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Background: Cytotoxic medicine contamination of preparation and administration areas of oncology healthcare facilities poses a risk to staff facing repeated low‐level exposure over time. The use of closed‐system transfer devices (CSTDs) during preparation and administration of cytotoxic products may reduce the levels of contamination. The primary aim was to determine the levels of cytotoxic medicine contamination in preparation and administration areas of hospitals that use CSTDs compared to those that do not. Aim: The primary aim was to determine the levels of cytotoxic medicine contamination in preparation and administration areas of hospitals that use CSTDs compared to those that do not. Method: A retrospective, cross‐sectional study across four Australian hospitals was conducted. Cytotoxic medicine contamination was determined via surface wipe sampling on six specified surfaces. The samples were tested for cyclophosphamide, docetaxel, etoposide, ifosfamide, irinotecan, methotrexate, paclitaxel, pemetrexed, topotecan, and vinblastine. This project was exempt due to the local policy requirements that constitute research by the South Eastern Sydney Local Health District Human Research Ethics Committee (Reference no: ETH01899). The justification for this ethics exemption was as follows: this was a study involving sample testing only and did not include human participants or participation. Results: Environmental contamination with cytotoxic medications was observed at all hospitals, regardless of the CSTD used. Of the 24 samples tested, the agent most frequently seen was ifosfamide with 29% (n = 7), followed by cyclophosphamide 13% (n = 3), and methotrexate 8% (n = 2). There was no statistically significant difference between hospitals that used CSTDs compared to hospitals that did not (25% vs 42%, p = 0.67). Contamination was more extensive in preparation areas than administration areas, and was observed on the biological safety cabinets (BSC) worktop, packaging bench, and floor in front of the BSCs. Conclusion: All sites had contamination present for cytotoxic medicines. There was no statistically significant difference in the proportion of contaminated surfaces between sites that used CSTDs versus sites where CSTDs were not used. Only ifosfamide contamination was identified in pharmacy areas that used CSTDs. Safe work practices and staff training are encouraged to further minimise exposure risk. [ABSTRACT FROM AUTHOR]

Chemotherapy induced alopecia (CIA) is one of the most common side effects in cancer patients, however; it doesn't have an effective pharmacological treatment yet. In this study we aimed to research the protective effect of newly developed HDDPiW-jSB solution on docetaxel (DTX) -induced rat alopecia model. Docetaxel (10 mg/kg/week) was administered to the 6–8 months old rats for three weeks. HDDPiW-jSB solution was applied once or twice a week for 4 weeks beginning prior to one week before DTX. Rat hair follicles were evaluated with hematoxylin-eosin and immune-histochemical staining. In the first stage of this study, alopecia was successfully developed by DTX (10 mg/kg/three times) application. In the second stage of the study, application of HDDPiW-jSB solution, did not change the study parameters significantly on control group. The solution improved the anagen hair follicle count and Bcl-2 levels in the skin samples of DTX-induced alopecic rat groups, especially when applied twice weekly. Additionally, level of Caspase 3 was decreased. HDDPiW-jSB solution was safe when applied on the skin. Topical HDDPiW-jSB solution could be effective and safe for the protection of DTX-induced alopecia in rat models. [ABSTRACT FROM AUTHOR]

