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Cochrane Database of Systematic Reviews Protocol - Intervention

Low‐dose rate brachytherapy for men with localized prostate cancer

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness and safety of LDR brachytherapy compared to RP, EBRT, AS, WW in men with localized prostatic cancer.

Background

Description of the condition

Epidemiology

Prostate cancer is the most common cancer in men. Incidence rates vary widely between countries. The age‐standardized rate (ASR) in 2008 for mortality per 100,000 was 84 in the USA and 83 in Germany (Globocan 2010). From 2003 to 2007 in the USA, the median age for cancer of the prostate was 67 years at diagnosis and was 80 years at death (NCI 2010a).

Pathogenesis

Age, ethnic group, positive family history, tobacco smoking, and dietary fat intake are discussed as risk factors for the development of prostate cancer and it was suggested that prostate cancer results from an interplay between endogenous hormones and environmental influences (Pienta 1993; Plaskon 2003). The risk is increased in African Americans and in men with a positive family background (NCI 2010a). First‐degree relatives of patients with prostate cancer have a two‐fold to three‐fold increased risk for developing prostate cancer (Grönberg 2003). Carriers of BRCA1 and BRCA2 mutation have a higher risk of prostate cancer and of more aggressive phenotype (Mitra 2008).

Symptoms

Low‐risk prostate cancer is a slow growing tumor in many affected men and stays localized within the prostate gland for many years. Digital rectal examination (DRE) and blood test for prostate‐specific antigen (PSA) are two screening tests that are used to detect prostate cancer while subclinical (Wolf 2010). Serum free circulating DNA may be a useful biomarker to distinguish benign versus malignant prostate disease (Gordian 2010). Some tumors grow moderately fast and threaten the patient's life.

Classification and staging

Prostate cancer is an adenocarcinoma of the prostate gland in most cases and its different histologic subtypes are classified in the World Health Organization (WHO) 2004 classification (WHO 2004).

Tumor‐Node‐Metastasis (TNM) staging system combines depth and size of the tumor as well as regional lymph node involvement and distant metastases, and describes the extent of a cancer's spread from Stage I to IV (Sobin 2009). Localized prostate cancer is defined by the T codes T1a, T1b, T1c, T2a, T2b, and T2c if combined with an absence of both regional lymph node metastasis (N0) and distant metastasis (M0). Advanced prostate cancer is defined by extending beyond the prostate (T3a, T3b, and T4).

D'Amico 1998 proposed a risk classification utilizing pretreatment prostate‐specific antigen (PSA) (Oesterling 1995), T stage of TNM system (Sobin 2009), and biopsy Gleason score (Gleason 1977).

  • Low risk: PSA < 10 ng/mL and T1c to T2a and Gleason score < 7

  • Intermediate risk: PSA 10 to < 20 ng/mL or T2b or Gleason score = 7

  • High risk: PSA ≥ 20 ng/mL or > T2b or Gleason score > 7

Description of the intervention

Definition

Test intervention
Low‐dose rate brachytherapy (BT)

Brachytherapy (Heidenreich 2010) is short‐distance radiotherapy where a radiation source is placed in or near tumors (AUA 2007). Low‐dose rate (LDR) brachytherapy means implanting low‐energy radioactive sources, the so called seeds, permanently into the prostate through a transperineal technique guided by ultrasound. These interstitially placed seeds are titanium pellets of the size of rice grains that are filled with the radioisotopes iodine‐125 (half‐life 60 days, dose 145 Gy (Gray), energy 28 keV (kiloelectronvolt)) or palladium‐103 (half‐life 17 days, dose 125 Gy, energy 28 keV) to irradiate within the prostate (Grimm 2003). Between 70 and 100 seeds are typically inserted and the seeds may be used as stranded seeds that are tied together with other seeds (linked in an absorbable material used in surgery) or used as free (single) seeds.

LDR brachytherapy is a minimally invasive procedure that can be carried out as an outpatient treatment and completed in 45 to 90 minutes under spinal or general anesthesia. A large prostate volume of 60 mL or more can become technically challenging and basically represents a contraindication to LDR brachytherapy. Radiation continues over the period of a year. The implanted seeds do not represent a significant radiation hazard to others because the energy is very low and the radioisotopes emit low‐energy X‐rays that travel a short distance. Androgen deprivation therapy (ADT) is used in some patients in addition to brachytherapy as an adjuvant or neoadjuvant hormonal therapy. It can reduce the size of the prostate to facilitate implantation.

