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Platinum Priority – Review – Prostate Cancer

Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis

By: Christopher J.D. Wallis , Refik Saskin , Richard Choo , Sender Herschorn , Ronald T. Kodama , Raj Satkunasivam , Prakesh S. Shah , Cyril Danjoux and Robert K. Nam

European Urology, Volume 70 Issue 1, July 2016, Pages 21-30

Published online: 01 July 2016

Keywords: Prostatic neoplasms, Brachytherapy, Radiotherapy, Prostatectomy, Retropubic, Survival, Mortality

Abstract Full Text Full Text PDF (7,3 MB) Patient Summary

Abstract

Context

To date, there is no Level 1 evidence comparing the efficacy of radical prostatectomy and radiotherapy for patients with clinically-localized prostate cancer.

Objective

To conduct a meta-analysis assessing the overall and prostate cancer-specific mortality among patients treated with radical prostatectomy or radiotherapy for clinically-localized prostate cancer.

Evidence acquisition

We searched Medline, EMBASE, and the Cochrane Library through June 2015 without year or language restriction, supplemented with hand search, using Preferred Reporting Items for Systematic Reviews and Meta-Analysis and Meta-analysis of Observational Studies in Epidemiology guidelines. We used multivariable adjusted hazard ratios (aHRs) to assess each endpoint. Risk of bias was assessed using the Newcastle-Ottawa scale.

Evidence synthesis

Nineteen studies of low to moderate risk of bias were selected and up to 118 830 patients were pooled. Inclusion criteria and follow-up length varied between studies. Most studies assessed patients treated with external beam radiotherapy, although some included those treated with brachytherapy separately or with the external beam radiation therapy group. The risk of overall (10 studies, aHR 1.63, 95% confidence interval 1.54–1.73, p < 0.00001; I2 = 0%) and prostate cancer-specific (15 studies, aHR 2.08, 95% confidence interval 1.76–2.47, p < 0.00001; I2 = 48%) mortality were higher for patients treated with radiotherapy compared with those treated with surgery. Subgroup analyses by risk group, radiation regimen, time period, and follow-up length did not alter the direction of results.

Conclusions

Radiotherapy for prostate cancer is associated with an increased risk of overall and prostate cancer-specific mortality compared with surgery based on observational data with low to moderate risk of bias. These data, combined with the forthcoming randomized data, may aid clinical decision making.

Patient summary

We reviewed available studies assessing mortality after prostate cancer treatment with surgery or radiotherapy. While the studies used have a potential for bias due to their observational design, we demonstrated consistently higher mortality for patients treated with radiotherapy rather than surgery.

Take Home Message

We reviewed published observational data on overall and prostate-cancer specific mortality following radiotherapy or surgery in the treatment of clinically-localized prostate cancer. We demonstrated consistent evidence of increased mortality for patients treated with radiotherapy.

Keywords: Prostatic neoplasms, Brachytherapy, Radiotherapy, Prostatectomy, Retropubic, Survival, Mortality.

1. Introduction

Nonconservative treatment options for patients diagnosed with clinically-localized prostate cancer include radical prostatectomy and radiotherapy [1]. Currently, there are no published randomized controlled trials comparing their efficacy. For patients desiring nonconservative treatment, established clinical guidelines recommend either treatment option and patients must ultimately decide for themselves which treatment to undertake [2] and [3].

Few reviews and meta-analyses have been published on this subject. Recent reviews have focused on patients with high-risk prostate cancer [4] and [5]. These have reported a benefit of radical prostatectomy over radiotherapy for both overall and prostate cancer specific mortality [4] and [5]. The limited scope of previous reviews and recent publication of a number of studies assessing prostate cancer-specific and overall survival for patients treated with contemporary forms of radiotherapy [6], [7], and [8] requires a new, comprehensive meta-analysis.

Our objective was to systematically review and conduct a systematic review and meta-analysis to compare efficacy data on overall and prostate cancer-specific survival among patients treated with radiotherapy or radical prostatectomy for clinically-localized prostate cancer.

2. Evidence acquisition

2.1. Research question

Do patients treated with radical prostatectomy for clinically-localized prostate cancer have improved overall or prostate cancer-specific mortality compared with those treated with radiotherapy?

2.2. Types of studies

We included randomized controlled trials, cohort, and case-control studies. Case series lacking comparator groups were excluded. Other publications including editorials, commentaries, and review articles were excluded. Publications not subject to peer-review (ie, reports of data from vital statistics and dissertations or theses) were also excluded. Where there was more than one publication resulting from the same patient cohort, to prevent the duplication of patients from one cohort, for each of our analyses we selected one study based on a hierarchical assessment of comparability of study groups, time period of study (preference for more recent), and number of patients (Supplementary data).

