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European Urology Focus Mar 2022Novel prospective randomized controlled observations addressing combination therapy in metastatic hormone-sensitive prostate cancer (mHSPC) have demonstrated promising... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Novel prospective randomized controlled observations addressing combination therapy in metastatic hormone-sensitive prostate cancer (mHSPC) have demonstrated promising overall survival (OS) outcomes.
OBJECTIVE
To compare these novel findings and systematically review and address them within formal network meta-analyses (NMAs) that include observations from other prospective randomized controlled trials (RCTs).
EVIDENCE ACQUISITION
First, we focused on abiraterone, enzalutamide, apalutamide, and docetaxel effects on OS in mHSPC using the PRISMA methodology. PubMed and abstracts identified prospective RCTs in first-line mHSPC. Second, we focused on mature studies that reached median OS and tested OS between abiraterone and docetaxel with tumor burden stratification.
EVIDENCE SYNTHESIS
The first part included seven studies (n = 6639) and the second part, five studies (n = 4462). In the first part, abiraterone ranked first for high-volume mHSPC. Conversely, enzalutamide ranked first for low-volume mHSPC. In the second part, abiraterone treatment in high-volume mHSPC resulted in median OS of 50.1 mo and exceeded that with docetaxel (45.9 mo) and ADT alone (34.0 mo). Docetaxel treatment in low volume mHSPC resulted in median OS of 69.5 mo versus 67.7 mo with ADT alone.
CONCLUSIONS
In conventional NMA that relied on conventional hazard ratios, differences were identified with respect to the relative efficacy of the combination therapies examined; abiraterone dominated the alternatives in high-volume mHSPC. In part two, which relied on trials for which median OS is available, comparison of abiraterone versus docetaxel revealed a 4-mo difference in OS in high-volume mHSPC. Conventional NMA may have overestimated the importance of treatment efficacy instead of focusing on median OS duration, which might represent a more important clinical endpoint.
PATIENT SUMMARY
We reviewed studies on hormonal treatments and chemotherapy used for prostate cancer that has spread outside the prostate gland (metastatic prostate cancer, mPC). We found that the best overall survival was with the hormone agents abiraterone in high-volume mPC and enzalutamide in low-volume mPC. In comparison to the chemotherapy drug docetaxel, median overall survival with abiraterone was 4 months longer among patients with mPC.
Topics: Androgen Antagonists; Docetaxel; Hormones; Humans; Male; Network Meta-Analysis; Prostatic Neoplasms
PubMed: 33853754
DOI: 10.1016/j.euf.2021.04.003 -
Journal of Clinical Oncology : Official... Mar 2023Journal Journal of Clinical OncologyThe clinical discussion on the adjuvant chemotherapy in older patients with breast cancer (BC) should routinely include... (Review)
Review
Journal Journal of Clinical OncologyThe clinical discussion on the adjuvant chemotherapy in older patients with breast cancer (BC) should routinely include comprehensive considerations of the health implications of competitive comorbidities, the safety of the treatment itself, and the likelihood that an appropriate dose intensity will be received (ie, relative dose intensity > 85%). All these factors have prognostic implications, as recently confirmed in the secondary analysis of the Hurria Older PatiEnts clinical trial. Full-informed, shared decision making is essential to provide best care. Our clinical approach for women with BC age ≥ 65 years is based on a standardized screening for frailty, triggering comprehensive geriatric assessment, as appropriate. We only recommend evidence-based regimens that have showed to reduce the risk of cancer recurrence and potentially increase overall survival. We frequently prefer docetaxel-cyclophosphamide, for hormone receptor-positive BC, on the basis of the subgroup analysis of the USOR-9735 study in older population. We avoid single agents (eg, capecitabine or weekly docetaxel), as showed to be inferior treatments in the CALGB-49907 and ELDA trials, and modified nonstandard regimens, for the lack of strong evidence in support.
Topics: Humans; Female; Aged; Breast Neoplasms; Docetaxel; Neoplasm Recurrence, Local; Capecitabine; Chemotherapy, Adjuvant
PubMed: 36716418
DOI: 10.1200/JCO.22.02477 -
Supportive Care in Cancer : Official... Jul 2021Febrile neutropenia (FN) incidence during docetaxel and cyclophosphamide (TC) chemotherapy, known as a high-risk regimen, differs among countries. The role of...
PURPOSE
Febrile neutropenia (FN) incidence during docetaxel and cyclophosphamide (TC) chemotherapy, known as a high-risk regimen, differs among countries. The role of prophylactic granulocyte colony-stimulating factor (G-CSF) in FN is unclear. This study aimed to investigate FN frequency and relative dose intensity (RDI) of TC chemotherapy in patients with breast cancer and identify the correct population requiring prophylactic G-CSF.
