The efficacy of gemcitabine and docetaxel chemotherapy for the treatment of relapsed and refractory osteosarcoma: A systematic review and pre-clinical study.

INTRODUCTION: Osteosarcoma is the most common primary malignancy of the bone. There is a lack of effective treatments for patients who experience relapsed osteosarcoma. One treatment for relapsed patients is gemcitabine and docetaxel combination chemotherapy (GEMDOX). This systematic review aimed to establish the efficacy of this chemotherapy regimen, as well as identify the common severe toxicities that are associated with it. Resistant osteosarcoma cell lines developed from MG-63 and HOS-143B were used to represent relapsed osteosarcoma patients in a pre-clinical study. RESULTS: We identified 11 retrospective and Phase II studies that were suitable for inclusion in our review. 10.65% of patients had a response to gemcitabine and docetaxel combination therapy and the disease control rate was 35% (n = 197). 36%, 35.3% and 18.04% of patients experienced grade 3 or 4 neutropenia, thrombocytopenia and anaemia respectively (n = 133). Male patients (X2 = 9.14, p < 0.05) and those below the age of 18 (X 2 = 10.94, p < 0.05) responded better to GEMDOX treatment than females and patients older than 18 years. The resistant osteosarcoma cell lines remained sensitive to either single-agent gemcitabine, docetaxel, and the combination of both. Cisplatin-resistant models (MG-63/CISR8 & HOS-143B/CISR8) were the most responsive to GEMDOX treatment compared to doxorubicin, methotrexate, and triple-combination resistant models. CONCLUSION: GEMDOX treatment has potential efficacy in relapsed osteosarcoma patients especially those with cisplatin resistance. To directly compare the efficacy of GEMDOX therapy against other therapies randomised phase III clinical trials with adequate patient follow up must be performed to improve treatment options for osteosarcoma.

Outcomes of First Subsequent Taxane Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer Who Previously Received Docetaxel Intensification for Metastatic Castration-Sensitive Prostate Cancer.

BACKGROUND: The management of advanced prostate cancer continues to evolve rapidly, particularly with the earlier use of survival-prolonging therapies in metastatic castration-sensitive prostate cancer (mCSPC). Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is little evidence determining the outcomes of taxane chemotherapies as the first subsequent taxane (FST) in mCRPC pts who received docetaxel intensification (DI) in mCSPC. The purpose of this study is to compare outcomes between the survival-prolonging taxanes, docetaxel and cabazitaxel as FST after DI. METHODS: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 December 2020 were retrospectively reviewed. Pts were considered eligible if they received DI for mCSPC and then received either docetaxel or cabazitaxel in mCRPC. Variables of interest were collected from electronic medical records. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from the FST start date. PSA responses were compared using the chi-squared test, and time-based endpoints were compared using the Kaplan-Meier method. RESULTS: In total, 34 pts were identified: docetaxel = 22 and cabazitaxel = 12 as FST. 91.2% of pts (docetaxel 95.5% vs. cabazitaxel 83.3%) received FST in 2nd line mCRPC. The median age at diagnosis (63.1 vs. 67.1 yrs, p = 0.236) and the median time to CRPC (18.6 vs. 14.2 mos, p = 0.079) were similar for docetaxel and cabazitaxel, respectively. The median time to FST (24.1 vs. 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs. 52.7 mos, p = 0.002) were significantly shorter for pts receiving cabazitaxel vs. docetaxel. PSA responses occurred in 40.9% of pts treated with docetaxel compared to 25.0% treated with cabazitaxel (p = 0.645). There was no significant difference in median PFS (2.7 vs. 3.5 mos, p = 0.727) or median OS (11.4 vs. 8.1 mos, p = 0.132) from the time of FST for pts treated with docetaxel vs. cabazitaxel, respectively. CONCLUSIONS: Both docetaxel and cabazitaxel demonstrated activity as FST after DI in mCSPC. Pts who received cabazitaxel had a shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for cabazitaxel in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with docetaxel compared to cabazitaxel. While limited by its retrospective nature and small sample size, this study suggests that docetaxel is active as FST despite treatment with DI in mCSPC.