2.3. Types of participants and exposure

We reviewed studies reporting on men of any age with nonmetastatic prostate cancer treated with any commonly-utilized form of radiotherapy including conformal external beam (EBRT), intensity-modulated (IMRT), brachytherapy, or a combination of radiotherapy modalities with curative treatment intent. We excluded studies assessing adjuvant or salvage therapies as the specific objective. We included studies irrespective of dose and duration of radiotherapy. In order to be included, studies had to have a comparison group comprising patients treated with radical prostatectomy. Studies assessing nonstandard treatments (such as cryotherapy) were excluded.

2.4. Outcome measures

The primary outcome was overall mortality and the secondary outcome was prostate cancer-specific mortality. Studies reporting surrogate endpoints such as biochemical recurrence only were excluded. Since age, comorbidity, and histologic factors such as grade and stage significantly impact overall and prostate cancer-specific mortality [8] and [9], we considered studies only reporting multivariable adjusted hazard ratios (aHR). We excluded crude or unadjusted outcome measures since these would provide biased estimates given the known differences in age and comorbidity between patients treated with radiotherapy and surgery.

2.5. Methods of review

We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis of Observational studies in Epidemiology guidelines for reporting of this systematic review and meta-analysis [10] and [11].

2.6. Search strategy

Medline, EMBASE, and EBM Reviews Cochrane Central Register of Controlled Trials databases were searched using the OvidSP search platform for studies indexed from database inception to June 1, 2015 with the assistance of a professional librarian. We used both subject headings and text-word terms for “radical prostatectomy”, “prostate cancer surgery”, “radiotherapy”, “outcome”, “survival/mortality”, and related and exploded terms including medical subject headings terms in combination with keyword searching. A full search strategy is presented in the Supplementary data. No limitations were placed with respect to publication language or publication year. Following the literature search, all duplicates were excluded. References from review articles, commentaries, editorials, included studies, and conference publications of relevant medical societies were reviewed and cross-referenced to ensure completeness. Conference abstracts were excluded.

2.7. Review methods

Two authors performed the study selection independently (C.J.D.W. and R.S.). Disagreements were resolved by consensus with the senior author (R.K.N.). Titles and abstracts were used to screen for initial study inclusion. Full-text review was used where abstracts were insufficient to determine if the study met inclusion or exclusion criteria. The final list of selected studies was agreed upon by urologists (C.J.D.W. and R.K.N.), radiation oncologists (R.C. and C.D.), and an epidemiologist (R.S.). One author (C.J.D.W.) performed all data abstraction including evaluation of study characteristics, risk of bias, and outcome measures with independent verification performed by other authors.

2.8. Risk of bias assessment

We used the Newcastle-Ottawa Scale for risk of bias assessment. This scale assesses risk of bias in three domains [12]: (1) selection of the study groups; (2) comparability of groups; and (3) ascertainment of exposure and outcome [13]. Studies with scores ≥ 7 were considered as having a low risk of bias, scores of 4–6 as having a moderate risk of bias, and scores < 4 as having a high risk of bias. We assessed that follow-up was adequate if the median or mean follow-up was in excess of 5 yr.

2.9. Measures of treatment effect

We assessed the aHR for mortality for patients treated with radiotherapy and surgery.

2.10. Assessment of heterogeneity

We identified heterogeneity using the Q test, estimated it using the DerSimonian-Laird method, and quantified it using I2 values [14]. Furthermore, we employed random-effects models for each of our analyses given the identified clinical heterogeneity.

2.11. Assessment of reporting bias

We assessed publication bias for outcomes with more than 10 included studies using funnel plots.

2.12. Data synthesis

Meta-analysis was performed using Review Manager 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) software. We used the inverse variance technique for meta-analysis of hazard ratios. Due to the clinical heterogeneity inherent in our data, random-effects models were used for all meta-analyses.

2.13. Subgroup analysis

We performed a number of a priori subgroup analyses. We planned subgroup analyses restricted to EBRT, IMRT, brachytherapy, and brachytherapy with EBRT boost. However, data were only available for subgroup analyses of EBRT, IMRT, and brachytherapy. We also performed subgroup analysis assessing the impact of: (1) prostate cancer risk stage (low, intermediate, and high); (2) duration of follow-up (<5 yr, 5–8 yr, >8 yr); (3) study era (“old” if the accrual started prior to 1990 or ended prior to 2005 and “newer” otherwise); and (4) study location (USA and rest of the world).

