risk groups Low Intermediate High ADT duration (months) 0 6 12 36 Irradiation techniques Boost techniques Irradiation doses Total BED (αβ: 3) Total BED (αβ: 1.5) Oncological outcome @ 5 years b-PFS OS MFS Overall death PC specific death Metastatic disease Toxicity ≥ G3 Acute GU Acute GI Late GU Late GI
Table 1 Patient & treatment features.
Range
267
(10) (6) (4) (2)
3 2 7 2
(6) (4) (14) (4)
36 (71) 48 (94) 41 (80) 34 (67) 9 (17) 10 (20)
21 49 38 41 12 15
5 3 2 1
51 (49) 0 0 0 RC2D prostate LDR 192Ir 40 Gy/20f + 35 Gy (48 h) 125 175
53 (51) 0 0 0 RC2D prostate RC2D prostate 66 Gy/33f 110 154
(39) (92) (72) (77) (24) (28)
0 (0) 21 (41) 30 (59)
0 (0) 21 (40) 32 (60)
14 51 (49) 66 19 15 (30) 17 (33) 19 (37) 6.7 19 (37) 23 (45) 9 (18) 31 (61) 20 (39)
4–9
49–74 1.2–93
8.8–20
32 (60) 21 (40)
14 53 (51) 65 20.2 23 (43) 12 (23) 18 (34) 6.8 18 (34) 28 (53) 7 (13) 4–9
57–74 3.4–71
8.8–20
NA 16 (15) 32 (30) 6 (6)
65 (61) 94 (89) NA 19 (42) NA NA
26 (25) 28 (26) 0 (0) 52 (49) RC3D prostate RC3D prostate 55 Gy/20f 105 156
7 (7) 43 (40) 56 (53)
82 (77) 24 (23)
36 (34) 43 (41) 18 (17) NA 48 (45) 40 (38) 18 (17)
7.1 106 (49) 70 47–80
0.75–12.25
Range
EBRT (%)
BT (%)
EBRT (%)
Range
Hoskin et al. [19,29,31]
Sathya et al. [18,28]
NA 8 (7) 34 (31) 8 (7)
83 (75) 97 (88) NA 26 (58) NA NA
25 (23) 30 (27) 0 (0) 55 (50) RC3D prostate HDR 192Ir 35,75 Gy/13f + 2 × 8.5 Gy 134 214
2 (2) 48 (44) 60 (54)
76 (69) 34 (31)
35 (32) 45 (41) 30 (27) NA 46 (42) 44 (40) 20 (18)
7.1 110 (51) 70
BT (%)
47–80
0.67–12
Range
1 (1) 0 (0) 11 (6) 6 (3)
166 (85) 170 (88) 92.6 51 (26) 11 (6) 18 (9)
0 (0) 0 (0) 195 (1 0 0) 0 (0) RC3D pelvis RC3D prostate 78 Gy/39f 130 182
0 (0) 64 (33) 131 (67)
137 (70) 58 (30)
6.5 195 (52) 69 11 91 (47) 66 (34) 38 (19) NA 11 (5) 109 (56) 75 (38)
EBRT (%)
79.3–90.5 82.4–92.4 88.6–96.6
45–86 2.7–39.1
Range
ASCENDE-RT [20,21,30]
5 (3) 0 (0) 39 (21) 17 (9)
169 (90) 174 (92) 94.1 31 (17) 6 (3) 14 (7)
0 (0) 0 (0) 188 (1 0 0) 0 (0) RC3D pelvis 125I 46 Gy/23f + 115 Gy 192 222
0 (0) 54 (29) 134 (71)
135 (72) 53 (28)
6.5 188 (48) 67 10.8 89 (47) 63 (33) 38 (20) NA 10 (5) 97 (52) 81 (43)
BT (%)
84.8–94.5 88.2–96.6 90.5–97.7
50–85 2.4–40
Range
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Evidence synthesis
Biochemical progression-free survival (b-PFS) In the forest plot, the b-PFS data were homogeneous (I2 = 0%) (Fig. 2). There was a significant benefit at 5 years of BT boost vs. EBRT boost with HR: 0.49 (95% CI, 0.37–0.66, p < 0.01). For ASCENDE-RT trial, the 7- and 9-year b-PFS were 86%, 83% for BT vs. 75% and 62% for EBRT respectively. For Hoskin et al., the b-PFS at 7- and 10-year were 66% and 46% for BT vs. 48% and 39% for EBRT respectively. For Sathya et al., the b-PFS at 10.6- and 14-year were 67% and 53% for BT vs. 38% and 30% for EBRT respectively.
