Introduction
Prostate cancer ranks as the second most prevalent cancer among men globally and is the fifth leading cause of death due to cancer, with around 1.4 million new diagnoses each year [1]. Systemic treatments, such as androgen deprivation therapy (ADT) and chemotherapy, play a vital role in the management of metastatic hormone-sensitive prostate cancer (mHSPC) as well as metastatic castration-resistant prostate cancer (mCRPC) [2].
Docetaxel, a microtubule inhibitor derived from the taxane class, has emerged as a fundamental therapy [3]. In mCRPC, the combination of docetaxel and prednisone has demonstrated a survival advantage of 20–24% compared to treatment regimens based on mitoxantrone [4]. In the context of mHSPC, pivotal studies like CHAARTED and STAMPEDE have shown that the integration of docetaxel with ADT markedly enhances overall survival rates, particularly among patients presenting with high-volume disease [5].
Although the standard docetaxel regimen involves triweekly administration (75 mg/m2 every 3 weeks), alternative weekly (30 mg/m2) and biweekly (50 mg/m2) schedules have been explored to enhance tolerability and reduce toxicity, especially in frail or elderly patients [6]. Weekly and biweekly regimens have shown potential to lower adverse events, such as febrile neutropenia, while maintaining efficacy comparable to the triweekly schedule in mCRPC [7]. A recent retrospective study examining weekly, biweekly, and triweekly docetaxel treatment regimens in patients with mCRPC revealed no significant differences in prostate-specific antigen (PSA) response rates among the three dosing frequencies. Nevertheless, both biweekly and triweekly regimens demonstrated improved overall survival compared to the weekly regimen. Additionally, the time to disease progression was marginally extended with the less frequent dosing schedules. Notably, the rates of overall and high-grade toxicities were comparable across all treatment groups [8]. A randomized trial in mCRPC reported that a biweekly 50 mg/m2 regimen resulted in longer time to treatment failure and fewer severe toxicities compared to the triweekly 75 mg/m2 regimen [9]. These findings suggest that alternative dosing schedules may offer a better balance of efficacy and safety, particularly for patients with comorbidities.
However, the optimal weekly docetaxel regimen for prostate cancer remains unclear due to limited head-to-head comparisons and heterogeneity in study designs, patient populations, and outcome measures [10]. Despite extensive investigation of docetaxel-based therapy in prostate cancer, several clinically important gaps remain unresolved. Most available trials were not designed to inform individualized dosing strategies, and treatment selection is often guided by convention rather than patient-specific factors such as age, comorbidities, performance status, or frailty. Elderly patients and those with significant comorbid conditions, who represent a substantial proportion of the real-world prostate cancer population, are frequently underrepresented in randomized trials, limiting the applicability of standard triweekly dosing in routine practice [9, 10]. Additionally, direct head-to-head comparisons among weekly, biweekly, and triweekly regimens are scarce, and existing meta-analyses have primarily relied on pairwise comparisons rather than integrated evidence synthesis. In this context, network meta-analysis (NMA) offers an effective method for integrating both direct and indirect evidence, facilitating a thorough comparison of various treatment regimens at once and aiding in the selection of regimens tailored to individual patient characteristics [11].
To our knowledge, no previous NMA has systematically evaluated and compared the efficacy and safety of weekly, biweekly, and triweekly docetaxel regimens in prostate cancer [12]. This study aims to address this gap by conducting a systematic review and NMA of randomized controlled trials (RCTs), retrospective studies, and case-control studies. We will evaluate clinical outcomes such as PSA response rates and adverse events associated with various dosing regimens. The results of our study are intended to inform personalized treatment strategies and improve therapeutic results for men diagnosed with prostate cancer.
Materials and methods
This systematic review and meta-analysis were carried out in compliance with the guidelines given in the Cochrane Handbook for Systematic Reviews of Interventions [13] and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [14]. The study protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) CRD420251076649.
Data sources and searches
A systematic literature search was undertaken on three databases: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials using MESH terms and keywords related to [Prostate Cancer] and [Docetaxel] from inception till February 2025. During screening, we did not use any filter based on author, title, study type, or year of publication. In order to enhance the diversity of our study, a supplementary search was conducted by reviewing the references of all included articles. The detailed search strategy is provided in Table S1.
Study selection and eligibility criteria
All studies were imported to Rayyan, and with the help of a filter, all duplicates generated by our literature search were removed. Screening of titles and abstracts was carried out independently by two authors (OA and FS) to exclude all irrelevant studies. Full-text screening was then carried out on the remaining studies in compliance with our eligibility criteria. All disputes regarding the selection of studies were resolved by a third author (SR).