We did not encounter any issues with repeated measures, unit of analyses, or missing data.

3. Evidence synthesis

Our literature search identified 1624 unique references (Fig. 1). After full text review of 73 manuscripts, 19 were selected for inclusion. The reasons for exclusion are provided in Figure 1 and the Supplementary data. In particular, there were multiple publications arising from the same clinical cohorts over the same time period. To prevent the duplication of patients, a single study was chosen to represent each cohort for each comparison as outlined in the Supplementary data.

gr1

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram outlining search strategy and final included and excluded studies.

3.1. Study description

Three studies were from single centers, five were from multiple institutions, and the remaining 11 were from administrative databases (Table 1). The inclusion criteria and length of follow-up varied significantly between included studies (Table 1). Some studies imposed minimum age requirements while others imposed maximum age requirements which resulted in significant differences in age distribution between studies. Patients treated with radiotherapy were generally older in all of the included studies.

Table 1

Characteristics of included studies

Author (yr)Data source (study interval)Follow–up (median)Inclusion criteriaRadiation modalityRadiation doseStudy sizeAdjuvant therapiesAgeOutcome
RPXRT
Abdollah (2012)SEER (1992–2005)52 moClinically localized, age 65–79UnspecifiedNA68 665ADT:
RP: 0%
XRT: 9%
65–69: 53%
70–74: 39%
75–79: 9%
65–69: 24%
70–74: 41%
75–79: 35%
PCM
Albersten (2007)Connecticut Tumor Registry (1992–2005)Mean 13.3 yrClinically localized, age < 75EBRTNA1618Excludedmedian 65median 71PCM
Arvold (2011)21st Century Oncology, Chicago Prostate Centre, Duke University (1988–2008)6.1 yr (RP) and 3.6 yr (XRT)Low risk or intermediate riskaBrachymin 115 Gy8839Included but proportion not specifiedmedian low risk: 61.4; int risk: 62.9median low risk: 68.8; int risk: 71.2PCM
Boorjian (2011)Mayo Clinic, Fox Chase (1988–2004)10.2 yr (RP) and 6.0–7.3 yr (XRT)High riskaEBRT
(conformal, 3DCRT, IMRT)
median 72 Gy
(range, 50–79)
1847ADT:
RP: not specified
XRT: 56%
median 66.0median with ADT: 68.8; no ADT: 69.3OM, PCM
Cooperberg (2010)CaPSURE (1987–2007)3.9 yr (RP) and 4.5 yr (XRT)Clinically localizedEBRTNA6209bADT
RP: 6.7%
XRT: 49.7%
Postop XRT: 3%
median 62median 72OM, PCM
DeGroot (2013)Ontario Cancer Registry (1990–1998)NR“Candidate for therapy”: low and intermediate riskaEBRTmedian 64 Gy (range, 40–70)1090ADT
RP: 29%
XRT: 22%
mean 63mean 69PCM
Hoffman (2013)PCOS (1994–2010)15 yrClinically localized, age 55–74EBRTNA1655ADT:
RP: 0%
XRT: 11%
55–64: 52%
65–74: 48%
55–64: 23%
65–74: 77%
OM, PCM
Jeldres (2008)Quebec Health Plan (1989–2000)7.4 yrAge > 70EBRTNA6183Included but proportion not specifiedmedian 71median 74OM
Kibel (2012)Barnes–Jewish Hospital (BJ), Cleveland Clinic (CC) (1995–2005)67 moClinically localizedEBRT (3DCRT, IMRT), brachymedian 74 Gy (BJ) and 78 Gy (CC)10 429ADT:
RP: not specified
XRT: 34%
median
BJ: 61;
CC: 60
median
BJ–EBRT: 70;
BJ–brachy: 69;
CC–EBRT: 69;
CC–brachy: 68
OM, PCM
Ladjevardi (2010)Swedish National Prostate Cancer Registry (1996–2006)4.4 yrT1–3, N0–X, M0–X, PSA < 20, age < 75EBRT, brachyNA19 258cNot specified<55: 10%
55–59: 23%
60–64: 33%
65–69: 27%
70–75: 8%
<55: 4%
55–59: 13%
60–64: 25%
65–69: 33%
70–75: 25%
OM
Lee (2014)Severance Hospital, Seoul Korea (1990–2009)76 moClinically localized high riskaEBRT74–79 Gy376ADT
RP: 0%
XRT: 100%
Postop XRT: 10%
mean 67.5mean 68.6PCM
Merglen (2007)Geneva Cancer Registry (1989–1998)6.8 yrClinically localizedEBRTNA363ADT
RP: not specified
XRT: 26%
<60: 23%
60–69: 52%
70–79: 18%
≥80: 7%
<60: 9%
60–69: 52%
70–79: 38%
≥80: 1%
OM, PCM
Merino (2013)Pontificia Universidad Catolica de Chile (1999–2010)92 mo (RP) and 76 mo (XRT)Clinically localizedIMRT76 Gy1200ADT:
RP: 0%
XRT: 42%
Postop XRT: 5%
mean 63mean 70PCM
Rice (2013)CPDR (1989–2009)6.4 yrLow riska, age > 70EBRTNA446dNot specifiedmean 72.2mean 74.1OM
Sooriakumaran (2014)PcBaSe Sweden (1996–2010)5.4 yrAllUnspecifiedNA32 846eNot specifiedmedian 62median 66PCM
Sun (2013)SEER (1998–2005)NRClinically localized, age 65–80EBRT, brachyNA49 145fNot specifiedmedian 69median 73OM, PCM
Tewari (2007)Henry Ford Health System (1980–1997)68 mo (RP) and 54 mo (XRT)Clinically localized, high riska, age < 75UnspecifiedNA256gADT.
RP: 18.5%
XRT: 19%
mean 62.9mean 68.0OM, PCM
Westover (2012)21st Century Oncology, Chicago Prostate Centre, Duke University (1988–2008)4.6 yrClinically localized, Gleason score 8–10, age < 75Combination EBRT+brachy45 Gy EBRT + min 90–108 Gy brachy657ADT
RP: 6%
XRT: 100%
Postop XRT: 6%
median 65median 70PCM
Zelefsky (2010)Baylor College, Memorial Sloan Kettering (1993–2002)5.1 yr (RP) and 5.0 yr (XRT)T1c–T3bIMRT81 Gy (79%) or 86.4 Gy (21%)2380ADT
RP: 1%
XRT: 56%
Postop XRT: 6%
median 60median 69PCM