Chemotherapy-Induced Alopecia by Docetaxel: Prevalence, Treatment and Prevention.

Docetaxel is a commonly used taxane chemotherapeutic agent in the treatment of a variety of cancers, including breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, gastric cancer, and head and neck cancer. Docetaxel exerts its anti-cancer effects through inhibition of the cell cycle and induction of proapoptotic activity. However, docetaxel also impacts rapidly proliferating normal cells in the scalp hair follicles (HFs), rendering the HFs vulnerable to docetaxel-induced cell death and leading to chemotherapy-induced alopecia (CIA). In severe cases, docetaxel causes persistent or permanent CIA (pCIA) when hair does not grow back completely six months after chemotherapy cessation. Hair loss has severe negative impacts on patients' quality of life and may even compromise their compliance with treatment. This review discusses the notable prevalence of docetaxel-induced CIA and pCIA, as well as their prevention and management. At this moment, scalp cooling is the standard of care to prevent CIA. Treatment options to promote hair regrowth include but are not limited to minoxidil, photobiomodulation (PBMT), and platelet-rich plasma (PRP). In addition, a handful of current clinical trials are exploring additional agents to treat or prevent CIA. Research models of CIA, particularly ex vivo human scalp HF organ culture and in vivo mouse models with human scalp xenografts, will help expedite the translation of bench findings of CIA prevention and/or amelioration to the clinic.

177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial.

BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolongs radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibitor (ARPI) and taxane therapy. We aimed to investigate the efficacy of 177Lu-PSMA-617 in patients with taxane-naive metastatic castration-resistant prostate cancer. METHODS: In this phase 3, randomised, controlled trial conducted at 74 sites across Europe and North America, taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI were randomly allocated (1:1) to open-label, intravenous 177Lu-PSMA-617 at a dosage of 7·4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or a change of ARPI (to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling). Crossover from ARPI change to 177Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. The primary endpoint was radiographic progression-free survival, defined as the time from randomisation until radiographic progression or death, assessed in the intention-to-treat population. Safety was a secondary endpoint. This study is registered with ClinicalTrials.gov (NCT04689828) and is ongoing. In this primary report of the study, we present primary (first data cutoff) and updated (third data cutoff) analyses of radiographic progression-free survival; all other data are based on the third data cutoff. FINDINGS: Overall, of the 585 patients screened, 468 met all eligibility criteria and were randomly allocated between June 15, 2021 and Oct 7, 2022 to receive 177Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Baseline characteristics were mostly similar between groups; median number of 177Lu-PSMA-617 cycles was 6·0 (IQR 4·0-6·0). Of patients assigned to ARPI change, 134 (57%) crossed over to receive 177Lu-PSMA-617. In the primary analysis (median time from randomisation to first data cutoff 7·26 months [IQR 3·38-10·55]), the median radiographic progression-free survival was 9·30 months (95% CI 6·77-not estimable) in the 177Lu-PSMA-617 group versus 5·55 months (4·04-5·95) in the ARPI change group (hazard ratio [HR] 0·41 [95% CI 0·29-0·56]; p<0·0001). In the updated analysis at time of the third data cutoff (median time from randomisation to third data cutoff 24·11 months [IQR 20·24-27·40]), median radiographic progression-free survival was 11·60 months (95% CI 9·30-14·19) in the 177Lu-PSMA-617 group versus 5·59 months (4·21-5·95) in the ARPI change group (HR 0·49 [95% CI 0·39-0·61]). The incidence of grade 3-5 adverse events was lower in the 177Lu-PSMA-617 group (at least one event in 81 [36%] of 227 patients; four [2%] grade 5 [none treatment related]) than the ARPI change group (112 [48%] of 232; five [2%] grade 5 [one treatment related]). INTERPRETATION: 177Lu-PSMA-617 prolonged radiographic progression-free survival relative to ARPI change, with a favourable safety profile. For patients with PSMA-positive metastatic castration-resistant prostate cancer who are being considered for a change of ARPI after progression on a previous ARPI, 177Lu-PSMA-617 may be an effective treatment alternative. FUNDING: Novartis.