METHODS
In total, 205 patients with breast cancer were scheduled for TC chemotherapy (docetaxel/cyclophosphamide 75/600 mg/m, every 3 weeks, 4 cycles) as adjuvant chemotherapy. Trastuzumab (8 mg/kg; continued with 6 mg/kg) was administrated intravenously for human epidermal growth factor receptor 2 (HER2)-positive cancer. Fifty-five patients received primary prophylactic measures (G-CSF: 20 and antibiotics: 35). We investigated the frequency of FN and hospitalization, RDI, and the factors related to FN, adverse events, hospitalization, and RDI.
RESULTS
FN occurred in 70 patients (35.7%). FN incidence was noted in 41.1% without any prophylactic measures and in 5.0% with prophylactic G-CSF. In multivariate analysis, the independent risk factors of FN were older age (≥ 60 years, P = 0.017) and without primary prophylactic G-CSF (P = 0.011). Eleven patients (5.6%) were hospitalized of which 8 (72.7%) were elderly. The median RDIs of docetaxel and cyclophosphamide were 96.7% and 99.7%, respectively.
CONCLUSION
FN frequency during TC chemotherapy was high, and primary prophylactic G-CSF reduced FN incidence. Primary prophylactic G-CSF is an effective therapy for preventing FN during TC chemotherapy. However, prophylactic G-CSF should be considered for elderly patients based on the low hospitalization rate and the high RDI.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Docetaxel; Febrile Neutropenia; Female; Granulocyte Colony-Stimulating Factor; Humans; Middle Aged; Risk Factors
PubMed: 33146835
DOI: 10.1007/s00520-020-05868-1 -
Molecular Pharmaceutics Jan 2024Epithelial-mesenchymal transition (EMT) is a reversible and dynamic biological process in which epithelial cells acquire mesenchymal characteristics including enhanced...
Epithelial-mesenchymal transition (EMT) is a reversible and dynamic biological process in which epithelial cells acquire mesenchymal characteristics including enhanced stemness and migratory ability. EMT can facilitate cancer metastasis and is a known driver of cellular resistance to common chemotherapeutic drugs, such as docetaxel. Current chemotherapeutic practices such as docetaxel treatment can promote EMT and increase the chance of tumor recurrence and resistance, calling for new approaches in cancer treatment. Here we show that prolonged docetaxel treatment at a sub-IC concentration inhibits EMT in immortalized human mammary epithelial (HMLE) cells. Using immunofluorescence, flow cytometry, and bulk transcriptomic sequencing to assess EMT progression, we analyzed a range of cellular markers of EMT in docetaxel-treated cells and observed an upregulation of epithelial markers and downregulation of mesenchymal markers in the presence of docetaxel. This finding suggests that docetaxel may have clinical applications not only as a cytotoxic drug but also as an inhibitor of EMT-driven metastasis and multidrug resistance depending on the concentration of its use.
Topics: Humans; Docetaxel; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Antineoplastic Agents; Epithelial Cells
PubMed: 38029291
DOI: 10.1021/acs.molpharmaceut.3c00425 -
Scientific Reports Jan 2022Gastric cancer (GC) is the third cause of cancer-related mortality worldwide and is often diagnosed at advanced stages of the disease. This makes the development of more...
Gastric cancer (GC) is the third cause of cancer-related mortality worldwide and is often diagnosed at advanced stages of the disease. This makes the development of more comprehensive models and efficient treatments crucial. One option is based on repurposing already marketed drugs as adjuvants to chemotherapy. Accordingly, we have previously developed the combination of docetaxel and the cholesterol-lowering drug, lovastatin, as a powerful trigger of HGT-1 human GC cells' apoptosis using 2D cultures. Because 3D models, known as spheroids, are getting recognized as possibly better suited than 2Ds in toxicological research, we aimed to investigate the efficacy of this drug combination with such a model. We established monocellular spheroids from two human (GC) cell lines, HGT-1 and AGS, and bicellular spheroids from these cells mixed with cancer-associated fibroblasts. With these, we surveyed drug-induced cytotoxicity with MTT assays. In addition, we used the Incucyte live imaging and analysis system to follow spheroid growth and apoptosis. Taken together, our results showed that the lovastatin + docetaxel combination was an efficient strategy to eliminate GC cells grown in 2D or 3D cultures, lending further support in favor of repurposing lovastatin as an adjuvant to taxane-based anticancer treatment.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cancer-Associated Fibroblasts; Cell Culture Techniques, Three Dimensional; Cell Line, Tumor; Docetaxel; Drug Repositioning; Drug Screening Assays, Antitumor; Humans; Intravital Microscopy; Lovastatin; Spheroids, Cellular; Stomach Neoplasms
PubMed: 35087119
DOI: 10.1038/s41598-022-05426-1 -
Expert Opinion on Drug Metabolism &... Feb 2021: Peripheral neuropathy (PN) is an adverse effect of several classes of chemotherapy including the taxanes. Predictive PN biomarkers could inform individualized taxane... (Review)
Review
Exploring pharmacogenetics of paclitaxel- and docetaxel-induced peripheral neuropathy by evaluating the direct pharmacogenetic-pharmacokinetic and pharmacokinetic-neuropathy relationships.