Abstract Background Prostate cancer is a leading cause of cancer-related deaths among men worldwide. Docetaxel chemotherapy has proven effective in improving overall survival in patients with castration-resistant prostate cancer (CRPC), but drug resistance remains a considerable clinical challenge. Methods We explored the role of Ribonucleotide reductase subunit M2 (RRM2), a gene associated with senescence, in the sensitivity of prostate cancer to docetaxel. We evaluated the RRM2 expression, docetaxel resistance, and ANXA1 expression in prostate cancer cell lines and tumour xenografts models. In addition, We assessed the impact of RRM2 knockdown, ANXA1 over-expression, and PI3K/AKT pathway inhibition on the sensitivity of prostate cancer cells to docetaxel. Furthermore, we assessed the sensitivity of prostate cancer cells to the combination treatment of COH29 and docetaxel. Results Our results demonstrated a positive association between RRM2 expression and docetaxel resistance in prostate cancer cell lines and tumor xenograft models. Knockdown of RRM2 increased the sensitivity of prostate cancer cells to docetaxel, suggesting its role in mediating resistance. Furthermore, we observed that RRM2 stabilizes the expression of ANXA1, which in turn activates the PI3K/AKT pathway and contributes to docetaxel resistance. Importantly, we found that the combination treatment of COH29 and docetaxel resulted in a synergistic effect, further augmenting the sensitivity of prostate cancer cells to docetaxel. Conclusion Our findings suggest that RRM2 regulates docetaxel resistance in prostate cancer by stabilizing ANXA1-mediated activation of the PI3K/AKT pathway. Targeting RRM2 or ANXA1 may offer a promising therapeutic strategy to overcome docetaxel resistance in prostate cancer. Graphical Abstract

Background: Prostate cancer is a leading cause of cancer-related deaths among men worldwide. Docetaxel chemotherapy has proven effective in improving overall survival in patients with castration-resistant prostate cancer (CRPC), but drug resistance remains a considerable clinical challenge. Methods: We explored the role of Ribonucleotide reductase subunit M2 (RRM2), a gene associated with senescence, in the sensitivity of prostate cancer to docetaxel. We evaluated the RRM2 expression, docetaxel resistance, and ANXA1 expression in prostate cancer cell lines and tumour xenografts models. In addition, We assessed the impact of RRM2 knockdown, ANXA1 over-expression, and PI3K/AKT pathway inhibition on the sensitivity of prostate cancer cells to docetaxel. Furthermore, we assessed the sensitivity of prostate cancer cells to the combination treatment of COH29 and docetaxel. Results: Our results demonstrated a positive association between RRM2 expression and docetaxel resistance in prostate cancer cell lines and tumor xenograft models. Knockdown of RRM2 increased the sensitivity of prostate cancer cells to docetaxel, suggesting its role in mediating resistance. Furthermore, we observed that RRM2 stabilizes the expression of ANXA1, which in turn activates the PI3K/AKT pathway and contributes to docetaxel resistance. Importantly, we found that the combination treatment of COH29 and docetaxel resulted in a synergistic effect, further augmenting the sensitivity of prostate cancer cells to docetaxel. Conclusion: Our findings suggest that RRM2 regulates docetaxel resistance in prostate cancer by stabilizing ANXA1-mediated activation of the PI3K/AKT pathway. Targeting RRM2 or ANXA1 may offer a promising therapeutic strategy to overcome docetaxel resistance in prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The incidence of gastric cancer is known to be high in the elderly population. Identification of the best perioperative chemotherapy regimen is challenging in patients with resectable gastric cancer. In this study, we aimed to evaluate and compare the outcomes and safety of epirubicin, cisplatin, and 5-fluorouracil (ECF), docetaxel, cisplatin, and 5-fluorouracil (DCF), oxaliplatin plus 5-Fluorouracil and leucovorin (FOLFOX), and docetaxel, oxaliplatin, leucovorin, and 5-Fluorouracil (FLOT) chemotherapy regimens to identify the most appropriate treatment option for elderly patients with resectable gastric cancer. Materials and Methods: In this retrospective observational cohort study, data were extracted from the medical archives (2017-2021) of Omid Hospital, which is a tertiary oncology referral hospital in Isfahan, Iran. Patients with resectable gastric cancer, above 60 years of age, who were perioperatively treated with one of the mentioned chemotherapy regimens and met the inclusion criteria, were enrolled in this study. The survival parameters and safety profile of the regimens were evaluated and compared in this population. Results: A total of 63 patients were included in this study. The median follow-up period of the patients was 24 months (range, 7-51 months). The results of survival analysis revealed that the FLOT and DCF regimens were significantly associated with longer overall survival (OS) as compared to the other regimens (median OS: 38 and 33 months, respectively). Based on the results, the progression-free survival was longer in the DCF regimen (median: 24 months) compared to the other regimens; however, only the difference with the ECF regimen (median: 14 months) was significant. The results of Cox regression analysis showed no significant difference in the overall adjusted hazard ratio of mortality between the FLOT and DCF regimens (P = 0.802). The DCF and FOLFOX regimens accounted for the highest and lowest rates of adverse events (e.g., neutropenia and mucositis), respectively. Conclusion: Considering the higher rate of adverse events in the DCF group, besides the significant improvement of OS and the acceptable adverse event profile of patients treated with the FLOT regimen, it can be proposed that this chemotherapy regimen is the most appropriate treatment option for elderly patients with resectable gastric cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is the second most frequently occurring cancer in men, and patients with advanced prostate cancer have poor long-term survival. Chemotherapy is the cornerstone of systemic therapy for advanced prostate cancer and can prolong survival, both in castration-sensitive and castration-resistant disease. In this review, we summarize the data that underlie the integration of chemotherapy into the management of advanced prostate cancer, including data supporting the combination of chemotherapy with next generation androgen receptor signaling inhibitors. Prostate cancer is the second most common cancer among men. Despite advances in diagnosis and management, prostate cancer led to more than 300,000 deaths globally in 2020. Chemotherapy is a cornerstone of therapy for advanced prostate cancer and can prolong survival of patients with both castration-sensitive and castration-resistant disease. Herein, we present a comprehensive review of the data supporting implementation of chemotherapy in the modern treatment of advanced prostate cancer, with special attention to the use of chemotherapy for aggressive variant prostate cancer (e.g., neuroendocrine prostate cancer) and the combination of chemotherapy with androgen signaling inhibitors. As the field of prostate cancer research continues to rapidly evolve yielding novel agents and treatment modalities, chemotherapy continues to play an essential role in prolonging the survival of patients with advanced and metastatic prostate cancer. [ABSTRACT FROM AUTHOR]