Impact of taxanes after PD-1 blockade exposure in advanced esophageal squamous cell carcinoma.

BACKGROUND: Programmed cell death-1 (PD-1) blockade improves survival in patients with advanced esophageal squamous cell carcinoma (ESCC). However, the efficacy of taxanes after exposure to PD-1 blockade remains unclear in patients with advanced ESCC. METHODS: We retrospectively analyzed the clinical outcomes of advanced ESCC patients treated with taxanes (paclitaxel or docetaxel) with/without prior exposure to PD-1 blockade (Exposed /Naïve group) at National Cancer Center Hospital from June 2016 to December 2020. RESULTS: Ninety-nine patients (Exposed group, n = 32; Naïve group, n = 67) were included. The objective response rate (ORR) of the Exposed group was significantly higher than that of the Naïve group (37.5% vs. 13.4%, p = 0.009). The median progression-free survival was similar between the Exposed and Naïve groups (3.8 vs. 2.8 months, HR 1.12, 95% CI 0.65-1.86, p = 0.66). PD-1 blockade exposure independently predicated higher ORR to taxanes in multivariate analysis. Grade ≥ 3 adverse events were comparable between the Exposed and Naïve groups (45.8% vs. 40.3%, p = 0.64). CONCLUSIONS: Taxanes following PD-1 blockade in advanced ESCC showed a higher ORR but similar PFS compared to taxanes without prior PD-1 exposure.

Genomic and Chemical Evidence on Biosynthesis of Taxane Diterpenoids in Alternaria Isolates from Cupressaceae.

Alternaria species (Deuteromycetes, Ascomycota) as ubiquitous fungi and prolific producers of a variety of toxic compounds are a part of microbiomes of plants, humans, and animals, mainly causing disease, allergic reactions, and toxicosis. However, some species have also been reported as endophytic microorganisms with highly bioactive metabolites. Our previous results indicate that potentially endophytic Alternaria species from Cupressaceae produce bioactive metabolites that possibly contribute to plant holobiont's health. Here, a possible mechanism behind this bioactivity is elucidated. As some endophytic fungi are reported to produce cytotoxic taxane diterpenoids, eight potentially endophytic Alternaria isolates from our collection were analyzed for the presence of the key genes of the paclitaxel (Taxol) biosynthetic pathway, i.e., taxadin synthase (ts), 10-deacetylbaccatin III-10-O-acetyltransferase (dbat), and C-13-phenylpropanoid side-chain CoA acyltransferase (bapt). The presence of all genes, i.e., ts, dbat, and bapt, was detected by PCR in six isolates and dbat and bapt in two isolates. Chemical analyses of the fermentation broths by TLC and HPLC chromatography and IR spectroscopy indicated the synthesis of the final product, i.e., paclitaxel. So, we introduce the synthesis of taxane diterpenoids as a possible mechanism by which Alternaria occupies the plant niches and protects the plant holobiont in the presence of competing microorganisms.

Questionnaire survey of healthcare professionals on taxane-induced nail change in Japan.

PURPOSE: Taxanes are widely used chemotherapeutic agents that frequently cause nail changes and have a significant impact on patients' quality of life. Despite the prevalence of taxane-induced nail toxicity, limited data are available regarding evidence-based management strategies for the prevention or treatment of taxane-induced nail changes. Therefore, we aimed to gain insights into the prevention, treatment, and evaluation of nail changes in patients with cancer in Japan by conducting a questionnaire survey of physicians, pharmacists, and nurses involved in oncology treatment. METHODS: The questions addressed prophylactic methods, evaluation practices, and treatment approaches for various nail disorders. The questionnaires were distributed on March 1, 2022, with a response deadline of December 1, 2022. RESULTS: Of the 120 questionnaires distributed, 88 (73.3%) were returned, and all of them were analyzed. The respondents included 69 physicians (32 oncologists, 26 breast surgeons, 6 dermatologists, 3 obstetricians/gynecologists, 1 gastroenterological surgeon, and 1 urologist), 9 pharmacists, and 10 nurses. Prophylactic measures included moisturizing (58.0%), protection (42.0%), cooling therapy (37.5%), and cleanliness (33.0%). Approximately 70% of the respondents used the Common Criteria for Adverse Events (CTCAE), while approximately 30% did not use a specific evaluation method. Opinions regarding treatment with antimicrobial or corticosteroid ointments varied; however, all severe cases were referred by dermatologists. CONCLUSION: Our survey revealed that the management of chemotherapy-induced nail changes varies in clinical practice in Japan. These findings emphasize the need for standardized management strategies and further research.