a Low risk prostate cancer = prostate specific antigen (PSA) < 10, Stage T1c–2a, Gleason score ≤ 6; intermediate risk prostate cancer = PSA 10–20, Stage T2b–c, Gleason score 7; high risk prostate cancer = PSA > 20, Stage >T3, Gleason score ≥ 8.

b Total study size is 7538, 6209 patients treated with either surgery or radiotherapy were included.

c Total study size is 31 903, 19 258 patients treated with either surgery or radiotherapy were included.

d Total study size is 770, 446 patients treated with either surgery or radiotherapy were included.

e Total study size is 34 502, 32 846 patients with nonmetastatic prostate cancer treated with either surgery or radiotherapy were included.

f Total study size is 67 087, 49 145 patients treated with either surgery or radiotherapy were included.

g Total study size is 453, 256 patients treated with either surgery or radiotherapy were included.

3DCRT = 3-dimensional conformal radiotherapy; ADT = androgen deprivation therapy; brachy = brachytherapy; CaPSURE = Cancer of the Prostate Strategic Urologic Research Endeavor; CPDR = Center for Prostate Disease Research; EBRT = external beam radiotherapy; IMRT = intensity modulated radiotherapy; NA = not applicable; NR = not reported; OM = overall mortality; PCOS = Prostate Cancer Outcomes Study; PCM = prostate cancer mortality; RP = radical prostatectomy; SEER = Surveillance, Epidemiology and End Results; XRT = radiotherapy.

Most studies assessed the efficacy of EBRT with some including patients treated with brachytherapy. Two studies provided data restricted to patients treated with IMRT. The dosage of radiation was only available for eight of 19 (42%) studies. Brachytherapy dosage was in keeping with standard recommended doses, while only two studies provided “dose-escalated” EBRT treatments to all patients [7] and [15]. There was considerable variability in the use of adjuvant or salvage therapies. In some studies, patients receiving these treatments were excluded while in others all patients received adjuvant therapies.

Study inclusion criteria, including patient age and disease characteristics, significantly affected mortality rates for both all-cause and prostate cancer-specific mortality (Table 2). Overall mortality rates significantly exceeded prostate cancer-specific mortality, particular in patients with low-risk disease. Covariates included in the adjusted models varied significantly between studies though typically included age, clinical stage, Gleason score, and Charlson comorbidity (Supplementary Table 1).

