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Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males. A systematic review of randomised controlled trials (RCTs) of radiotherapy and other non-pharmacological management options for localised prostate cancer was undertaken.
Methods
A search of thirteen databases was carried out until March 2014. RCTs comparing radiotherapy (brachytherapy (BT) or external beam radiotherapy (EBRT)) to other management options i.e. radical prostatectomy (RP), active surveillance, watchful waiting, high intensity focused ultrasound (HIFU), or cryotherapy; each alone or in combination, e.g. with adjuvant hormone therapy (HT), were included.
Methods followed guidance by the Centre for Reviews and Dissemination and the Cochrane Collaboration. Indirect comparisons were calculated using the Bucher method.
Results
Thirty-six randomised controlled trials (RCTs, 134 references) were included. EBRT, BT and RP were found to be effective in the management of localised prostate cancer. While higher doses of EBRT seem to be related to favourable survival-related outcomes they might, depending on technique, involve more adverse events, e.g. gastrointestinal and genitourinary toxicity. Combining EBRT with hormone therapy shows a statistically significant advantage regarding overall survival when compared to EBRT alone (Relative risk 1.21, 95% confidence interval 1.12–1.30). Aside from mixed findings regarding urinary function, BT and radical prostatectomy were comparable in terms of quality of life and biochemical progression-free survival while favouring BT regarding patient satisfaction and sexual function.
There might be advantages of EBRT (with/without HT) compared to cryoablation (with/without HT). No studies on HIFU were identified.
Conclusions
Based on this systematic review, there is no strong evidence to support one therapy over another as EBRT, BT and RP can all be considered as effective monotherapies for localised disease with EBRT also effective for post-operative management. All treatments have unique adverse events profiles. Further large, robust RCTs which report treatment-specific and treatment combination-specific outcomes in defined prostate cancer risk groups following established reporting standards are needed. These will strengthen the evidence base for newer technologies, help reinforce current consensus guidelines and establish greater standardisation across practices.
Worldwide, prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males, accounting for 14% (903,500) of the total new cancer cases and 6% (258,400) of the total cancer deaths in males in 2008 [
]. It is currently estimated that 1 in 7 men in the USA will be diagnosed with prostate cancer at some time in their lives (15.3% of men, based on 2008–2010 data), with an estimated prevalence in 2011 of 2,707,821 men living with prostate cancer and an estimated 233,000 new cases for 2014. For those who have the disease, chances of surviving 5 years after diagnosis are good (98.9% based on data from 2004–2010). Nevertheless, it is estimated that 29,480 American men will die from prostate cancer in 2014 [
]. Aside from reducing life expectancy, prostate cancer is associated with reduced quality of life in terms of decreased sexual functioning, urinary incontinence and changes in bowel function, all of which may occur prior to treatment and/or worsen after treatment [
Prostate cancer also affects society as a whole through premature death and disability as well as resulting human and economic consequences. It has been estimated that approximately $11.9 billion is spent each year in the United States on prostate cancer treatment, with $4.6bn, $6.2bn and $1.1bn spent on initial treatment, continuing care and last year of life, respectively [
]. It is clearly important to ensure that, for those in need of treatment, expenditure is targeted so that the right patients are in receipt of the most effective treatment at the correct time.
Current widely accepted management options include active surveillance, watchful waiting, radical prostatectomy (RP), hormone therapy (HT), radiotherapy, (i.e. external beam radiotherapy (EBRT) or brachytherapy (BT)) and chemotherapy. These approaches are applied individually, sequentially or in combination. High intensity focused ultrasound (HIFU) and cryotherapy are also used but to a lesser degree [
However, there is a lack of systematic reviews of randomised controlled trials assessing these options for prostate cancer, i.e. RP, radiotherapy (EBRT and BT), HIFU and cryotherapy.
In this systematic review, we aim to assess the efficacy [
] and adverse events associated with radiotherapy (EBRT and/or BT) compared with other non-pharmacological management options in patients with localised prostate cancer.
2. Methods
The systematic review process followed published guidelines [
Higgins J.P.T. Green S. Cochrane handbook for systematic reviews of interventions [Internet]. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration,
2011
Our review was focused on non-pharmacological interventions. Pharmacological management of patients was only considered if it was an adjunct to main treatment. Published and unpublished randomised controlled trials were included when they reported on adult men (>18 years) with prostate cancer, treated with any form of radiotherapy (EBRT and/or BT), alone or in combination with HT or RP, in comparison to other relevant management options, i.e. RP, active surveillance, watchful waiting, HIFU and cryotherapy. Outcomes considered relevant for our review included mortality outcomes (overall survival, disease-specific survival), progression outcomes (clinical, biochemical and mixed progression-free survival), adverse events (AE; including genitourinary and gastrointestinal toxicities and sexual functioning), patient satisfaction, treatment failure (TF) and quality of life (QoL). The main outcome was overall survival (OS).
2.2 Literature search
Searches were undertaken to identify all relevant randomised controlled trials (RCTs), regardless of language or publication status (published, unpublished, in press and in progress). The following databases were searched up to February 2014: MEDLINE, MEDLINE In-Process Citations and Daily Updates, EMBASE (all via OvidSP) and Cochrane Central Register of Controlled Trials (CENTRAL). In addition, a search of PubMed was conducted in March 2014. The search strategies (keywords) were developed specifically for each database. Appendix 1 presents the search strategy developed to search MEDLINE.
Additional reference checking in retrieved articles and systematic reviews was undertaken and supplementary searches for secondary publications were conducted: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews or Effects (DARE), Health Technology Assessment (HTA) database (via CRD website), International Prospective Register of Systematic Reviews (PROSPERO), National Institute for Health and Care Excellence (NICE) guidance, Guidelines International Network (GIN), National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme and National Guidelines Clearinghouse (NGC).
2.3 Methods of study selection, quality assessment and data extraction
Two reviewers independently inspected the titles and abstracts identified by the search. For potentially relevant articles, or in cases of disagreement, the full article was obtained, independently inspected and pre-specified inclusion criteria applied.
For each study, data were extracted by one reviewer and checked for accuracy by a second reviewer. A quality assessment based on the methods described in the Cochrane Handbook was performed [
]. Study characteristics and quality were presented in tables. Where details on the risk group (i.e. D’Amico classification) were missing, a surrogate was created which was based on the reported baseline characteristics of included patients. The choice of risk stratification system is considered in the discussion section. D’Amico classified prostate cancer patients into 3 groups: low-risk (prostate-specific antigen [PSA] < 10 ng/ml and clinical stage T1c-T2a and Gleason score ⩽ 6), intermediate risk (PSA ⩾ 10 ng/ml, but ⩽ 20 ng/mL or clinical stage T2b or Gleason score = 7) and high-risk (PSA > 20 ng/ml or clinical stage ⩾ T2c or Gleason score ⩾ 8) [
Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era.
]. Three pre-specified categories were agreed with clinical experts following consideration of the literature and used to allow the comparison of different dosages of EBRT as monotherapy: low dose (<75 Gy), intermediate dose (75–78 Gy), high dose (⩾78 Gy).