: Peripheral neuropathy (PN) is an adverse effect of several classes of chemotherapy including the taxanes. Predictive PN biomarkers could inform individualized taxane treatment to reduce PN and enhance therapeutic outcomes. Pharmacogenetics studies of taxane-induced PN have focused on genes involved in pharmacokinetics, including enzymes and transporters. Contradictory findings from these studies prevent translation of genetic biomarkers into clinical practice. : This review discusses the progress toward identifying pharmacogenetic predictors of PN by assessing the evidence for two independent associations; the effect of pharmacogenetics on taxane pharmacokinetics and the evidence that taxane pharmacokinetics affects PN. Assessing these direct relationships allows the reader to understand the progress toward individualized taxane treatment and future research opportunities. : Paclitaxel pharmacokinetics is a major determinant of PN. Additional clinical trials are needed to confirm the clinical benefit of individualized dosing to achieve target paclitaxel exposure. Genetics does not meaningfully contribute to paclitaxel pharmacokinetics and may not be useful to inform dosing. However, genetics may contribute to PN sensitivity and could be useful for estimating patients' optimal paclitaxel exposure. For docetaxel, genetics has not been demonstrated to have a meaningful effect on pharmacokinetics and there is no evidence that pharmacokinetics determines PN.
Topics: Animals; Antineoplastic Agents; Biomarkers; Docetaxel; Dose-Response Relationship, Drug; Humans; Paclitaxel; Peripheral Nervous System Diseases; Pharmacogenetics; Precision Medicine
PubMed: 33401943
DOI: 10.1080/17425255.2021.1856367 -
Journal of Translational Medicine May 2024The intersection of nanotechnology and pharmacology has revolutionized the delivery and efficacy of chemotherapeutic agents, notably docetaxel, a key drug in cancer... (Review)
Review
The intersection of nanotechnology and pharmacology has revolutionized the delivery and efficacy of chemotherapeutic agents, notably docetaxel, a key drug in cancer treatment. Traditionally limited by poor solubility and significant side effects, docetaxel's therapeutic potential has been significantly enhanced through its incorporation into nanoplatforms, such as nanofibers and nanoparticles. This advancement offers targeted delivery, controlled release, and improved bioavailability, dramatically reducing systemic toxicity and enhancing patient outcomes. Nanofibers provide a versatile scaffold for the controlled release of docetaxel, utilizing techniques like electrospinning to tailor drug release profiles. Nanoparticles, on the other hand, enable precise drug delivery to tumor cells, minimizing damage to healthy tissues through sophisticated encapsulation methods such as nanoprecipitation and emulsion. These nanotechnologies not only improve the pharmacokinetic properties of docetaxel but also open new avenues in regenerative medicine by facilitating targeted therapy and cellular regeneration. This narrative review highlights the transformative impact of docetaxel-loaded nanoplatforms in oncology and beyond, showcasing the potential of nanotechnology to overcome the limitations of traditional chemotherapy and pave the way for future innovations in drug delivery and regenerative therapies. Through these advancements, nanotechnology promises a new era of precision medicine, enhancing the efficacy of cancer treatments while minimizing adverse effects.
Topics: Humans; Docetaxel; Regenerative Medicine; Neoplasms; Animals; Nanoparticles; Antineoplastic Agents; Treatment Outcome; Drug Delivery Systems
PubMed: 38816723
DOI: 10.1186/s12967-024-05347-9 -
Pharmaceutical Research Aug 2021The current study aimed to develop a novel milk-based formulation of docetaxel, a sparingly soluble antineoplastic agent, administered so far exclusively by the...
OBJECTIVE
The current study aimed to develop a novel milk-based formulation of docetaxel, a sparingly soluble antineoplastic agent, administered so far exclusively by the intravenous route and evaluate its oral bioavailability.
METHODS
Pre-formulation studies included the determination of docetaxel solubility in water-alcohol mixtures as well as short-term content uniformity experiments of the final formulation. The pharmacokinetic (PK) performance of the developed milk-based formulations was further evaluated in vivo in mice using ritonavir, a potent P-glycoprotein inhibitor, as an absorption enhancer of docetaxel and the marketed intravenous docetaxel formulation, Taxotere®, as a control.
