How many cycles of docetaxel

JAMA Oncol. August 25, early release online. Toggle navigation. Ronald de Wit, MD. Among all patients, median overall survival was Nov We enrolled 46 patients in this study, and patient characteristics are listed in Table 1.

In this study, data on the performance status, the number of metastatic sites, and the tumor volume within the metastatic sites could not be collected. At the end of the follow-up period, 35 patients However, there was no significant differences in both groups , , respectively; Figure 1. The median follow-up period for these patients was 9. Recent studies have shown that the administration of ARATs before chemotherapy improves OS [ 7 , 9 ]; therefore, there has been a therapeutic shift toward the use of ARATs as first-line treatment in patients with CRPC who have no or low-volume metastases [ 16 ].

Many patients have achieved remission owing to the clinical effectiveness of ARATs, but several patients have experienced rapid progression [ 17 ]. Patients with disease progression receive DOC in combination with prednisone as second-line treatment. However, the optimal sequence of treatment after DOC remains unclear because different treatment options are available at present, including CBZ [ 5 ], ARATs [ 6 , 8 ], and radium [ 10 ], without an adequate number of prospective randomized trials [ 13 ].

CBZ, a second-generation taxane, exhibits stronger suppression of microtubule dynamics, faster cellular uptake, and better intracellular retention than DOC and was selected for testing in clinical trials after it demonstrated an activity in DOC-resistant cell lines [ 18 ].

Angelergues et al. Group 1 [ 12 ]. Likewise, Oh et al. Time to PSA progression was significantly longer in patients receiving chemotherapy after adjusting for covariates [ 17 ]. The clinical use of DOC chemotherapy has usually been limited to 10 cycles. On the other hand, Shiota et al. Similarly, Tanaka et al. In Japan, the incidence of PCa has increased over the previous decades. For this reason, ADT is considered an effective treatment option for localized or locally advanced disease [ 25 ].

In addition, several studies reported that there were significant differences between Japanese and Western populations such as the characteristic manifestations of PCa or in terms of their tolerability to anticancer drugs [ 26 ]. In addition, Belderbos et al. However, it is difficult to obtain sufficient information about the primary tumor profile and castration-resistant metastatic sites. For these reasons, the biologic drivers of growth and cell-surface targets may change as the disease progresses through various treatments.

Therefore, the Prostate Cancer Clinical Trials Working Group 3 recommends serial biologic profiling using tumor samples from biopsies or blood-based assays of circulating tumor cells CTCs or cell-free nucleic acids [ 15 ].

However, these biologic assessments are not available in general clinical practice in Japan. Therefore, a treatment tool is needed to select individualized therapies for individualized patients at individualized times [ 31 ].

The present study has several limitations. First, it was a retrospective study and was conducted using multicenter data. Therefore, this study had an inherent potential for bias, with diagnostic and therapeutic variations among these institutions.

Second, data on the performance status and tumor volume in the metastatic sites were not available in this study. Conversely, initial PSA levels in Group A were relatively lower and the time to castrate resistance after initial ADT was relatively shorter than those in Group B, although there were no significant differences in both groups.

Furthermore, there were relatively more patients with bone and visceral metastases in Group A than in Group B.

To this end, Group A may have more aggressive features and several poor prognostic factors, including the number of visceral metastases or the duration from the initiation of ADT to castration resistance, relative to Group B. In addition, patients in Group B may achieve better oncological outcomes than those in Group A. Third, a relatively small number of patients were enrolled in this study. Therefore, a multivariate analysis could not be performed because of the small number of patients in each group.

Further large-scale clinical or case-control observational studies are needed to validate these findings. The data used to support the findings of this study are available from the corresponding author upon request. The authors declare that there are no conflicts of interest regarding the publication of this paper. All authors read and approved the final manuscript.

This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors.

Read the winning articles. Journal overview. Special Issues. Academic Editor: Tomasz Brzozowski. Received 25 Sep Revised 27 Dec Accepted 04 Jan Published 12 Jan Abstract Background.

Introduction In Japan, prostate cancer is the fourth commonest cancer in men and the seventh cause of cancer mortality and has shown a rapid increase in prevalence in recent years [ 1 ]. Methods 2. Results 3. Patient Characteristics We enrolled 46 patients in this study, and patient characteristics are listed in Table 1.

Table 1. Table 2. Treatment arm was not a significant factor affecting survival in either the univariate or the multivariate analysis Table 3. Patients who had received 10 or more cycles of docetaxel had the greatest median OS of The same holds true when the arms were analyzed separately eFigure 4 in the Supplement : in the DPL arm, median OS for patients receiving more than 10 cycles, 8 to 10 cycles, and 5 to 7 cycles of docetaxel was All comparisons for OS between the cohorts receiving 5 or 6, vs more 6 cycles, 5 to 7 vs 8 to 10 cycles, and 8 to 10 vs more than 10 cycles of docetaxel, and cumulative dose of docetaxel, were significant in the univariate model.

The cutoff 5 or 6 cycles of docetaxel vs more than 6 cycles had the strongest independent significance and was thus retained in the multivariate model.