Any disagreement during data extraction was resolved through discussion. Abstracts were also included where full manuscripts were unavailable, in line with current guidance [
Higgins J.P.T. Green S. Cochrane handbook for systematic reviews of interventions [Internet]. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration,
2011
Tables were used to present relevant results for all studies. All ‘head-to-head’ comparisons of comparator treatments were performed in line with the Cochrane Handbook [
Higgins J.P.T. Green S. Cochrane handbook for systematic reviews of interventions [Internet]. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration,
2011
]. Pooled effect sizes (relative risks (RR)) and 95% confidence intervals (95%-CIs) using random effects (inverse–variance, I–V) methods were only reported where trials were considered to be clinically and statistically homogeneous.
3. Results
Literature searches yielded 25,867 references. Additionally, searches were undertaken to identify relevant systematic reviews, technology appraisals, guidance and guidelines. These additional searches, aimed to identify supplementary primary studies, retrieved a total number of 826 hits. After removing 9,143 duplicates, a total of 17,550 references were available for screening (see Fig. 1).
Fig. 1Flow diagram of study searches and inclusion based on PRISMA.
Titles and abstracts were screened and 492 potentially relevant papers ordered as full texts. Of these, 134 references (relating to 36 individual studies) were included. A list of excluded studies is available on request.
3.1 Characteristics and risk of bias of included studies
Nearly all of the included studies have been conducted in Europe or North America, (34 out of 36) and two studies were carried out in Australia and New Zealand as well as China, respectively. On average, the 36 studies included 345 patients (median 212, total 11,731; two abstracts did not report patient numbers).
As detailed in Table 2, few studies reported patient risk stratification and those that did used a variety of classifications. Five studies [
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.
Short term hormone therapy and dose escalated radiation for localized prostate cancer: a randomized phase III study. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9–13 May 2012; Barcelona: Spain.
The prostate cancer intervention versus observation trial: VA/NCI/AHRQ cooperative studies program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy with watchful waiting for men with clinically localized prostate cancer.
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.
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.
Hypofractionation versus conventionally fractionated radiation therapy for prostate cancer: our first results. Paper presented at 20th Annual Meeting of the Italian Society of Uro-Oncology; 23–25 Jun 2010; Rome: Italy.
] defined low risk patients based on Gleason score and WHO grade. In order to allow a more transparent way of comparing the risk grouping of included patients, a D’Amico surrogate was extracted based on the baseline characteristics reported by each study (see Table 1). Two studies included patients stratified to a single risk group ([
Short term hormone therapy and dose escalated radiation for localized prostate cancer: a randomized phase III study. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9–13 May 2012; Barcelona: Spain.
]). The other studies assigned patients to two (n = 10) or three risk groups (n = 22), while two studies provided insufficient baseline data which prevented assignment of their patients to risk groups [
A phase III randomized trial to evaluate the efficacy of neoadjuvant therapy prior to curative radiotherapy in locally advanced prostate cancer patients: a Canadian Urologic Oncology Group study.
Impact of a multi-disciplinary patient education session on accrual to a difficult clinical trial: the Toronto experience with the surgical prostatectomy versus interstitial radiation intervention trial.
Comparison of health-related quality of life 5 years after treatment for men who either chose or were randomized to radical prostatectomy or brachytherapy after a SPIRIT (ACOSOG Z0070) trial education session. Paper presented at 31st Annual Meeting of the American Brachytherapy Society; 29 Apr–1 May 2010; Atlanta: USA.
Comparison of health-related quality of life 5 years after radical prostatectomy (RP) or brachytherapy (BT): the spirit (surgical prostatectomy versus interstitial radiotherapy intervention trial) cohort. Paper presented at Annual Scientific Meeting Research, Discovery, Collaboration and Education in Radiation Oncology and Physics; 22-25 Sep 2010; Vancouver: Canada.
Comparison of health-related quality of life 5 years after brachytherapy (BT) or radical prostatectomy (RP): the SPIRIT (surgical prostatectomy vs. interstitial radiotherapy intervention trial) cohort (ACOSOG Z0070). Paper presented at 52nd Annual Meeting of the American Society for Radiation Oncology; 31 Oct–04 Nov 2010; San Diego: USA.
Long-term outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (T2c–T3b). Paper presented at Annual Meeting of the American Urological Association; 14–19 May 2011; Washington, DC: USA.
Long-term outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (T2c–T3b). Paper presented at 32nd Congress of the Societe Internationale d’Urologie; 30 Sep–4 Oct 2012; Fukuoka: Japan.
Long-term outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (T2c–T3b). Paper presented at 26th Annual Congress of the European Association of Urology; 18–22 Mar 2011; Vienna: Austria.
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.
Quality of Life after radical radiotherapy for prostate cancer: results from a randomised trial of EBRT+/− HDR-BT. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9–13 May 2012; Barcelona: Spain.
Randomised trial of external beam radiotherapy alone or with high-dose-rate brachytherapy boost in localised prostate cancer. Paper presented at European Society for Therapeutic Radiology and Oncology; 12–16 Sep 2010; Barcelona: Spain.
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.
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.
Intermediate risk localized prostate cancer treated with three-dimensional conformal RT (3DCR) versus 3DCR with low dose rate brachytherapy boost (3DCR+BT). Paper presented at European Society for Therapeutic Radiology and Oncology; 12–16 Sep 2010; Barcelona: Spain.
External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.
Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial.
Three years of adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy: results at 10 years of EORTC trial 22863. Paper presented at Joint ECCO 15–34th ESMO Multidisciplinary Congress; 20–24 Sep 2009; Berlin: Germany.
Long term results of immediate adjuvant hormonal therapy with goserelin in patients with locally advanced prostate cancer treated with radiotherapy: a phase III EORTC study. Paper presented at 41st meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO); 31 Oct-4 Nov 1999; San Antonio: USA.
6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial.
10 year main endpoints data from the TROG 9601 trial. Paper presented at European Society for Therapeutic Radiology and Oncology; 12–16 Sep 2010; Barcelona: Spain.
Important mortality reductions by short term androgen deprivation and radiotherapy for locally advanced prostate cancer: 10 year trial data from TROG 96.01. Paper presented at ESTRO Anniversary Congress; 8–12 May 2011; London: United Kingdom.
Time to biochemical failure and prostate-specific antigen doubling time as surrogates for prostate cancer-specific mortality: evidence from the TROG 96.01 randomised controlled trial.
Cardiovascular mortality following short-term androgen deprivation in clinically localized prostate cancer: an analysis of RTOG 94–08. Paper presented at 53rd Annual Meeting of the American Society for Radiation Oncology; 2–6 Oct 2011; Miami Beach: USA.
Radiation Therapy Oncology Group (RTOG) 9408: a secondary analysis of the risk of death from second cancers comparing whole pelvic (WP) radiation therapy (RT) to prostate only (PO) RT and neoadjuvant hormonal therapy (NHT) + RT to RT alone. Paper presented at 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO); 22–25 Sep 2013; Atlanta: USA.
Inferior clinical outcomes for patients with positive post-radiation therapy prostate biopsy: results from prospective randomized trial RTOG 94–08. Paper presented at 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO); 22–25 Sep 2013; Atlanta: USA.
Cardiovascular mortality following short-term androgen deprivation in clinically localized prostate cancer: an analysis of RTOG 94–08. Paper presented at 2012 Genitourinary Cancers Symposium; 2–4 Feb 2012; San Francisco: USA.
Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group.