To develop a sustainable three-step method for titrating first and second taxane exposures through integration of best practices in patient and environmental safety; and to evaluate the impact on immediate hypersensitivity rates.A quality improvement study was initiated at a large, NCI-designated comprehensive cancer center in the U.S. to determine a sustainable method of slow, upward titration for reducing taxane-related hypersensitivity reactions. Multidisciplinary collaboration led to the incorporation of best practices for safe preparation and administration of high risk, hazardous drugs. Retrospective data from the electronic health records of 690 patients who received 1221 taxane doses were analyzed. Non-titrated infusions were compared with infusions titrated using a method initially tested for efficacy; and infusions titrated using a method revised for greater compliance with safety standards. Two-sided Fisher's exact tests at a 0.1 level of significance were used to detect differences in the rate of HSR between the three groups.A method of taxane titration that incorporated standardized, preprogrammed infusion rates and tubing primed with inert IV fluid showed a significant reduction in HSR incidence in comparison to non-titrated infusions (6% v. 19%, P = 0.001) and a similar decrease in the rate of HSR (6%) to the initial method previously studied (7%) (P = 0.659) which was not sustainable due to patient and environmental safety concerns.A three-step titration method using standardized, preprogrammed infusion rates and tubing primed with inert IV fluid reduced taxane-related HSRs and was adopted as sustainable practice in ambulatory cancer care. [ABSTRACT FROM AUTHOR]