Control interventions
Active surveillance (AS)

Active surveillance (Heidenreich 2010) means monitoring men, typically with repeated PSA tests, DRE, and sometimes prostate biopsies, and deferring invasive treatment unless tumor progression occurs (AUA 2007). Its goal is to reduce overtreatment and harms while maintaining equivalent long‐term survival. Active surveillance may be confused with watchful waiting, which is an option to wait until symptoms appear. Watchful waiting means observation with palliative treatment for symptomatic disease progression while still permitting potentially curative intervention.

External beam radiotherapy (EBRT)

External beam radiotherapy (Heidenreich 2010) is the irradiation of the prostate from outside the body, which also has the effect of irradiating tissue outside the prostate gland.. EBRT includes 3‐dimensional conformal (3D‐CRT) and intensity‐modulated radiation therapy (IMRT).

Radical prostatectomy (RP)

Radical prostatectomy (Heidenreich 2010) is an open surgery procedure and mostly includes two different approaches, retropubic or perineal. Prostatectomy is the removal of the prostate. A radical prostatectomy is the complete surgical removal of the prostate plus the seminal vesicles and other tissue around it, with an operating time of 2 to 5 hours. RP allows a nerve‐sparing technique in an attempt to preserve erectile function for selected men based on tumor and patient characteristics (Walsh 2000). Robotic and laparoscopic prostatectomy are alternative methods of RP.

How the intervention might work

Radiation therapy is used with curative intent. Placing short‐ranging radioactive sources into the tumor or near the tumor may reduce the probability of adverse events, such as injured tissues around the prostate that are not the target of the treatment. Sparing the destruction of nerves, blood vessels, seminal vesicles, or damage to the urinary bladder and rectum, may provide patients a better quality of life as well as a cure from prostate cancer.

Why it is important to do this review

A systematic review of the literature is needed to assess whether LDR brachytherapy can be recommended as a first choice treatment for patients with localized prostate cancer. Previous systematic reviews have focused on biochemical recurrence in single treatment arms (Koukourakis 2009), or did not identify randomized trials that evaluated brachytherapy (Wilt 2008).

Objectives

To assess the effectiveness and safety of LDR brachytherapy compared to RP, EBRT, AS, WW in men with localized prostatic cancer.

Methods

Criteria for considering studies for this review

Types of studies

Inclusion criteria

RCTs.

Exclusion criteria

None.

Types of participants

Patients with localized prostatic cancer according to the TNM staging system: T categories T1a, T1b, T1c, T2a, T2b, and T2c, if combined with an absence of both regional lymph node metastasis (N0) and distant metastasis (M0). Studies will be included as long as at least 70% of patients have localized prostate cancer.

Types of interventions

  • Intervention: Low‐dose rate brachytherapy (LDR‐BT), with or without androgen deprivation therapy (ADT)

  • Comparison 1: Open radical retropubic or perineal prostatectomy (RP) with or without androgen deprivation therapy (ADT)

  • Comparison 2: External beam radiotherapy (EBRT) including 3‐D conformal (3DCRT), or intensity‐modulated radiation therapy (IMRT) with or without androgen deprivation therapy (ADT)

  • Comparison 3: Active surveillance (AS)

  • Comparison 4: Watchful waiting (WW)

We will not address LDR‐BT versus ADT or compare different variants or dosages of LDR‐BT, such as trials comparing different isotopes.

Types of outcome measures

Primary outcomes

  • Overall survival (OS): chance of staying alive; the event is death by all causes.

  • Cause‐specific survival

  • Metastatic‐free survival

  • Biochemical disease‐free, progression‐free, failure‐free, or recurrence‐free survival: chance of staying free of recurrence of disease (PSA level within a certain range) according to the Phoenix definition of the American Society for Therapeutic Radiology and Oncology (ASTRO) and the Radiation Therapy Oncology Group (RTOG) (Roach 2006); a rise of 2 ng/mL or more above the nadir PSA will be considered the standard definition for biochemical failure.