Phase III radiation therapy oncology group (RTOG) trial 86–10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate.
Hypofractionation versus conventionally fractionated radiation therapy for prostate cancer: late toxicity. Paper presented at 21st Annual Meeting of the Italian Society of Uro-Oncology; 22–24 Jun 2011; Naples: Italy.
Hypofractionation versus conventionally fractionated radiation therapy for prostate cancer: our first results. Paper presented at 20th Annual Meeting of the Italian Society of Uro-Oncology; 23–25 Jun 2010; Rome: Italy.
Short term hormone therapy and dose escalated radiation for localized prostate cancer: a randomized phase III study. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9–13 May 2012; Barcelona: Spain.
A randomized hypofractionation dose escalation trial for high risk prostate cancer patients: interim analysis of acute toxicity and quality of life in 124 patients.
Acute toxicity of the randomized phase III Dutch hypofractionation trial (hypro) for prostate cancer. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9-13 May 2012; Barcelona: Spain.
Updated results and pattern of failure in a randomized hypofractionation trial for high-risk prostate cancer. Paper presented at 54th Annual Meeting of the American Society for Radiation Oncology; 28–31 Oct 2012; Boston: USA.
A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Paper presented at European Society for Therapeutic Radiology and Oncology; 12–16 Sep 2010; Barcelona: Spain.
Modeling of alpha/beta for late rectal toxicity from a randomized phase II study: conventional versus hypofractionated scheme for localized prostate cancer.
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.
Urinary obstruction in prostate cancer patients from the dutch trial (68 Gy vs. 78 Gy): relationships with local dose acute effects and baseline characteristics.
Dose escalation and quality of life in patients with localized prostate cancer treated with radiotherapy: long-term results of the dutch randomized dose-escalation trial (CKTO 96–10 Trial).
Preliminary results of a randomized dose-escalation study comparing 70 Gy to 78 Gy for the treatment of prostate cancer. Paper presented at 41st meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO); 31 Oct–4 Nov 1999; San Antonio: USA.
Rectal dose-volume histogram parameters are associated with long-term patient-reported gastrointestinal quality of life after conventional and high-dose radiation for prostate cancer: a subgroup analysis of a randomized trial.
Update on PROG 95–09: 10 year outcomes of 79 Gy versus 70 Gy conformal RT in low- and intermediate-risk prostate cancer. Paper presented at European Society for Therapeutic Radiology and Oncology; 12–16 Sep 2010; Barcelona: Spain.
Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95–09.
Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. [Erratum appears in JAMA 2008 Feb 27;299(8):899–900].
n = 90 Stage: T1-T2N0M0 (clinical stage A2 or B) PSA at baseline: not reported Gleason score: not reported Age: not reported Normal prostatic acid phosphatase levels, negative isotopic bone scans, no pelvic nodal extension
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Low-intermediate risk
RP
EBRT (no further details)
TF
External beam radiation therapy (low dose) vs. watchful waiting
A phase III randomized trial to evaluate the efficacy of neoadjuvant therapy prior to curative radiotherapy in locally advanced prostate cancer patients: a Canadian Urologic Oncology Group study.
Brachytherapy in localized prostate cancer with or without androgen deprivation. Paper presented at 17th Meeting of the Radiation Oncology Spanish Society (SEOR); 18–21 Jun 2013; Vigo: Spain.
Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911).
Long term results of immediate postoperative radiotherapy after radical prostatectomy in PT3N0 prostate cancer (EORTC 22911). Paper presented at European Society for Therapeutic Radiology and Oncology; 12–16 Sep 2010; Barcelona: Spain.
10-Year results of adjuvant radiotherapy after radical prostatectomy in PT3N0 prostate cancer (EORTC 22911). Paper presented at 52nd Annual Meeting of the American Society for Radiation Oncology; 31 Oct–04 Nov 2010; San Diego, USA.
Preliminary results for EORTC trial 22911: radical prostatectomy followed by postoperative radiotherapy in prostate cancers with a high risk of progression.
Acute toxicity of curative radiotherapy for intermediate risk localized prostate cancer in the EORTC trial 22991. Paper presented at Joint ECCO 15–34th ESMO Multidisciplinary Congress; 20–24 Sep 2009; Berlin: Germany.
n = 1005 Stage: cT0–cT3N0 (UICC 1989) PSA at baseline (ng/ml, median): 12.4 Gleason score: not reportedvAge: ⩽75 years Untreated. WHO performance status 0–2
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Low–high risk
RP
RP + EBRT (60 Gy in 30 fractions)
AE, bPFS, DSS, mPFS, OS, toxicity, urinary function (pad test)
The prognostic impact of seminal vesicle involvement found at prostatectomy and the effects of adjuvant radiation: data from Southwest Oncology Group 8794.
Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial.
Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96–02/AUO AP 09/95.
Phase III study of adjuvant RT for prostate cancer: impact of pathologic review on analysis. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9–13. Barcelona: Spain.
Phase III results of adjuvant radiotherapy (RT) versus, wait and see” (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96–02/AUO AP 09/95).
Phase III results of adjuvant radiotherapy (RT) versus wait-and-see (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96–02/AUO AP 09/95): ten years follow-up. Paper presented at 2013 Genitourinary Cancers Symposium; 14–16 Feb 2013; Orlando: USA.
Time, symptom burden, androgen deprivation, and self-assessed quality of life after radical prostatectomy or watchful waiting: the randomized Scandinavian prostate cancer group study number 4 (SPCG-4) clinical trial.
Individualized estimation of the benefit of radical prostatectomy: data from SPCG4, the Scandinavian randomized trial of radical prostatectomy. Paper presented at Annual Meeting of the American Urological Association; 14–19 May 2011; Washington: USA.
Long-term distress after radical prostatectomy versus watchful waiting in prostate cancer: a longitudinal study from the Scandinavian Prostate Cancer Group-4 randomized clinical trial.
n = 695 Stage: T0c/d-2 (IUAC 1978/1987) PSA at baseline (ng/ml): <50 Gleason score: not reported Age: 64 years (mean) Life expectance > 10 years. Untreated. Negative bone scan. Risk (Gleason/WHO): 38% low, no further details
n = 142 Stage: T0-T2 (stage I and II adenocarcinoma of prostate) PSA at baseline: not reported Gleason score: 87% ⩽ 6, 13% 7–10 Age (median): 67 years (stage I), 61 years (stage II)
The prostate cancer intervention versus observation trial: VA/NCI/AHRQ cooperative studies program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy with watchful waiting for men with clinically localized prostate cancer.
Prostate Intervention Versus Observation Trial (PIVOT): a randomized trial comparing radical prostatectomy with palliative expectant management for treatment of clinically localized prostate cancer.
The prostate cancer intervention versus observation trial: a randomized trial comparing radical prostatectomy versus expectant management for the treatment of clinically localized prostate cancer.
Early intervention or expectant management for prostate cancer: the prostate cancer intervention versus observation trial (PIVOT); a randomized trial comparing radical prostatectomy with expectant management for the treatment of clinically localized prostate cancer.
The prostate cancer intervention versus observation trial (PIVOT): a randomized trial comparing radical prostatectomy versus expectant management for the treatment of clinically localized prostate cancer.
