Monoterapia con antiandrógeno no esteroideo comparada con los agonistas de la hormona liberadora de hormona luteinizante o castración quirúrgica para el cáncer de próstata avanzado
Resumen
Antecedentes
Los antiandrógenos no esteroideos y la castración son las principales opciones de tratamiento para los estadios avanzados del cáncer de próstata. Sin embargo, continúa el debate sobre el valor de estas opciones terapéuticas.
Objetivos
Evaluar los efectos de la monoterapia con antiandrógeno no esteroideo comparada con los agonistas de la hormona liberadora de hormona luteinizante o la monoterapia con castración quirúrgica para tratar los estadios avanzados del cáncer de próstata.
Métodos de búsqueda
Se hicieron búsquedas en el registro especializado del Grupo Cochrane de Enfermedades de la Próstata y Cáncer Urológico (Cochrane Prostatic Diseases and Urologic Cancers Group) (PROSTATE), Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, tres registros de ensayos y resúmenes de tres congresos principales hasta el 23 de diciembre de 2013, junto con las listas de referencias y se estableció contacto con expertos en el campo y fabricantes seleccionados.
Criterios de selección
Se incluyeron los ensayos controlados aleatorios que compararon la monoterapia con antiandrógeno no esteroideo con la monoterapia con castración médica o quirúrgica en hombres con estadios avanzados del cáncer de próstata.
Obtención y análisis de los datos
Un revisor examinó todos los títulos y resúmenes; solamente las citas que eran claramente irrelevantes se excluyeron en esta etapa. Luego, dos revisores de forma independiente evaluaron los informes de texto completo, identificaron los estudios relevantes, evaluaron la elegibilidad de los estudios para inclusión, evaluaron la calidad de los ensayos y extrajeron los datos. Se estableció contacto con los autores de los estudios para solicitar información adicional. Se utilizó Review Manager 5 para la síntesis de los datos y se utilizó el modelo de efectos fijos cuando la heterogeneidad fue menor del 50%; se utilizó el modelo de efectos aleatorios cuando la heterogeneidad fue significativa o considerable.
Resultados principales
Once estudios con 3060 participantes asignados al azar se incluyeron en esta revisión. La calidad de las pruebas está afectada por el riesgo de sesgo. La administración de antiandrógenos no esteroideos disminuyó la supervivencia general (cociente de riesgos instantáneos [CRI] 1,24; intervalo de confianza [IC] del 95%: 1,05 a 1,48; seis estudios, 2712 participantes) y aumentó la progresión clínica (un año: cociente de riesgos [CR] 1,25; IC del 95%: 1,08 a 1,45; cinco estudios, 2067 participantes; 70 semanas: CR 1,26; IC del 95%: 1,08 a 1,45; seis estudios, 2373 participantes; dos años: CR 1,14; IC del 95%: 1,04 a 1,25; tres estudios, 1336 participantes), así como el fracaso del tratamiento (un año: CR 1,19%; IC del 95%: 1,02 a 1,38; cuatro estudios, 1539 participantes; 70 semanas: CR 1,27; IC del 95%: 1,05 a 1,52; cinco estudios, 1845 participantes; dos años: CR 1,14; IC del 95%: 1,05 a 1,24; dos estudios, 808 participantes), en comparación con la castración médica o quirúrgica. La calidad de las pruebas para la supervivencia general, la progresión clínica y el fracaso del tratamiento se consideró moderada según GRADE. Los análisis predefinidos de subgrupos mostraron que la administración de antiandrógenos no esteroideos, comparados con la castración, fue menos favorable para la supervivencia general, la evolución clínica (al año, a las 70 semanas, a los dos años) y el fracaso del tratamiento (al año, a las 70 semanas, a los dos años) en los hombres con enfermedad metastásica. La administración de antiandrógenos no esteroideos también aumentó el riesgo de interrupción del tratamiento debido a eventos adversos (CR 1,82; IC del 95%: 1,13 a 2,94; ocho estudios, 1559 participantes), incluidos eventos como dolor de la mama (CR 22,97; IC del 95%: 14,79 a 35,67; ocho estudios, 2670 participantes), ginecomastia (CR 8,43; IC del 95%: 3,19 a 22,28; nueve estudios, 2774 participantes) y astenia (CR 1,77; IC del 95%: 1,36 a 2,31; cinco estudios, 2073 participantes). El riesgo de otros eventos adversos como sofocos (CR 0,23; IC del 95%: 0,19 a 0,27; nueve estudios, 2774 participantes), hemorragia (CR 0,07; IC del 95%: 0,01 a 0,54; dos estudios, 546 participantes), nicturia (CR 0,38; IC del 95%: 0,20 a 0,69; un estudio, 480 participantes), fatiga (CR 0,52; IC del 95%: 0,31 a 0,88; un estudio, 51 participantes), pérdida del interés sexual (CR 0,50; IC del 95%: 0,30 a 0,83; un estudio, 51 participantes) y polaquiuria (CR 0,22; IC del 95%: 0,11 a 0,47; un estudio, 480 participantes) disminuyó cuando se utilizaron los antiandrógenos no esteroideos. La calidad de las pruebas para el dolor de la mama, la ginecomastia y los sofocos se consideró moderada según GRADE. Los efectos de los antiandrógenos no esteroideos sobre la supervivencia específica del cáncer y la evolución bioquímica aún son inciertos.
Conclusiones de los autores
Las pruebas actualmente disponibles indican que el uso de monoterapia con antiandrógeno no esteroideo comparada con monoterapia con castración médica o quirúrgica para el cáncer de próstata avanzado es menos eficaz en cuanto a la supervivencia general, la progresión clínica, el fracaso del tratamiento y la interrupción del tratamiento debido a eventos adversos. La calidad de las pruebas se consideró moderada según GRADE. Es probable que estudios de investigación adicionales tengan una repercusión importante sobre los resultados de los pacientes con cáncer de próstata avanzado pero no metastásico tratados con monoterapia con antiandrógeno no esteroideo. Sin embargo, se considera que es probable que no sean necesarios estudios de investigación sobre la monoterapia con antiandrógeno no esteroideo para hombres con cáncer de próstata metastásico. Solamente se deben realizar ensayos controlados aleatorios de alta calidad y con seguimiento a largo plazo. Si se planifican estudios de investigación adicionales acerca de la progresión bioquímica, se deben realizar estudios con esquemas de seguimiento estandarizados que utilicen mediciones del antígeno específico de la próstata según las guías actuales.
PICOs
Resumen en términos sencillos
Monoterapia de supresión de andrógeno para el tratamiento del cáncer de próstata avanzado
Pregunta de la revisión
Se examinaron las pruebas sobre los efectos de las monoterapias con supresión de andrógeno (antiandrógenos no esteroideos en comparación con monoterapia con castración médica o quirúrgica) en hombres con cáncer de próstata avanzado.
Antecedentes
El cáncer de próstata está entre los seis cánceres más mortales y el tratamiento implica una alta carga de morbilidad para los pacientes. El cáncer de próstata avanzado se ha diseminado fuera de la glándula prostática o ha hecho metástasis a los ganglios linfáticos, los huesos u otras áreas. Actualmente no se conoce un tratamiento curativo para el cáncer de próstata avanzado, aunque el tratamiento con supresión de andrógeno se utiliza con frecuencia para tratar la enfermedad en este estadio. Se intentó descubrir los efectos de las monoterapias con supresión de andrógeno para el tratamiento de los pacientes con estadios avanzados del cáncer de próstata.
Características de los estudios
Las pruebas están actualizadas hasta diciembre de 2013. Se incluyeron 11 estudios con 3060 participantes asignados al azar, con estadios avanzados del cáncer de próstata. El período de seguimiento de los participantes varió de seis meses a seis años. En siete estudios, los autores informaron de posibles conflictos de intereses. En tres estudios no se declararon conflictos de intereses. En un estudio los autores informaron que habían recibido una subvención educacional del patrocinador, el cual no tenía función alguna en cualquier aspecto del análisis o la interpretación de los datos.
Resultados clave
La administración de antiandrógenos no esteroideos redujo la supervivencia general y aumentó la progresión clínica y el fracaso del tratamiento. Los análisis de subgrupos mostraron que los antiandrógenos no esteroideos, comparados con la castración, fueron menos favorables para la supervivencia general, la progresión clínica y el fracaso del tratamiento en hombres con enfermedad metastásica. Los participantes que recibieron antiandrógenos también tuvieron más probabilidades de interrumpir el tratamiento como resultado de los efectos secundarios. El riesgo de presentar dolor de la mama, aumento de volumen del tejido de la mama o síntomas de debilidad física también aumentó con los antiandrógenos no esteroideos. Los riesgos de sentir calor intenso con sudoración y latidos cardíacos rápidos y hemorragia, necesidad de levantarse por la noche a orinar, pérdida del interés sexual, cansancio extremo y la necesidad de orinar más a menudo que lo habitual aumentaron con la castración. No se observaron diferencias para otros efectos secundarios. El efecto de los antiandrógenos no esteroideos sobre la supervivencia específica del cáncer y la progresión bioquímica aún es incierto.
Calidad de la evidencia
Los estudios incluidos tuvieron una realización deficiente y la calidad de las pruebas se calificó como moderada. Lo anterior significa que es probable que estudios de investigación adicionales tengan un impacto importante sobre la confianza en la exactitud de los resultados.
Authors' conclusions
Summary of findings
| Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy for advanced prostate cancer | ||||||
| Patient or population: men with advanced prostate cancer Comparison: LHRH agonists or surgical castration monotherapy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Hazard ratio/ Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Castration | Non‐steroidal antiandrogen | |||||
| Overall survival | 296 per 1000 | 353 per 1000 | HR 1.24 | 2712 | ⊕⊕⊕⊝ | Overall survival was evaluated using the random‐effects model because of heterogeneity (I2 = 51%). Sensitivity analyses showed comparable results. Numbers of absolute risks relate to deaths |
| Clinical progression | 420 per 1000 | 529 per 1000 | RR 1.26 | 2373 | ⊕⊕⊕⊝ | Clinical progression after median 70 weeks was evaluated using the random‐effects model because of heterogeneity (I2 = 64%). Sensitivity analyses showed comparable results. After imputation of event numbers: RR 1.43, 95% CI 1.19 to 1.73, I2 = 0%; fixed‐effect model |
| Treatment failure | 527 per 1000 | 669 per 1000 | RR 1.27 | 1845 | ⊕⊕⊕⊝ | Treatment failure after median 70 weeks was evaluated using the random‐effects model because of heterogeneity (I2 = 81%). Sensitivity analyses showed comparable results. After imputation of event numbers: RR 1.21, 95% CI 1.09 to 1.35, I2 = 0%; fixed‐effect model |
| Breast pain | 17 per 1000 | 397 per 1000 | RR 22.97 | 2670 | ⊕⊕⊕⊝ | Breast pain was evaluated using the fixed‐effect model (I2 = 0%) |
| Gynaecomastia | 44 per 1000 | 374 per 1000 | RR 8.43 | 2774 | ⊕⊕⊕⊝ | Gynaecomastia was evaluated using the random‐effects model because of heterogeneity (I2 = 92%). Sensitivity analyses showed comparable results |
| Hot flashes | 451 per 1000 | 104 per 1000 | RR 0.23 | 2774 | ⊕⊕⊕⊝ | Hot flashes were evaluated using the fixed‐effect model (I2 = 0%) |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1Downgraded for study limitations (‐1): high risk of bias: 'allocation concealment' (Tyrrell 2006); unclear risk of bias: 'random sequence generation' (Study 0301; Study 0302; Study 0303; Study 306; Study 307); 'allocation concealment' (Study 0301;Study 0302; Study 0303; Study 306; Study 307); 'blinding of participants and personnel' (all included studies); 'other bias' (all included studies). | ||||||
Background
Description of the condition
Prostate cancer is a frequently occurring tumour that leads to 85,200 cancer deaths per year in Europe (Boyle 2005). Worldwide, tumours of this type are associated with significant morbidity and are among the top six most lethal cancers (Eheman 2012; GLOBOCAN 2012); therefore, optimising therapy for prostate cancer is crucial.
Prostate cancer is usually classified as localised disease that is limited to the prostate gland (localised, stage T1‐2, N0, M0) or more advanced disease that has spread locally outside the prostate gland (locally advanced, stage T3‐4, N0, M0), disseminated to regional lymph nodes (local to regionally advanced, stage T1‐4, N1, M0) or metastasised to bones and/or to other areas (advanced, stage T1‐4, N0‐1, M1). Localised and locally advanced prostate cancers are amenable to curative treatment. However, currently no curative therapy is known for patients at local to regionally advanced and advanced stages of prostate cancer. Androgen suppression therapy is usually recommended to treat patients at this stage of the disease (ASCO 2007; EAU 2013).
Description of the intervention
Several different approaches to androgen suppression monotherapy can be used at advanced stages of prostate cancer, including oestrogens, bilateral orchiectomy, luteinising hormone–releasing hormone (LHRH) agonists, LHRH antagonists, antiandrogens (non‐steroidal antiandrogens and steroidal antiandrogens) and 5‐alpha reductase inhibitors.
Oestrogens were among the first drugs used to treat patients at advanced stages of prostate cancer. They act through negative hormonal feedback. However, their side effects, even at low doses, are significantly greater than those observed with surgical castration. Therefore, their use is no longer recommended under current guidelines (ASCO 2007; EAU 2013).
Surgical castration removes the source of testicular androgen production and can be performed totally (bilateral orchiectomy) or by a subcapsular technique (preservation of tunica albuginea and epididymis). This intervention has been effectively used for decades, and current guidelines still consider it to be the 'gold standard' (EAU 2013). However, it is irreversible and might cause psychological distress.
LHRH agonists (e.g. leuprorelin, goserelin, buserelin, triptorelin) have been found to be as effective as surgical castration via orchiectomy, and no difference in overall survival has been reported among the different LHRH agonists (Seidenfeld 2000). These medications are recommended as standard initial treatment options for advanced stages of prostate cancer (ASCO 2007; EAU 2013).
LHRH antagonists are newer agents. They block hormonal effects at the pituitary gland. Whether they provide advantages over LHRH agonists has not yet been determined (EAU 2013).