Secondary outcomes

  • General HRQOL, health‐related quality of life: measured using a validated questionnaire, for example

    • EORTC‐QLQ‐C30 ‐ European Organisation for Research and Treatment of Cancer quality of life questionnaire cancer 30‐item form

    • SCA ‐ Service Satisfaction Scale for Cancer Care

    • SF‐36 ‐ medical outcomes study 36‐item‐short‐form health survey

  • Prostate‐specific HRQOL, health‐related quality of life: measured using validated questionnaire, for example

    • BSFI ‐ Brief Sexual Function Inventory

    • EORTC‐QLQ‐PR25 ‐ European Organisation for Research and Treatment of Cancer quality of life questionnaire prostate cancer disease specific module 25‐item form

    • EPIC ‐ Expanded Prostate Cancer Index composite

    • FACT‐P ‐ Functional Assessment of Cancer Therapy Prostate

    • ICS‐male ‐ International Continence Society questionnaire

    • IIEF‐5 ‐ International Index of Erectile Function 5‐item form

    • IPSS ‐ International Prostate Symptom Score

    • PCSI ‐ Prostate Cancer Symptom Indices

    • UCLA‐PCI ‐ University of California Los Angeles Prostate Ccancer Index

  • Adverse events

    • Urinary tract problems, such as incontinence, irritation (due to residual urine or infection), stricture, or catheterization

    • Bowel problems such as rectal incontinence

    • Sexual problems such as erectile dysfunction

    • Urogenital or gastrointestinal acute or late toxicity

    • Other adverse events

Search methods for identification of studies

Search methods as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009) and by the Cochrane Prostatic Diseases and Urologic Cancers Group will be used. Articles in any language will be included. Translations will be carried out if necessary.

Electronic searches

The following electronic databases will be searched: the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (from 1950 to 2010), Ovid EMBASE (from 1980 to 2010). See 'Appendix 1' for the medical subject headings (MeSH) and text words for Ovid MEDLINE and the search strategies for the other databases will be converted from that.

Searching other resources

Information about trials not registered in CENTRAL, MEDLINE or EMBASE, either published or unpublished, will be located by searching the reference lists of relevant articles and review articles. We also plan to scan electronically the conference proceedings of the American Society of Clinical Oncology (ASCO) annual meeting abstracts from 2006 to 2010.

We will search for ongoing trials by scanning online registers:

  • ClinicalTrials.gov (ClinicalTrials.gov 2010);

  • World Health Organization International Clinical Trials Registry Platform (ICTRP 2010);

  • International Standard Randomised Controlled Trial Number Register (ISRCTN Register 2010);

  • National Institute for Health Research UK Clinical Research Network's (NIHR UKCRN 2010) Portfolio Database;

  • National Cancer Institute Physician Data Query (NCI 2010b) Clinical Trial.

We will also search for ongoing trials by contacting researchers involved in this area.

Data collection and analysis

Selection of studies

All titles and abstracts retrieved by electronic searching will be downloaded to the reference management database EndNote® Version X3 (Thomson Reuters Corp 2010); duplicates will be removed and the remaining references will be examined by two review authors independently. Those studies which clearly do not meet the inclusion criteria will be excluded and copies of the full text of potentially relevant references will be obtained. The eligibility of retrieved papers will be assessed independently by two authors. Disagreements will be resolved by discussion between the two review authors and consultation with a third review author if necessary. Reasons for exclusion will be documented.

Data extraction and management

For included studies, data on characteristics of studies, patients and interventions, risk of bias, duration of follow up, outcomes and deviations from protocol will be abstracted independently by two review authors. Differences between reviewers will be resolved by discussion or by appeal to a third review author.

Characteristics of studies

  • Design

  • Primary and secondary outcomes

  • Observation period (calendar years)

  • Key inclusion/exclusion criteria

  • Number and location of participating centers

  • Duration of follow up (mean/median; range)

  • Ethnicity

  • Comorbidities, such as diabetes mellitus and hypertension

Characteristics of patients

  • Age

  • Stage at diagnosis

  • PSA level at diagnosis

  • Gleason score at diagnosis

  • Volume of prostate at diagnosis

  • Number of recruited and analyzed patients.

Characteristics of interventions

  • Type of LDR‐BT (isotopes, dosage, neoadjuvant ADT)

  • Type of control interventions (surgical technique, type and dosage of EBRT, frequency of PSA measurement)

Survival measures

  • Kaplan‐Meier survival estimate at 1, 2, 5, and 10‐year follow up (where both the number of events and the number at risk are provided)

  • Hazard ratio (HR)

  • 95% confidence interval; standard error

Health related quality of life

  • Score after treatment, change from baseline

  • Mean (total score and dimension score)

  • 95% confidence interval, standard error, standard deviation

Morbidity

  • Hazard ratio (HR)

  • 95% confidence interval; standard error

  • Incidence of adverse effects

Where possible, all data extracted will be those relevant to an intention‐to‐treat analysis analysis (ITT), in which all participants will be analyzed in groups to which they were assigned. The time points at which outcomes were collected and reported will be noted.