The prostate cancer intervention versus observation trial:VA/NCI/AHRQ cooperative studies program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer.
n = 731 Stage: T1a-T2cNxM0 PSA at baseline (ng/ml, mean): 10.2 Gleason score: 74% ⩽6, 19% 7, 7% 8–10 Age: 66.9 years (mean) Risk (D’Amico): 42% low, 36% intermediate, 22% high
/?/?/?//
Low–high risk
RP
WW
Bowel function, cPFS, DSS, OS, QoL, sexual function, urinary function
∗Risk of bias items [Cochrane Handbook]: Randomisation; Allocation concealment; Patient/personnel blinding; Outcome assessor blinding; Incomplete outcome reporting; Selective outcome reporting. = low risk of bias; = high risk of bias; ? = unclear of bias; 3DCR = Three-Dimensional Conformal Radiotherapy; AE = Adverse event; bPFS = Biochemical progression-free survival; BT = Brachytherapy; CFRT = Conventionally fractionated radiotherapy; cPFS = Clinical progression-free survival; CT = Computer tomography; DSS = Disease-specific survival; EBRT = External Beam Radiotherapy; EORTC = European Organization for Research and Treatment of Cancer; EPIC = Expanded Prostate Cancer Index Composite; FACT-P = Functional Assessment of Cancer Therapy specific for prostate cancer; GETUG = Groupe d’Etude des Tumeurs Uro-Génitales; Gy = Gray (SI unit of absorbed radiation); HDR = High-dose radiation; HFRT = Hypofractionated radiotherapy; HT = Hormone therapy; IIEF = International Index of Erectile Function; IPSS = International Prostate Symptom Score; IUAC = International union against cancer; MC = Multicentre; ml = Millilitre; mPFS = Mixed (biochemical and clinical) progression-free survival; months = Months; NCCN = National Comprehensive Cancer Network; ng = Nanogram; NR = Not reported; OS = Overall survival; PCI = Prostate Cancer Index; PCSS = Prostate Cancer Symptom Scale; PR25 = Prostate-specific module of QLQ-C30; PSA = Prostate-Specific Antigen; QLQ-C30 = EORTC Quality of Life Questionnaire 30-item cancer-specific module; QoL = Quality of life; RP = Radical prostatectomy; SPCG-4 = Scandinavian Prostate Cancer Group study number 4; SPIRIT = Surgical Prostatectomy versus Interstitial Radiotherapy Intervention Trial; TF = Treatment failure; TROG = Trans-Tasman Radiation Oncology Group; UICC = Union for International Cancer Control; UK = United Kingdom; USA = United States of America; WHO = World Health Organization; WW = Watchful Waiting.
]. Common sources for potential risk of bias included missing or insufficient details on randomisation procedure, allocation concealment and the lack of blinding of patients, physicians and outcome assessors.
3.2 Summary of direct comparisons
Key survival-related findings for each treatment are presented in Table 2. Relative effects are grouped as ‘greater than’ (i.e. statistically significant difference (p ⩽ 0.05) in favour of A), ‘no significant difference’ (p > 0.05) and ‘worse than’ (i.e. statistically significant difference (p ⩽ 0.05) in favour of B; see columns). A full version of the table, including all assessed outcomes, is available as an online Appendix.
Table 2Key survival-related findings by comparator. (Please note that a full version of this table is available as an online Appendix.)
Intervention
Relative effect
Effect greater than
No significant difference
Effect worse than
Brachytherapy
RP: bPFS, (Giberti, 2009, n = 174, low-intermediate risk)
Cryoablation
EBRT (low dose): mPFS (36 months, difference 3.9%, 95%-CI −5.3 to 13.2) (Donnelly, 2010, n = 231, low–high risk); DSS, OS (Al-Zahrani, 2011; Donnelly, 2010), n = 293, low–high risk)
EBRT (low dose): bPFS (8 yrs: 17.4% vs. 59.1%, p = 0.01) (Al-Zahrani, 2011, n = 62, intermediate-high risk)
EBRT (low dose)
Cryoablation: bPFS (8 yrs: 17.4% vs. 59.1%, p = 0.01) (Al-Zahrani 2011, n = 62, intermediate-high risk) EBRT (high dose, CFRT) [vs. EBRT (low dose, HFRT)]: bPFS (79% vs. 87%, p = 0.035) (Arcangeli, 2010, n = 114, intermediate-high risk)
Cryoablation: mPFS (36 months, difference 3.9%, 95%-CI −5.3 to 13.2) (Donnelly 2010, n = 231, low–high risk); DSS, OS (2 studies (Al-Zahrani, 2011; Donnelly, 2010), n = 293, low–high risk) EBRT (low dose)±BT: bPFS (n = 0 after mean FUP 22.7 months, PSA after 17.5 months: 0.68 ng/ml vs. 0.88 ng/ml, p = 0.44) (Zapatero-Ortuno, 2010, n = 30, low-intermediate risk); OS (n = 0 after mean FUP 22.7 months; HR 1.36, 95%-CI 0.50–3.65, p = 0.54; 10 yrs, p = 0.2) (3 studies (Hoskin, 2007; Sathya, 2005; Zapatero-Ortuno, 2010), n = 352, low–high risk) EBRT (low dose)±HT: bPFS (2 yrs) (Laverdière, 1997, n = 120, low–high risk); OS (10 yrs, 8.7 vs. 7.3 yrs, p = 0.12; 15 yrs, no significant difference) (2 studies (Pilepich, 1995; Zagars, 1988), n = 534, low–high risk) EBRT (high dose): cPFS (clinical failure, HR 0.89, 95%-CI 0.69–1.15) (Peeters, 2006, n = 664, low–high risk); DSS (54 months, p = 0.61; 110 months, HR 0.96, 95%-CI 0.63–1.45) (2 studies (Beckendorf, 2004; Peeters, 2006), n = 968, low–high risk); bPFS (5 yrs, Phoenix, 23.5 vs. 32%; 10 yrs, Phoenix, p = 0.001) (2 studies (Beckendorf, 2004; Zietman, 2005), n = 699, low–high risk); OS (54 months, p = 0.52; 110 months, HR 0.99, 95%-CI 0.75–1.3; 8 yrs, no overall difference) (4 studies (Beckendorf, 2004; Peeters, 2006; Pollack, 2000; Zietman), n = 1662, low–high risk)
EBRT (low dose)±BT: bPFS (Hoskin, 2007, n = 218, low–high risk); mPFS (HR 0.42, 95%–CI 0.23–0.75, p = 0.0024; Median FUP 7.1 yrs: p = 0.01) (2 studies (Hoskin, 2007; Sathya, 2005), n = 312, low–high risk) EBRT (low dose)±HT: bPFS (10 yrs. p = 0.003/p < 0.001; 10 yrs, HR 1.74, 95%-CI 1.48–2.04, 1 yr, p < 0.0001; 10 yrs, p < 0.01), cPFS (10 yrs, p = 0.002/p < 0.001; 10 yrs, HR 1.45, 95%-CI 1.03–2.06, 2 yrs; p < 0.01; 10 yrs, distant metastases, p = 0.006) (4 studies (Denham, 2008; Jones, 2011; Laverdière, 1997; Pilepich, 1995), n = 3357, low–high risk); OS (10 yrs, HR 0.60, 95%-CI 0.45–0.80; 7.6 yrs. HR 1.8, 95%-CI 1.1–2.9; 10 yrs, HR 0.63, 95%-CI 0.48–0.83; 10 years, HR 1.17, 95%-CI 1.01–1.35) (4 studies (Bolla, 2002; D’Amico, 2004; Denham, 2008; Jones, 2011). n = 3388, low–high risk); DSS (10 yrs, HR 0.42, 95%-CI 0.33–0.55; 4.5 yrs, p = 0.02; 10 yrs, HR 0.49, 95%-CI 0.32–0.74; 10 yrs, HR 1.87, 95%-CI 1.27–2.74; 10 yrs, p = 0.01; 15 yrs, p = 0.008) (5 studies (Bolla, 2002; D’Amico, 2004; Denham, 2008; Jones, 2011; Pilepich, 1995; Zagars, 1988). n = 3922, low–high risk) EBRT (high dose): bPFS (Phoenix, HR 0.80, 95%-CI 0.64–0.97), mPFS (110 months, HR 0.79, 95%-CI 0.64–0.97; 6 yrs, 64% vs. 70%, p = 0.03) (Peeters, 2006, n = 664, low–high risk); cPFS (10 yrs, HR 0.57, 95%-CI 0.43–0.74) (Zietman, 2005, n = 393, low-intermediate risk) RP: mPFS (Time to first event, p = 0.037) (Paulson, 1982, n = 90, low-intermediate risk)