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer.

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. Design, Setting, and Participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Main Outcomes and Measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Conclusions and Relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Improved therapeutic index of the liposomal docetaxel-glutathione prepared by active click loading.

The clinical usage of docetaxel (DTX) is severely hindered by the dose-limiting neutropenia and peripheral neurotoxicity of polysorbate 80-solubilized DTX injection, and there are no alternative formulations until now. In this study, we developed a new liposomal formulation of DTX to reduce its toxicities, accompanying with the greatly improved antitumor activity. The DTX was encapsulated into liposomes in the form of hydrophilic glutathione (GSH)-conjugated prodrugs using a click drug loading method, which achieved a high encapsulation efficiency (∼95 %) and loading capacity (∼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (∼50 % within 48 h) in plasma, resulting in a greatly improved antitumor activities as compared with that of polysorbate 80-solubilized DTX injection in the subcutaneous and orthotopic 4T1 breast tumor bearing mice. Even large tumors > 500 mm3 could be effectively inhibited and shrunk after the administration of liposomal DTX-GSH. More importantly, the liposomal DTX-GSH significantly decreased the neutropenia and peripheral neurotoxicity as compared with that of polysorbate 80-solubilized DTX injection at the equivalent dose. These data suggested that the liposomal DTX-GSH might become a superior alternative formulation to the commercial DTX injection.

The Omission of Anthracycline Chemotherapy in Women with Early HER2-Negative Breast Cancer-A Systematic Review and Meta-Analysis.

BACKGROUND: Anthracycline-taxane is the standard chemotherapy strategy for treating high-risk early breast cancer despite the potentially life-threatening adverse events caused by anthracyclines. Commonly, the combination of docetaxel and cyclophosphamide (TC) is considered an alternative option. However, the efficacy of TC compared to anthracycline-taxane chemotherapy is unclear. This study compares disease-free survival (DFS), overall survival (OS) and cardiotoxicity between adjuvant TC and anthracycline-taxane for stages I-III, HER2-negative breast cancer. METHODS: A systematic search on MEDLINE, Embase and Cochrane CENTRAL for randomized-controlled trials published until 11 March 2024, yielded 203 studies with 11,803 patients, and seven trials were included. RESULTS: TC results in little to no difference in DFS (HR 1.09, 95% CI 0.98-1.20; moderate-certainty of evidence); OS (1.02, 95% CI 0.89-1.16; high-certainty of evidence); and cardiotoxicity (RR 0.54, 95% CI 0.16-1.76; high-certainty of evidence), compared to anthracycline-taxane. In the subgroup analysis, patients with ≥4 lymph nodes had improved DFS from anthracycline-taxane over TC. CONCLUSIONS: Overall, there was no difference between TC and anthracycline-taxane in DFS, OS and cardiotoxicity. In women with ≥4 nodes, anthracycline-taxane was associated with a substantial reduction in relapse events, compared to TC. Our study supports the current standard of practice, which is to use anthracycline-taxane and TC chemotherapy as a reasonable option in select cases.

Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors.

Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.

A novel step towards the heterologous biosynthesis of paclitaxel: Characterization of T1ßOH taxane hydroxylase.