RESULTS
In vivo PK results in mice showed that all the administered oral docetaxel formulations had limited absorption in the absence of ritonavir. On the contrary, ritonavir co-administration given as pre-treatment significantly enhanced oral bioavailability of both the marketed and milk-based docetaxel formulations; an even more marked increase in drug exposure was observed when ritonavir was incorporated within the docetaxel milk-based formulation. The fixed-dose combination also showed a more prolonged absorption of the drug compared to separate administrations.
CONCLUSIONS
The current study provides insights for the discovery of a novel milk-based formulation that could potentially serve as an alternative, non-toxic and patient-friendly carrier for an acceptable docetaxel oral chemotherapy.
Topics: Administration, Oral; Animals; Biological Availability; Docetaxel; Drug Compounding; Male; Mice; Mice, Inbred C57BL; Milk; Ritonavir; Solubility
PubMed: 34382143
DOI: 10.1007/s11095-021-03085-x -
Clinical Genitourinary Cancer Oct 2021Combination therapy with docetaxel and androgen deprivation therapy (ADT) prolongs overall survival (OS) in men with metastatic hormone-sensitive prostate cancer. We... (Clinical Trial)
Clinical Trial
BACKGROUND
Combination therapy with docetaxel and androgen deprivation therapy (ADT) prolongs overall survival (OS) in men with metastatic hormone-sensitive prostate cancer. We assessed the benefits and adverse effects of docetaxel and ADT in relation to advancing age.
METHODS
We performed a post hoc analysis of the CHAARTED trial comparing docetaxel and ADT vs. ADT alone (n = 773). Patients were stratified in age groups <60, 60-70, and >70 years old. Multivariable-adjusted progression-free survival (PFS) and OS were assessed using Kaplan-Meier curves and compared using multivariable Cox regressions with calculated interaction terms between age group and treatment arm. In the combination arm, the incidence of ≥1 adverse event (grade ≥3) and the number of adverse events per patient were compared for each age group using multivariable logistic and linear regressions, respectively.
RESULTS
After adjusting for clinical variables, docetaxel's effect did not vary by age group for PFS and OS. There was no significant difference in the odds ratio of ≥1 adverse event (P > .1 for age groups 60-70 and >70 years old compared with <60 years old). However, men age >70 years old experienced +0.37 more adverse events per patient compared with men age <60 years old (95% CI, 0.11-0.64; P = .006).
CONCLUSIONS
PFS and OS were similar across age groups for the combination of docetaxel and ADT compared with ADT. Older men experienced a modest increase in adverse events per patient, highlighting the importance of balancing treatment benefits and adverse effects in this age group.
Topics: Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Hormones; Humans; Male; Middle Aged; Progression-Free Survival; Prostatic Neoplasms
PubMed: 33906801
DOI: 10.1016/j.clgc.2021.03.016 -
European Journal of Cancer (Oxford,... Sep 2021Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling. The aim of this study is to assess the efficacy... (Randomized Controlled Trial)
Randomized Controlled Trial
Docetaxel and prednisone with or without enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer: CHEIRON, a randomised phase II trial.
BACKGROUND
Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling. The aim of this study is to assess the efficacy of their concurrent administration in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC).
METHODS
In this open-label, randomised, phase II trial, previously untreated mCRPC patients were randomised 1:1 to receive eight 21-d courses of docetaxel 75 mg/m, oral prednisone 5 mg twice daily and oral enzalutamide 160 mg/d (arm DE), or the same treatment without enzalutamide (arm D). The primary end-point was the percentage of patients without investigator-assessed disease progression 6 months after the first docetaxel administration.
RESULTS
The 246 eligible patients were randomly assigned to receive docetaxel, prednisone and enzalutamide (n = 120) or docetaxel and prednisone (n = 126). The 6-month progression rate was 12.5% (95% confidence interval [CI] 8.1-20.6) in arm DE and 27.8% (95% CI 22.8-39.4) in arm D (chi-squared test 10.01; P = 0.002). The most frequent grade III-IV adverse events were fatigue (12.5% in arm DE versus 5.6% in arm D), febrile neutropenia (9.3% versus 4.0%) and neutropenia (7.6% versus 5.6%).
CONCLUSIONS
The combination of enzalutamide and docetaxel appears to be more clinically beneficial than docetaxel alone in previously untreated mCRPC patients, although serious adverse events were more frequent. Our findings suggest that first-line treatment with this combination could lead to an additional clinical benefit when prompt and prolonged disease control is simultaneously required. Clearly, these results should be considered cautiously because of the study's phase II design and the absence of an overall survival benefit.
TRIAL REGISTRATION NUMBERS
EudraCT 2014-000175-43 - NCT02453009.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Female; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant
PubMed: 34358777
DOI: 10.1016/j.ejca.2021.06.016