EBRT (low dose) + BT
EBRT (low dose): bPFS (Hoskin 2007, n = 218, low–high risk); mPFS (HR 0.42, 95%-CI 0.23–0.75, p = 0.0024; Median FUP 7.1 yrs: p = 0.01) (2 studies (Hoskin, 2007; Sathya, 2005), n = 312, low–high risk)
EBRT (low dose): bPFS (n = 0 after mean FUP 22.7 months, PSA after 17.5 months: 0.68 ng/ml vs. 0.88 ng/ml, p = 0.44) (Zapatero-Ortuno, 2010, n = 30, low-intermediate risk); OS (n = 0 after mean FUP 22.7 months; HR 1.36, 95%-CI 0.50–3.65, p = 0.54; 10 yrs, p = 0.2) (3 studies (Hoskin, 2007; Sathya, 2005; Zapatero-Ortuno, 2010), n = 352, low–high risk)
EBRT (low dose): cPFS (clinical failure, HR 0.89, 95%-CI 0.69–1.15) (Peeters, 2006, n = 664, low–high risk); DSS (54 months, p = 0.61; 110 months, HR 0.96, 95%-CI 0.63–1.45) (2 studies (Beckendorf, 2004; Peeters, 2006), n = 968, low–high risk); bPFS (5 yrs, Phoenix, 23.5 vs. 32%; 10 yrs, Phoenix, p = p = 0.001) (2 studies (Beckendorf, 2004; Zietman, 2005), n = 699, low–high risk); OS (54 months, p = 0.52; 110 months, HR 0.99, 95%-CI 0.75–1.3; 8 yrs, no overall difference) (4 studies (Beckendorf, 2004; Peeters, 2006; Pollack, 2000; Zietman), n = 1662, low–high risk)
EBRT (low dose, HFRT) [vs. EBRT (high dose, CFRT)]: bPFS (79% vs. 87%, p = 0.035) (Arcangeli, 2010, n = 114, intermediate-high risk)
EBRT (unclear dose)
RP: bPFS (median time to failure: 55.5 vs. 56 months), cPFS (median time to local progression: 65 vs. 64 months), DSS (3/70 vs. 1/67) (Stasi 2006, n = 137, low–high risk)
EBRT (unclear dose) + BT
EBRT (unclear dose)±BT±HT: bPFS (60 months, Phoenix, 83 vs. 90%, p = 0.4), cPFS (60 months, no significant difference for distal metastases and locoregional control) (García Blanco 2013, n = 62, intermediate-high risk)
EBRT (unclear dose) + BT + HT
EBRT (unclear dose)±BT: bPFS (60 months, Phoenix, 83 vs. 90%, p = 0.4), cPFS (60 months, no significant difference for distal metastases and locoregional control) (García Blanco, 2013, n = 62, intermediate-high risk)
RP
EBRT (low dose): mPFS (Time to first event, p = 0.037) (Paulson, 1982, n = 90, low-intermediate risk) Watchful waiting: DSS (6 yrs: HR 0.50, 95%-CI 0.27–0.91, p = 0.02) (Holmberg, 2002, n = 695, low-intermediate risk); cPFS (local progression, 15 yrs: RR 0.34, 95%-CI 0.26–0.45; distant metastases: HR 0.63, 95%-CI 0.41–0.96, p = 0.03; bone metastases, HR 0.40, 95%-CI 0.22–0.70, p < 0.001) (2 studies (Wilt, 2012; Holmberg, 2002), n = 1426, low–high risk)
Brachytherapy: bPFS (Giberti, 2009, n = 174, low-intermediate risk) (Giberti, 2009, Crook, 2011), n = 208, low-intermediate risk) ERBT (unclear dose): bPFS (median time to failure: 55.5 vs. 56 months), cPFS (median time to local progression: 65 vs. 64 months), DSS (3/70 vs. 1/67) (Stasi 2006, n = 137, low–high risk) RP± EBRT: DSS (10 yr, 25/502 vs. 34/503) (Bolla, 2005, n = 1005, low–high risk); cPFS (10 yrs, metastasis-free survival, p = 0.56) (Wiegel ,2009, n = 307, intermediate-high risk) (2 studies (Bolla, 2005; Thompson, 2006)), n = 532, low–high risk); OS (HR 1.18, 95%-CI 0.91–1.53; 10 yrs, p = 0.59) (2 studies (Bolla, 2005; Wiegel, 2009), n = 1312, low–high risk) Watchful waiting: OS (10 yrs: HR 0.88, 95%-CI 0.71–1.08, p = 0.22; 6 yrs: p = 0.31) (3 studies (Madsen, 1988; Wilt, 2012; Holmberg, 2002), n = 1568, low–high risk)
RP± EBRT: cPFS (Median FUP 12 yrs: HR 0.71, 95%-CI 0.54–0.94, p = 0.016), OS (Median follow-up 12 yrs: HR 0.72, 95%-CI 0.55–0.96, p = 0.023) (Thompson, 2006, n = 425, intermediate-high risk); mPFS (10 yrs; biochemical, chemical, death: HR 0.49 (95%-CI 0.41–0.59), p = 0.001; 5 yrs: HR 0.53, 95%-CI 0.37–0.79, p = 0.015) (2 studies (Bolla, 2005; Wiegel, 2009), n = 1312, low–high risk); bPFS (10 yr, 105/502 vs. 238/503; Median FUP 10.6 yrs: HR 0.62, 95%-CI 0.46–0.82, p = 0.001; 10 yr, p < 0.01) (3 studies (Bolla, 2005; Thompson, 2006; Wiegel, 2009), n = 1737, low–high risk)
RP + EBRT
RP: cPFS (Median FUP 12 yrs: HR 0.71, 95%-CI 0.54–0.94, p = 0.016), OS (Median follow-up 12 yrs: HR 0.72, 95%-CI 0.55–0.96, p = 0.023) (Thompson 2006, n = 425, intermediate-high risk); bPFS (10 yr, 105/502 vs. 238/503; Median FUP 10.6 yrs: HR 0.62, 95%-CI 0.46–0.82, p = 0.001) (2 studies (Bolla, 2005; Thompson, 2006), n = 1430, low–high risk); mPFS (10 yrs; biochemical, chemical, death: HR 0.49 (95%-CI 0.41–0.59), p = 0.001; 5 yrs: HR 0.53, 95%-CI 0.37–0.79, p = 0.015) (2 studies (Bolla, 2005; Wiegel, 2009), n = 1312, low–high risk)
RP: DSS (10 yr, 25/502 vs. 34/503) (Bolla 2005, n = 1005, low–high risk); OS (HR 1.18 (95%-CI 0.91–1.53), p = p = 0.2024) (2 studies (Bolla, 2005, Wiegel, 2009), n = 1312, low–high risk)
Watchful waiting
RP: DSS (10 yrs, HR 0.63, 95%-CI 0.36–1.09, p = 0.09) (Wilt, 2012, n = 731, low–high risk); OS (10 yrs: HR 0.88, 95%-CI 0.71–1.08, p = 0.22; 6 yrs: p = 0.31) (3 studies (Madsen, 1988; Wilt, 2012; Holmberg, 2002), n = 1568, low–high risk)
RP: DSS (6 yrs: HR 0.50, 95%-CI 0.27–0.91, p = 0.02) (Holmberg, 2002, n = 695, low-intermediate risk); cPFS (local progression, 15 yrs: RR 0.34, 95%-CI 0.26–0.45; distant metastases: HR 0.63, 95%-CI 0.41–0.96, p = 0.03; bone metastases, HR 0.40, 95%-CI 0.22–0.70, p < 0.001) (2 studies (Wilt, 2012; Holmberg, 2002), n = 1426, low–high risk)
Reading advice: Outcome (follow-up, main finding) (number of studies, number of patients, D’Amico surrogate).