Antiandrogens are classified as non‐steroidal (e.g. bicalutamide, flutamide, nilutamide) or steroidal antiandrogens (e.g. cyproterone acetate). Non‐steroidal antiandrogens are mentioned in current guidelines as an alternative to medical or surgical castration in selected patients with non‐metastatic prostate cancer (ASCO 2007; EAU 2013).
5‐alpha reductase inhibitors also have antiandrogenic activity. This form of androgen manipulation has a potential role in prevention and treatment of prostate cancer (Azzouni 2012). Antiandrogens combined with 5‐alpha reductase inhibitors for the treatment of biochemical disease recurrence after local therapy might be a therapeutic option (EAU 2013), but discussions on this topic are still controversial.
Oestrogens, LHRH antagonists, steroidal antiandrogens and 5‐alpha reductase inhibitors are not part of this review and will not be discussed further. This systematic review focuses on the effectiveness of non‐steroidal antiandrogens compared with LHRH agonists or surgical castration.
How the intervention might work
All treatment modalities that reduce androgen activity are referred to as androgen suppression therapy (EAU 2013). Androgen suppression therapy is usually recommended for patients with advanced prostate cancer to slow down progression and to increase the chance of survival (EAU 2013; Schmitt 1999). The androgen testosterone is essential for the growth of prostate cells; suppression of testosterone is therefore important in prostate cancer therapy. Testosterone is produced mainly in the testes but also to a lesser extent in the adrenal glands. The release of testosterone is regulated by the hypothalamic‐pituitary‐gonadal axis. Hypothalamic LHRH stimulates the pituitary gland to release luteinising hormone (LH) and follicle‐stimulating hormone (FSH). LH stimulates the testes to secrete testosterone. Testosterone is then converted to oestrogens, which contribute to negative feedback control of hypothalamic hormone secretion. This negative feedback in turn diminishes the secretion of LH, thereby reducing testicular testosterone production (Gibbs 1996; Huggins 2002).
Antiandrogens compete with testosterone and dihydrotestosterone at the receptor level in the prostate cell nucleus and thereby inhibit prostate cancer cell growth. Because non‐steroidal antiandrogens do not affect the pituitary gland and do not block the negative feedback mechanism, testosterone levels are not affected, but testosterone is still converted to oestrogens. This provides potential benefits for sexual function, but it also stimulates gynaecomastia (Iversen 2002).
Bilateral orchiectomy and LHRH agonists reduce testosterone to a castration level and have been used for decades. Surgical castration removes the source of testicular androgen production, which leads to a rapid reduction in testosterone. LHRH agonists stimulate the pituitary gland continuously, which leads to desensitisation of LH and testosterone secretion (medical castration). However, before the hormonal receptors are downregulated, LHRH agonists cause an initial stimulation of LH, FSH and thereby testosterone. This process is called 'testosterone flare' and can lead to potential exacerbations of clinical symptoms in metastatic disease by stimulating the growth of prostate cancer cells. Premedication with antiandrogens can be used for a few days before the start of LHRH agonist therapy to prevent flares (Gibbs 1996). However, castration therapies do not affect adrenal secretion of testosterone.
Why it is important to do this review
A systematic review published in 2000 concluded that survival rates might be lower with non‐steroidal antiandrogens than with medical or surgical castration (Seidenfeld 1999; Seidenfeld 2000). However, no update of the review has been performed, and no other current evaluation of this comparison has been published. Clinical practice guidelines on androgen suppression monotherapy for advanced stages of prostate cancer support antiandrogens for selected and motivated patients with low prostate‐specific antigen (PSA) (EAU 2013). Non‐steroidal antiandrogens have been argued to have fewer side effects (e.g. hot flashes), and they do not affect testosterone levels. This might offer potential benefits for sexual function. However, non‐steroidal antiandrogens have other side effects; testosterone is converted to oestrogens, and this stimulates gynaecomastia (Iversen 2002). Additionally, effectiveness has been challenged, and the debate concerning the value of different treatment options, especially the comparison between non‐steroidal antiandrogens and medical or surgical castration, continues. As current guidelines are based upon older literature, there is a need to revisit the topic to update our understanding in light of more recent data.
Objectives
To assess the effects of non‐steroidal antiandrogen monotherapy compared with luteinising hormone–releasing hormone agonists or surgical castration monotherapy for treating advanced stages of prostate cancer.
Methods
Criteria for considering studies for this review
Types of studies
We reviewed parallel‐group randomised controlled trials comparing non‐steroidal antiandrogens versus castration (surgical or medical) for advanced stages of prostate cancer.
Types of participants
Studies recruiting men at advanced stages of prostate cancer who had not received prior androgen suppression therapy were eligible. We included studies evaluating men with prostate cancer that had spread locally outside the prostate gland (locally advanced, T3‐4, N0, M0), to regional lymph nodes (local to regionally advanced, T1‐4, N1, M0), to the bones or to other areas (advanced, T1‐4, N0‐1, M1), or those who had recurrent disease after local therapy. No exclusions were based on age or ethnicity.
Types of interventions
For androgen suppression monotherapies, the following comparison was considered: non‐steroidal antiandrogen monotherapy versus medical or surgical castration monotherapy.
Medical castration and surgical castration are two different treatment options that are thought to be equally effective (EAU 2013; Seidenfeld 2000). For this reason, we decided to include randomised trials even if they did not differentiate between medical and surgical castration.
We defined medical castration monotherapy as androgen suppression therapy using LHRH agonists (e.g. leuprorelin, goserelin, buserelin, triptorelin).
Bilateral surgical castration included total and subcapsular techniques.
LHRH antagonists, oestrogen and steroidal antiandrogen monotherapies were not a topic of this review, and trials investigating these treatment options were not included in our analysis (see Description of the intervention). This review did not consider maximal androgen blockade (combination therapy of antiandrogens with medical or surgical castration). However, we did not exclude trials that used antiandrogens as short‐term flare protection for up to four weeks after medical castration (see Description of the intervention).
Types of outcome measures
Primary outcomes
Overall survival.
Secondary outcomes
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Cancer‐specific survival (we assessed data for cancer‐specific mortality because data for cancer‐specific survival were not available).
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Treatment discontinuation due to adverse events.
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Clinical progression (time from random assignment to progression; determined by an increase in prostatic dimension, appearance of new or increase in existing bone or extraskeletal metastases confirmed by imaging or physical examination).
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Biochemical progression (time from random assignment to progression; determined by an increase of more than 25% in serum PSA concentration from the nadir value on two determinations).
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Treatment failure (determined by death; disease progression, i.e. an increase in prostatic dimensions, appearance of new or increase in existing bone or extraskeletal metastases confirmed by imaging or physical examination; addition of other systemic therapies for prostate cancer; loss to follow‐up; refusal to begin or continue with randomly assigned therapy; or discontinuation due to adverse events or for other reasons).
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Adverse events, such as breast pain, pelvic pain, bone pain, back pain, headache, abdominal pain, general pain, gynaecomastia, constipation, diarrhoea, vomiting, cardiovascular events, hypertension, loss of sexual interest, asthenia, insomnia, hot flashes, night sweats, anaemia, hepatic enzyme increase, rash, pruritus, dyspnoea, infection, pharyngitis, arthritis, sinusitis, urinary tract infection, dizziness, haemorrhage, haematuria, nocturia, urinary frequency, urinary retention, oedema, anorexia, gastrointestinal disorders, loss of sexual function and lethargy, as well as serious adverse events (defined as adverse events causing death or events that are life threatening, require inpatient hospitalisation, result in persistent or significant disability/incapacity or require intervention to prevent permanent impairment or damage).
Search methods for identification of studies
Both electronic and manual searches were conducted.
Electronic searches
We searched the following electronic databases on 26 February 2013 and updated the search on 23 December 2013: Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE; 23 December 2013); Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 12 (part of The Cochrane Library); Ovid MEDLINE, In‐Process & Other Non‐Indexed Citations, Daily (1946 to 23 December 2013); EMBASE via DIMDI (www.dimdi.de/static/en/index.html; 1947 to 23 December 2013); and Web of Science with Conference Proceedings (Thomson Reuters Web of Knowledge; 1945 to 23 December 2013). The search strategy was adapted for each electronic database. For the search strategies used by the review authors, see Appendix 1, Appendix 2, Appendix 3, Appendix 4 and Appendix 5. No language restriction was applied.
Searching other resources
The reference lists of all identified articles were screened to identify additional potentially relevant citations. We contacted selected experts in the field as well as manufacturers of non‐steroidal androgen suppression drugs to request information on unpublished studies. We searched all other resources on 26 February 2013 and updated the search on 23 December 2013.
We performed an electronic search of abstracts from three major conferences: the American Society of Clinical Oncology (ASCO; jco.ascopubs.org; 2004 to 23 December 2013), the European Association of Urology (EAU; www.uroweb.org; 2004 to 23 December 2013) and the American Urological Association (AUA; www.jurology.com/; 2008 to 23 December 2013). For keywords used to search meeting abstracts, see Appendix 6.
Additionally, we searched three trial registries for completed or ongoing studies: Current Controlled Trials (ISRCTN; www.controlled‐trials.com/; last searched 23 December 2013), ClinicalTrials.gov (www.clinicaltrials.gov/; last searched 23 December 2013) and the World Health Organization International Clinical Trials Registry Platform Search Portal (WHO ICTRP Search Portal; www.who.int/ictrp/en/; last searched 23 December 2013). For keywords used to search trial registries, see Appendix 7.
Data collection and analysis
Selection of studies
For the initial search, one review author (FK) screened all titles and abstracts of records identified by the search for relevance. Only records that were clearly irrelevant were excluded at this stage (e.g. animal/in vitro research and testing). Next, two review authors (FK, HG) independently examined the full‐text reports of the remaining records, identified relevant studies and assessed the eligibility of studies for inclusion. We resolved disagreements regarding study eligibility through discussion and consensus or, if necessary, with the help of a third review author (JM). We recorded details of excluded studies and the reasons for exclusion. One review author (FK) performed the search update, which included only records published since the time of our initial search (between 26 February 2013 and 23 December 2013). Few records were published since the time of our last search, and we retrieved no reference that fitted our inclusion criteria. Therefore we performed no full‐text screening.
Data extraction and management
In addition to details related to the quality (risk of bias) of the included studies, we extracted the following types of data.
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Study characteristics: population characteristics, setting, detailed nature of the intervention, detailed nature of the comparator and outcomes, place of publication and date of publication. The key purpose of collecting these data was to explore the clinical heterogeneity of the included studies.
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Results of the included studies: We extracted the results with respect to each of the main outcomes (see Types of outcome measures). We recorded the reasons why an included study did not contribute data on a particular outcome and considered the possibilities of selective reporting of the results of particular outcomes.
Two review authors (FK, HG) independently extracted data using a data extraction form based on the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). The review authors resolved disagreements by consensus or through discussion with a third review author (JM). In addition, when necessary, we contacted the original investigators.
Assessment of risk of bias in included studies
Two review authors (FK, HG) independently assessed all studies using our data extraction form and followed the domain‐based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a) to assess the following domains as low risk of bias, unclear risk of bias or high risk of bias: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias.
We reviewed the assessments and discussed inconsistencies in the interpretation of information given and their significance for the selected studies. We resolved disagreements through discussion with a third review author (JM). In assessing the risk of bias, we did not automatically exclude any study as a result of an unclear or high risk of bias rating.
Measures of treatment effect
We analysed extracted data using Review Manager 5 (Review Manager 2012).
We extracted hazard ratios (HRs) with 95% confidence intervals (CIs) for time‐to‐event outcomes. If HRs were not given, we used indirect estimation methods (described by Parmar et al (Parmar 1998) and Williamson et al (Williamson 2002)) to calculate them. If we were unable to extract these data from the study reports or to receive the necessary information from the primary investigators, we alternatively used the proportions of participants with the respective outcomes measured at certain time points to calculate risk ratios (RRs) with 95% CIs.
We expressed results for binary outcomes as RRs with 95% CIs as measures of uncertainty.
Unit of analysis issues
Only randomised controlled trials were included; cluster‐randomised or cross‐over trials were excluded.
Dealing with missing data
We contacted the original investigators to request missing data. We analysed the data using an intention‐to‐treat (ITT) analysis. If we did not receive all required data, and if a substantial departure of people assigned to the intervention or control group was noted, we conducted best‐case and worst‐case scenarios, as proposed by Gamble 2005 and described briefly in the Cochrane Handbook for Systematic Reviews of Interventions (Section 16.2.2; Higgins 2011c), and presented the results as sensitivity analyses.
Assessment of heterogeneity
Statistical heterogeneity was examined by using the I2 statistic (Higgins 2002; Higgins 2003). Our definitions of the thresholds for interpretation of I2 are consistent with the definitions presented in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2008): 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% substantial heterogeneity; 75% to 100% considerable heterogeneity. Clinical heterogeneity was examined by performing subgroup analyses. For details, see Subgroup analysis and investigation of heterogeneity section.
Assessment of reporting biases
To minimise the impact of possible publication bias, we conducted electronic and manual searches of multiple databases, without imposing a language restriction, to identify published and unpublished studies. We performed a funnel plot asymmetry analysis to assess possible publication bias.
Data synthesis
For data synthesis, we used Review Manager 5 (Review Manager 2012), as provided by The Cochrane Collaboration. Meta‐analyses of the data from all contributing studies were conducted using a fixed‐effect model if I2 was less than 50%, and using a random‐effects model for substantial or considerable heterogeneity if I2 was greater than or equal to 50% (≥ 50%). We reported results from both models.
Subgroup analysis and investigation of heterogeneity
We explored the following potential sources of heterogeneity using subgroup analyses.
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Disease stage: non‐metastatic (M0) versus metastatic (M1) disease.
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Dose of non‐steroidal antiandrogen (e.g. bicalutamide 50 mg vs bicalutamide 150 mg).
We planned in advance to also evaluate a subgroup analysis regarding the effects of different control interventions (medical vs surgical castration). However, the largest included studies (Study 0302; Study 0303; Study 306; Study 307; Tyrrell 2006) permitted both control interventions but did not report results of subgroups. This involves 925 of the 1288 participants randomly assigned to the control groups (72%). We decided therefore not to evaluate subgroup analyses regarding the effects of different control interventions.