In the quest for innovative cancer therapeutics, paclitaxel remains a cornerstone in clinical oncology. However, its complex biosynthetic pathway, particularly the intricate oxygenation steps, has remained a puzzle in the decades following the characterization of the last taxane hydroxylase. The high divergence and promiscuity of enzymes involved have posed significant challenges. In this study, we adopted an innovative approach, combining in silico methods and functional gene analysis, to shed light on this elusive pathway. Our molecular docking investigations using a library of potential ligands uncovered TB574 as a potential missing enzyme in the paclitaxel biosynthetic pathway, demonstrating auspicious interactions. Complementary in vivo assays utilizing engineered S. cerevisiae strains as novel microbial cell factory consortia not only validated TB574's critical role in forging the elusive paclitaxel intermediate, T5αAc-1ß,10ß-diol, but also achieved the biosynthesis of paclitaxel precursors at an unprecedented yield including T5αAc-1ß,10ß-diol with approximately 40 mg/L. This achievement is highly promising, offering a new direction for further exploration of a novel metabolic engineering approaches using microbial consortia. In conclusion, our study not only furthers study the roles of previously uncharacterized enzymes in paclitaxel biosynthesis but also forges a path for pioneering advancements in the complete understanding of paclitaxel biosynthesis and its heterologous production. The characterization of T1ßOH underscores a significant leap forward for future advancements in paclitaxel production using heterologous systems to improve cancer treatment and pharmaceutical production, thereby holding immense promise for enhancing the efficacy of cancer therapies and the efficiency of pharmaceutical manufacturing.

Platinum/taxane/pembrolizumab vs platinum/5FU/pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC).

OBJECTIVES: Pembrolizumab +/- chemotherapy is standard therapy for r/m HNSCC. Despite regulatory approval of platinum/5FU/pembrolizumab, a taxane is often substituted for 5FU for convenience and tolerability. We aimed to characterize nationwide use patterns and compare outcomes between platinum/taxane/pembrolizumab vs platinum/5FU/pembrolizumab. METHODS: Patients in a US nationwide database with r/m HNSCC treated from 2017 to 2022 with pembrolizumab plus platinum chemotherapy were included. Demographic and cancer-specific characteristics were summarized. Overall survival (OS) was estimated using Kaplan-Meier methodology, and compared between groups using log-rank test and multivariable Cox regression. Time on treatment, number of cycles, receipt of second-line therapy, and toxicities were compared between groups. RESULTS: Of 438 patients, 320 (73 %) received 5FU and 118 (27 %) received a taxane. Taxane use became more frequent over time and was higher in academic vs community practices (51 % vs 23 %, p < 0.001). OS did not differ between taxane and 5FU groups (mOS 12.2 vs 13.4 months, p = 0.662). On multivariable Cox regression, HR for death associated with taxane vs 5FU was 0.99 (95 %CI 0.71-1.38). Receipt of 2L therapy was numerically higher for 5FU patients (46 %) compared to taxane patients (35 %, p = 0.071). Grade ≥ 3 anemia was more common in taxane patients (33 % vs 20 %, p = 0.003), whereas grade ≥ 3 lymphopenia and thrombocytopenia were numerically higher in 5FU patients. CONCLUSION: In patients with r/m HNSCC undergoing chemoimmunotherapy, taxane vs 5FU use varies by practice setting and geographical region. Platinum/taxane/pembrolizumab was associated with similar survival as platinum/5FU/pembrolizumab; these results suggest that chemoimmunotherapy with taxane is a reasonable alternative to 5FU.

The impact of time to postoperative recurrence on the prognosis of patients with esophageal cancer post recurrence: exploratory analysis of OGSG 1003.