Table 2

Absolute mortality rates for included studies


Author
Inclusion criteriaOverall mortalityProstate cancer mortality
RPXRTRPXRT
Abdollah (2012)Clinically localized, age 65–79NANA10 yr low/int: 1.4%
10 yr high: 6.8%
10 yr low/int: 3.9%
10 yr high: 11.5%
Albersten (2007)Clinically localized, age < 7510 yr: 17%a10 yr: 22%a10 yr low: 3%
10 yr int: 6%
10 yr high: 10%
10 yr low: 7%
10 yr int: 12%
10 yr high: 20%
Arvold (2011)Low risk or intermediate riskNANA10 yr low: 0.4%a
10 yr int: 0%a
10 yr low: 0.8%a
10 yr int: 3.5%a
Boorjian (2011)High risk10 yr: 23%10 yr RT + ADT: 33%
10 yr RT: 48%
10 yr: 8%10 yr RT + ADT: 8%
10 yr RT: 12%
Cooperberg (2010)Clinically localizedNANA10 yr: 5%a10 yr: 12%a
DeGroot (2013)“Candidate for therapy”: low and intermediate riskNANANANA
Hoffman (2013)Clinically localized, age 55–7415 yr: 35%a15 yr: 58%aNANA
Jeldres (2008)Age > 7010 yr: 40.7%
15 yr: 72.7%
10 yr: 69.7%
15 yr: 86.7%
NANA
Kibel (2012)Clinically localized10 yr: 11.1%10 yr EBRT: 17.4%
10 yr brachy: 18.3%
10 yr: 1.8%10 yr EBRT: 2.9%
10 yr brachy: 2.3%
Ladjevardi (2010)T1–3, N0–X, M0–X, PSA<20, age < 75Relative survival is given resulting in survival estimates > 100% and therefore mortality < 0.
Lee (2014)Clinically localized high riskNANA10 yr: 10%a10y r: 20%a
Merglen (2007)Clinically localizedNANA10 yr: 17%10 yr: 25%
Merino (2013)Clinically localized5 yr: 3.8%
7 yr: 6.3%
5 yr: 11.6%
7 yr: 16.9%
7 yr: 1.9%7 yr: 7.9%
Rice (2013)Low risk, age > 7010 yr: 18%a10 yr: 30%a
Sooriakumaran (2014)All10 yr low: 10%a
10 yr int: 15%a
10 yr high: 20%a
10 yr low: 16%a
10 yr int: 22%a
10 yr high: 30%a
10 yr low: 1%a
10 yr int: 3%a
10 yr high: 8%a
10 yr low: 1%a
10 yr int:8%a
10 yr high: 15%a
Sun (2013)Clinically localized, age 65–8010 yr: 20%10 yr: 37%NANA
Tewari (2007)Clinically localized, high risk, age < 7510 yr: 54%10 yr: 75%10 yr: 25%10 yr: 43%
Westover (2012)Clinically localized, Gleason score 8–10, age < 75NANA5 yr: 0%5 yr: 1.5%
Zelefsky (2010)T1c–T3bNANA8 yr: 1.4%8 yr: 4.7%

a Denotes that estimate is imputed from a graph or figure in the original manuscript.

ADT = androgen deprivation therapy; brachy = brachytherapy; EBRT = external beam radiotherapy; NA = not applicable or assessed in the manuscript; PSA = prostate specific antigen; RP = radical prostatectomy; RT = radiotherapy; XRT = radiotherapy.

3.2. Risk of bias assessment

The majority of included studies were felt to have low to moderate risk of bias (Table 3). Some studies used radiotherapy and surgery patients from different clinical centers, thus introducing the risk of a selection bias. The adequacy of follow-up was often not described in the included studies which raise concern for attrition bias.

Table 3

Newcastle-Ottawa Scale for risk of bias assessment of studies included in the meta-analysis

StudySelectionComparabilityOutcomeOverall
Representativeness of exposed cohortSelection of nonexposedAscertainment of exposureOutcome not present at startAssessment of outcomeAdequate follow-up lengthAdequacy of follow-up
Abdollah (2012)fx1fx1fx1fx1fx3fx1fx2fx27
Albertsen (2007)fx1fx1fx1fx1fx3fx1fx1fx28
Arvold (2011)fx1fx2fx1fx1fx3fx2fx2fx25
Boorjian (2011)fx1fx2fx1fx1fx3fx1fx1fx27
Cooperberg (2010)fx1fx1fx1fx1fx3fx1fx2fx27
DeGroot (2013)fx1fx1fx1fx1fx3fx1fx1fx28
Hoffman (2013)fx1fx1fx1fx1fx3fx1fx1fx19
Jeldres (2008)fx1fx1fx1fx1fx3fx1fx1fx28
Kibel (2012)fx1fx1fx1fx1fx3fx1fx1fx28
Ladjevardi (2010)fx1fx1fx1fx1fx3fx1fx2fx18
Lee (2014)fx1fx1fx1fx1fx3fx1fx1fx28
Merglen (2007)fx1fx1fx1fx1fx3fx1fx1fx19
Merino (2013)fx1fx1fx1fx1fx3fx2fx1fx27
Rice (2013)fx1fx1fx1fx1fx3fx1fx1fx28
Sooriakumaran (2014)fx1fx1fx1fx1fx3fx1fx1fx19
Sun (2013)fx1fx1fx1fx1fx3fx1fx2fx17
Tewari (2007)fx1fx1fx1fx1fx3fx1fx2fx27
Westover (2012)fx1fx2fx1fx1fx3fx1fx2fx26
Zelefsky (2010)fx1fx2fx1fx1fx3fx1fx2fx17