A current guideline mentioned that non‐steroidal antiandrogen monotherapy using bicalutamide at a dose of 150 mg daily for non‐metastatic prostate cancer might be an alternative to castration for selected patients (EAU 2013). A narrative review suggested that non‐steroidal antiandrogen monotherapy might be an established treatment option in patients with prostate cancer, but an unexplained trend towards decreased survival should prohibit their uncritical use (Wirth 2007). Therefore for the primary outcome of overall survival, we performed post hoc subgroup analyses regarding disease stage (non‐metastatic or metastatic disease) in combination with different doses of non‐steroidal antiandrogens (bicalutamide 50, 150, 450 or 600 mg daily; Analysis 1.1).
In accordance with the recommendation of Higgins et al, we did not perform subgroup analyses if only a few studies were included in the meta‐analysis (Higgins 2004).
Sensitivity analysis
We performed sensitivity analyses to evaluate the effects of data imputations for best‐case and worst‐case scenarios (Analysis 1.5; Analysis 1.7; Analysis 1.9). Additionally, we investigated the robustness of results through sensitivity analyses when heterogeneity was substantial or considerable (I2 50% to 90% or 75% to 100%, respectively) by excluding smaller studies from the meta‐analysis (Analysis 1.1; Analysis 1.2; Analysis 1.4; Analysis 1.8; Analysis 1.17).
Summary of findings table
We summarised the findings in a summary of findings table (summary of findings Table for the main comparison) in accordance with GRADE methodology (Guyatt 2011; Schünemann 2011).
Results
Description of studies
See Characteristics of included studies and Characteristics of excluded studies.
Results of the search
For details of the search results, see Figure 1. A total of 16 articles on 11 studies were finally included in the review. None of these studies was available in abstract form only. All included studies were published in English. We did not identify ongoing studies. We also did not identify further relevant studies through the search update.
Study flow diagram (searched 26 February 2013; updated 23 December 2013).
Included studies
For details on the included studies, see Characteristics of included studies.
We included 11 studies that randomly assigned 3060 participants. All of the included studies fit our inclusion criteria and provided information on study population demographics. The type of non‐steroidal antiandrogen and the doses given varied among the included studies (flutamide 250 mg three times daily: Boccon‐Gibod 1997; bicalutamide 50 mg daily: Study 0301, Study 0302 and Study 0303; bicalutamide 150 mg daily: Dockery 2009, Sciarra 2004a, Sieber 2004, Smith 2004, Study 306 and Study 307; bicalutamide 450 mg daily and 600 mg daily: Tyrrell 2006). Two studies (Boccon‐Gibod 1997; Study 0301) used surgical castration, and four studies used medical castration (goserelin 10.8 mg three times monthly: Dockery 2009; triptorelin 3.75 mg monthly: Sciarra 2004a; leuprorelin 22.5 mg every three months: Smith 2004; drug not specified: Sieber 2004). In five studies, participants could choose between medical (using goserelin) and surgical castration (Study 0302; Study 0303; Study 306; Study 307; Tyrrell 2006). In two studies (Dockery 2009; Smith 2004), participants randomly assigned to castration also received a non‐steroidal antiandrogen for two (Dockery 2009) or four weeks (Smith 2004) to prevent a flare reaction. Four studies included participants with non‐metastatic prostate cancer (Dockery 2009; Sciarra 2004a; Sieber 2004; Smith 2004), and four studies included participants with metastatic prostate cancer (Boccon‐Gibod 1997; Study 0301; Study 0302; Study 0303). Three studies included participants with non‐metastatic or metastatic disease (Study 306; Study 307; Tyrrell 2006). The follow‐up period of participants ranged from six months (Dockery 2009) to six years (Study 306; Study 307).
In seven studies (Boccon‐Gibod 1997; Sieber 2004; Smith 2004; Study 0303; Study 306; Study 307; Tyrrell 2006), the trial authors reported possible conflicts of interest. In three studies (Sciarra 2004a; Study 0301; Study 0302), no conflicts of interest were declared. The authors of only one study (Dockery 2009) reported that they received an educational grant from the sponsor; however, they claimed that this sponsor had no role in any aspect of the study plan, protocol or analysis; data interpretation; or writing of the manuscript.
Excluded studies
Figure 1 and the table titled Characteristics of excluded studies provide information on the numbers of and reasons for exclusions from the review.
Risk of bias in included studies
We conducted a funnel plot asymmetry analysis for our primary outcome to assess potential publication bias (Figure 2). We found no indication of bias. However, the sensitivity of this analysis to assess publication bias might be low because fewer than 10 studies were included in the meta‐analyses performed. All studies were published in peer‐reviewed publications. For details on risk of bias, see Figure 3 and the table titled Characteristics of included studies.
Funnel plot: Outcome: 1.1 Overall survival, 1.1.1 Total.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Random sequence generation
Three studies (Dockery 2009; Smith 2004; Tyrrell 2006) reported adequate sequence generation (low risk of bias). In all of the other studies, information on sequence generation was not reported or was insufficient to permit a judgement (unclear risk of bias).
Allocation concealment
Only one study (Boccon‐Gibod 1997) provided information indicating adequate allocation concealment using central random assignment (low risk of bias). One study (Tyrrell 2006) contained a high risk of bias because participant numbers were allocated sequentially as men entered the trial. No other studies reported information on allocation concealment (unclear risk of bias).
Blinding
We assessed risk of bias for blinding of participants and personnel and for blinding of outcome assessment on an outcome‐specific basis.
Blinding of participants and personnel
All included studies were open randomised trials that did not involve blinding of participants and/or personnel. Blinding was not feasible because of differences in the interventions, which included surgical therapy (orchiectomy), medical castration by injection (LHRH agonists) and oral medications (non‐steroidal antiandrogens).
Overall survival, cancer‐specific mortality, biochemical progression
We were uncertain to what extent outcomes such as overall survival, cancer‐specific mortality and biochemical progression were influenced by lack of blinding. We judged therefore that risk of bias regarding these outcomes for most of the included studies was unclear (Boccon‐Gibod 1997; Sciarra 2004a; Smith 2004; Study 0301; Study 0302; Study 0303; Study 306; Study 307; Tyrrell 2006). Two studies (Dockery 2009; Sieber 2004) did not assess these outcomes (unclear risk of bias).
Clinical progression, treatment failure, treatment discontinuation due to adverse events, adverse events
Outcomes such as clinical progression, treatment failure, treatment discontinuation due to adverse events and adverse events could be influenced by lack of blinding. These outcomes therefore present a high risk of bias in most of the included studies (Boccon‐Gibod 1997; Dockery 2009; Sciarra 2004a; Sieber 2004; Study 0301; Study 0302; Study 0303; Study 306; Study 307; Tyrrell 2006). Risk of bias was unclear for one study (Smith 2004). The original investigators responded that "subjects and study investigators were blinded to treatment assignment." However, the method of blinding bicalutamide 150 mg by mouth daily for 12 months compared with leuprorelin three‐month depot (22.5 mg intramuscularly every three months) for treatment discontinuation due to adverse events and adverse events remained unclear (unclear risk of bias).
Blinding of outcome assessment
Overall survival, cancer‐specific mortality, biochemical progression
In all studies, no blinding was provided or blinding was not reported. However, we judged that it was not likely that outcome assessments for overall survival, cancer‐specific mortality and biochemical progression were influenced by lack of blinding (low risk of bias). Two studies (Dockery 2009; Sieber 2004) did not assess these outcomes (unclear risk of bias).
Clinical progression, treatment failure, treatment discontinuation due to adverse events, adverse events
We judged that for most studies (Boccon‐Gibod 1997; Dockery 2009; Sciarra 2004a; Sieber 2004; Study 0301; Study 0302; Study 0303; Study 306; Study 307; Tyrrell 2006) it was likely that outcome assessments of clinical progression, treatment failure, treatment discontinuation due to adverse events and adverse events were influenced by lack of blinding. For one study (Smith 2004), the original investigators responded that blinding was performed ("subjects and study investigators were blinded to treatment assignment"). However, blinding of outcome assessments for treatment discontinuation due to adverse events and adverse events remained unclear (unclear risk of bias).
Incomplete outcome data
We assessed risk of bias for incomplete outcome data on an outcome‐specific basis.
Overall survival, cancer‐specific mortality
Five studies (Study 0301; Study 0302; Study 0303; Study 306; Study 307) were judged to report adequate information leading to low risk of attrition bias. In the study published by Tyrrell et al, the proportion of missing outcomes might not have had a clinically relevant impact on the intervention effect estimate, leading to low risk of bias (Tyrrell 2006). Boccon‐Gibod et al reported data on overall survival incompletely (Boccon‐Gibod 1997). Therefore risk of bias regarding overall survival was high. Four studies (Dockery 2009; Sciarra 2004a; Sieber 2004; Smith 2004) did not measure/report these outcomes (unclear risk of bias).
Treatment discontinuation due to adverse events, adverse events
Three studies (Boccon‐Gibod 1997; Study 306; Study 307) were judged to report adequate information leading to low risk of attrition bias. In four studies, the proportion of missing outcomes might not have had a clinically relevant impact on the intervention effect estimate, leading to low risk of bias (Dockery 2009; Sieber 2004; Smith 2004; Tyrrell 2006). One study (Sciarra 2004a) did not measure/report these outcomes (unclear risk of bias). Three studies (Study 0301; Study 0302; Study 0303) present high risk of attrition bias. These studies reported data on an 'as‐treated' analysis with a high rate of dropout from the intervention assigned at randomisation.
Clinical progression, biochemical progression
Two studies (Study 306; Study 307) were judged to report adequate information leading to low risk of attrition bias. Five studies (Boccon‐Gibod 1997; Sciarra 2004a; Study 0301; Study 0302; Study 0303) present high risk of attrition bias. These studies reported data on an 'as‐treated' analysis with a high rate of dropout from the intervention group. Two studies (Dockery 2009; Sieber 2004) did not measure/report these outcomes (unclear risk of bias). In two studies, the proportion of missing outcomes might not have had a clinically relevant impact on the intervention effect estimate, leading to low risk of bias (Smith 2004; Tyrrell 2006).
Treatment failure
Two studies (Study 306; Study 307) were judged to report adequate information, leading to low risk of attrition bias. Four studies (Boccon‐Gibod 1997; Study 0301; Study 0302; Study 0303) were judged as having high risk of attrition bias. These studies reported data on an 'as‐treated' analysis with a high rate of dropout from the intervention group. One study (Sciarra 2004a) provided an outcome definition for treatment failure in the report but did not report any data for this outcome (high risk of bias). Four studies (Dockery 2009; Sieber 2004; Smith 2004; Tyrrell 2006) did not measure/report this outcome (unclear risk of bias).
Selective reporting
Three studies (Boccon‐Gibod 1997; Dockery 2009; Sciarra 2004a) had a high risk of reporting bias. Boccon‐Gibod et al reported incomplete data on overall survival at 69 months. They reported only "identical" survival in both groups, which was irrespective of the second‐line treatment given (Boccon‐Gibod 1997). Thus, their study could not be entered into the meta‐analysis. Dockery et al reported data on treatment discontinuation due to adverse events but did not report any data concerning individual adverse events (Dockery 2009), and Sciarra et al did not report data on adverse events, treatment discontinuation due to adverse events or treatment failure (Sciarra 2004a). We expected that these outcomes would be reported for such studies. We did not identify study protocols with adequate information on primary or secondary outcomes for all other studies; however, published reports included all of the expected outcomes.
Other potential sources of bias
In seven studies (Boccon‐Gibod 1997; Sieber 2004; Smith 2004; Study 0303; Study 306; Study 307; Tyrrell 2006), the trial authors reported possible conflicts of interest. In three studies (Sciarra 2004a; Study 0301; Study 0302), no conflicts of interest were declared. The authors of only one study (Dockery 2009) reported that they received an educational grant from the sponsor; however, they claimed that this sponsor had no role in any aspect of the study plan, protocol or analysis; data interpretation; or writing of the manuscript. Potential conflicts of interest may exist in any study, but we believe that in itself, this is not a reason for high risk of bias. Therefore, the risk of bias remains unclear for all studies.
Effects of interventions
Overall survival
Of the 11 included studies, six studies (Study 0301; Study 0302; Study 0303; Study 306; Study 307; Tyrrell 2006) involving 2712 randomly assigned participants measured overall survival. The quality of evidence for this outcome was moderate (summary of findings Table for the main comparison). One study (Boccon‐Gibod 1997) reported incomplete data and therefore could not be entered into the meta‐analysis. Overall survival was significantly decreased when non‐steroidal antiandrogens were used as opposed to castration (HR 1.24, 95% CI 1.10 to 1.40, fixed‐effect model; not shown). A random‐effects model for heterogeneity (I2 = 51%) still revealed a significant result (HR 1.24, 95% CI 1.05 to 1.48, 2712 participants; Analysis 1.1). We performed a sensitivity analysis because heterogeneity was noted (I2 = 51%). After exclusion of the smallest study (Tyrrell 2006), results still showed significant differences with lower heterogeneity (HR 1.31, 95% CI 1.12 to 1.53, I2 = 33%; not shown).
Subgroup: disease stage
A meta‐analysis of three studies (Study 306; Study 307; Tyrrell 2006) on non‐metastatic disease showed no significant difference in overall survival between non‐steroidal antiandrogens and castration (HR 1.00, 95% CI 0.79 to 1.26, 608 participants; Analysis 1.1). However, a meta‐analysis of six studies (Study 0301; Study 0302; Study 0303; Study 306; Study 307; Tyrrell 2006) showed that overall survival was significantly decreased with non‐steroidal antiandrogens in participants with metastatic disease when compared with castration (HR 1.34, 95% CI 1.14 to 1.57, 2103 participants; Analysis 1.1).
Subgroup: dose of non‐steroidal antiandrogen
The non‐steroidal antiandrogen bicalutamide given in doses of 50 mg daily or 150 mg daily significantly decreased overall survival when compared with castration using the fixed‐effect model (bicalutamide 50 mg daily: HR 1.45, 95% CI 1.20 to 1.74, 1196 participants; bicalutamide 150 mg daily: HR 1.19, 95% CI 1.00 to 1.41, 1288 participants; not shown). However, the random‐effects model showed that bicalutamide 50 mg daily still significantly decreased overall survival (HR 1.45, 95% CI 1.19 to 1.75, 1196 participants), although the effect was compatible with benefit or harm when bicalutamide 150 mg daily was used (HR 1.18, 95% CI 0.96 to 1.45, 1288 participants; Analysis 1.1). No significant difference was noted between high‐dose bicalutamide (450 mg daily or 600 mg daily) and castration (HR 0.88, 95% CI 0.62 to 1.25, 228 participants; Analysis 1.1).