All observational studies and RCTs that compare weekly, biweekly, and triweekly docetaxel regimens in patients with histologically or cytologically confirmed prostate cancer were included in this meta-analysis. Those patients were excluded who had no complete information available or who did not match the inclusion criteria. Study designs other than cohorts, case-control studies, and RCTs were excluded. Studies conducted on animals, case reports, reviews, and systematic reviews and meta-analyses were also excluded. No language or date restrictions were applied.
Data extraction and outcomes
All relevant data were extracted into an Excel sheet comprised of three domains. The first domain consists of the author’s name, study design, inclusion and exclusion criteria, duration of follow-up, intervention name, dosing, and route of administration. The second domain comprised baseline characteristics, and the third one reported outcome data. Data extraction was independently carried out by two authors, and conflicts were resolved by a third author. The primary outcomes of this study included PSA response rate and time for treatment failure or progression. The secondary outcomes comprised hepatotoxicity, vomiting, any adverse event, thrombocytopenia, anemia, arthralgia, neuropathy, neutropenia, fatigue, febrile neutropenia, nausea, anorexia, and diarrhea.
Risk of bias assessment
The methodological quality of included studies was evaluated using design-specific appraisal tools. RCTs were assessed with the revised Cochrane risk of bias tool for randomized trials (RoB 2) [15], which examines potential bias across five domains: the randomization process, deviations from intended interventions, completeness of outcome data, outcome measurement, and selective reporting. Based on these domains, each trial was assigned an overall judgment of low risk of bias, some concerns, or high risk of bias.
Observational studies were appraised using the Newcastle-Ottawa Scale (NOS) for observational research [16], which evaluates study quality across three domains: selection of participants, comparability of study groups, and assessment of outcomes. To facilitate interpretation, NOS scores were mapped to Agency for Healthcare Research and Quality (AHRQ) categories of good, fair, or poor quality. The maximum achievable scores were four stars for selection, two for comparability, and three for outcome assessment. Studies receiving 7–9 stars were classified as low risk of bias, those with 5–6 stars as having some concerns, and those scoring fewer than 5 stars as high risk of bias. All assessments were conducted independently by two reviewers (AK and UJ), and any discrepancies were resolved through consensus or by involving a third reviewer (AA), ensuring a rigorous and transparent quality appraisal process.
Statistical analysis
The NMA was conducted using the netmeta package of the R statistical tool (R Development Core Team), version 3.2.3. A frequentist random-effects model was used in the NMA to compare the efficacy of weekly (referred to as 1), biweekly (referred to as 2), and triweekly (referred to as 3) docetaxel therapy using the netmeta package of R. Dichotomous outcomes were analyzed using risk ratios (RRs) and 95% confidence intervals (CIs) through a frequentist NMA. Both direct and indirect effect sizes were calculated, and global and local inconsistencies were assessed (with statistical significance for inconsistencies set at < 0.05). Forest plots were created using the common comparator of control to demonstrate network estimates (RRs, CIs, and p-values). Data was demonstrated in the form of league tables containing network estimates for all possible comparisons. Each intervention’s probability of being the most effective was ranked based on probability-scores (P-scores) values. Heterogeneity was assessed using the DerSimonian-Laird estimator for tau2. All analyses were performed using R version 4.4.1, and a p-value of less than 0.05 was considered statistically significant.
Discussion
This NMA evaluated and compared the efficacy and safety profiles of weekly, biweekly, and triweekly docetaxel regimens in patients with prostate cancer, using data from 11 RCTs and retrospective studies. Weekly docetaxel demonstrated the highest PSA response rate, while the triweekly regimen was associated with a significantly longer time to treatment failure. In terms of safety, biweekly and triweekly regimens showed a significantly higher incidence of hepatotoxicity and vomiting compared to weekly dosing. Weekly docetaxel had a higher incidence of anemia and thrombocytopenia, though these differences were not statistically significant. Triweekly dosing showed the highest rates of febrile neutropenia, fatigue, and nausea, whereas biweekly regimens were more frequently associated with arthralgia, neuropathy, and neutropenia. Most adverse events did not reach statistical significance and were characterized by varying degrees of heterogeneity. These findings highlight distinct risk-benefit profiles among the three regimens, providing valuable insights for tailoring docetaxel-based therapy in clinical practice.