BACKGROUND: The association between recurrence timing and prognosis in patients with locally advanced resectable esophageal cancer undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy remains unclear. This study aimed to clarify this association using multicenter prospective clinical trial data. METHODS: Among 162 patients enrolled in a NAC phase II study comparing the efficacy of cisplatin and fluorouracil plus docetaxel with cisplatin and fluorouracil plus adriamycin, 64 patients with recurrence after R0 resection were included in this study. We evaluated the association between recurrence timing and overall survival after recurrence (OSr), along with clinicopathological factors associated with recurrence timing and OSr. RESULTS: Among 64 patients, 46 (71.9%) and 59 (92.2%) experienced recurrence within 1 and 2 years after surgery, respectively. Groups based on recurrence timing, including ≤ 6, 6-12, and > 12 months, had median OSr of 3.6, 13.9, and 13.4 months, respectively. The prognosis was significantly poorer for patients with recurrence ≤ 6 months after surgery than for other patients (P < 0.001). Multivariate analysis revealed pathological lymph node staging as an independent factor associated with early recurrence (odds ratio: 3.46, 95% confidence interval: 1.47-8.02, P = 0.0045). On the other hand, multivariate analysis for factors associated with OSr revealed pT (hazard ratio [HR]: 1.91, 95%CI 1.26-2.88, P = 0.0022), early recurrence (HR: 6.88, 95%CI 2.68-17.6, P < 0.001), and treatment after recurrence, with both local treatment (HR: 0.47, 95%CI 0.22-0.98, P = 0.043) and chemotherapy (HR: 0.25, 95%CI 0.11-0.58, P = 0.0011) as independent prognostic factors. CONCLUSION: Patients with advanced esophageal cancer experiencing recurrence within 6 months after esophagectomy following NAC have an extremely poor prognosis, suggesting that an advanced pN stage is associated with early recurrence.

Multifunctional targeting of docetaxel plus bakuchiol micelles in the treatment of invasion and metastasis of ovarian cancer.

The invasion and metastasis of tumors pose significant challenges in the treatment of ovarian cancer (OC), making it difficult to cure. One potential treatment approach that has gained attention is the use of matrix metalloproteinase reactive controlled release micelle preparations. In this study, we developed a novel PEG5000-PVGLIG-hyaluronic acid docetaxel/bakuchiol (PP-HA-DTX/BAK) micelles formulation with desirable characteristics such as particle size, narrow polydispersity index, and a ZETA potential of approximately -5 mV. The surface modification with HA facilitates tumor penetration into the tumor interior, while the incorporation of DSPE-PEG2000-PVGLIG-PEG5000helps conceal DSPE-PEG2000-HA, reducing off-target effects and prolonging drug circulation timein vivo. Bothin vitroandin vivoexperiments demonstrated that these micelles effectively inhibit proliferation, invasion, and metastasis of OC cells while promoting apoptosis. Therefore, our findings suggest that PP-HA-DTX/BAK micelles represent a safe and effective therapeutic strategy for treating OC.

Incidence and prognosis of taxane-induced macular edema: a retrospective study from the Japan Clinical REtina Study Group (J-CREST).

Macular edema is a known side effect of taxane-based anticancer drugs. We retrospectively investigated data from 11 centers between January 2016 and December 2021. Among 14,260 patients, 30 (0.21%) developed macular edema; from these, the number of cases associated with nab-paclitaxel was 16 (0.43%), significantly higher than the number of cases associated with paclitaxel or docetaxel (P < 0.01). Visual acuity (VA) and retinal choroidal change were examined in 27 patients, with a follow-up of at least 3 months. The patients' mean age was 67.2 years; 14 (51.3%) were male and four (14.8%) had unilateral onset. The mean interval between anticancer drug initiation and the first ophthalmology visit was 290.1 days. Among the 20 patients who discontinued anticancer drugs, VA and edema significantly improved 2 months after discontinuation (LogMAR VA: 0.50 vs. 0.28, central retinal thickness: 472.7 µm vs. 282.5 µm, both P < 0.01). No significant changes were observed in the central choroidal thickness. A correlation was found between duration of taxane treatment and VA immediately before discontinuation of anticancer drugs (ß = 0.00050; 95% confidence interval: 0.00036-0.00097; P < 0.05). Although taxane-induced macular edema is reversible, slower anticancer drug discontinuation worsened VA, highlighting the need for regular ophthalmologic evaluation during treatments.

Study on the Chemical Constituents, Pharmacological Activities, and Clinical Application of Taxus.