After applying inclusion criteria and considering only articles comparing BT versus EBRT boost after initial EBRT for intermediateand high-risk prostate cancer (BT monotherapy and BT as first treatment were excluded), 8 articles from 3 RCTs were identified. Only common data at 5 years were shown on forest plots: b-PFS, OS, ≥ grade 3 (G3) late genito-urinary (GU) and gastro-intestinal (GI) toxicities, using hazard ratio (HR) for b-PFS and OS and relative risk (RR) statistical analysis for GU and GI toxicities. Specific data provided by each article were reported independently, notably b-PFS and OS at the last follow-up of each study and quality of life scores.
Overall survival (OS) In the forest plot, the OS data were homogeneous (I2 = 0%) (Fig. 3). There was no difference at 5 years in OS with HR: 0.92 (95% CI, 0.64 to 1.33, p = 0.65). For ASCENDE-RT trial, the 7- and 9-year OS were 86%, 78% for BT vs. 82% and 74% for EBRT respectively. For Hoskin et al., the OS at 7and 10-year were 81% and 67% for BT vs. 88% and 79% for EBRT respectively. For Sathya et al., the OS at 10.6- and 14-year were 80% and 33% for BT vs. 87% and 23% for EBRT respectively.
Interpretation of data The characteristics of the 703 patients are shown in Table 1 and were generally homogeneous for age and NCCN risk groups apart from a few low-risk patients in Hoskin et al. study (< 10%). In each study, association of ADT with radiotherapy and ADT duration time were different: no ADT (Sathya and Hoskin et al.), 6 months and 36 months (Hoskin et al.), and 12 months (ASCENDE-RT trial). The EBRT technique used was 3D conformal apart from Sathy et al. who used 2D technique. The radiotherapy field was mainly prostate while ASCENDERT trial had pelvic field. BT technique used was also different: Sathya et al. [18,28] used low-dose rate (LDR) temporary iridium implant for 48 h delivering 35 Gy; Hoskin et al. [19,29] used high-dose rate (HDR) temporary iridium BT delivering 8.5 Gy × 2 in 24 h; ASCENDE-RT trial [20] used LDR BT with permanent iodine seeds delivering 115 Gy. In order to accurately compare the doses delivered by BT vs. EBRT boost techniques, the cumulative biological effective dose (BED) to the prostate was calculated using the following formula: for BT:
≥G3 late genito-urinary (GU) toxicity In the forest plot, there was detectable heterogeneity between trials for data concerning ≥ G3 late GU toxicity (I2 = 84%) (Fig. 4). There was no significant difference with RR: 2.19 [95%CI, 0.76 to 6.30], p = 0.15. ≥G3 late gastro-intestinal (GI) toxicity In the forest plot, the ≥ G3 late GI toxicity data were homogeneous (I2 = 0%) (Fig. 5). There was no significant difference with RR: 1.85 [95%CI, 1.00 to 3.41] p = 0.05. Quality of life (QoL) Only 2 RCTs investigated the QoL [30,31] and the authors did not use the same questionnaires: ASCENDE-RT used “SF36v2” while Hoskin et al. used “version 3 of FACT-P, FACT-G and FACT-P Trial Outcome Index (TOI) measurements”. Sexual function declines from baseline on both studies. Decline in physical and urinary functions in the BT group was observed in ASCENDE-RT trial but not in Hoskin et al. trial.
BED = d+ g{d2/(α / β )} g = {2/(µT)2}{µT − 1 + e(−µT)}; µ = 0.693/T1/2; T1/2 = 0.5 ; T = total treatment time for EBRT:
Quality assessment and risk of bias
BED = nd(1 + d/(a/b)) Identified reports were reviewed according to CONSORT checklist detailed in Table 2 (supplementary data) whereas risk of bias assessment was presented and detailed in Fig. 6 (supplementary data). Three main sources of biases include: (1) lack of accessibility to full trial protocol for the three RCTs; (2) unblinded design; (3) Sathya et al. trial stopped prematurely and the decision to terminate a trial early can bias results in favor of BT in terms of toxicity. The evaluation of this study
n = number of fractions, d = dose per fraction. α/β was 1.5 for prostate cancer and 3 for organs at risks. Consequently, the BED for prostate cancer (α/β = 1.5) in BT arm vs. EBRT arm were respectively 175 Gy vs 154 Gy for Sathya et al., 215 Gy vs 156 Gy for Hoskin et al., and 222 Gy vs 182 Gy in ASCENDE-RT trial (Table 1).
Fig. 2. Forest plots of 5-year biochemical progression free survival for brachytherapy boost versus external beam boost in intermediate and high-risk prostate cancer. 268
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Fig. 3. Forest plots of 5-year overall survival for brachytherapy boost versus external beam boost in intermediate and high-risk prostate cancer.