3DCR = Three-Dimensional Conformal Radiotherapy; bPFS = Biochemical progression-free survival; BT = Brachytherapy; CFRT = Conventionally fractionated radiotherapy; CI = Confidence interval; cPFS = Clinical progression-free survival; DSS = Disease-specific survival; EBRT = External Beam Radiotherapy; EORTC = European Organization for Research and Treatment of Cancer; FUP = Follow-up; HDR = High-dose radiation; HFRT = Hypofractionated radiotherapy; HR = Hazard ratio; ml = Millilitre; mPFS = Mixed (biochemical and clinical) progression-free survival; ng = Nanogram; OS = Overall survival; RD = Risk difference; RP = Radical Prostatectomy; RR = Relative risk; wk = Weeks; yrs = Year(s).
These results are also presented in a network diagram showing the survival-related relative effects of all included studies for each identified comparison (see Fig. 2). Endpoints for which no statistically significant differences were reported are represented by the grey double lines. In contrast, endpoints for which a statistically significant effect was found are represented by the coloured lines where the arrow points to the treatment with the higher relative effect. The numbers of studies reporting on each outcome are given in brackets while letters refer to the risk grade of patients included in the studies (D’Amico surrogate). A full version of the network is available as an online Appendix. Outcomes relevant to mortality and/or disease progression are highlighted in bold.
Fig. 2Network diagram showing all survival-related relative effects. (Please note that a full version of this figure is available as an online Appendix.)
For some comparisons of overall survival, available data allowed pooling. Comparisons of EBRT (low dose) with: (1) EBRT (low dose) combined with HT; (2) EBRT (low dose) + BT, i.e. combined dose escalation; as well as (3) EBRT (high dose) were all possible. Furthermore, pooling was possible for two studies comparing RP with watchful waiting and RP with RP followed by EBRT. Only one of these comparisons showed a statistically significant advantage, as shown in Fig. 3. Based on six studies, the pooled estimate for comparison of EBRT (low dose) with EBRT (low dose) + HT was RR 1.21 (95%-CI 1.12–1.30) in favour of the combined treatment. Life expectancy for low to high risk patients does appear to improve when HT is added to low dose EBRT, however there is a suggestion that this improvement may be at the cost of a loss of sexual functioning (see information on D’Amico et al. [
6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial.
Where ‘head-to-head’ trials (i.e. A versus B) were not identified, it was originally planned to perform indirect comparisons. The RRs (with 95%-CIs) for A versus B would have been estimated using ‘indirect’ methods [
]. However, clinical differences in patient populations prohibited indirect comparisons.
3.4 Findings of the review
Based on an extensive search of the current literature, 36 relevant studies were identified, allowing twelve different pair-wise comparisons.
Findings from direct comparisons suggest that EBRT, BT and RP are effective treatments for localised prostate cancer and that post-operative EBRT is also effective but might be associated with additional toxicity; see Fig. 2 and Table 2.
Evidence from two smaller trials (n = 208), comparing BT with RP in patients with low to intermediate risk cancer suggest similar biochemical disease-free survival when compared with RP, with favourable results for BT in terms of sexual functioning [
Impact of a multi-disciplinary patient education session on accrual to a difficult clinical trial: the Toronto experience with the surgical prostatectomy versus interstitial radiation intervention trial.
Comparison of health-related quality of life 5 years after treatment for men who either chose or were randomized to radical prostatectomy or brachytherapy after a SPIRIT (ACOSOG Z0070) trial education session. Paper presented at 31st Annual Meeting of the American Brachytherapy Society; 29 Apr–1 May 2010; Atlanta: USA.
Comparison of health-related quality of life 5 years after radical prostatectomy (RP) or brachytherapy (BT): the spirit (surgical prostatectomy versus interstitial radiotherapy intervention trial) cohort. Paper presented at Annual Scientific Meeting Research, Discovery, Collaboration and Education in Radiation Oncology and Physics; 22-25 Sep 2010; Vancouver: Canada.
Comparison of health-related quality of life 5 years after brachytherapy (BT) or radical prostatectomy (RP): the SPIRIT (surgical prostatectomy vs. interstitial radiotherapy intervention trial) cohort (ACOSOG Z0070). Paper presented at 52nd Annual Meeting of the American Society for Radiation Oncology; 31 Oct–04 Nov 2010; San Diego: USA.
]. The effects on urinary function are unclear. While one study reports statistically significant greater and more short-term urinary problems, the other study suggests late changes (after 5 years) in urinary function in favour of BT. Use of BT in higher risk patients has not been evaluated in any of the included RCTs.
In the light of the specific techniques employed in trials, higher doses of EBRT result in favourable survival-related outcomes (overall and progression-free survival) but might be associated with more side effects (GI- and GU-toxicity), depending on technique. Combining EBRT (low dose) with hormone therapy showed statistically significant advantages in terms of overall survival (see Fig. 2 and Table 2).
4. Discussion
In this systematic review, we aimed to assess the efficacy and adverse events associated with radiotherapy (EBRT and/or BT) compared with other management options in patients with prostate cancer.
4.1 Comparison with other reviews
A number of recently published systematic reviews assessed comparators identified and discussed here. Most of these reviews did not identify any RCTs relevant to the respective question which is in agreement with the findings of this report, e.g. Cordeiro 2012 (HIFU) [
] aimed to “review the data concerning the pros and cons of immediate or adjuvant RT, or of an approach involving delayed or salvage RT once BCR [biochemical recurrence] occurs”. They identified three RCTs also included in this review [
Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96–02/AUO AP 09/95.