Our NMA indicated that weekly docetaxel administration achieved the highest PSA response rate, while triweekly dosing exhibited the lowest, though these differences were not statistically significant. This finding is consistent with previous meta-analyses. For instance, a systematic review and meta-analysis by Neto et al. [25] evaluated 12 randomized clinical trials involving 2,244 patients and found no significant difference in PSA response rates between weekly and triweekly docetaxel regimens. Similarly, a meta-analysis by Francini et al. [26] analyzed 22 trials encompassing 7,677 patients and reported a moderate correlation between PSA response and overall survival, suggesting that variations in dosing schedules did not markedly impact PSA response rates. These studies support the notion that while weekly dosing may offer a marginally higher PSA response, the differences among the various schedules are not statistically significant, emphasizing the importance of considering patient-specific factors such as tolerability and comorbidities when selecting a docetaxel regimen.
Our analysis demonstrated that the triweekly docetaxel regimen was associated with a significantly longer time to treatment failure compared to the weekly regimen, with high heterogeneity. This finding is supported by a meta-analysis by Neto et al. [25], which evaluated 12 randomized trials and found that triweekly regimens were more effective in delaying disease progression than weekly schedules, likely due to their higher cumulative dose intensity and pharmacodynamic effects. Further support comes from RCTs. A phase III trial by Kellokumpu-Lehtinen et al. [9] comparing biweekly to triweekly docetaxel in CRPC found a longer median time to treatment failure in the biweekly arm (5.6 months vs. 4.9 months, p = 0.014), suggesting that altering the schedule can influence treatment durability. Additionally, Petrylak et al. [27], in their landmark trial, reported a median time to progression of 10.1 months with triweekly docetaxel plus prednisone, reinforcing the efficacy of this regimen in delaying progression.
The observed discordance between the higher PSA response rate with weekly docetaxel and the longer time to treatment failure with triweekly dosing has important clinical implications. PSA response reflects early biochemical tumor activity and treatment sensitivity [28], whereas time to treatment failure is a composite outcome influenced by durability of disease control, cumulative dose intensity, and tolerance to ongoing therapy [29]. Weekly docetaxel, administered at lower per-dose intensity, may achieve more frequent cytotoxic exposure leading to early PSA declines, but this effect may be less durable due to reduced cumulative drug exposure over time.
In contrast, triweekly docetaxel delivers a higher dose intensity per cycle, which may result in deeper tumor cytoreduction and more sustained disease control, despite a lower initial PSA response rate [30]. This suggests that PSA response alone may not fully capture long-term therapeutic benefit and reinforces the limitation of PSA kinetics as a surrogate endpoint for treatment durability. Clinically, these findings imply that weekly docetaxel may be preferable for patients prioritizing tolerability or early biochemical response, such as frail or elderly individuals, whereas triweekly dosing may be better suited for patients with adequate performance status in whom prolonged disease control is the primary objective. This trade-off highlights the need for individualized treatment selection based on both short-term response and long-term disease management goals.
Moreover, we also revealed that both biweekly and triweekly docetaxel regimens are associated with a significantly higher incidence of hepatotoxicity compared to the weekly regimen. Specifically, biweekly docetaxel showed an RR of 3.71 (95% CI: 1.41–9.73), while triweekly docetaxel had an RR of 3.21 (95% CI: 1.50–6.89), with low heterogeneity (I2 = 0%). These findings align with previous studies indicating increased hepatotoxicity with less frequent, higher-dose docetaxel schedules. Regarding gastrointestinal toxicity, our analysis demonstrated that triweekly docetaxel is associated with a significantly higher incidence of vomiting compared to the weekly regimen (RR: 2.47, 95% CI: 1.31–4.63), also with low heterogeneity (I2 = 0%). This observation is consistent with findings from a meta-analysis by van Eijk et al. [31], which reported increased gastrointestinal adverse events, including vomiting, in patients treated with triweekly docetaxel compared to weekly regimens. The higher peak plasma concentrations achieved with triweekly dosing may contribute to the increased gastrointestinal toxicity observed. These findings suggest that weekly docetaxel regimens may offer a more favorable toxicity profile concerning hepatotoxicity and vomiting. However, regimen selection should remain individualized based on patient comorbidities, tolerability, and treatment objectives. Our NMA found that triweekly docetaxel was associated with a slightly higher incidence of anorexia (RR 1.04, 95% CI 0.47–2.30) and diarrhea (RR 1.27, 95% CI 0.27–6.01) compared to biweekly and weekly regimens, although these differences did not reach statistical significance and were accompanied by low heterogeneity for anorexia and high heterogeneity for diarrhea. When compared with van Eijk et al.’s [31] findings on Grade 3/4 toxicities, there is notable inconsistency. van Eijk et al. [31] reported a non-significant reduction in severe diarrhea with weekly docetaxel compared to triweekly (RR 0.50, 95% CI 0.22–1.14, p = 0.10), and no significant difference in anorexia was documented as a separate outcome, suggesting that anorexia might not be a frequent Grade 3/4 event or was variably reported.