Assessment of risk of bias in included studies

The assessment of risk of bias in included studies will be applied at the study level independently by two review authors according to Table 1 and to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). Assessment of risk of bias includes randomisation, blinding, and ITT analysis.

The assessment of risk of bias in included studies will be applied at the study level independently by two review authors according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). Assessment of risk of bias includes 'adequate sequence generation', 'allocation concealment', 'blinding', 'incomplete outcome data addressed', 'free of selective reporting', 'intention‐to‐treat analysis', and 'industry funded'. This data will be presented in the review in 'Figure 1'. Two reviewers will independently assess the quality of the included studies using the same criteria but also including an a priori definition of outcome measures. This will be included in 'Figure 2' of the review.

Measures of treatment effect

For meta‐analyses of time‐to‐event data, the primary effect measure will be the hazard ratio. If the hazard ratio is not directly given in the publication, we will extract summary statistics from Kaplan‐Meier survival functions and estimated hazard ratios according to methods proposed by Parmar 1998. For estimation, we will apply a tool that uses P values of the appropriate log‐rank test comparing the two survival functions of interest, number of patients analyzed, and number of events of each arm (Tierney 2007). If this information is not available, hazard ratios will be deduced from the graphical display of the survival curves, if possible.

As described in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009), we will calculate odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous outcomes. In case of rare events, Peto odds ratio will be used instead. If continuous outcomes will be reported in parametric form (e.g. means with standard deviations), they will be entered directly in RevMan 5 for meta‐analysis. Data reported in nonparametric form (e.g. medians with ranges) cannot be used for meta‐analysis, but they will be taken into account when describing the overall results. Continuous data will be analyzed and presented as weighted mean differences (WMD), if all results were measured on the same scale (e.g. length of hospital stay). If different scales are combined (e.g. pain or quality‐of‐life), standardized mean differences (SMD) will be used.

Dealing with missing data

Authors of primary studies will be contacted to resolve the following issues:

  • study methods unclear (e.g. allocation concealment);

  • study results unclear or in unsuitable format (e.g. medians reported, ITT data missing).

Assessment of heterogeneity

The data will be entered in Review Manager 5 and analyzed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009).

Heterogeneity between studies will be assessed by visual inspection of forest plots, by estimation of the per cent heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001) and, if possible, by subgroup analyses (see 'Subgroup analysis and investigation of heterogeneity'). If there is evidence of substantial heterogeneity (see 'Data synthesis' below), the possible reasons for this will be investigated and reported.

Since surgical and radiation procedures usually vary from centre to centre and from surgeon to surgeon, the random‐effects model with inverse variance weighting will be used for statistical pooling (DerSimonian 1986). In order to quantify heterogeneity, we will calculate the I2 statistics (Higgins 2009). We will classify the results as follows:

  • 0% to 40% ‐ might not be important;

  • 30% to 60% ‐ may represent moderate heterogeneity;

  • 50% to 90% ‐ may represent substantial heterogeneity;

  • 75% to 100% ‐ considerable heterogeneity.

Data synthesis

If sufficient, clinically similar studies are available, their results will be pooled in meta‐analyses. If included studies are not sufficiently homogeneous to be combined in a meta‐analysis, or if studies have features believed to reflect susceptibility to bias then we will consider presenting the results as forest plots without the pooled estimates. We will judge pooling not appropriate if the I2 statistics is greater than or equal to 50%.

Subgroup analysis and investigation of heterogeneity

We plan subgroup analyses for the following variables:

  • Risk profile ‐ low, intermediate, high (based on PSA, TNM, and Gleason score); parameters as described in the background section

  • Length of follow up ‐ short (< 1 year), middle (1 to 3 years), or long‐term (> 3 years);

  • Age groups <70 versus >=70 years of age.

Sensitivity analysis

Sensitivity analyses will be conducted to determine the impact of the following methodological quality factors: low (I2 < 50%) versus high (≥ 50%) or unclear risk of bias.