Permanent interstitial low-dose-rate brachytherapy for patients with localised prostate cancer: a systematic review of randomised and nonrandomised controlled clinical trials.
Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group.
]. Based on 140 non-randomised studies which assessed 11 different treatment types, Grimm et al. concluded that “in terms of biochemical-free progression, brachytherapy provides superior outcome in patients with low-risk disease”. This conclusion is broadly in line with the findings of our review of randomised controlled trials where the study by Giberti et al. [
] including 174 patients showed no significant difference of biochemical progression-free survival between BT and RP. However, the RCT showed a statistically significant advantage of brachytherapy regarding patient satisfaction and self-reported sexual functioning (see Fig. 2 and Table 2).
4.2 Strengths, limitations, uncertainties
The systematic review process followed published guidelines [
Higgins J.P.T. Green S. Cochrane handbook for systematic reviews of interventions [Internet]. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration,
2011
]. In order to try to identify all potentially relevant evidence relating to the review question as well as to reduce the risk of publication bias, an extensive range of resources was searched. In addition, reference lists of included studies were checked to identify further relevant studies. Published and unpublished trials (such as conference abstracts) irrespective of size or follow up period were eligible for inclusion. However, the size and duration of trials was considered when appraising the evidence.
Although this review sought wherever possible to reduce the risk of bias during the review processes and analyses, the findings may still be subject to certain limitations and uncertainties beyond our control. One such factor would be the small size of trials which means that important effects, or non-effects cannot necessarily be detected because of underpowering.
The reliability of the findings might be further limited by methodological or reporting weaknesses of the included studies. Results of four studies were only reported in abstracts, which made it difficult to assess the risk of bias and hence comment on the reliability of the findings. Our inclusion criteria are designed to be comprehensive so that no study of potential value is missed. However, this inevitably means that some studies will be included which provide very little evidence of direct use but future researchers can be confident that nothing has been overlooked.
Matching of patients to treatment is facilitated by stratifying patients into risk groups. There is currently a debate as to how patients should be stratified according to risk factors [
Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era.
] because it was most prevalent within the literature although we are aware that other systems have been used, e.g. the system of the National Comprehensive Cancer Network (NCCN) [
However, there was considerable variation in the way eligible populations were described and definitions of patient characteristics were sometimes imprecise, meaning that patients could only be described as having “low to high risk” disease.
We have sought to report on evidence which has already been reported. We are aware that many ongoing studies (e.g. the Prostate Testing for Cancer and Treatment (ProtecT) trial) offer potential to considerably increase the knowledge pool. Keeping abreast of emerging research is a challenge faced by all systematic reviews.
4.3 Implications and recommendations for further research
Further large, methodologically robust randomised controlled trials are needed. These need to be compliant with established reporting standards, use relevant outcome measures collected over long follow-up periods and report data in a form that can be extracted and incorporated into databases and meta-analyses.
It should be noted that such trials are logistically very difficult to complete due to funding issues and patient and physician preferences. However, this review identified ten ongoing studies which might be able to fill gaps in the current evidence base, thereby demonstrating that RCTs are actively being conducted in this area but it should be noted that this list might not be complete [
Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial.
Transperineal prostate brachytherapy, using I-125 seed with or without adjuvant androgen deprivation, in patients with intermediate-risk prostate cancer: study protocol for a phase III, multicenter, randomized, controlled trial.
Prostate brachytherapy with or without adjuvant ADT in intermediate prostate cancer: study protocol. Paper presented at ESTRO Anniversary – GEC-ESTRO – EIOF – 11th Biennial; 8–12 May 2011; London: United Kingdom.
The Study of Active Monitoring in Sweden (SAMS): a randomized study comparing two different follow-up schedules for active surveillance of low-risk prostate cancer.
Testosterone variation in intermediate risk prostate cancer treated with androgen blockade and radiotherapy. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9–13 May 2012; Barcelona: Spain.
A phase III randomized, open-label multicenter trial to evaluate the benefit of leuprorelin acetate for 24 months after radical prostatectomy in patients with high risk of recurrence (AFU-GETUG 20/0310). Paper presented at 2012 Genitourinary Cancers Symposium; 2–4 Feb 2012.
Successful patient acceptance of randomization within the PACE study (Prostate Advances in Comparative Evidence). Paper presented at 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO); 22–25 Sep 2013; Atlanta: USA.
]. The ProtecT trial will help in this regard and should inform which of radiotherapy, radical prostatectomy and active surveillance should be used in daily clinical practice [
Evidence from this systematic review suggest that, when used appropriately, external beam radiotherapy, brachytherapy and radical prostatectomy can result in improved overall survival, progression-free survival as well as functioning (urinary/bowel/sexual) in localised disease. All treatments have their unique adverse events profiles.
Our ability to make firm recommendations for specific risk-stratified sub-groups or variants of main technologies is limited by the way these issues have been described in the literature. This review provides information as to how such issues might be addressed in future studies.
Further large, methodologically robust, randomised controlled trials are needed to report treatment-specific and treatment combination-specific outcomes in defined prostate cancer risk groups. These will provide the evidence base for the relatively newer therapies, e.g. HIFU, help reinforce current consensus guidelines, establish greater standardisation across practices and point the way towards research gaps.
Authors’ contributions
JK developed the concept for the project. SD and Diana Hilmer formulated the search strategy and carried out searches. Study inclusion, quality assessment and data extraction were done by MB, SR and RFW. Statistical analyses were conducted by RFW and GW. In a series of meetings, ABo, ABri, JC, AH, JKa, LP, TdR and NS provided advice on clinical aspects related to study inclusion, quality assessment, data extraction, analyses and results interpretation. The manuscript was prepared by RFW, SR and JK. All authors read and approved the final manuscript.
Conflict of interest statement
Work on this systematic review was sponsored by Elekta. Elekta was given the opportunity to comment on the draft paper, but the authors had full editorial freedom.
((Prostate or prostatic) adj3 (carcinoma$ or cancer$ or neoplas$ or tumo?r$ or malignan$ or adenocarcinoma$ or adenoma$)).ti,ab,ot. (87042)
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(16)
14 and 15 (590)∗
Trials filter (best sensitivity and specificity) from:
Lefebvre C, Manheimer E, Glanville J. Chapter 6: searching for studies. Box 6.4.c: Cochrane Highly sensitive search strategy for identifying randomised controlled trials in Medline 2008 version; OVID format. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
∗This search updated a previous search. Therefore the number of references does not match the number reported in the flow chart.
Cancer trends progress report - 2011/2012 update: costs of cancer care [Internet].
National Cancer Institute,
Bethesda, MD2012 ([accessed 06.05.14]. Available from: http://progressreport.cancer.gov/doc_detail.asp?pid=1&did=2007&chid=75&coid=726&)
Higgins J.P.T. Green S. Cochrane handbook for systematic reviews of interventions [Internet]. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration,
2011 (Available from: http://www.cochrane-handbook.org/)
Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era.
Impact of a multi-disciplinary patient education session on accrual to a difficult clinical trial: the Toronto experience with the surgical prostatectomy versus interstitial radiation intervention trial.