Subgroup (post hoc analysis): non‐metastatic disease and dose of non‐steroidal antiandrogen
No significant difference was found between non‐steroidal antiandrogens (bicalutamide 150 mg daily compared with 450 mg daily or 600 mg daily) and castration in participants with non‐metastatic prostate cancer (Analysis 1.1).
Subgroup (post hoc analysis): metastatic disease and dose of non‐steroidal antiandrogen
The non‐steroidal antiandrogen bicalutamide given in doses of 50 mg daily or 150 mg daily decreased overall survival in participants with metastatic disease when compared with castration (bicalutamide 50 mg daily: HR 1.45, 95% CI 1.19 to 1.75, 1196 participants; bicalutamide 150 mg daily: HR 1.30, 95% CI 1.04 to 1.63, 808 participants; Analysis 1.1). No significant difference was found between high‐dose bicalutamide (450 mg daily or 600 mg daily) and castration in participants with metastatic disease (HR 0.91, 95% CI 0.56 to 1.48, 99 participants; Analysis 1.1).
Cancer‐specific mortality
We presented data for cancer‐specific mortality in place of cancer‐specific survival based on availability of data in the included studies. Three studies (Study 0301; Study 0302; Tyrrell 2006) involving 904 randomly assigned participants provided data on cancer‐specific mortality. Non‐steroidal antiandrogens probably increased cancer‐specific mortality when compared with castration (RR 1.26, 95% CI 1.00 to 1.59, fixed‐effect model; not shown). However, this difference was no longer statistically significant when a random‐effects model was applied as the result of heterogeneity (I2 = 67%, RR 1.32, 95% CI 0.86 to 2.05, 904 participants; Analysis 1.2). We performed a sensitivity analysis because heterogeneity was noted (I2 = 67%). After the smallest study had been excluded (Tyrrell 2006), results were still comparable but heterogeneity was greater (RR 1.63, 95% CI 0.71 to 3.73, I2 = 79%; not shown). The included studies reported cancer‐specific mortality based on different follow‐up periods (Study 0301 and Study 0302: after a minimum 12 months of follow‐up; Tyrrell 2006: after a median of five years of follow‐up). Analysis of the different follow‐up periods showed that non‐steroidal antiandrogens might increase cancer‐specific mortality after a minimum of 12 months when compared with castration (RR 1.43, 95% CI 1.05 to 1.95, fixed‐effect model; not shown). However, this difference was no longer significant after a random‐effects model was applied because of heterogeneity (RR 1.63, 95% CI 0.71 to 3.73, 680 participants, I2 = 79%; Analysis 1.2). We performed a sensitivity analysis because heterogeneity was present (I2 = 79%). After the smaller of the two included studies had been excluded (Study 0302), results of Study 0301 showed a significant difference (RR 2.60, 95% CI 1.30 to 5.07; not shown). No difference was found between these therapies after a median of five years (RR 1.04, 95% CI 0.73 to 1.47, 224 participants; Analysis 1.2). The overall effect of non‐steroidal antiandrogens on cancer‐specific mortality and even more on cancer‐specific survival therefore remains unclear.
Subgroup: disease stage
We did not perform subgroup analyses because very few studies were included for this outcome for which results were reported after different follow‐up periods. The conduct and presentation of meta‐analyses therefore did not seem appropriate.
Subgroup: dose of non‐steroidal antiandrogen
We did not perform subgroup analyses because very few studies were included for this outcome for which results were reported after different follow‐up periods. The conduct and presentation of meta‐analyses therefore did not seem appropriate.
Treatment discontinuation due to adverse events
Eight studies (Boccon‐Gibod 1997; Dockery 2009; Sieber 2004; Smith 2004; Study 0301; Study 0302; Study 0303; Tyrrell 2006) involving 1559 randomly assigned participants reported data on treatment discontinuation due to adverse events. Non‐steroidal antiandrogens significantly increased the rate of withdrawal due to adverse events (RR 1.82, 95% CI 1.13 to 2.94, 1559 participants; Analysis 1.3).
Two studies (Study 306; Study 307) provided incomplete data on treatment discontinuation due to adverse events; thus, the data from these studies could not be included in the meta‐analysis. The trial authors reported that after 6.3 years, 4.1% of participants with non‐metastatic disease treated with bicalutamide (n = 314) were withdrawn; 1.3% of these withdrawals were due to breast pain and/or gynaecomastia (Study 306; Study 307). They reported no data for participants treated with castration. Two studies (Study 0301; Tyrrell 2006) did not specify the adverse events that led to discontinuation, and four studies (Sieber 2004; Study 0303; Study 306; Study 307) provided only partial information on adverse events. Smith et al reported that two participants in the leuprorelin group discontinued treatment early as the result of adverse events such as hot flashes and fatigue (Smith 2004). Additionally, treatment with bicalutamide was interrupted in one participant for three months because of elevated liver enzymes (Smith 2004). In the study conducted by Sieber et al, five of nine participants who withdrew from the study in the bicalutamide group discontinued treatment as the result of asthenia (Sieber 2004). In another study, four participants discontinued treatment because of adverse events; two participants withdrew because of impotence (one in each group for bicalutamide and castration) and two withdrew because of a skin reaction (both in the bicalutamide group) (Dockery 2009). In Study 0303, six participants discontinued treatment (three with rash and one with constipation), and in Study 0302, three participants withdrew from the study (in the group treated with bicalutamide, one withdrew because of gynaecomastia and back pain; in the group treated with castration, one withdrew because of severe hot flashes). Boccon‐Gibod et al reported that four participants discontinued therapy; two were suffering from nausea or vomiting, one reported diarrhoea and another showed an increase in hepatic enzymes before discontinuing therapy (Boccon‐Gibod 1997).
Subgroup: disease stage
The subgroup analysis included seven studies: three studies (Dockery 2009; Sieber 2004; Smith 2004) including participants with non‐metastatic disease, and four studies (Boccon‐Gibod 1997; Study 0301; Study 0302; Study 0303) including participants with metastatic disease. No significant difference was found between non‐steroidal antiandrogens and castration for participants with non‐metastatic (RR 1.47, 95% CI 0.66 to 3.28, 194 participants) or metastatic disease (RR 1.39, 95% CI 0.54 to 3.54, 1141 participants; Analysis 1.3). Data reported by Tyrrell et al could not be included into this analysis because they were not reported for subgroups of participants on the basis of disease stage (Tyrrell 2006).
Subgroup: dose of non‐steroidal antiandrogen
One study evaluated the non‐steroidal antiandrogen flutamide 250 mg three times daily (Boccon‐Gibod 1997), three studies evaluated the non‐steroidal antiandrogen bicalutamide 50 mg daily (Study 0301; Study 0302; Study 0303), three studies evaluated bicalutamide 150 mg daily (Dockery 2009; Sieber 2004; Smith 2004) and one study evaluated bicalutamide 450 mg daily and 600 mg daily (Tyrrell 2006). No significant differences were found for bicalutamide 50 mg daily, bicalutamide 150 mg daily or flutamide 250 mg three times daily (Analysis 1.3). However, the numbers of treatment discontinuations due to adverse events were significantly increased when bicalutamide 450 mg daily was used (RR 2.66, 95% CI 1.17 to 6.01, 182 participants). No significant differences were found between bicalutamide 600 mg daily and castration (RR 2.45, 95% CI 0.95 to 6.31, 132 participants; Analysis 1.3).
Clinical progression
Seven studies (Sciarra 2004a; Study 0301; Study 0302; Study 0303; Study 306; Study 307; Tyrrell 2006) involving 2591 randomly assigned participants were included in the meta‐analyses for clinical progression. For the definitions of clinical progression, see the Characteristics of included studies table. Two studies (Boccon‐Gibod 1997; Smith 2004) reported data on an outcome they referred to as “clinical progression.” However, we included the data in an analysis of biochemical progression because the definition provided in the reports was consistent with our previously established definition of biochemical progression. Non‐steroidal antiandrogens significantly increased clinical progression at one year, at 70 weeks and at two years when compared with castration, but no significant differences were found at three, four or five years when the fixed‐effect model was used (at one year: RR 1.27, 95% CI 1.14 to 1.41, 2067 participants; at 70 weeks: RR 1.27, 95% CI 1.16 to 1.38, 2373 participants; at two years: RR 1.13, 95% CI 1.03 to 1.24, 1336 participants; at three years: RR 1.04, 95% CI 0.87 to 1.23, 480 participants; at four years: RR 1.07, 95% CI 0.91 to 1.26, 480 participants; at five years: RR 0.96, 95% CI 0.87 to 1.06, 698 participants; not shown). The random‐effects model due to heterogeneity (I2 = 64%) at 70 weeks still showed comparable results (at one year: RR 1.25, 95% CI 1.08 to 1.45, 2067 participants; at 70 weeks: RR 1.26, 95% CI 1.08 to 1.45, 2373 participants; at two years: RR 1.14, 95% CI 1.04 to 1.25, 1336 participants; at three years: RR 1.04, 95% CI 0.87 to 1.23, 480 participants; at four years: RR 1.07, 95% CI 0.91 to 1.26, 480 participants; at five years: RR 0.96, 95% CI 0.88 to 1.06, 698 participants; Analysis 1.4). We performed a sensitivity analysis for clinical progression at 70 weeks because we noted heterogeneity (I2 = 64%). After the smallest study had been excluded (Study 0302), results still showed significant differences with lower heterogeneity (RR 1.33, 95% CI 1.19 to 1.48, I2 = 13%; not shown). Five studies (Sciarra 2004a; Study 0301; Study 0302; Study 0303; Tyrrell 2006) did not report ITT analysis data, but findings were summarised instead according to treatment received. An analysis that considered data imputations for the best‐case and worst‐case scenarios still showed significant results at one year, 70 weeks and two years but not at five years (Analysis 1.5). This analysis involved 2771 randomly assigned participants. The quality of evidence for clinical progression was moderate (summary of findings Table for the main comparison).
Subgroup: disease stage
No significant differences were found between non‐steroidal antiandrogens and castration for participants with non‐metastatic disease at all evaluated time points (Analysis 1.4). An analysis considering data imputations for the best‐case and worst‐case scenarios showed comparable results (Analysis 1.5). Five studies were included in the subgroup analysis of participants with metastatic disease (Study 0301; Study 0302; Study 0303; Study 306; Study 307). Clinical progression at one year (RR 1.25, 95% CI 1.05 to 1.49, I2 = 64%, 1539 participants), at 70 weeks (RR 1.27, 95% CI 1.07 to 1.51, I2 = 74%, 1845 participants) and at two years (RR 1.17, 95% CI 1.05 to 1.29, 808 participants) increased with non‐steroidal antiandrogens when compared with castration in participants with metastatic disease (Analysis 1.4). We performed sensitivity analyses for clinical progression at one year and at 70 weeks because heterogeneity was present. After the smallest study had been excluded (Study 0302), results still showed significant differences with lower heterogeneity (at one year: RR 1.35, 95% CI 1.13 to 1.61, I2 = 42%; at 70 weeks: RR 1.35, 95% CI 1.18 to 1.55, I2 = 34%; not shown). The results remained significant after an analysis was performed by considering data imputations for best‐case and worst‐case scenarios (Analysis 1.5).
Subgroup: dose of non‐steroidal antiandrogen
The non‐steroidal antiandrogen bicalutamide at a dose of 50 mg daily showed no significant difference when compared with castration (at one year: RR 1.27, 95% CI 0.91 to 1.76, I2 = 83%, 731 participants; at 70 weeks: RR 1.30, 95% CI 0.99 to 1.71, 1037 participants, I2 = 84%; Analysis 1.4). We performed sensitivity analyses because heterogeneity was present. After the smallest study had been excluded (Study 0302), results showed significant differences with lower heterogeneity (at one year: RR 1.49, 95% CI 1.21 to 1.85; at 70 weeks: RR 1.47, 95% CI 1.26 to 1.72, I2 = 0%; not shown). The analysis considering data imputations for best‐case and worst‐case scenarios showed a significant increase in clinical progression with bicalutamide 50 mg daily at 70 weeks (RR 1.40, 95% CI 1.04 to 1.88, 1196 participants), but no difference was found at one year (Analysis 1.5). The non‐steroidal antiandrogen bicalutamide at a dose of 150 mg daily might increase clinical progression at one year (RR 1.25, 95% CI 1.07 to 1.46, 1336 participants), at 70 weeks (RR 1.22, 95% CI 1.07 to 1.39, 1336 participants) or at two years (RR 1.14, 95% CI 1.04 to 1.25, 1336 participants), but no differences were noted when compared with castration at three, four or five years (Analysis 1.4). An analysis considering data imputations for best‐case and worst‐case scenarios showed comparable results (Analysis 1.5). No significant differences were found between high‐dose bicalutamide (450 mg daily or 600 mg daily) and castration at five years.
Biochemical progression
Three studies (Boccon‐Gibod 1997; Sciarra 2004a; Smith 2004) involving 185 randomly assigned participants were included in the analysis of biochemical progression. For the definitions of biochemical progression in included studies, see the Characteristics of included studies table. The analysis considering data imputations for best‐case and worst‐case scenarios involved 214 randomly assigned participants. No significant differences were found between the non‐steroidal antiandrogen and castration groups at any of the evaluated time points (Analysis 1.6; Analysis 1.7). The study conducted by Smith et al was not designed to evaluate clinical cancer outcomes including clinical or biochemical progression (for details, see Characteristics of included studies). The overall effect on biochemical progression therefore remains unclear.
Subgroup: disease stage
We did not perform subgroup analyses because very few studies were included for this outcome for which results were reported after different follow‐up periods. The conduct and presentation of meta‐analyses therefore did not seem appropriate.
Subgroup: dose of non‐steroidal antiandrogen
We did not perform subgroup analyses because very few studies were included for this outcome for which results were reported after different follow‐up periods. The conduct and presentation of meta‐analyses therefore did not seem appropriate.
Treatment failure
Six studies (Boccon‐Gibod 1997; Study 0301; Study 0302; Study 0303; Study 306; Study 307) involving 2411 randomly assigned participants reported data on treatment failure. For the definition of treatment failure, see the Characteristics of included studies table. Non‐steroidal antiandrogens increased treatment failure at one year, at 70 weeks and at two years, but no difference was found at three or four years (Analysis 1.8). The random‐effects model for heterogeneity revealed significant results (at one year: I2 = 63%, RR 1.19, 95% CI 1.02 to 1.38, 1539 participants; at 70 weeks: I2 = 81%, RR 1.27, 95% CI 1.05 to 1.52, 1845 participants; at two years: RR 1.14, 95% CI 1.05 to 1.24, 808 participants; Analysis 1.8). We performed sensitivity analyses because heterogeneity was present. After the smallest study had been excluded (Study 0302), results still showed significant differences with lower heterogeneity (at one year: RR 1.26, 95% CI 1.08 to 1.47, I2 = 53%; at 70 weeks: RR 1.36, 95% CI 1.14 to 1.62, I2 = 69%; not shown). An analysis considering data imputations for best‐case and worst‐case scenarios showed comparable results (Analysis 1.9). This analysis involved 2004 randomly assigned participants. The quality of evidence for treatment failure was moderate (summary of findings Table for the main comparison).
Subgroup: disease stage
The subgroup analysis for non‐metastatic prostate cancer included two studies (Study 306; Study 307) and showed no significant differences between non‐steroidal antiandrogens and castration at four years (RR 1.04, 95% CI 0.93 to 1.16, 480 participants; Analysis 1.8). For participants with metastatic prostate cancer, non‐steroidal antiandrogens increased treatment failure at one year (RR 1.19, 95% CI 1.02 to 1.38, I2 = 63%, 1539 participants), at 70 weeks (RR 1.27, 95% CI 1.05 to 1.52, I2 = 81%, 1845 participants) and at two years (RR 1.14, 95% CI 1.05 to 1.24, 808 participants). We performed sensitivity analyses for treatment failure at one year and at 70 weeks because heterogeneity was present. After the smallest study had been excluded (Study 0302), results still showed significant differences with lower heterogeneity (at one year: RR 1.26, 95% CI 1.08 to 1.47, I2 = 53%; at 70 weeks: RR 1.36, 95% CI 1.14 to 1.62, I2 = 69%; not shown). No significant difference was found at three years (Analysis 1.8). An analysis considering data imputations for best‐case and worst‐case scenarios revealed comparable results (Analysis 1.9).
Subgroup: dose of non‐steroidal antiandrogen
No significant differences were found between the non‐steroidal antiandrogen bicalutamide at a dose of 50 mg daily and castration at any of the time points assessed using the random‐effects model for heterogeneity (Analysis 1.8). However, the analysis considering data imputations for best‐case and worst‐case scenarios showed that without heterogeneity, bicalutamide at 50 mg daily significantly increased treatment failure at one year and at 70 weeks (Analysis 1.9). Additionally, the non‐steroidal antiandrogen bicalutamide at a dose of 150 mg daily significantly increased treatment failure at one year (RR 1.17, 95% CI 1.01 to 1.35, 808 participants), at 70 weeks (RR 1.18, 95% CI 1.05 to 1.34, 808 participants) and at two years (RR 1.14, 95% CI 1.05 to 1.24, 808 participants). No difference was found at four years (Analysis 1.8; Analysis 1.9). One study (Boccon‐Gibod 1997) assessed the non‐steroidal antiandrogen flutamide at a dose of 250 mg three times daily compared with castration and showed no significant differences at three years (Analysis 1.8; Analysis 1.9).
Adverse events
Nine studies (Boccon‐Gibod 1997; Sieber 2004; Smith 2004; Study 0301; Study 0302; Study 0303; Study 306; Study 307; Tyrrell 2006) reported data on adverse events associated with treatment with non‐steroidal antiandrogens compared with castration.
Non‐steroidal antiandrogens were associated with a significantly increased occurrence of breast pain (RR 22.97, 95% CI 14.79 to 35.67, 2670 participants; Analysis 1.10). Subgroup analyses showed that this was also evident for bicalutamide at a dose of 50 mg, 150 mg, 450 mg or 600 mg daily (Analysis 1.10).
The risk of suffering gynaecomastia was increased with non‐steroidal antiandrogens (RR 8.43, 95% CI 3.19 to 22.28, 2774 participants; Analysis 1.17). We performed a sensitivity analysis because considerable heterogeneity was noted (I2 = 92%). After the smallest study had been excluded (Smith 2004), results still showed significant differences with lower heterogeneity (RR 9.34, 95% CI 5.43 to 16.05, I2 = 53%; not shown). Subgroup analyses showed that gynaecomastia occurred more often with bicalutamide 50 mg daily (RR 14.07, 95% CI 3.74 to 52.85), flutamide 250 mg three times daily (RR 3.70, 95% CI 1.33 to 10.33), bicalutamide 450 mg daily (RR 27.88, 95% CI 7.02 to 110.79) and bicalutamide 600 mg daily (RR 20.36, 95% CI 4.97 to 83.40). However, no significant difference was found between bicalutamide 150 mg daily and castration. We performed a sensitivity analysis because heterogeneity (I2 = 97%) was present for this comparison. After the smallest study had been excluded (Smith 2004), a significant increase in gynaecomastia with reduced heterogeneity was found with bicalutamide 150 mg daily (RR 8.79, 95% CI 3.88 to 18.94, I2 = 67%; not shown).
The occurrence of asthenia was significantly increased when non‐steroidal antiandrogens were used compared with castration (RR 1.77, 95% CI 1.36 to 2.31, 2073 participants; Analysis 1.23). Subgroup analyses showed higher incidences of asthenia with bicalutamide 50 mg, 150 mg and 450 mg daily (Analysis 1.23). No significant difference was found between bicalutamide 600 mg daily and castration (RR 2.45, 95% CI 0.95 to 6.31, 132 participants; Analysis 1.23).
No differences in the risk of suffering arthralgia were found between non‐steroidal antiandrogens and castration in overall analysis and subgroup analysis for bicalutamide 600 mg daily (Analysis 1.46). However, the occurrence of arthralgia was significantly increased with the non‐steroidal antiandrogen bicalutamide at a dose of 450 mg daily compared with castration (RR 1.96, 95% CI 1.01 to 3.80, 182 participants; Analysis 1.46).
One small study (Smith 2004) of participants receiving bicalutamide 150 mg daily showed that non‐steroidal antiandrogens might preserve sexual interest compared with castration (RR 0.50, 95% CI 0.30 to 0.83, 51 participants; Analysis 1.22).
Risk of hot flashes (RR 0.23, 95% CI 0.19 to 0.27, 2774 participants; Analysis 1.25), haemorrhage (RR 0.07, 95% CI 0.01 to 0.54, 546 participants; Analysis 1.38), nocturia (RR 0.38, 95% CI 0.20 to 0.69, 480 participants; Analysis 1.40), urinary frequency (RR 0.22, 95% CI 0.11 to 0.47, 480 participants; Analysis 1.41) and occurrence of fatigue (RR 0.52, 95% CI 0.31 to 0.88, 51 participants; Analysis 1.49) was decreased with non‐steroidal antiandrogens compared with castration. These significant differences were also evident for all subgroup analyses regarding the different doses of non‐steroidal antiandrogens.
The overall risk to suffer night sweats was decreased with non‐steroidal antiandrogens compared with castration (RR 0.29, 95% CI 0.17 to 0.49, 1571 participants; Analysis 1.26). However, although a significant difference was noted in the subgroup of participants treated with bicalutamide 150 mg daily (RR 0.26, 95% CI 0.14 to 0.49, 1268 participants), this finding was not evident for participants treated with bicalutamide 50 mg daily (RR 0.36, 95% CI 0.12 to 1.09, 303 participants).
Infection occurred less frequently with bicalutamide at 50 mg daily but showed no significant difference for overall analysis or bicalutamide at 150 mg daily when compared with castration (Analysis 1.32).
The occurrence of peripheral oedema was significantly decreased for bicalutamide at 50 mg daily (RR 0.42, 95% CI 0.21 to 0.82, 480 participants); however, we found no statistically significant difference for bicalutamide at 150 mg daily compared with castration and in overall analysis (Analysis 1.43).
We found an increased occurrence of constipation (Analysis 1.18) and a decreased risk of anaemia (Analysis 1.27) with higher doses of non‐steroidal antiandrogens compared with castration.
No significant difference between non‐steroidal antiandrogens and castration was noted for occurrence of haematuria (Analysis 1.39). However, results of the meta‐analysis including two studies (Study 0303; Study 306) show considerable heterogeneity (I2 = 97%). Subgroup analyses showed a significantly decreased risk with bicalutamide 50 mg daily but an increased risk with bicalutamide 150 mg daily to suffer haematuria when compared with castration (bicalutamide 50 mg daily: RR 0.41, 95% CI 0.26 to 0.67, 480 participants; bicalutamide 150 mg daily: RR 3.49, 95% CI 2.01 to 6.05, 474 participants; Analysis 1.39).
Conflicting results were found for the occurrence of vomiting because events in both groups were very rare (Analysis 1.20).
We identified no statistically significant differences for the following adverse events when we compared non‐steroidal antiandrogens with castration: pelvic pain (Analysis 1.11), bone pain (Analysis 1.12), back pain (Analysis 1.13), headache (Analysis 1.14), abdominal pain (Analysis 1.15), general pain (Analysis 1.16), gastralgia (Analysis 1.47), diarrhoea (Analysis 1.19), hypertension (Analysis 1.21), nausea (Analysis 1.48), insomnia (Analysis 1.24), hepatic enzyme increase (Analysis 1.28), rash (Analysis 1.29), pruritus (Analysis 1.30), dyspnoea (Analysis 1.31), pharyngitis (Analysis 1.33), arthritis (Analysis 1.34), sinusitis (Analysis 1.35), urinary tract infection (Analysis 1.36), dizziness (Analysis 1.37), urinary retention (Analysis 1.42), anorexia (Analysis 1.44), loss of sexual function (Analysis 1.45), dry skin (Analysis 1.50), aggravation reaction (Analysis 1.51) and serious adverse events (Analysis 1.52).
No study reported data on the predefined outcomes of cardiovascular events, gastrointestinal disorders and lethargy.
The quality of evidence for breast pain, gynaecomastia and hot flashes was moderate (summary of findings Table for the main comparison).
Discussion
Summary of main results
Eleven studies were included. The quality of the evidence for overall survival, clinical progression, treatment failure, breast pain, gynaecomastia and hot flashes was moderate (summary of findings Table for the main comparison). Non‐steroidal antiandrogens significantly decreased overall survival and increased clinical progression as well as treatment failure. Subgroup analyses showed that non‐steroidal antiandrogens, compared with castration, were consistently less favourable for overall survival, clinical progression and treatment failure in men with metastatic disease. Additionally, less favourable effects were seen with the non‐steroidal antiandrogen bicalutamide 50 mg daily for overall survival, clinical progression with imputed event numbers at 70 weeks and treatment failure with imputed event numbers at 70 weeks, as well as for the non‐steroidal antiandrogen bicalutamide 150 mg daily for clinical progression and treatment failure at one year, 70 weeks and two years, when compared with castration. Non‐steroidal antiandrogens also increased the risk for treatment discontinuation due to adverse events and increased the risk of breast pain, gynaecomastia and asthenia. The risk of other adverse events, such as hot flashes, fatigue, loss of sexual interest, haemorrhage, nocturia and urinary frequency, was significantly increased with castration. Effects of non‐steroidal antiandrogens on cancer‐specific survival and biochemical progression remained unclear.
Overall completeness and applicability of evidence
The included studies examined clinically important populations that were representative of patients seen in routine clinical practice. These participants and assessed interventions directly conformed to the review question. However, several points must be considered regarding the applicability of evidence.
The included studies provided data on our predefined outcomes. However, four studies (Dockery 2009; Sciarra 2004a; Sieber 2004; Smith 2004) did not address the review question directly and instead assessed primary outcomes that were not relevant to the review question, such as bone mineral density (Sieber 2004; Smith 2004), arterial stiffness (Dockery 2009), metabolic changes (Sieber 2004; Smith 2004) and markers of neuroendocrine differentiation (Sciarra 2004a). However, these studies also reported data on adverse events and/or progression and therefore were included in the review.
Only three studies were evaluated for biochemical progression. However, this outcome was defined by the authors in two of the three studies (Boccon‐Gibod 1997; Smith 2004) as clinical progression. In accordance with our predetermined definition, we classified these reported outcomes as biochemical progression because a PSA measurement was used for the definition of this outcome. The definition of biochemical progression varied among the included studies. The results of this outcome assessment should be interpreted carefully.
The two largest included studies (Study 306; Study 307) assessed participants with non‐metastatic and metastatic prostate cancer. PSA values were measured for participants with non‐metastatic disease only. For participants in the non‐steroidal antiandrogen group, these values ranged between 0.1 and 7691 ng/mL (median 69.2 ng/mL, mean 173.2 ng/mL). These rather high PSA values might no longer represent populations with non‐metastatic disease and might lead to bias in the evaluations.
We included seven studies (Boccon‐Gibod 1997; Study 0301; Study 0302; Study 0303; Study 306; Study 307; Tyrrell 2006) that assessed men treated with surgical castration. This therapy is suggested as a potential alternative to medical castration (Abrahamsson 2005; ASCO 2004; ASCO 2007; Seidenfeld 1999; Seidenfeld 2000). However, surgical castration could lead to potential psychological strain, and the resulting adverse events are only partially treatable. Nyman et al suggested that when patients can choose between different androgen suppression therapy options (non‐steroidal antiandrogens and medical or surgical castration) and receive comprehensive information about the treatment, nearly all patients are satisfied with their choice after three months of treatment (Nyman 2005). However, it should be mentioned that the clinical heterogeneity of these treatments might lead to bias in our results regarding treatment discontinuation due to adverse events because reversal of surgical castration is not possible.
Quality of the evidence
Most of the included studies reported insufficient information on sequence generation and allocation concealment.
No study performed blinding of participants and personnel because different therapy options were included (surgical castration, oral medication and injection therapy). Opinions vary as to whether lack of blinding has a relevant impact on outcomes such as overall survival, cancer‐specific mortality and biochemical progression. It might be conceivable that these outcomes are influenced by lack of blinding. Therefore we judged that risk of bias for most of the included studies is unclear regarding overall survival, cancer‐specific mortality and biochemical progression. Outcomes such as clinical progression, treatment failure, treatment discontinuation due to adverse events and adverse events could be influenced by lack of blinding, presenting a high risk of bias in most of the included studies. Therefore the effects of intervention may have been overestimated (Als‐Nielsen 2004; Pildal 2007; Wood 2008).
In all studies, no blinding of outcome assessment was performed or blinding was not reported or underlying methodology remained unclear. However, this type of blinding would have been feasible and could have been expected in all studies. We suggest that it is not likely that outcome assessments for overall survival, cancer‐specific mortality and biochemical progression are influenced by lack of blinding. For outcomes such as clinical progression, treatment failure, treatment discontinuation due to adverse events and adverse events, this lack of blinding might, however, introduce detection bias due to potentially overestimated intervention effects (Pildal 2007).
The results of five studies (Boccon‐Gibod 1997; Sciarra 2004a; Study 0301; Study 0302; Study 0303) were based on data for which risk for incomplete outcomes was high. A risk of bias is present because per‐protocol analyses may lead to overestimated effects (Akl 2012; Meerpohl 2010; Porta 2007; Schulz 1996; Tierney 2005; Wood 2004). We performed sensitivity analyses based on best‐/worst‐case scenarios for outcomes such as treatment failure (Analysis 1.9), biochemical progression (Analysis 1.7) and clinical progression (Analysis 1.5) with imputations of missing data to minimise this bias because ITT analyses are regarded as the preferred way to estimate the effects of interventions in randomised controlled trials (Newell 1992).
Possible conflicts of interest should be considered for all of the included studies because the trial authors reported a possible conflict of interest or provided no disclosure statement. Conflicts of interest are common in the field of urology (Hampson 2012; Ramm 2012). Conflicts of interest may introduce a risk of bias because studies funded by industry have been shown to be more likely to report positive results than studies with other funding sources (Gøtzsche 2006; Okike 2007; Shah 2005). However, the risk of bias remains unclear because lack of a disclosure statement in itself is not an indicator of bias. Peer reviewers and journal editors may require conflict of interest disclosures at any step of the peer review process without providing a summary statement on the issue (Meerpohl 2010).
Non‐steroidal antiandrogens were assessed using subgroup analyses regarding disease stage. The two largest included studies (Study 306; Study 307) recruited participants with metastatic or non‐metastatic prostate cancer. However, participants with metastatic disease withdrew from the study early (after 100 weeks) and were excluded from further evaluations. We did not examine the protocols for these studies; it is therefore unclear whether the subgroup analyses were predefined. Post hoc subgroup analyses are common and might introduce a risk that differences in effect sizes across subgroups could produce statistically significant differences (Sun 2009; Sun 2012; Wang 2010). The influence of subgroup effects might be low (Sun 2012; Wang 2010) and should be interpreted carefully.
Overall, we identified several methodological limitations during our assessment of risk of bias, leading to downgrading of the quality of evidence for study limitations (section Characteristics of included studies; Figure 3). No indication of publication bias was found by funnel plot asymmetry analysis for our primary outcome, and we believe that risk of publication bias might be low (Risk of bias in included studies; Figure 2). Heterogeneity was noted for overall survival, clinical progression, treatment failure and gynaecomastia. However, this heterogeneity might be explained by subgroup or sensitivity analyses (see Effects of interventions); we believe that it should not be required that the quality of the evidence should be downgraded for inconsistency. Additionally, we believe that it might not be necessary to downgrade the quality of the evidence because of imprecision. The quality of the body of evidence for outcomes such as overall survival, clinical progression, treatment failure, breast pain, gynaecomastia and hot flashes was therefore rated as moderate (summary of findings Table for the main comparison).
Potential biases in the review process
Limitations of the review at the study or outcome level
All studies were published in peer‐reviewed publications. However, results might be hampered by several limitations. As discussed above, included participants might no longer represent the contemporary population (see Overall completeness and applicability of evidence). Additionally, only two included studies (Sciarra 2004a; Smith 2004) measured PSA as a marker for clinical or biochemical progression. Nowadays, PSA plays an important role in the follow‐up of patients with prostate cancer and in early detection of disease progression. This certainly has an effect on clinical and biochemical progression and might be important for outcomes such as overall and cancer‐specific mortality.
Limitations of the review at the review level
We followed the recommendations outlined in the Cochrane Handbook for Systematic Reviews of Interventions to minimise potential biases (Higgins 2011a). We performed an extensive literature search and contacted selected experts in the field, as well as manufacturers of non‐steroidal androgen suppression drugs, to request information on unpublished studies. Therefore it is not likely that relevant studies were overlooked. Two review authors independently assessed the information given in the reports of included studies and contacted the investigators of the identified studies to request supplemental data. This review therefore assessed the best evidence available from published randomised controlled trials. Unfortunately, even after contacting the primary investigators, we received no additional data.
Limitations of the review related to detection of serious and/or rare adverse events
We considered only randomised controlled trials for inclusion in this review. However, for evaluation of serious and/or rare adverse events, it is also necessary to consider non‐randomised studies such as controlled clinical trials, cohort studies and case‐control studies. Observational studies often utilise large databases and likely or possibly show greater external validity when compared with data from randomised controlled trials (Gartlehner 2008). Additionally, data on adverse events from randomised controlled trials could underestimate rare but serious adverse events as the result of small sample size and might be susceptible to bias due to the inclusion of highly selected participants (Chou 2010).
Agreements and disagreements with other studies or reviews
We identified that overall survival was significantly decreased with non‐steroidal antiandrogens when compared with castration. This is consistent with the findings of other studies. A systematic review published in 2000 by Seidenfeld et al already suggested that overall survival might be lower when non‐steroidal antiandrogens are used (Seidenfeld 1999; Seidenfeld 2000). However, no update was performed of the review published by Seidenfeld et al, and no other systematic review evaluating overall or cancer‐specific survival was published comparing non‐steroidal antiandrogens with medical or surgical castration. A narrative review suggested that non‐steroidal antiandrogen monotherapy is an established treatment option in men with prostate cancer, but that an unexplained trend towards increased mortality should prohibit their uncritical use (Wirth 2007). The Early Prostate Cancer program investigated the effect of bicalutamide 150 mg daily compared with placebo. It showed that bicalutamide might delay clinical progression, but that for overall survival, it provided an advantage only when combined with external beam radiotherapy for locally advanced prostate cancer (EPC program; Wirth 2008).
Non‐steroidal antiandrogens are thought to provide advantages such as oral application and the potential preservation of libido, potency and muscle mass or bone mineral density when compared with castration (EAU 2013; Daniell 1997; Prezioso 2007; Sciarra 2004b; Sieber 2004; Smith 2002; Smith 2004; Study 306; Study 307; Wadhwa 2011). However, adverse events should be considered. This review suggests that the occurrence of adverse events such as breast pain, gynaecomastia and asthenia is increased with non‐steroidal antiandrogens. Breast events were the most common adverse events in recent reports of treatment with non‐steroidal antiandrogens (Boccardo 1999; Boccardo 2002; EPC program; Kotake 1996b; Lunglmayr 1995; Raina 2007; Tyrrell 1994; Wadhwa 2011), and hot flashes occurred in approximately 30% to 40% of these participants (Boccardo 1999; EPC program; Lunglmayr 1995). Results of studies evaluating non‐steroidal antiandrogens assume that the incidence of adverse events ranges between 40% and 74% (EPC program; Kotake 1996b; Raina 2007). Castration, on the other hand, increased adverse events such as hot flashes, haemorrhage, nocturia, urinary frequency, fatigue and loss of sexual interest, as indicated by this review. Side effects that have an impact on physiological and psychological health should be considered when androgen suppression therapies are prescribed because these effects can interfere with compliance as soon as the patient notices symptoms; thus, these patients might require additional treatment (Kunath 2012).
Non‐steroidal antiandrogens lead to an increased rate of treatment discontinuation compared with castration because of their associated adverse events. This finding is consistent with the results of the systematic review published by Seidenfeld et al, as well as other studies, and accounts for 4% to 10% of patients receiving non‐steroidal antiandrogens (EPC program; Seidenfeld 2000; Study 306; Study 307; Tyrrell 1994). The main reasons for discontinuing treatment were elevated liver enzymes (Boccon‐Gibod 1997; Smith 2004; Tyrrell 1994) and breast events (EPC program).
We found no data on the impact of androgen suppression therapy on cardiovascular events. However, androgen suppression might adversely affect cardiovascular risk (Dockery 2002; Dockery 2009), and men with existing cardiovascular disease might have increased mortality (Efstathiou 2009). However, adjuvant castration does not appear to increase cardiovascular mortality in men with advanced prostate cancer who do not have notable cardiovascular risk (Efstathiou 2008; Nguyen 2011).
In the included studies, bicalutamide was the most frequently assessed non‐steroidal antiandrogen. Only one study (Boccon‐Gibod 1997) with a small sample size evaluated flutamide; we identified no studies evaluating nilutamide. This observation is consistent with common prescribing practices. A recent study evaluated men registered in the National Prostate Cancer Register of Sweden to determine the prescribing patterns of therapy with bicalutamide (Grundmark 2012). Of the 58,143 patients with prostate cancer registered in the National Prostate Cancer Register of Sweden, 4.4% (n = 2558) were treated with non‐steroidal antiandrogens and 1406 received bicalutamide monotherapy. Of these, 79% received a dosage of 150 mg per day. The prescription of other antiandrogens was very rare (n = 88) (Grundmark 2012).
We did not include studies that compared non‐steroidal antiandrogens with placebo. Evidence from large randomised controlled trials suggests that non‐steroidal antiandrogens (bicalutamide at 150 mg daily) given as an adjuvant to radiotherapy significantly improve progression‐free survival compared with radiotherapy alone. However, these studies showed no significant differences in overall survival after 9.7 years (EPC program).
Study flow diagram (searched 26 February 2013; updated 23 December 2013).
Funnel plot: Outcome: 1.1 Overall survival, 1.1.1 Total.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 1 Overall survival.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 2 Cancer‐specific mortality.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 3 Treatment discontinuation due to adverse events.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 4 Clinical progression.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 5 Clinical progression (with imputed event numbers).
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 6 Biochemical progression.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 7 Biochemical progression (with imputed event numbers).
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 8 Treatment failure.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 9 Treatment failure (with imputed event numbers).
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 10 Breast pain.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 11 Pelvic pain.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 12 Bone pain.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 13 Back pain.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 14 Headache.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 15 Abdominal pain.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 16 General pain.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 17 Gynaecomastia.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 18 Constipation.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 19 Diarrhoea.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 20 Vomiting.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 21 Hypertension.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 22 Loss of sexual interest.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 23 Asthenia.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 24 Insomnia.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 25 Hot flashes.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 26 Night sweats.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 27 Anaemia.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 28 Hepatic enzyme increase.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 29 Rash.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 30 Pruritus.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 31 Dyspnoea.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 32 Infection.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 33 Pharyngitis.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 34 Arthritis.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 35 Sinusitis.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 36 Urinary tract infection.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 37 Dizziness.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 38 Haemorrhage.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 39 Haematuria.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 40 Nocturia.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 41 Urinary frequency.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 42 Urinary retention.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 43 Peripheral oedema.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 44 Anorexia.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 45 Loss of sexual function.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 46 Arthralgia.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 47 Gastralgia.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 48 Nausea.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 49 Fatigue.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 50 Dry skin.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 51 Aggravation reaction.
Comparison 1 Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy, Outcome 52 Serious adverse events.
| Non‐steroidal antiandrogen monotherapy versus LHRH agonists or surgical castration monotherapy for advanced prostate cancer | ||||||
| Patient or population: men with advanced prostate cancer Comparison: LHRH agonists or surgical castration monotherapy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Hazard ratio/ Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Castration | Non‐steroidal antiandrogen | |||||
| Overall survival | 296 per 1000 | 353 per 1000 | HR 1.24 | 2712 | ⊕⊕⊕⊝ | Overall survival was evaluated using the random‐effects model because of heterogeneity (I2 = 51%). Sensitivity analyses showed comparable results. Numbers of absolute risks relate to deaths |
| Clinical progression | 420 per 1000 | 529 per 1000 | RR 1.26 | 2373 | ⊕⊕⊕⊝ | Clinical progression after median 70 weeks was evaluated using the random‐effects model because of heterogeneity (I2 = 64%). Sensitivity analyses showed comparable results. After imputation of event numbers: RR 1.43, 95% CI 1.19 to 1.73, I2 = 0%; fixed‐effect model |
| Treatment failure | 527 per 1000 | 669 per 1000 | RR 1.27 | 1845 | ⊕⊕⊕⊝ | Treatment failure after median 70 weeks was evaluated using the random‐effects model because of heterogeneity (I2 = 81%). Sensitivity analyses showed comparable results. After imputation of event numbers: RR 1.21, 95% CI 1.09 to 1.35, I2 = 0%; fixed‐effect model |
| Breast pain | 17 per 1000 | 397 per 1000 | RR 22.97 | 2670 | ⊕⊕⊕⊝ | Breast pain was evaluated using the fixed‐effect model (I2 = 0%) |
| Gynaecomastia | 44 per 1000 | 374 per 1000 | RR 8.43 | 2774 | ⊕⊕⊕⊝ | Gynaecomastia was evaluated using the random‐effects model because of heterogeneity (I2 = 92%). Sensitivity analyses showed comparable results |
| Hot flashes | 451 per 1000 | 104 per 1000 | RR 0.23 | 2774 | ⊕⊕⊕⊝ | Hot flashes were evaluated using the fixed‐effect model (I2 = 0%) |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence. | ||||||
| 1Downgraded for study limitations (‐1): high risk of bias: 'allocation concealment' (Tyrrell 2006); unclear risk of bias: 'random sequence generation' (Study 0301; Study 0302; Study 0303; Study 306; Study 307); 'allocation concealment' (Study 0301;Study 0302; Study 0303; Study 306; Study 307); 'blinding of participants and personnel' (all included studies); 'other bias' (all included studies). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall survival Show forest plot | 6 | Hazard Ratio (Random, 95% CI) | Subtotals only | |
| 1.1 Total | 6 | 2712 | Hazard Ratio (Random, 95% CI) | 1.24 [1.05, 1.48] |
| 1.2 Subgroup analysis: non‐metastatic disease | 2 | 608 | Hazard Ratio (Random, 95% CI) | 1.00 [0.79, 1.26] |
| 1.3 Subgroup analysis: metastatic disease | 5 | 2103 | Hazard Ratio (Random, 95% CI) | 1.34 [1.14, 1.57] |
| 1.4 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1196 | Hazard Ratio (Random, 95% CI) | 1.45 [1.19, 1.75] |
| 1.5 Subgroup analysis: bicalutamide 150 mg daily | 2 | 1288 | Hazard Ratio (Random, 95% CI) | 1.18 [0.96, 1.45] |
| 1.6 Subgroup analysis: bicalutamide 450 mg daily or 600 mg daily | 1 | 228 | Hazard Ratio (Random, 95% CI) | 0.88 [0.62, 1.25] |
| 1.7 Subgroup analysis: non‐metastatic disease and bicalutamide 150 mg daily | 1 | 480 | Hazard Ratio (Random, 95% CI) | 1.05 [0.81, 1.36] |
| 1.8 Subgroup analysis: non‐metastatic disease and bicalutamide 450 mg daily or 600 mg daily | 1 | 128 | Hazard Ratio (Random, 95% CI) | 0.79 [0.46, 1.36] |
| 1.9 Subgroup analysis: metastatic disease and bicalutamide 50 mg daily | 3 | 1196 | Hazard Ratio (Random, 95% CI) | 1.45 [1.19, 1.75] |
| 1.10 Subgroup analysis: metastatic disease and bicalutamide 150 mg daily | 1 | 808 | Hazard Ratio (Random, 95% CI) | 1.30 [1.04, 1.63] |
| 1.11 Subgroup analysis: metastatic disease and bicalutamide 450 mg daily or 600 mg daily | 1 | 99 | Hazard Ratio (Random, 95% CI) | 0.91 [0.56, 1.48] |
| 2 Cancer‐specific mortality Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 Total | 3 | 904 | Risk Ratio (M‐H, Random, 95% CI) | 1.32 [0.86, 2.05] |
| 2.2 Total after a minimum 12 months | 2 | 680 | Risk Ratio (M‐H, Random, 95% CI) | 1.63 [0.71, 3.73] |
| 2.3 Total after median 5 years | 1 | 224 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.73, 1.47] |
| 3 Treatment discontinuation due to adverse events Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Total | 8 | 1559 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.82 [1.13, 2.94] |
| 3.2 Subgroup analysis: non‐metastatic disease | 3 | 194 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.47 [0.66, 3.28] |
| 3.3 Subgroup analysis: metastatic disease | 4 | 1141 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.39 [0.54, 3.54] |
| 3.4 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1037 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.29, 2.56] |
| 3.5 Subgroup analysis: bicalutamide 150 mg daily | 3 | 194 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.47 [0.66, 3.28] |
| 3.6 Subgroup analysis: flutamide 250 mg 3 times daily | 1 | 104 | Risk Ratio (M‐H, Fixed, 95% CI) | 8.35 [0.46, 151.19] |
| 3.7 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.66 [1.17, 6.01] |
| 3.8 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.45 [0.95, 6.31] |
| 4 Clinical progression Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4.1 Total at 1 year | 5 | 2067 | Risk Ratio (M‐H, Random, 95% CI) | 1.25 [1.08, 1.45] |
| 4.2 Total at 70 weeks | 6 | 2373 | Risk Ratio (M‐H, Random, 95% CI) | 1.26 [1.08, 1.45] |
| 4.3 Total at 2 years | 3 | 1336 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [1.04, 1.25] |
| 4.4 Total at 3 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.87, 1.23] |
| 4.5 Total at 4 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.91, 1.26] |
| 4.6 Total at 5 years | 2 | 698 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.88, 1.06] |
| 4.7 Subgroup analysis: non‐metastatic disease at 1 year | 2 | 528 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.82, 1.96] |
| 4.8 Subgroup analysis: non‐metastatic disease at 70 weeks | 2 | 528 | Risk Ratio (M‐H, Random, 95% CI) | 1.18 [0.83, 1.68] |
| 4.9 Subgroup analysis: non‐metastatic disease at 2 years | 2 | 528 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.81, 1.31] |
| 4.10 Subgroup analysis: non‐metastatic disease at 3 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.87, 1.23] |
| 4.11 Subgroup analysis: non‐metastatic disease at 4 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.91, 1.26] |
| 4.12 Subgroup analysis: non‐metastatic disease at 5 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.88, 1.06] |
| 4.13 Subgroup analysis: metastatic disease at 1 year | 3 | 1539 | Risk Ratio (M‐H, Random, 95% CI) | 1.25 [1.05, 1.49] |
| 4.14 Subgroup analysis: metastatic disease at 70 weeks | 4 | 1845 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [1.07, 1.51] |
| 4.15 Subgroup analysis: metastatic disease at 2 years | 1 | 808 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [1.05, 1.29] |
| 4.16 Subgroup analysis: bicalutamide 50 mg daily at 1 year | 2 | 731 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.91, 1.76] |
| 4.17 Subgroup analysis: bicalutamide 50 mg daily at 70 weeks | 3 | 1037 | Risk Ratio (M‐H, Random, 95% CI) | 1.30 [0.99, 1.71] |
| 4.18 Subgroup analysis: bicalutamide 150 mg daily at 1 year | 3 | 1336 | Risk Ratio (M‐H, Random, 95% CI) | 1.25 [1.07, 1.46] |
| 4.19 Subgroup analysis: bicalutamide 150 mg daily at 70 weeks | 3 | 1336 | Risk Ratio (M‐H, Random, 95% CI) | 1.22 [1.07, 1.39] |
| 4.20 Subgroup analysis: bicalutamide 150 mg daily at 2 years | 3 | 1336 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [1.04, 1.25] |
| 4.21 Subgroup analysis: bicalutamide 150 mg daily at 3 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.87, 1.23] |
| 4.22 Subgroup analysis: bicalutamide 150 mg daily at 4 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.91, 1.26] |
| 4.23 Subgroup analysis: bicalutamide 150 mg daily at 5 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.88, 1.06] |
| 4.24 Subgroup analysis: bicalutamide 450 mg daily at 5 years | 1 | 177 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.54, 1.86] |
| 4.25 Subgroup analysis: bicalutamide 600 mg daily at 5 years | 1 | 127 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.33, 1.86] |
| 5 Clinical progression (with imputed event numbers) Show forest plot | 7 | Risk Ratio (Fixed, 95% CI) | Subtotals only | |
| 5.1 Total (with imputed event numbers) at 1 year | 5 | 2167 | Risk Ratio (Fixed, 95% CI) | 1.43 [1.16, 1.76] |
| 5.2 Total (with imputed event numbers) at 70 weeks | 6 | 2543 | Risk Ratio (Fixed, 95% CI) | 1.43 [1.19, 1.73] |
| 5.3 Total (with imputed event numbers) at 2 years | 3 | 1347 | Risk Ratio (Fixed, 95% CI) | 1.39 [1.09, 1.78] |
| 5.4 Total (with imputed event numbers) at 5 years | 2 | 708 | Risk Ratio (Fixed, 95% CI) | 0.86 [0.56, 1.31] |
| 5.5 Subgroup analysis: non‐metastatic disease (with imputed event numbers) at 1 year | 2 | 539 | Risk Ratio (Fixed, 95% CI) | 1.33 [0.80, 2.22] |
| 5.6 Subgroup analysis: non‐metastatic disease (with imputed event numbers) at 70 weeks | 2 | 539 | Risk Ratio (Fixed, 95% CI) | 1.23 [0.78, 1.94] |
| 5.7 Subgroup analysis: non‐metastatic disease (with imputed event numbers) at 2 years | 2 | 539 | Risk Ratio (Fixed, 95% CI) | 1.05 [0.71, 1.55] |
| 5.8 Subgroup analysis: non‐metastatic disease (with imputed event numbers) at 5 years | 1 | 480 | Risk Ratio (Fixed, 95% CI) | 0.84 [0.52, 1.36] |
| 5.9 Subgroup analysis: metastatic disease (with imputed event numbers) at 1 year | 3 | 1628 | Risk Ratio (Fixed, 95% CI) | 1.45 [1.16, 1.82] |
| 5.10 Subgroup analysis: metastatic disease (with imputed event numbers) at 70 weeks | 4 | 2004 | Risk Ratio (Fixed, 95% CI) | 1.48 [1.20, 1.83] |
| 5.11 Subgroup analysis: metastatic disease (with imputed event numbers) at 2 years | 1 | 808 | Risk Ratio (Fixed, 95% CI) | 1.69 [1.22, 2.32] |
| 5.12 Subgroup analysis: bicalutamide 50 mg daily (with imputed event numbers) at 1 year | 2 | 820 | Risk Ratio (Fixed, 95% CI) | 1.40 [0.99, 1.98] |
| 5.13 Subgroup analysis: bicalutamide 50 mg daily (with imputed event numbers) at 70 weeks | 3 | 1196 | Risk Ratio (Fixed, 95% CI) | 1.40 [1.04, 1.88] |
| 5.14 Subgroup analysis: bicalutamide 150 mg daily (with imputed event numbers) at 1 year | 3 | 1347 | Risk Ratio (Fixed, 95% CI) | 1.45 [1.12, 1.87] |
| 5.15 Subgroup analysis: bicalutamide 150 mg daily (with imputed event numbers) at 70 weeks | 3 | 1347 | Risk Ratio (Fixed, 95% CI) | 1.46 [1.14, 1.87] |
| 5.16 Subgroup analysis: bicalutamide 150 mg daily (with imputed event numbers) at 2 years | 3 | 1347 | Risk Ratio (Fixed, 95% CI) | 1.39 [1.09, 1.78] |
| 5.17 Subgroup analysis: bicalutamide 150 mg daily (with imputed event numbers) at 5 years | 1 | 480 | Risk Ratio (Fixed, 95% CI) | 0.84 [0.52, 1.36] |
| 5.18 Subgroup analysis: bicalutamide 450 mg daily (with imputed event numbers) at 5 years | 1 | 185 | Risk Ratio (Fixed, 95% CI) | 1.00 [0.41, 2.47] |
| 5.19 Subgroup analysis: bicalutamide 600 mg daily (with imputed event numbers) at 5 years | 1 | 133 | Risk Ratio (Fixed, 95% CI) | 0.78 [0.27, 2.25] |
| 6 Biochemical progression Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 Total at 1 year | 2 | 99 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.12 [0.13, 73.06] |
| 6.2 Total at 2 years | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6.3 Total at 3 years | 1 | 86 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.94, 1.26] |
| 7 Biochemical progression (with imputed event numbers) Show forest plot | 3 | Risk Ratio (Fixed, 95% CI) | Subtotals only | |
| 7.1 Total (with imputed event numbers) at 1 year | 2 | 110 | Risk Ratio (Fixed, 95% CI) | 2.29 [0.15, 34.62] |
| 7.2 Total (with imputed event numbers) at 2 years | 1 | 59 | Risk Ratio (Fixed, 95% CI) | 0.96 [0.00, 196.72] |
| 7.3 Total (with imputed event numbers) at 3 years | 1 | 104 | Risk Ratio (Fixed, 95% CI) | 1.07 [0.72, 1.58] |
| 8 Treatment failure Show forest plot | 6 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 8.1 Total at 1 year | 3 | 1539 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [1.02, 1.38] |
| 8.2 Total at 70 weeks | 4 | 1845 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [1.05, 1.52] |
| 8.3 Total at 2 years | 1 | 808 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [1.05, 1.24] |
| 8.4 Total at 3 years | 1 | 86 | Risk Ratio (M‐H, Random, 95% CI) | 1.59 [0.63, 3.99] |
| 8.5 Total at 4 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.93, 1.16] |
| 8.6 Subgroup analysis: non‐metastatic disease at 4 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.93, 1.16] |
| 8.7 Subgroup analysis: metastatic disease at 1 year | 3 | 1539 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [1.02, 1.38] |
| 8.8 Subgroup analysis: metastatic disease at 70 weeks | 4 | 1845 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [1.05, 1.52] |
| 8.9 Subgroup analysis: metastatic disease at 2 years | 1 | 808 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [1.05, 1.24] |
| 8.10 Subgroup analysis: metastatic disease at 3 years | 1 | 86 | Risk Ratio (M‐H, Random, 95% CI) | 1.59 [0.63, 3.99] |
| 8.11 Subgroup analysis: bicalutamide 50 mg daily at 1 year | 2 | 731 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.90, 1.57] |
| 8.12 Subgroup analysis: bicalutamide 50 mg daily at 70 weeks | 3 | 1037 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [0.98, 1.75] |
| 8.13 Subgroup analysis: bicalutamide 150 mg daily at 1 year | 1 | 808 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [1.01, 1.35] |
| 8.14 Subgroup analysis: bicalutamide 150 mg daily at 70 weeks | 1 | 808 | Risk Ratio (M‐H, Random, 95% CI) | 1.18 [1.05, 1.34] |
| 8.15 Subgroup analysis: bicalutamide 150 mg daily at 2 years | 1 | 808 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [1.05, 1.24] |
| 8.16 Subgroup analysis: bicalutamide 150 mg daily at 4 years | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.93, 1.16] |
| 8.17 Subgroup analysis: flutamide 250 mg 3 times daily at 3 years | 1 | 86 | Risk Ratio (M‐H, Random, 95% CI) | 1.59 [0.63, 3.99] |
| 9 Treatment failure (with imputed event numbers) Show forest plot | 5 | Risk Ratio (Fixed, 95% CI) | Subtotals only | |
| 9.1 Total (with imputed event numbers) at 1 year | 3 | 1628 | Risk Ratio (Fixed, 95% CI) | 1.19 [1.06, 1.35] |
| 9.2 Total (with imputed event numbers) at 70 weeks | 4 | 2004 | Risk Ratio (Fixed, 95% CI) | 1.21 [1.09, 1.35] |
| 9.3 Total (with imputed event numbers) at 3 years | 1 | 104 | Risk Ratio (Fixed, 95% CI) | 1.51 [0.32, 7.06] |
| 9.4 Subgroup analysis: metastatic disease (with imputed event numbers) at 1 year | 3 | 1628 | Risk Ratio (Fixed, 95% CI) | 1.19 [1.06, 1.35] |
| 9.5 Subgroup analysis: metastatic disease (with imputed event numbers) at 70 weeks | 4 | 2004 | Risk Ratio (Fixed, 95% CI) | 1.21 [1.09, 1.35] |
| 9.6 Subgroup analysis: metastatic disease (with imputed event numbers) at 3 years | 1 | 104 | Risk Ratio (Fixed, 95% CI) | 1.51 [0.32, 7.06] |
| 9.7 Subgroup analysis: bicalutamide 50 mg daily (with imputed event numbers) at 1 year | 2 | 820 | Risk Ratio (Fixed, 95% CI) | 1.27 [1.01, 1.60] |
| 9.8 Subgroup analysis: bicalutamide 50 mg daily (with imputed event numbers) at 70 weeks | 3 | 1196 | Risk Ratio (Fixed, 95% CI) | 1.29 [1.05, 1.57] |
| 9.9 Subgroup analysis: bicalutamide 150 mg daily (with imputed event numbers) at 1 year | 1 | 808 | Risk Ratio (Fixed, 95% CI) | 1.17 [1.01, 1.35] |
| 9.10 Subgroup analysis: bicalutamide 150 mg daily (with imputed event numbers) at 70 weeks | 1 | 808 | Risk Ratio (Fixed, 95% CI) | 1.18 [1.05, 1.34] |
| 9.11 Subgroup analysis: flutamide 250 mg 3 times daily (with imputed event numbers) at 3 years | 1 | 104 | Risk Ratio (Fixed, 95% CI) | 1.51 [0.32, 7.06] |
| 10 Breast pain Show forest plot | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 10.1 Total | 7 | 2670 | Risk Ratio (M‐H, Fixed, 95% CI) | 22.97 [14.79, 35.67] |
| 10.2 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1026 | Risk Ratio (M‐H, Fixed, 95% CI) | 19.39 [10.26, 36.66] |
| 10.3 Subgroup analysis: bicalutamide 150 mg daily | 3 | 1420 | Risk Ratio (M‐H, Fixed, 95% CI) | 25.82 [13.34, 49.97] |
| 10.4 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 23.48 [5.88, 93.73] |
| 10.5 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 25.71 [6.37, 103.78] |
| 11 Pelvic pain Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 11.1 Total | 5 | 2395 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.78, 1.24] |
| 11.2 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1026 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.64, 1.22] |
| 11.3 Subgroup analysis: bicalutamide 150 mg daily | 2 | 1369 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.79, 1.53] |
| 12 Bone pain Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 12.1 Bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.68, 1.72] |
| 13 Back pain Show forest plot | 5 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 13.1 Total | 5 | 1351 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.70, 1.61] |
| 13.2 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1026 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.54, 1.94] |
| 13.3 Subgroup analysis: bicalutamide 150 mg daily | 1 | 101 | Risk Ratio (M‐H, Random, 95% CI) | 2.04 [0.54, 7.71] |
| 13.4 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.59, 1.80] |
| 13.5 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.29, 1.57] |
| 14 Headache Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 14.1 Total | 2 | 584 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.53 [0.24, 1.15] |
| 14.2 Subgroup analysis: bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.20, 1.05] |
| 14.3 Subgroup analysis: flutamide 250 mg 3 times daily | 1 | 104 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.78 [0.12, 66.75] |
| 15 Abdominal pain Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 15.1 Total | 3 | 1058 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [0.90, 2.48] |
| 15.2 Subgroup analysis: bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.58, 2.70] |
| 15.3 Subgroup analysis: bicalutamide 150 mg daily | 1 | 474 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.87 [0.92, 3.81] |
| 15.4 Subgroup analysis: flutamide 250 mg 3 times daily | 1 | 104 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.31 [0.01, 7.42] |
| 16 General pain Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 16.1 Total | 4 | 2073 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.80, 1.16] |
| 16.2 Subgroup analysis: bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.65, 1.32] |
| 16.3 Subgroup analysis: bicalutamide 150 mg daily | 2 | 1369 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.71, 1.16] |
| 16.4 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.41 [0.80, 2.48] |
| 16.5 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.34 [0.67, 2.70] |
| 17 Gynaecomastia Show forest plot | 8 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 17.1 Total | 8 | 2774 | Risk Ratio (M‐H, Random, 95% CI) | 8.43 [3.19, 22.28] |
| 17.2 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1026 | Risk Ratio (M‐H, Random, 95% CI) | 14.07 [3.74, 52.85] |
| 17.3 Subgroup analysis: bicalutamide 150 mg daily | 3 | 1420 | Risk Ratio (M‐H, Random, 95% CI) | 5.01 [0.88, 28.69] |
| 17.4 Subgroup analysis: flutamide 250 mg 3 times daily | 1 | 104 | Risk Ratio (M‐H, Random, 95% CI) | 3.70 [1.33, 10.33] |
| 17.5 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 27.88 [7.02, 110.79] |
| 17.6 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Random, 95% CI) | 20.36 [4.97, 83.40] |
| 18 Constipation Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 18.1 Total | 4 | 1250 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [0.65, 1.95] |
| 18.2 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1026 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.50, 1.73] |
| 18.3 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 1.54 [0.84, 2.81] |
| 18.4 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Random, 95% CI) | 1.99 [1.03, 3.85] |
| 19 Diarrhoea Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 19.1 Total | 7 | 1929 | Risk Ratio (M‐H, Random, 95% CI) | 1.73 [0.80, 3.71] |
| 19.2 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1026 | Risk Ratio (M‐H, Random, 95% CI) | 1.96 [1.00, 3.82] |
| 19.3 Subgroup analysis: bicalutamide 150 mg daily | 2 | 575 | Risk Ratio (M‐H, Random, 95% CI) | 1.29 [0.14, 12.28] |
| 19.4 Subgroup analysis: flutamide 250 mg 3 times daily | 1 | 104 | Risk Ratio (M‐H, Random, 95% CI) | 8.35 [0.46, 151.19] |
| 19.5 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 1.35 [0.57, 3.19] |
| 19.6 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Random, 95% CI) | 2.14 [0.86, 5.32] |
| 20 Vomiting Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 20.1 Total | 3 | 650 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.88 [1.38, 10.87] |
| 20.2 Subgroup analysis: bicalutamide 50 mg daily | 2 | 546 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.05 [0.99, 9.35] |
| 20.3 Subgroup analysis: flutamide 250 mg 3 times daily | 1 | 104 | Risk Ratio (M‐H, Fixed, 95% CI) | 10.2 [0.58, 179.88] |
| 21 Hypertension Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 21.1 Bicalutamide 150 mg daily | 1 | 101 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.29 [0.06, 1.34] |
| 22 Loss of sexual interest Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 22.1 Bicalutamide 150 mg daily | 1 | 51 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.50 [0.30, 0.83] |
| 23 Asthenia Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 23.1 Total | 4 | 2073 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.77 [1.36, 2.31] |
| 23.2 Subgroup analysis: bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.74 [1.11, 2.72] |
| 23.3 Subgroup analysis: bicalutamide 150 mg daily | 2 | 1369 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.58 [1.10, 2.28] |
| 23.4 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.07 [1.38, 6.84] |
| 23.5 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.45 [0.95, 6.31] |
| 24 Insomnia Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 24.1 Total | 2 | 325 | Risk Ratio (M‐H, Random, 95% CI) | 0.51 [0.11, 2.37] |
| 24.2 Subgroup analysis: bicalutamide 150 mg daily | 1 | 101 | Risk Ratio (M‐H, Random, 95% CI) | 0.17 [0.02, 1.36] |
| 24.3 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.38, 2.06] |
| 24.4 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.29, 2.58] |
| 25 Hot flashes Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 25.1 Total | 8 | 2774 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.23 [0.19, 0.27] |
| 25.2 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1026 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.15, 0.27] |
| 25.3 Subgroup analysis: bicalutamide 150 mg daily | 3 | 1420 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.19, 0.30] |
| 25.4 Subgroup analysis: flutamide 250 mg 3 times daily | 1 | 104 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.28 [0.10, 0.82] |
| 25.5 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.22 [0.12, 0.40] |
| 25.6 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.31 [0.15, 0.63] |
| 26 Night sweats Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 26.1 Total | 2 | 1571 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.29 [0.17, 0.49] |
| 26.2 Subgroup analysis: bicalutamide 50 mg daily | 1 | 303 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.12, 1.09] |
| 26.3 Subgroup analysis: bicalutamide 150 mg daily | 1 | 1268 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.26 [0.14, 0.49] |
| 27 Anaemia Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 27.1 Total | 2 | 294 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.16, 5.35] |
| 27.2 Subgroup analysis: bicalutamide 50 mg daily | 1 | 243 | Risk Ratio (M‐H, Random, 95% CI) | 3.18 [0.34, 30.13] |
| 27.3 Subgroup analysis: bicalutamide 150 mg daily | 1 | 51 | Risk Ratio (M‐H, Random, 95% CI) | 0.52 [0.31, 0.88] |
| 28 Hepatic enzyme increase Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 28.1 Total | 2 | 205 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.91 [0.59, 40.86] |
| 28.2 Subgroup analysis: bicalutamide 150 mg daily | 1 | 101 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.14 [0.38, 134.72] |
| 28.3 Subgroup analysis: flutamide 250 mg 3 times daily | 1 | 104 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.78 [0.12, 66.75] |
| 29 Rash Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 29.1 Total | 3 | 805 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.77, 2.16] |
| 29.2 Subgroup analysis: bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.50, 1.92] |
| 29.3 Subgroup analysis: bicalutamide 150 mg daily | 1 | 101 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.10 [0.62, 42.12] |
| 29.4 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [0.47, 3.61] |
| 29.5 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.79 [0.58, 5.52] |
| 30 Pruritus Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 30.1 Total | 2 | 723 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.59 [0.93, 7.19] |
| 30.2 Subgroup analysis: bicalutamide 50 mg daily | 2 | 723 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.59 [0.93, 7.19] |
| 31 Dyspnoea Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 31.1 Bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.24, 1.31] |
| 32 Infection Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 32.1 Total | 4 | 2294 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.58, 1.03] |
| 32.2 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1026 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.34, 0.91] |
| 32.3 Subgroup analysis: bicalutamide 150 mg daily | 1 | 1268 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.65, 1.33] |
| 33 Pharyngitis Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 33.1 Total | 2 | 325 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.47, 1.34] |
| 33.2 Subgroup analysis: bicalutamide 150 mg daily | 1 | 101 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.11, 1.36] |
| 33.3 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.56, 1.93] |
| 33.4 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.34, 1.91] |
| 34 Arthritis Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 34.1 Bicalutamide 150 mg daily | 1 | 101 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.12, 1.60] |
| 35 Sinusitis Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 35.1 Bicalutamide 150 mg daily | 1 | 101 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.36, 4.48] |
| 36 Urinary tract infection Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 36.1 Total | 2 | 698 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.53, 1.19] |
| 36.2 Subgroup analysis: bicalutamide 150 mg daily | 1 | 474 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.43, 1.14] |
| 36.3 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.40, 1.99] |
| 36.4 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.36 [0.57, 3.27] |
| 37 Dizziness Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 37.1 Total | 2 | 581 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.61, 1.95] |
| 37.2 Subgroup analysis: bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.49, 1.97] |
| 37.3 Subgroup analysis: bicalutamide 150 mg daily | 1 | 101 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.49, 4.20] |
| 38 Haemorrhage Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 38.1 Total | 2 | 546 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.07 [0.01, 0.54] |
| 38.2 Subgroup analysis: bicalutamide 50 mg daily | 2 | 546 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.07 [0.01, 0.54] |
| 39 Haematuria Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 39.1 Total | 2 | 954 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.14, 9.87] |
| 39.2 Subgroup analysis: bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 0.41 [0.26, 0.67] |
| 39.3 Subgroup analysis: bicalutamide 150 mg daily | 1 | 474 | Risk Ratio (M‐H, Random, 95% CI) | 3.49 [2.01, 6.05] |
| 40 Nocturia Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 40.1 Bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.20, 0.69] |
| 41 Urinary frequency Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 41.1 Bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.22 [0.11, 0.47] |
| 42 Urinary retention Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 42.1 Bicalutamide 150 mg daily | 1 | 1268 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.55, 1.24] |
| 43 Peripheral oedema Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 43.1 Total | 2 | 1748 | Risk Ratio (M‐H, Random, 95% CI) | 0.61 [0.33, 1.15] |
| 43.2 Subgroup analysis: bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Random, 95% CI) | 0.42 [0.21, 0.82] |
| 43.3 Subgroup analysis: bicalutamide 150 mg daily | 1 | 1268 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.54, 1.17] |
| 44 Anorexia Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 44.1 Bicalutamide 50 mg daily | 1 | 480 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.57, 2.18] |
| 45 Loss of sexual function Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 45.1 Bicalutamide 50 mg daily | 1 | 303 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.14, 6.87] |
| 46 Arthralgia Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 46.1 Total | 1 | 224 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.65 [0.86, 3.15] |
| 46.2 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.96 [1.01, 3.80] |
| 46.3 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.36, 2.63] |
| 47 Gastralgia Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 47.1 Flutamide 250 mg 3 times daily | 1 | 104 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.78 [0.12, 66.75] |
| 48 Nausea Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 48.1 Total | 3 | 1026 | Risk Ratio (M‐H, Random, 95% CI) | 3.24 [0.95, 11.02] |
| 48.2 Subgroup analysis: bicalutamide 50 mg daily | 3 | 1026 | Risk Ratio (M‐H, Random, 95% CI) | 3.24 [0.95, 11.02] |
| 49 Fatigue Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 49.1 Bicalutamide 150 mg daily | 1 | 51 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.31, 0.88] |
| 50 Dry skin Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 50.1 Total | 1 | 224 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.41 [0.42, 132.46] |
| 50.2 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 8.81 [0.48, 161.24] |
| 50.3 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.35 [0.26, 152.67] |
| 51 Aggravation reaction Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 51.1 Bicalutamide 150 mg daily | 1 | 474 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.45, 1.05] |
| 52 Serious adverse events Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 52.1 Total | 2 | 325 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.79, 1.28] |
| 52.2 Subgroup analysis: bicalutamide 150 mg daily | 1 | 101 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.49, 4.20] |
| 52.3 Subgroup analysis: bicalutamide 450 mg daily | 1 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.73, 1.25] |
| 52.4 Subgroup analysis: bicalutamide 600 mg daily | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.71, 1.37] |