Taxus, a rare and protected genus predominantly distributed across the Northern Hemisphere's temperate regions, has garnered global attention due to its significant potential in medical research and pharmaceutical development, bolstered by advancements in cultivation techniques and medical technology. This review primarily focuses on the chemical constituents and pharmacological activities of Taxus, underscoring the progress and potential of these components in clinical applications. Recent studies have revealed that Taxus contains not only taxane active components but also flavonoids and polysaccharides with distinct activities. These compounds from Taxus exhibit potent antitumor, anti-inflammatory, immunomodulatory, antibacterial, and antidiabetic properties with evident mechanisms of action. Notably, the representative compound, paclitaxel, has demonstrated significant efficacy in treating various cancers, such as ovarian, breast, and lung cancer. This paper also reviews the basic situation of Taxus drug formulations, with extracts primarily administered orally and monomeric taxanes typically via injection, reflecting a mature development stage with ongoing research into oral formulations. Finally, this review summarizes the pharmacokinetic characteristics of crucial compounds in Taxus, including their absorption, distribution, metabolism, and excretion patterns in the human body. These pharmacokinetic profiles provide crucial guidance for evaluating the overall dosing regimen of Taxus and its components. The paper concludes with a forward-looking analysis of the potential applications of these compounds in disease treatment, envisioning their role in the future of medical and pharmaceutical advancements.

Injectable dual thermoreversible hydrogel for sustained intramuscular drug delivery.

Herein, we reported novel docetaxel-decorated solid lipid nanoparticle (DCT-SLN)-loaded dual thermoreversible system (DCT-DRTS) for intramuscular administration with reduced burst effect, sustained release and improved antitumor efficacy. The optimized DCT-DRTs was subjected to in-vitro and in-vivo analyses. Antitumor evaluation of the DCT-DRTS was executed and compared with DCT-hydrogel, and DCT-suspension trailed by the histopathological and immune-histochemical analyses. The DCT-SLN gave a mean particle size of 157 nm and entrapment efficiency of 93 %. It was a solid at room temperature, and changed to liquid at physiological temperature due to its melting point of about 32 °C. Unlikely, poloxamer mixture remained liquefied at 25-27 °C, however converted to gel at physiological temperature. This behavior demonstrated opposed reversible property of the DCT-SLN and poloxamer hydrogel in DCT-DRTS system, making it ideal for intramuscular administration and quick gelation inside the body. The DCT-DRTS sustained the drugs release and unlike DCT-hydrogel, the preliminary plasma concentration of DCT-DRTS was significantly reduced, overcoming the burst release. A meaningfully enhanced antitumor efficacy and improved survival rate was observed from DCT-DRTS in tumor cell xenograft athymic nude mice. Additionally, increased apoptotic and reduced proliferation markers were observed in DCT-DRTS treated tumor masses. It was concluded that DCT-DRTS may be a suitable choice for intramuscular administration of DCT with sustained release, improved bioavailability, reduced toxicity and enhanced antitumor effects.

Bisdemethoxycurcumin Augments Docetaxel Efficacy for Treatment of Prostate Cancer.

Bisdemethoxycurcumin (BDMC) is one of major forms of curcuminoids found in the rhizomes of turmeric. Docetaxel (DTX) is the standard of care for men diagnosed with androgen-independent prostate cancers. Here we report for the first time that BDMC could reinforce the effect of DTX against prostate cancer in vitro and in vivo. In vitro study, PC3 and LNCaP cells were cultured and treated with BDMC and DTX alone or in combination. The effects on cell viability were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by annexin V/propidium iodide (PI) staining, while cell cycle was assessed by PI staining. Bax, Bcl-2, caspase, poly(ADP-ribose)polymerase (PARP), cyclin B1 and CDK1 expression were assayed by Western blot. We found that a combination treatment of BDMC (10 µM) with DTX (10 nM) was more effective in the inhibition of PC3 and LNCaP cell growth and induction of apoptosis as well as G2/M arrest, which is accompanied with the significant inhibition of Bcl-2, cyclin B1, CDK1 expression and significant increase of Bax, cleaved caspase-9, cleaved caspase-3 and cleaved PARP, than those by treatment of BDMC or DTX alone. Moreover, in vivo evaluation further demonstrated the superior anticancer efficacy of BDMC and DTX compared to DTX alone in a murine prostate cancer model. These results suggest that BDMC can be an attractive therapeutic candidate in enhancing the efficacy of DTX in prostate cancer treatment.