3.3. Overall mortality

Ten studies reporting on 95 791 patients were aggregated to assess the effect of treatment modality on overall mortality. Patients treated with radiotherapy experienced an increased risk of overall mortality compared with those treated with radical prostatectomy (aHR 1.63, 95% confidence interval [CI] 1.54–1.73, p < 0.00001; I2 = 0%; Fig. 2a). Where authors provided outcome data for patients treated with radiotherapy alone and radiotherapy with androgen deprivation therapy (ADT), we used the aggregate results for both groups.

gr2

Fig. 2

Forrest plot assessing the risk of (a) overall mortality and (b) prostate cancer-specific mortality following radiotherapy and surgery for prostate cancer.

CI = confidence interval; IV = inverse variance; SE = standard error.

We found a similar direction of effect when we examined patients with low risk prostate cancer (aHR 1.47, 95% CI 1.19–1.83, p = 0.0004, I2 = 59%), intermediate risk prostate cancer (aHR1.50, 95% CI 1.24–1.82, p < 0.0001; I2 = N/A), or high risk prostate cancer (aHR 1.88, 95% CI 1.64–2.16, p < 0.00001; I2 = 0%).

Further subgroup analyses did not differ in direction from the primary results (Table 4). Patients treated with radiotherapy who were treated in the earlier era (study accrual period prior to 2005) had similar outcomes to those treated in the newer era (p = 0.14; Table 4). While assessing by radiotherapy modality, we found a similar risk for patients treated with EBRT (conformal radiation therapy [CRT] or IMRT) and with brachytherapy (Table 4). No studies were identified that reported on the risk of overall survival while comparing IMRT to surgery. There were no “between group” differences observed with respect to duration of follow-up (p = 0.24; I2 = 30%; Table 4). One study did not report follow-up duration. Similarly, there were no differences between the treatment eras (p = 0.14; I2 = 53%). Finally, there was no difference observed whether the study cohort was from the USA or the rest of the world (p = 0.52; I2 = 0%; Table 4).

Table 4

Subgroup analysis assessing risk of overall mortality and prostate cancer-specific mortality following treatment with surgery or radiotherapy

Overall mortalityProstate cancer-specific mortality
Adjusted HR (95% CI, p value)I2Adjusted HR (95% CI, p value)I2
Risk category
 Low risk1.47 (1.19–1.83, p = 0.0004)59%1.70 (1.36–2.13, p < 0.00001)0%
 Intermediate risk1.50 (1.24–1.82, p < 0.0001)NA1.80 (1.45–2.25, p < 0.0001)0%
 High risk1.88 (1.64–2.16, p < 0.00001)0%1.83 (1.51–2.22, p = 0.0001)42%
Radiotherapy modality
 EBRT (CRT and IMRT)1.69 (1.55–1.85, p < 0.00001)8%2.26 (1.94–2.63, p < 0.00001)0%
 IMRTNo studies available2.26 (1.21–4.21, p = 0.01)0%
 Brachytherapy1.70 (1.40–2.10, p < 0.001)NA1.58 (1.01–2.49, p = 0.05)0%
Duration of follow-up
 <5 yr1.54 (1.38–1.71, p < 0.00001)0%1.51 (0.25–9.19, p = 0.66)89%
 5–8 yr1.73 (1.49–2.02, p < 0.00001)18%1.80 (1.57–2.05, p < 0.00001)0%
 >8 yr1.74 (1.55–1.95, p < 0.00001)0%2.26 (1.60–3.20, p < 0.00001)65%
Era of accrual
 Early1.75 (1.57–1.97, p < 0.00001)5%2.04 (1.54–2.72, p < 0.00001)44%
 Later1.59 (1.48–1.70, p < 0.00001)0%2.12 (1.69–2.66, p < 0.00001)58%
Geographic region
 United States1.63 (1.54–1.73, p < 0.00001)0%2.11 (1.65–2.69, p < 0.00001)59%
 Rest of the world1.65 (1.55–1.76, p < 0.0001)42%1.85 (1.59–2.15, p < 0.00001)0%

CI = confidence interval; CRT = conformal radiation therapy; EBRT = external beam radiotherapy; HR = hazard ratio; IMRT = intensity modulated radiotherapy; NA = not applicable.