Purpose: The dose-limiting factor of ramucirumab plus docetaxel (RAM + DTX) in patients with non-small cell lung cancer (NSCLC) is febrile neutropenia (FN), which has a high incidence in Asians. This study aimed to evaluate the cost-effectiveness of pegfilgrastim (Peg-G) in patients with NSCLC receiving RAM + DTX in Japan. Methods: We simulated model patients treated with RAM + DTX in Japan and developed a decision-analytical model for patients receiving Peg-G prophylaxis or no primary prophylaxis. The expected cost, quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio (ICER) of each treatment were calculated from the perspective of a Japanese healthcare payer. The willingness-to-pay (WTP) threshold was set at 45,867 United States dollars (USD) (5 million Japanese yen) per QALY gained. The probabilities, utility values, and other costs were obtained from published sources. Deterministic sensitivity analysis (DSA) and probabilistic analysis were conducted to evaluate the effect of each parameter and robustness of the base-case results. Results: The expected cost and QALYs were 20,275 USD and 0.701 for Peg-G prophylaxis and 17,493 USD and 0.672 for no primary prophylaxis, respectively. The ICER was calculated to be 97,519 USD per QALY gained. The results were most sensitive to FN risk with Peg-G. When FN risk with no primary prophylaxis exceeded 51% or the cost of Peg-G was less than 649 USD per injection, the ICER was below the WTP threshold. The probabilistic analysis revealed a 9.1% probability that the ICER was below the WTP threshold. Conclusion: Peg-G is not cost-effective in patients with NSCLC receiving RAM + DTX in Japan. [ABSTRACT FROM AUTHOR]

Background: Use of docetaxel in low- and high-burden metastatic hormone-sensitive prostate cancer presents considerable controversy. There is literature suggesting lack of benefit for low-volume of metastases. Objective: The study aims to develop a systematic review and methodological assessment of subset analysis about use of docetaxel in metastatic hormone-sensitive prostate cancer regarding volume of metastatic disease. Methods: A systematic review in the Pubmed ® database was conducted up to 25 September 2020. A reference tracking was also developed. Randomised clinical trials with subgroup analysis according volume of metastatic disease for overall survival were selected. Two methodologies were used. One of them considered statistical interaction of subsets (p (i) < 0.1), pre-specification, biological plausibility and consistency among subset results of similar randomised clinical trials. The second methodology was a two-part validated tool: preliminary questions to discard subset analysis without minimal relevance and a checklist The checklist provides recommendations for applicability of subgroup analysis in clinical practice. Results: A total of 31 results were found in systematic reviews in the Pubmed® database. One result was identified in the reference tracking. Of the total of 32 results, four randomised clinical trials were included in the study. About first methodology, statistical interaction among subgroups was obtained in one randomised clinical trial. Subgroup analysis was pre-specified in two randomised clinical trials. Biological plausibility was reasonable. No external consistency among results of subgroup analyses in randomised clinical trials was observed. Preliminary questions of second methodology rejected applicability of subgroup analysis in three randomised clinical trials. A 'null' recommendation for applicability of subset results was obtained in the remaining randomised clinical trial. Conclusions: Patients with low- and high-burden metastatic hormone-sensitive prostate cancer would benefit from docetaxel therapy. No consistent differences for overall survival were observed in subgroup analyses regarding volume of metastatic disease. [ABSTRACT FROM AUTHOR]

This study was designed to demonstrate the non-inferiority (NI) in overall survival (OS) of suspension of androgen deprivation therapy (ADT) versus maintenance and intermittent versus continuous docetaxel administration in metastatic castration-resistant prostate cancer (mCRPC) patients. mCRPC patients were randomised to first-line docetaxel with maintenance or suspension of ADT. Patients attaining a prostate-specific antigen (PSA) response after four chemotherapy cycles underwent second randomisation to receive continuous or intermittent docetaxel therapy. Six hundred patients were to be randomised to achieve 80% statistical power to demonstrate an NI hazard ratio (HR) of 1.25 of interruption versus maintenance of ADT. The trial was prematurely closed when 198 participants were randomised. OS was similar in patients who continued (N = 96) versus those who interrupted (n = 102) ADT during docetaxel therapy (HR 0.98, 95% confidence interval [CI] 0.72–1.33] and those on a continuous (N = 35) versus an intermittent (N = 42) docetaxel schedule (HR 0.86, 95% CI 0.55–1.43). No difference in radiological progression-free survival, PSA response, or toxicity was observed between the study arms. The actual NI hazard margins of OS in Arms A and B patients were 1.33 and 1.43, respectively. This trial enrolled one-third of the planned patients; this main weakness dramatically limits the interpretation of the results. ADT discontinuation and switching to an intermittent schedule did not seem to affect docetaxel efficacy. The absence of testosterone recovery in the majority of patients could have been a contributory factor. In men with mCRPC, ADT discontinuation should only be done with regular biochemical and clinical monitoring, with the option of quickly restarting ADT at disease progression. • Docetaxel efficacy in metastatic castration-resistant prostate cancer patients may be not worsened by androgen deprivation therapy (ADT) discontinuation. • Few patients discontinuing ADT achieved testosterone levels above castration. • Switching to an intermittent schedule may not affect the docetaxel toxicity. • The study was stopped prematurely due to low accrual. [ABSTRACT FROM AUTHOR]

