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NIHR Signal Early suppression of male hormones is better than delayed therapy for advanced prostate cancer on balance

Published on 2 October 2019

doi: 10.3310/signal-000823

Offering early hormone suppression therapy to men with advanced prostate cancer that is causing no symptoms improves outcomes compared with waiting until symptoms of cancer spread arise. Early treatment is associated with 23 to 57 fewer deaths per 1,000 men over five years, depending on the men’s baseline risk. However, this comes with an increased chance of some non-serious side effects.

Hormone suppression works by lowering levels of the male sex hormones that fuel the cancer’s growth. It is the mainstay of treatment for advanced prostate cancer, but the best time to initiate therapy has been debated. This updated Cochrane review identified 10 trials comparing early suppression therapy with delaying treatment until there was evidence that the cancer had spread or the patient developed symptoms.

Early treatment is likely to be the better strategy, particularly as findings relating to side effects are less certain. Individual treatment decisions would need to be based on informed discussion between patient and doctor.

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Why was this study needed?

Prostate cancer is the most common cancer in men, with around 47,500 new diagnoses and 11,500 deaths every year in the UK. For locally advanced or metastatic prostate cancer that has already grown or spread to lymph nodes or other organs (advanced cancer), management usually involves suppressing the male sex hormones called androgens. Androgens can be suppressed surgically by removal of the testicles or with drugs.

The best time to start androgen suppression is unclear. There has been evidence that treating early (when there are no symptoms) might reduce disease progression. However, this exposes the man to longer treatment and a greater potential for side effects. An earlier Cochrane review addressed this topic in 2002 but further data has been published since. The authors, therefore, wanted to update the review.

What did this study do?

This review identified eight new randomised controlled trials in addition to the two already included (total 15,355 participants). Eligible trials included men with advanced cancer that was large or had either spread to lymph nodes or to other organs, or men who had received potentially curative treatment but in whom prostate-specific antigen (PSA) levels suggested that this treatment had failed.

Early suppression was defined as treatment at the point of diagnosis when the patient was asymptomatic. Late treatment involved waiting to treat until symptoms appeared, such as bone pain, or imaging showed evidence of spread. The individual trials varied in their exact treatment strategies.

Several trials were conducted across more than one centre or country. One trial was conducted in the UK. Patients and medical personnel were aware of treatment allocation in all trials. There was a high risk of bias because randomisation methods were unclear in most trials, which can lead to uncertainty about whether the groups were well balanced.

What did it find?

  • Early androgen suppression reduced the risk of dying from any cause during follow-up compared to late treatment (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.75 to 0.90; moderate-certainty evidence, 10 trials, 4,767 men). This corresponded to 57 fewer deaths per 1,000 men at five years for the moderate-risk group (men with local spread or positive lymph nodes) and 23 fewer deaths per 1,000 men in the low-risk group (previously-treated men with rising PSA levels but no lymph node or organ involvement).
  • Early androgen suppression also reduced the risk of dying from prostate cancer specifically (HR 0.69, 95% CI 0.57 to 0.84; moderate-certainty evidence, seven trials, 3,677 men). This equated to between 62 fewer prostate cancer deaths per 1,000 moderate-risk men and 24 fewer deaths per 1,000 low-risk men over five years.
  • Early treatment may reduce the risk of problems from cancer spreading to the bones, but this finding came from low-certainty evidence (relative risk [RR] 0.37, 95% CI 0.17 to 0.80; 23 fewer events per 1,000 men; three trials, 2,209 men).
  • There was no indication that early treatment increased serious adverse events compared with late treatment (RR 1.05, 95% CI 0.95 to 1.16; five trials, 10,575 men). Early therapy was, however, associated with increased risk of non-serious side effects such as fatigue (RR 1.41, 95% CI 1.23 to 1.62; two trials, 8,209 men) and heart failure (RR 1.90, 95% CI 1.09 to 3.33; one trial, 1,214 men). All evidence on adverse effects was low-certainty, decreasing confidence in these findings.
  • Evidence on quality of life was of moderate quality and came from one small trial (285 men). It suggested that on average, overall quality of life was probably similar with early and late treatment.

What does current guidance say on this issue?

NICE prostate cancer guidelines (2019) give recommendations for locally-advanced (including high-risk localised) and metastatic prostate cancer, which fall under the advanced definition used in this review.

Radical radiotherapy plus androgen suppression therapy is recommended for high-risk localised cancer. NICE advises that suppression may be given before, during or after radiotherapy, but don’t state a precise timing in relation to diagnosis. Chemotherapy plus androgen suppression is recommended for newly diagnosed metastatic prostate cancer.

What are the implications?

This updated review appears to support starting androgen suppression at the time of diagnosis of advanced prostate cancer, rather than waiting for further evidence of spread.

However, there would be a need to balance the increase in survival against the potential for non-serious side effects such as tiredness or cardiovascular effects. There is unlikely to be a one-size-fits-all approach. The possible risks and likely benefits of treatment, taking account of individual patient characteristics, would need to be discussed with patients.

Citation and Funding

Kunath F, Jensen K, Pinart M et al. Early versus deferred standard androgen suppression therapy for advanced hormone-sensitive prostate cancer. Cochrane Database Syst Rev. 2019;(6):CD003506

This study was supported by a grant from the German Federal Ministry of Education and Research. 

Bibliography

NICE. Prostate cancer: diagnosis and management. NG131. London: National Institute for Health and Care Excellence; 2019.

Prostate Cancer UK. About prostate cancer. London: Prostate Cancer UK; 2018.

Why was this study needed?

Prostate cancer is the most common cancer in men, with around 47,500 new diagnoses and 11,500 deaths every year in the UK. For locally advanced or metastatic prostate cancer that has already grown or spread to lymph nodes or other organs (advanced cancer), management usually involves suppressing the male sex hormones called androgens. Androgens can be suppressed surgically by removal of the testicles or with drugs.

The best time to start androgen suppression is unclear. There has been evidence that treating early (when there are no symptoms) might reduce disease progression. However, this exposes the man to longer treatment and a greater potential for side effects. An earlier Cochrane review addressed this topic in 2002 but further data has been published since. The authors, therefore, wanted to update the review.

What did this study do?

This review identified eight new randomised controlled trials in addition to the two already included (total 15,355 participants). Eligible trials included men with advanced cancer that was large or had either spread to lymph nodes or to other organs, or men who had received potentially curative treatment but in whom prostate-specific antigen (PSA) levels suggested that this treatment had failed.

Early suppression was defined as treatment at the point of diagnosis when the patient was asymptomatic. Late treatment involved waiting to treat until symptoms appeared, such as bone pain, or imaging showed evidence of spread. The individual trials varied in their exact treatment strategies.

Several trials were conducted across more than one centre or country. One trial was conducted in the UK. Patients and medical personnel were aware of treatment allocation in all trials. There was a high risk of bias because randomisation methods were unclear in most trials, which can lead to uncertainty about whether the groups were well balanced.

What did it find?

  • Early androgen suppression reduced the risk of dying from any cause during follow-up compared to late treatment (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.75 to 0.90; moderate-certainty evidence, 10 trials, 4,767 men). This corresponded to 57 fewer deaths per 1,000 men at five years for the moderate-risk group (men with local spread or positive lymph nodes) and 23 fewer deaths per 1,000 men in the low-risk group (previously-treated men with rising PSA levels but no lymph node or organ involvement).
  • Early androgen suppression also reduced the risk of dying from prostate cancer specifically (HR 0.69, 95% CI 0.57 to 0.84; moderate-certainty evidence, seven trials, 3,677 men). This equated to between 62 fewer prostate cancer deaths per 1,000 moderate-risk men and 24 fewer deaths per 1,000 low-risk men over five years.
  • Early treatment may reduce the risk of problems from cancer spreading to the bones, but this finding came from low-certainty evidence (relative risk [RR] 0.37, 95% CI 0.17 to 0.80; 23 fewer events per 1,000 men; three trials, 2,209 men).
  • There was no indication that early treatment increased serious adverse events compared with late treatment (RR 1.05, 95% CI 0.95 to 1.16; five trials, 10,575 men). Early therapy was, however, associated with increased risk of non-serious side effects such as fatigue (RR 1.41, 95% CI 1.23 to 1.62; two trials, 8,209 men) and heart failure (RR 1.90, 95% CI 1.09 to 3.33; one trial, 1,214 men). All evidence on adverse effects was low-certainty, decreasing confidence in these findings.
  • Evidence on quality of life was of moderate quality and came from one small trial (285 men). It suggested that on average, overall quality of life was probably similar with early and late treatment.

What does current guidance say on this issue?

NICE prostate cancer guidelines (2019) give recommendations for locally-advanced (including high-risk localised) and metastatic prostate cancer, which fall under the advanced definition used in this review.

Radical radiotherapy plus androgen suppression therapy is recommended for high-risk localised cancer. NICE advises that suppression may be given before, during or after radiotherapy, but don’t state a precise timing in relation to diagnosis. Chemotherapy plus androgen suppression is recommended for newly diagnosed metastatic prostate cancer.

What are the implications?

This updated review appears to support starting androgen suppression at the time of diagnosis of advanced prostate cancer, rather than waiting for further evidence of spread.

However, there would be a need to balance the increase in survival against the potential for non-serious side effects such as tiredness or cardiovascular effects. There is unlikely to be a one-size-fits-all approach. The possible risks and likely benefits of treatment, taking account of individual patient characteristics, would need to be discussed with patients.

Citation and Funding

Kunath F, Jensen K, Pinart M et al. Early versus deferred standard androgen suppression therapy for advanced hormone-sensitive prostate cancer. Cochrane Database Syst Rev. 2019;(6):CD003506

This study was supported by a grant from the German Federal Ministry of Education and Research. 

Bibliography

NICE. Prostate cancer: diagnosis and management. NG131. London: National Institute for Health and Care Excellence; 2019.

Prostate Cancer UK. About prostate cancer. London: Prostate Cancer UK; 2018.

Early versus deferred standard androgen suppression therapy for advanced hormone-sensitive prostate cancer

Published on 14 June 2019

Kunath, F.,Jensen, K.,Pinart, M.,Kahlmeyer, A.,Schmidt, S.,Price, C. L.,Lieb, V.,Dahm, P.

Cochrane Database Syst Rev Volume 6 , 2019

BACKGROUND: Standard androgen suppression therapy (AST) using surgical or medical castration is considered a mainstay of advanced hormone-sensitive prostate cancer treatment. AST can be initiated early when disease is asymptomatic or deferred when patients suffer symptoms of disseminated prostate cancer. OBJECTIVES: To assess the effects of early versus deferred standard AST for advanced hormone-sensitive prostate cancer. SEARCH METHODS: For this Cochrane Review update, we performed a comprehensive search of multiple databases (CENTRAL, MEDLINE, Embase, Web of Science; last searched November 2018) and two clinical trial registers, with no restrictions on the language of publication or publication status. We also searched bibliographies of included studies and conference proceedings (last searched January 2019). SELECTION CRITERIA: We included all randomised controlled trials (RCTs) with a direct comparison of early versus deferred standard AST. We excluded all other study designs. Participants included had advanced hormone-sensitive prostate cancer receiving surgical or medical castration. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies and abstracted data. The primary outcomes were time to death of any cause and serious adverse events. Secondary outcomes were time to disease progression, time to death from prostate cancer, adverse events and quality of life. We performed statistical analyses using a random-effects model and assessed the certainty of evidence according to GRADE. We performed subgroup analyses for advanced but non-metastatic disease (T2-4/N+ M0), metastatic disease (M1), and prostate-specific antigen (PSA) relapse. MAIN RESULTS: We identified seven new RCTs since publication of the original review in 2002. In total, we included 10 RCTs.Primary outcomesEarly AST probably reduces the risk of death from any cause over time (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75 to 0.90; moderate-certainty evidence; 4767 participants). This corresponds to 57 fewer deaths (95% CI 80 fewer to 31 fewer) per 1000 participants at 5 years for the moderate risk group and 23 fewer deaths (95% CI 32 fewer to 13 fewer) per 1000 participants at 5 years in the low risk group. We downgraded for study limitations. Early versus deferred AST may have little or no effect on serious adverse events (risk ratio (RR) 1.05, 95% CI 0.95 to 1.16; low-certainty evidence; 10,575 participants) which corresponds to 6 more serious adverse events (6 fewer to 18 more) per 1000 participants. We downgraded the certainty of evidence for study limitations and selective reporting.Secondary outcomesEarly AST probably reduces the risk of death from prostate cancer over time (HR 0.69, 95% CI 0.57 to 0.84; moderate-certainty evidence). This corresponds to 62 fewer prostate cancer deaths per 1000 (95% CI 87 fewer to 31 fewer) at 5 years for the moderate risk group and 24 fewer death from prostate cancer (95% CI 34 fewer to 12 fewer) per 1000 men at 5 years in the low risk group. We downgraded the certainty of evidence for study limitations.Early AST may decrease the rate of skeletal events (RR 0.37, 95% CI 0.17 to 0.80; low-certainty evidence) corresponding to 23 fewer skeletal events per 1000 (95% CI 31 fewer to 7 fewer). We downgraded for study limitations and imprecision. It may also increase fatigue (RR 1.41, 95% CI 1.23 to 1.62; low-certainty evidence), corresponding to 31 more men with this complaint per 1000 (95% CI 18 more to 48 more). We downgraded for study limitations and imprecision. It may increase the risk of heart failure (RR 1.90, 95% CI 1.09 to 3.33; low-certainty evidence) corresponding to 27 more events per 1000 (95% CI 3 more to 69 more). We downgraded the certainty of evidence for study limitations and imprecision.Global quality of life is probably similar after two years as assessed with the EORTC QLQ-C30 (version 3.0) questionnaire (mean difference -1.56, 95% CI -4.50 to 1.38; moderate-certainty evidence) with higher scores reflecting better quality of life. We downgraded the certainty of evidence for study limitations. AUTHORS' CONCLUSIONS: Early AST probably extends time to death of any cause and time to death from prostate cancer. It may slightly decrease the rate of skeletal events. Rates of serious adverse events and quality of life may be similar. It may increase fatigue and may increase the risk of heart failure. Better quality trials would be particularly important to better understand the outcomes related to possible treatment-related harm, for which we only found low-certainty evidence.

Expert commentary

This review confirms that giving men with prostate cancer that has spread outside the prostate androgen deprivation therapy as soon as possible, is likely to give them a better chance of survival. However, for some men, the side effects of androgen deprivation therapy are significant and reduce their quality of life. 

Androgen deprivation therapy should continue to be considered the best standard of treatment but, with guidance from their healthcare team, men should weigh up the pros and cons and their own personal circumstances before making a decision on whether it is right for them.

Prostate Cancer UK’s specialist nurse service can help any man trying to make that decision or experiencing side effects from androgen deprivation therapy.

Matthew Hobbs, Deputy Director of Research, Prostate Cancer UK