3.4. Prostate cancer-specific mortality

Fifteen studies reporting on 118 830 patients were aggregated to assess the effect of treatment modality on prostate cancer specific mortality. Patients treated with radiotherapy had an increased risk of prostate cancer-specific mortality (aHR 2.08, 95% CI 1.76–2.47, p < 0.00001; I2 = 48%; Fig. 2b) compared with those treated with surgery.

We found similar results when we examined only patients with low risk prostate cancer (aHR 1.70, 95% CI 1.36–2.13, p < 0.00001; I2 = 0%), intermediate risk prostate cancer (aHR1.80, 95% CI 1.45–2.25, p < 0.0001; I2 = 0%), or high risk prostate cancer (aHR 1.83, 95% CI 1.51–2.22, p = 0.0001; I2 = 42%).

Subanalyses for this endpoint also had similar direction of results to the primary analysis. We observed no between-subgroup differences when examining the effect of study era (p = 0.85; I2 = 0%; Table 4). Assessing the effect of specific radiotherapy modalities, we found an increased risk for those treated with EBRT (CRT or IMRT), IMRT alone, and brachytherapy alone (Table 4). There were no “between-group” differences observed with respect to duration of follow-up (p = 0.47; I2 = 0%), although the magnitude of effect increased with increasing length of follow-up (Table 4). Two studies did not report follow-up duration. Similarly, results were consistent regardless of geographic location of publication (p = 0.26; I2 = 22%; Table 4).

3.5. Publication bias

We assessed publication bias using funnel plots comparing effect size and measure of precision of the effect size for the main analysis of our primary and secondary analyses (Supplementary Fig. 1). We did not identify any evidence of publication bias.

4. Discussion

In this review and meta-analysis of 19 studies with low to moderate risk of bias, we identified an increased overall and prostate cancer-specific mortality for patients treated with radiotherapy compared with those treated with surgery for clinically localized prostate cancer. These findings were supported with subgroup analyses which assessed the impact of prostate cancer risk category, radiotherapy modality, duration of follow-up, era of study accrual, and geographic region.

To our knowledge, this represents the most comprehensive and up-to-date review on this topic. Petrelli et al [5] conducted a meta-analysis examining the survival outcomes among patients with only high risk prostate cancer treated with surgery or radiotherapy [5]. They found better overall and prostate cancer-specific survival for patients treated with surgery compared with radiotherapy. A key limitation of this study was that they used adjusted and unadjusted odds ratios which do not take into account the time-to-event outcome measures as our study has done [16]. Other recent reviews have been restricted to randomized controlled trials [17], to high-risk patients [4], or did not provide aggregate risk estimates [18].

Two small randomized controlled trials have compared survival outcomes for patients treated with surgery or radiotherapy for prostate cancer [19] and [20]. These were largely underpowered and have not been used to guide treatment decision making. Other trials have closed prematurely due to poor accrual [21] because of patients’ unwillingness to leave their treatment to chance [22].

We performed a number of prespecified subgroup analyses to explore potential areas of bias, but analyses stratified by prostate cancer risk category, radiotherapy modality, duration of follow-up, era of study accrual, and geographic region did not differ from the overall analysis. Recently, radiation dose escalation was associated with improved overall survival in patients with intermediate- and high-risk prostate cancer compared with standard dosing [23]. While we were not able to ascertain specific radiation doses from many studies, the majority of included patients were treated with standard-dose regimens. Zelefsky et al [15] used dose-escalated IMRT (>81 Gy) and found results similar to the other included studies.

We found statistically significant between-study heterogeneity for our pooled analysis of prostate cancer-specific mortality, but not overall mortality. This is likely due to increased uncertainty and methodologic differences in assigning cause of death. Some studies used administrative death records. Other studies used outcome determination at the discretion of the treating physician [15] and [24], and yet others used a combination of death certificates and physician correspondence [25] and [9].

Major strengths of this review include a comprehensive search strategy, careful selection of studies, critical and thorough quality appraisal of included studies, a priori subgroup analyses, and the use an outcome measure which incorporates the time-to-event nature of the data and adjusts for known confounders. A meta-analysis depends on the validity of the included studies to draw accurate conclusions. Therefore, a key limitation of our study is the effect of residual confounding as this analysis is based on observational data. It is well established that patients treated with radiotherapy tend to be older and have a higher level of comorbidity. As the vast majority of the included studies measured comorbidity using the Charlson comorbidity index, there remains the potential for heterogeneity within the categories resulting in residual confounding. Giordano et al [26] postulate that this may be driven by unmeasured differences in functional status and self-reported health. While current statistical methodologies such as regression and matching are unable to fully adjust for selection bias and unmeasured confounders [26], we only used multivariable aHRs in our study in an attempt to provide more accurate risk estimates. Also, the use of salvage therapies may explain some of the survival differences between the groups. Patients initially treated with surgery may undergo salvage radiotherapy while patients who fail after radiotherapy are less often offered salvage surgery. In contrast, patients with recurrence following radiotherapy are typically managed with ADT. In the included studies, the use of adjuvant or salvage radiotherapy varied—many did not specify the use of this therapy, some excluded these patients, and usage ranged from 3–10% in the remainder. Additionally, the use of ADT, either as adjuvant or salvage therapy, varied widely as expected given the heterogeneity of prostate cancer disease characteristics included. ADT usage was higher in patients treated with radiotherapy in the vast majority of studies. This is in keeping with expectations as the use of neoadjuvant, concurrent, or adjuvant ADT is often part of standard care in the radiotherapy setting, as its benefit has been shown in several large randomized radiotherapy studies. Also, for overall survival, there were insufficient data to assess the efficacy of IMRT, which has largely supplanted three-dimensional CRT in many jurisdictions [27]. Finally, a pathological review is rarely undertaken in large databases. As a result, heterogeneity may exist within pathological grading in these data sources due to interobserver variability.

Implications for future research assessing the comparative efficacy of surgery and radiotherapy in prostate cancer will largely depend on the results of the upcoming randomized ProtecT trial [28]. Clinical implications will likely depend on the congruence of the observational and randomized data. Prospective data derived from randomized controlled trials will allow for better management of confounding in addition to allowing for longitudinal quality-of-life assessment which is unavailable from large administrative datasets. As is emphasized in current clinical guidelines, both treatment modalities should be discussed with eligible patients prior to initiation of either therapy [1]. Given that current clinical guidelines do not discriminate patients by age and comorbidity level, the results of this study would be an important consideration for patients and physicians.

5. Conclusions

We identified an increased risk of overall and prostate cancer-specific mortality for patients treated with radiotherapy compared with surgery after adjustment for common patient and tumor prognostic factors. Methodologic limitations of the observational studies included should be considered while interpreting these results.


Author contributions: Christopher J.D. Wallis had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: CJDW, RC, CD, RKN.

Acquisition of data: CJDW, RS.

Analysis and interpretation of data: CJDW, PSS.

Drafting of the manuscript: CJDW, PSS, RKN.

Critical revision of the manuscript for important intellectual content: RS, RC, SH, RTK, RS, CD.

Statistical analysis: CJDW, PSS.

Obtaining funding: RKN.

Administrative, technical, or material support: PSS, RKN.

Supervision: RTK.

Other: None.

Financial disclosures: Christopher J.D. Wallis certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

Appendix A. Supplementary data

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Footnotes

a Division of Urology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, Canada

b Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada

c Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada

d Institute of Clinical Evaluative Sciences, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON, Canada

e Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA

f Department of Pediatrics, Mount Sinai Hospital, Toronto, ON, Canada

g Department of Pediatrics, University of Toronto, Toronto, ON, Canada

h Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada

Corresponding author. Tel. +1 416 480 5075; Fax: +1 416 480 6934.

Comments

  • Drew Moghanaki - 26 January 2016

    "When the cause of death is unknown, there are simply no statistical models available that can adjust for gatekeeping and a preference to refer surgical rejects for radiotherapy. Comparing these cohorts can therefore only be speculative, at best. The conclusions illuminate the lack of scientific understanding by suggesting a hypothesis generating study should be used with patients to "aid clinical decision making". Such a statement is potentially harmful, as the common practitioner and patients understand these issues even less. Ultimately, no patent should subject himself to the risk of incontinence and need for postoperative radiotherapy with the false hope that this approach is helping him live longer. It should only be if they want to take a chance to avoid radiotherapy and hormones. Even when framed this way, the consent process must disclose that they may still end up getting all three treatments, and may have done just as well without surgery in the first place."

  • Krzisch - 22 December 2015

    The eternal problem in these comparisons is the systematic bias resulting from the pre selection of fitter patients for surgery. Only a randomized study demonstrates. A meta analysis orientates only.

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