We also observed that triweekly docetaxel was associated with a higher incidence of fatigue, febrile neutropenia, and nausea compared to weekly docetaxel regimens, although the differences were statistically insignificant for some outcomes. Notably, the risk of febrile neutropenia was markedly elevated with triweekly dosing (RR: 12.3), indicating a clinically relevant safety concern despite low heterogeneity among studies. These findings align closely with the systematic review and meta-analysis by van Eijk et al. [31], who evaluated the impact of docetaxel scheduling on treatment tolerability and efficacy in metastatic breast cancer patients. van Eijk and colleagues [31] reported that weekly docetaxel was better tolerated, with significantly fewer hematologic toxicities, including febrile neutropenia, and reduced incidence of fatigue and gastrointestinal side effects compared to triweekly administration. This improved safety profile of weekly dosing was also associated with fewer treatment discontinuations due to adverse events, emphasizing the importance of scheduling in maintaining patient adherence and quality of life during therapy [28].
Clinicians should weigh the trade-offs between efficacy and tolerability when selecting a docetaxel regimen, tailoring the dosing schedule based on individual patient factors such as age, comorbidities, performance status, and treatment objectives. Routine monitoring for adverse effects and proactive management of toxicity are essential to maximize therapeutic benefit while minimizing harm.
Strength and limitations
This NMA has several notable strengths, including adherence to PRISMA and Cochrane guidelines, prospective registration with PROSPERO, and a comprehensive literature search across major databases without language or date restrictions. The inclusion of both RCTs and high-quality retrospective studies enhances the generalizability of findings, while the use of NMA allows for robust indirect and direct comparisons across weekly, biweekly, and triweekly docetaxel regimens. A wide range of efficacy and safety outcomes were assessed, and study quality was rigorously evaluated using established tools. However, this study also has limitations.
Many studies did not report hazard ratios or provide survival data in non-comparable formats, and substantial variability in outcome definitions and follow-up duration precluded reliable pooling or network comparison.
A key limitation of this analysis is the substantial heterogeneity observed in several pooled outcomes, most notably time to treatment failure (I2 = 96.8%) and anemia (I2 = 91.1%). Such high heterogeneity reduces the precision and reliability of the pooled effect estimates and indicates that the observed summary measures should be interpreted with caution. The direction of effect for these outcomes was generally consistent across studies; however, the magnitude of benefit varied considerably, limiting confidence in the exact size of the estimated effects.
This heterogeneity likely reflects clinical and methodological diversity across included studies, including differences in disease stage (mHSPC vs. mCRPC), docetaxel dose intensity, prior systemic therapies, follow-up duration, and variability in outcome definitions and toxicity grading. In addition, the inclusion of both randomized and observational studies may have further contributed to between-study variability. As a result, while the findings provide useful comparative insights into dosing schedules, conclusions, particularly for outcomes with very high heterogeneity, should be viewed as hypothesis-generating rather than definitive.
Conclusion
This NMA provides a comprehensive evaluation of the efficacy and safety of weekly, biweekly, and triweekly docetaxel regimens in patients with prostate cancer. Weekly docetaxel demonstrated the highest PSA response rate and a more favorable safety profile, particularly with lower incidences of hepatotoxicity and gastrointestinal side effects. In contrast, triweekly dosing was associated with a significantly longer time to treatment failure, indicating potentially greater disease control, but at the cost of increased adverse events such as febrile neutropenia and fatigue. While triweekly dosing offers longer disease control, clinicians must carefully monitor and manage increased toxicities to maintain the patient’s quality of life. These findings highlight the importance of balancing efficacy with tolerability and underscore the need for personalized treatment decisions based on patient characteristics, comorbidities, and treatment goals. Further high-quality, head-to-head randomized trials are needed to confirm these findings and clarify the optimal dosing schedule in clinical practice. Additionally, incorporating quality of life assessments and cost-effectiveness analyses in future research will be essential to support informed clinical decision-making and guide healthcare policy.