Introduction: Low surface contamination levels of hazardous drugs in compounding areas can be used as indicators of exposure and efficacy of cleaning procedures. We report the efficacy results of the KIRO® Oncology self-cleaning automated compounding system for decontamination of cytotoxic drugs, assessed in an oncology health center using a sanitizing method and an alkaline method. Methods: The study was conducted for six-days over a three-week period. A mixture with known levels of 5-fluorouracil, ifosfamide, cyclophosphamide, gemcitabine, etoposide, methotrexate, paclitaxel, docetaxel and carboplatin was added to the KIRO® Oncology's compounding area surface before each self-cleaning method was used. Contamination levels were determined, with a surface wipe sampling kit, at the end of the self-cleaning process. Results: Background surface contamination for quantified levels of cytotoxic drugs during routine use of KIRO® Oncology was below limit of quantification (99.8% for all cytotoxic drugs analyzed. Conclusion: This study provides evidence on the efficacy of the KIRO® Oncology automatic self-cleaning system for surface area decontamination during the preparation of cytotoxic drugs. [ABSTRACT FROM AUTHOR]

Docetaxel is a widely prescribed chemotherapy drug in oncology and post expiry of its patent, the drug has been marketed as a generic by multiple manufacturers. It is also classified as a narrow therapeutic window drug. Through enhanced permeability and retention effect, polymeric micelles can passively target agents to tumor tissue, thereby decreasing toxicity of the drug in normal tissue. However, various studies have raised concerns that generic docetaxel leads to greater incidences of toxicities among patients with cancer. Thus, we herein review the pharmaceutical challenges associated with different docetaxel formulations and provide insights into the dissimilarities in the quality and safety of branded and generic docetaxel formulations. Literature review reported that 90% of the generic formulations of docetaxel contain inadequate quantity of active drug and high levels of impurities. Higher amounts of solvents such as polysorbate 80 and ethanol in docetaxel formulation lead to severe toxicities such as febrile neutropenia, hematological, and cutaneous toxicities. In most of the studies, even minor changes in excipients, solvents, unbound fraction of docetaxel were associated with adverse events, while in few, the source of docetaxel remained unidentified. One study reported incidence of febrile neutropenia due to a switch in the formulation from branded to generic. The quality, safety, and efficacy of medicines will directly affect the life of patients, and therefore, use of docetaxel formulations that guarantee safety of patients are the necessity of the hour. Being an injectable anti-cancer drug, it is important to determine the consistency of the various formulations of docetaxel globally, conduct bioequivalence studies as per the regulatory standards, taking into account the permissible limits of the excipients or the presence of such unapproved excipients. [ABSTRACT FROM AUTHOR]

Decipher is a prognostic genomic classifier (GC) validated in several prospective NRG Oncology Phase III trials. Herein, we validate the GC in pre-treatment biopsy samples for risk stratification in a cohort of high-risk men treated with definitive radiotherapy and androgen suppression with or without docetaxel chemotherapy. As per a pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on the NRG/RTOG 0521 randomized phase III trial. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA) and GC scores were obtained. Pre-specified categorical GC scores, adjusted for archival tissue analysis, were used to define higher (>0.46) and lower (≤0.46) risk groups. The primary objective was to validate the independent prognostic ability of GC for metastasis-free survival (MFS) with Cox multivariable analyses (MVA). