Adding taxane-based chemotherapy to androgen deprivation therapy for the treatment of metastatic hormone-sensitive prostate cancer

Review question

The aim of this review was to find out if adding taxane-based chemotherapy to hormone therapy improved outcomes in men with metastatic, hormone-sensitive prostate cancer. We collected and analysed all relevant studies to answer this question and found three studies.

Background

Of the men diagnosed with prostate cancer, approximately 16% will present with cancer that has spread at diagnosis. In addition, another 15% to 30% of men will get the disease again after having primary treatment. Hormone therapy (drugs to reduce the level of male hormones) has been the first treatment for advanced cancer but it does not cure it and eventually the cancer comes back. Recently studies have looked at whether chemotherapy (chemicals that kill cancer cells), when given early, improve how patients do.

Study characteristics

The evidence is current to August 2018. We found three studies (specifically, randomized controlled trials) with a total of 2,261 people. The studies compared docetaxel (an anti-cancer drug) and hormone therapy to hormone therapy alone.

Key results

Taxane-based chemotherapy in addition to hormone therapy likely improves overall and cancer-specific survival and reduces disease progression. There may also be a small but unimportant improvement in quality of life at 12 months. There may also be an increase in side effects when people are treated with taxane-based chemotherapy.

Certainty of evidence

We judged the certainty of the evidence to be moderate for time-to-death from any cause, risk of prostate cancer-specific death and the time to disease progression. This means that our estimates are likely to be close to the truth, but there were limitations in the studies that reduce our confidence in the results. The certainty of the evidence was low for Grade III to V adverse events (side effects), adverse events of all grades, people stopping treatment due to adverse events, and quality of life. This means that the true effect of the treatment may be substantially different from what this review shows, because of limitations in the studies and imprecision (variability in estimates).

Authors' conclusions: 

Compared to ADT alone, the early (within 120 days of beginning ADT) addition of taxane-based chemotherapy to ADT for hormone-sensitive prostate cancer probably prolongs both overall and disease-specific survival and delays disease progression. There may be an increase in toxicity with taxane-based chemotherapy in combination with ADT. There may also be a small, clinically unimportant improvement in quality of life at 12 months with taxane-based chemotherapy and ADT treatment.

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Background: 

There has been considerable development in the treatment of advanced prostate cancer over the last decade. A number of agents, including docetaxel, cabazitaxel, abiraterone acetate, enzalutamide and sipuleucel-T, have been reported to improve outcomes in men with castration-resistant disease and their use is being explored in hormone-sensitive prostate cancer.

Objectives: 

To assess the effects of early taxane-based chemohormonal therapy for newly diagnosed, metastatic, hormone-sensitive prostate cancer.

Search strategy: 

We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, Google Scholar, and Web of Science), trials registries, other sources of grey literature, and conference proceedings, up to 10 August 2018. We applied no restrictions on publication language or status.

Selection criteria: 

We included randomized or quasi-randomized controlled trials in which participants were administered taxane-based chemotherapy with systemic androgen deprivation therapy (ADT) within 120 days of beginning ADT versus ADT alone at the time of diagnosis of metastatic disease.

Data collection and analysis: 

Two review authors independently classified studies and abstracted data from the included studies. We performed statistical analyses using a random-effects model. We rated the quality of evidence according to the GRADE approach.

Main results: 

The search identified three studies in which 2,261 participants were randomized to receive either ADT alone, or taxane-based chemotherapy at a dose of 75mg per square meter of body surface area at three-weekly intervals for six or nine cycles in addition to ADT.

Primary outcomes

Early treatment with taxane-based chemotherapy in addition to ADT probably reduces death from any cause compared to ADT alone (hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.68 to 0.87; moderate-certainty evidence); this would result in 94 fewer deaths per 1,000 men (95% CI 51 to 137 fewer deaths). We downgraded the certainty of evidence due to study limitations related to potential performance bias. Based on the results of one study with 375 participants, the addition of taxane-based chemotherapy to ADT may increase the incidence of Grade III to V adverse events compared to ADT alone (risk ratio (RR) 2.98, 95% CI 2.19 to 4.04; low-certainty evidence); this would result in 405 more Grade III to V adverse events per 1,000 men (95% CI 243 to 621 more events). We downgraded the certainty of evidence due to study limitations and imprecision.

Secondary outcomes

Early taxane-based chemotherapy in addition to ADT probably reduces the risk of prostate cancer-specific death (RR 0.79, 95% CI 0.70 to 0.89; moderate-certainty evidence). We downgraded the certainty of evidence due to study limitations related to potential performance and detection bias. The addition of taxane-based chemotherapy also probably reduces disease progression compared to ADT alone (HR 0.63, 95% CI 0.56 to 0.71; moderate-certainty evidence). We downgraded the certainty of evidence because of study limitations related to potential performance bias. The addition of taxane-based chemotherapy to ADT may result in a large increase in the risk of treatment discontinuation due to adverse events (RR 79.41, 95% CI 4.92 to 1282.78; low-certainty evidence). We downgraded the certainty of evidence due to study limitations and imprecision. This estimate is derived from a single study with no events in the control arm but a discontinuation rate of 20% in the intervention arm. Taxane-based chemotherapy may increase the incidence of adverse events of any grade (RR 1.11, 95% CI 1.06 to 1.17; low-certainty evidence). We downgraded our assessment of the certainty of evidence due to very serious study limitations. There may be a small improvement, which may not be clinically important, in quality of life at 12 months with combination treatment (mean difference (MD) 2.85 on the Functional Assessment of Cancer Therapy—Prostate scale, 95% CI 0.13 higher to 5.57 higher; low-certainty evidence). We downgraded the certainty of evidence for study limitations related to potential performance, detection and attrition bias.

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