Comparison of health-related quality of life 5 years after treatment for men who either chose or were randomized to radical prostatectomy or brachytherapy after a SPIRIT (ACOSOG Z0070) trial education session. Paper presented at 31st Annual Meeting of the American Brachytherapy Society; 29 Apr–1 May 2010; Atlanta: USA.
Comparison of health-related quality of life 5 years after radical prostatectomy (RP) or brachytherapy (BT): the spirit (surgical prostatectomy versus interstitial radiotherapy intervention trial) cohort. Paper presented at Annual Scientific Meeting Research, Discovery, Collaboration and Education in Radiation Oncology and Physics; 22-25 Sep 2010; Vancouver: Canada.
Comparison of health-related quality of life 5 years after brachytherapy (BT) or radical prostatectomy (RP): the SPIRIT (surgical prostatectomy vs. interstitial radiotherapy intervention trial) cohort (ACOSOG Z0070). Paper presented at 52nd Annual Meeting of the American Society for Radiation Oncology; 31 Oct–04 Nov 2010; San Diego: USA.
Permanent interstitial low-dose-rate brachytherapy for patients with localised prostate cancer: a systematic review of randomised and nonrandomised controlled clinical trials.
Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group.
Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial.
Transperineal prostate brachytherapy, using I-125 seed with or without adjuvant androgen deprivation, in patients with intermediate-risk prostate cancer: study protocol for a phase III, multicenter, randomized, controlled trial.
Prostate brachytherapy with or without adjuvant ADT in intermediate prostate cancer: study protocol. Paper presented at ESTRO Anniversary – GEC-ESTRO – EIOF – 11th Biennial; 8–12 May 2011; London: United Kingdom.
The Study of Active Monitoring in Sweden (SAMS): a randomized study comparing two different follow-up schedules for active surveillance of low-risk prostate cancer.
Testosterone variation in intermediate risk prostate cancer treated with androgen blockade and radiotherapy. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9–13 May 2012; Barcelona: Spain.
A phase III randomized, open-label multicenter trial to evaluate the benefit of leuprorelin acetate for 24 months after radical prostatectomy in patients with high risk of recurrence (AFU-GETUG 20/0310). Paper presented at 2012 Genitourinary Cancers Symposium; 2–4 Feb 2012.
Successful patient acceptance of randomization within the PACE study (Prostate Advances in Comparative Evidence). Paper presented at 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO); 22–25 Sep 2013; Atlanta: USA.
Long-term outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (T2c–T3b). Paper presented at Annual Meeting of the American Urological Association; 14–19 May 2011; Washington, DC: USA.
Long-term outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (T2c–T3b). Paper presented at 32nd Congress of the Societe Internationale d’Urologie; 30 Sep–4 Oct 2012; Fukuoka: Japan.
Long-term outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (T2c–T3b). Paper presented at 26th Annual Congress of the European Association of Urology; 18–22 Mar 2011; Vienna: Austria.
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.
Quality of Life after radical radiotherapy for prostate cancer: results from a randomised trial of EBRT+/− HDR-BT. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9–13 May 2012; Barcelona: Spain.
Randomised trial of external beam radiotherapy alone or with high-dose-rate brachytherapy boost in localised prostate cancer. Paper presented at European Society for Therapeutic Radiology and Oncology; 12–16 Sep 2010; Barcelona: Spain.
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.
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.
Intermediate risk localized prostate cancer treated with three-dimensional conformal RT (3DCR) versus 3DCR with low dose rate brachytherapy boost (3DCR+BT). Paper presented at European Society for Therapeutic Radiology and Oncology; 12–16 Sep 2010; Barcelona: Spain.
External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.
Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial.
Three years of adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy: results at 10 years of EORTC trial 22863. Paper presented at Joint ECCO 15–34th ESMO Multidisciplinary Congress; 20–24 Sep 2009; Berlin: Germany.
Long term results of immediate adjuvant hormonal therapy with goserelin in patients with locally advanced prostate cancer treated with radiotherapy: a phase III EORTC study. Paper presented at 41st meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO); 31 Oct-4 Nov 1999; San Antonio: USA.
6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial.
10 year main endpoints data from the TROG 9601 trial. Paper presented at European Society for Therapeutic Radiology and Oncology; 12–16 Sep 2010; Barcelona: Spain.
Important mortality reductions by short term androgen deprivation and radiotherapy for locally advanced prostate cancer: 10 year trial data from TROG 96.01. Paper presented at ESTRO Anniversary Congress; 8–12 May 2011; London: United Kingdom.
Time to biochemical failure and prostate-specific antigen doubling time as surrogates for prostate cancer-specific mortality: evidence from the TROG 96.01 randomised controlled trial.
Cardiovascular mortality following short-term androgen deprivation in clinically localized prostate cancer: an analysis of RTOG 94–08. Paper presented at 53rd Annual Meeting of the American Society for Radiation Oncology; 2–6 Oct 2011; Miami Beach: USA.
Radiation Therapy Oncology Group (RTOG) 9408: a secondary analysis of the risk of death from second cancers comparing whole pelvic (WP) radiation therapy (RT) to prostate only (PO) RT and neoadjuvant hormonal therapy (NHT) + RT to RT alone. Paper presented at 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO); 22–25 Sep 2013; Atlanta: USA.
Inferior clinical outcomes for patients with positive post-radiation therapy prostate biopsy: results from prospective randomized trial RTOG 94–08. Paper presented at 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO); 22–25 Sep 2013; Atlanta: USA.
Cardiovascular mortality following short-term androgen deprivation in clinically localized prostate cancer: an analysis of RTOG 94–08. Paper presented at 2012 Genitourinary Cancers Symposium; 2–4 Feb 2012; San Francisco: USA.
Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group.
Phase III radiation therapy oncology group (RTOG) trial 86–10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate.
Hypofractionation versus conventionally fractionated radiation therapy for prostate cancer: late toxicity. Paper presented at 21st Annual Meeting of the Italian Society of Uro-Oncology; 22–24 Jun 2011; Naples: Italy.
Hypofractionation versus conventionally fractionated radiation therapy for prostate cancer: our first results. Paper presented at 20th Annual Meeting of the Italian Society of Uro-Oncology; 23–25 Jun 2010; Rome: Italy.
Short term hormone therapy and dose escalated radiation for localized prostate cancer: a randomized phase III study. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9–13 May 2012; Barcelona: Spain.
A randomized hypofractionation dose escalation trial for high risk prostate cancer patients: interim analysis of acute toxicity and quality of life in 124 patients.
Acute toxicity of the randomized phase III Dutch hypofractionation trial (hypro) for prostate cancer. Paper presented at Annual Conference of the European Society for Radiotherapy and Oncology; 9-13 May 2012; Barcelona: Spain.
Updated results and pattern of failure in a randomized hypofractionation trial for high-risk prostate cancer. Paper presented at 54th Annual Meeting of the American Society for Radiation Oncology; 28–31 Oct 2012; Boston: USA.
A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Paper presented at European Society for Therapeutic Radiology and Oncology; 12–16 Sep 2010; Barcelona: Spain.
Modeling of alpha/beta for late rectal toxicity from a randomized phase II study: conventional versus hypofractionated scheme for localized prostate cancer.
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.
Urinary obstruction in prostate cancer patients from the dutch trial (68 Gy vs. 78 Gy): relationships with local dose acute effects and baseline characteristics.
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