Mainsail 4 is one of the largest phase 3 trials in the setting of mCRPC in the past decade that investigated the addition of a second active biological drug to standard docetaxel every 3 weeks plus prednisone. In Mainsail the greater myelotoxic effect caused by the addition of lenalidomide to docetaxel resulted in a reduction of the number of cycles of docetaxel that patients were able to tolerate, a median of 6 cycles in the DPL arm vs 8 in the DP arm.

Median OS was shorter in patients receiving lenalidomide, which could have attributed to either a direct adverse effect of lenalidomide on OS or alternatively because of the reduction in the number of docetaxel treatment cycles. In this study we investigated the effect of the cumulative dose of docetaxel as reflected by the total number of cycles of docetaxel on median OS, in univariate and multivariate analyses on the ITT population, both dependent upon the treatment arm, as well as irrespective of the treatment arm.

In subsequent sensitivity analyses we addressed potential confounding factors on the eventual survival outcome, such as disease progression as the main reason for stopping docetaxel treatment, and excluding patients from the analysis who received less than a minimum of 5 cycles for whom meaningful survival benefit due to docetaxel was questionable and could therefore bias the analysis.

We found that the total number of docetaxel cycles delivered was an independent and important contributor to the OS benefit provided by docetaxel chemotherapy that was independent of known prognostic factors for survival, including performance ECOG score , baseline LDH, baseline hemoglobin, and baseline albumin.

In the sensitivity analysis we corrected for confounding factors, including disease progression, as the reason for stopping docetaxel, though the main reason for stopping protocol treatment early was adverse effects. Enhanced toxic effects by the addition of lenalidomide to docetaxel in the experimental arm resulted in a lower cumulative dose of docetaxel, reflected by fewer docetaxel cycles administered and more frequent dose reductions.

Because the median dose achieved per cycle administered was only modestly affected respectively of the planned dose: These findings imply that the total dose of docetaxel, as reflected in total the number of cycles achieved, contributes to the eventual survival gain by chemotherapy in the patient population with mCRPC.

This finding has important implications for the optimal administration of docetaxel chemotherapy. To provide the greatest survival gain by docetaxel chemotherapy, those patients who appear to benefit by clinical or radiological evidence and who tolerate the chemotherapy well should continue beyond 6, and perhaps even beyond 10 cycles, until disease progression occurs or unacceptable adverse effects dictate otherwise.

An obvious limitation of this study is the post hoc nature of the analysis. Although all patients were treated according to the strict Mainsail study protocol, 4 some patients may have discontinued for reasons not fully reflected in the study case report file.

In addition, such potential unrecognized cessation of docetaxel treatment for nonspecified reasons is not likely to have a meaningful confounding effect given the sample size of the study and the robustness and consistency of the data. We conducted both an ITT analysis and sensitivity analysis, and all analyses point in the same direction.

Of note, the number of cycles was independent of the performance score and other known prognostic factors for survival. In and subsequent years, additional treatment options have become available in the post-docetaxel setting, including cabazitaxel, 6 abiraterone, 7 , 8 enzalutamide, 9 , 10 and radium Unfortunately, no information on poststudy treatment was collected in the Mainsail database.

We have no reason to anticipate any meaningful imbalance in post-docetaxel treatments between the groups, since the gap between halting docetaxel chemotherapy at 6 or 8 cycles and continuing additional cycles will be limited to a time gap of only a few months. A prospective study directly comparing 6 vs 10 cycles or beyond 10 cycles would be required to prove a survival benefit of docetaxel continuation.

Barriers to conducting such a study would include higher neurological and extramedullary toxic effects expected with higher cumulative doses, higher costs, and the robust findings of this present retrospective analysis. A similar question is what is the optimal number of docetaxel cycles in patients with metastatic hormone sensitive prostate cancer.

In 2 pivotal studies, the survival benefit by the early use of docetaxel has been obtained with 6 cycles, 12 , 13 while in the GETUG trial 14 9 doses of docetaxel were mandated. In the metastatic hormone sensitive prostate cancer setting, a study of 6 vs 10 cycles would help to answer that question.

We found a robust and independent effect on OS by the number of docetaxel cycles administered in the setting of mCRPC. These data indicate that patients who appear to have clinical, radiological, or biochemical benefit by docetaxel should continue beyond 6 cycles as long as they tolerate their treatment well. A prospective study, potentially in the setting of mHSPC, may lend further prospective evidence.

Published Online: August 25, Author Contributions: Drs J. Li and de Wit had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Li, de Wit. Conflict of Interest Disclosures: Dr Vogelzang has served in a consultant or advisory relationship for the Celgene Corporation and Veridex and in an employment or leadership position for US Oncology Research. Dr Petrylak has served in a consultant or advisory relationship for the Celgene Corporation and has received research funding from the Celgene Corporation and Sanofi-Aventis.

Dr Gschwend has served in a consultant or advisory relationship for the Celgene Corporation. Drs Barton, Fandi, Jungnelius, S. Li, and J. Li have served in employment or leadership positions for the Celgene Corporation and own stock from Celgene Corporation.

No other conflicts are reported. Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue.

Figure 1. View Large Download. Figure 2. Table 1. Baseline Patient Demographics and Characteristics. Table 2. Table 3. Overview of the patients included in the analysis eFigure 2. Protocol summary. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.