Regarding urinary function, BT could increase ≥ G3 late GU toxicity [37] even though this result was not confirmed in this meta-analysis. It should be noted that the result was heterogeneous leading to consider the random-effects model which did not show any difference between BT vs. EBRT. We also considered toxicity after 18 months as late toxicity for Sathya et al. study, using RR, meaning that we estimated the worst-case scenario in terms of toxicity risk. Meanwhile, ≥ G3 late GU toxicity could also be inherent to the BT technique (permanent vs. temporary implants). Better dose optimization using other BT techniques like HDR [11,38,39] and technological advances for definition and sparing critical structures can help decrease the urinary toxicity [10]. The analysis of ≥ G3 late GI toxicity results showed a trend favoring EBRT arm (but p = 0.05 and CI includes 1). However, the same calculation based on RR used for GU toxicity evaluation was also applied for GI toxicity. Consequently, the latter was probably over-estimated. The irradiation fields used in the 3 RCTs were also different (pelvic vs. prostatic irradiation only) and within Hoskin et al. trial, both pelvic and prostate fields could be used. This is an important confounding factor for late GI toxicity. The actual use of intensity modulated radiation therapy can help reduce this toxicity and ensure safer dose escalation without altering tumor control [20]. For QoL analysis, the difference in urinary function favoring EBRT was not clinically significant at last follow-up compared to baseline mean scores. Indeed, ≥ G3 GU toxicity occurring after BT boost was largely episodic in nature [30]. Sexual and physical decline may be mainly due to ADT. Indeed, the latter could be considered as a confounding factor due to different ADT duration between the 3 RCTs and within Hoskin et al. trial itself. Regarding bias risk, 2 RCTs [18,19] had selection, attribution and reporting bias. In the 3 RCTs, performance and detection bias were not applicable as blinding between BT vs. EBRT is technically not feasible (Fig. 6 – supplementary data). However, both b-PFS and OS are objective criteria that are homogeneous and have similar trend in both random-effects and fixed-effects models in this meta-analysis.
using AMSTAR tool showed a high-quality review. Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.ctrv.2018.10.004. Discussion In this meta-analysis, we confirmed the results of the individual RCTs that BT boost results in a significant benefit in b-PFS. Using CONSORT criteria, 2 RCTs [18,19] have major bias and concluded that the generalizability of their findings could not be proposed as the control EBRT arm was not the standard of care treatment (doses delivered in EBRT arm were too low). However, ASCENDE-RT trial showed that even with escalated EBRT, BT boost gives better benefit in terms of b-PFS. Another confounding factor for b-PFS analysis is the use of androgen deprivation therapy (ADT) and its optimal duration. In these 3 RCTs, the b-PFS was significantly better in every BT technique used (low or high-dose rate and permanent or temporary implants) independently of the duration of ADT. This can be due to higher BED delivered by BT (12–38%) compared to EBRT (Table 1) and/or inherent to the BT technique delivering a non-homogeneous dose escalation within the isodose prescription (“simultaneous integrated boost” to tumor index) [32]. Another criticism to these RCTs was that the gain was only on b-PFS and not in OS. It should be noted that none of these studies were designed to assess OS as a primary end point. However, ASCENDE-RT trial [20] showed that the improved b-PFS gained using BT was correlated with improved metastatic-free survival (MFS) as demonstrated by both Spratt et al. and Kishan et al. in large retrospective series [33,34]. With a hazard ratio of 0.49 in favor of BT boost at 5 years and still highly significant afterwards, it can be hypothesized that the b-PFS gain could lead to a significantly better OS rate if RCTs were correctly powered with a longer follow-up. This improvement in overall survival for BT boost has been recently published in 3 large retrospective by Johnson et al., Kishan et al. and Ennis et al [16,35,36].
Fig. 4. Forest plots of 5-year rates of late genito-urinary ≥ G3 toxicity for brachytherapy boost versus external beam boost in intermediate and high-risk prostate cancer. 269
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Fig. 5. Forest plots of 5-year rates of late gastro-intestinal ≥ G3 toxicity for brachytherapy boost versus external beam boost in intermediate and high-risk prostate cancer.
Meanwhile, toxicity results interpretation (using RR), should be analyzed with caution as there were clinical (EBRT dose and fields, technique and dose of BT), methodological (grading of toxicities) and statistical (time of report and statistical method used) heterogeneities. Even if there were only 3 RCTs, a systematic review of the nonrandomized studies on the interest of BT boost in intermediate- and high-risk prostate cancer was not performed as it has been already extensively published (with or without matched pair comparison with EBRT). In all of those reviews, BT boost was shown to significantly improve bio-chemical control whatever BT doses and techniques used. Furthermore, in terms of evidence-based medicine, the rules to consider level I evidence and subsequent grade A recommendations vary between different countries’ guidelines. Indeed, in France, UK and Australia a meta-analysis of RCTs is warranted while it is not necessary in North-America [40–43].
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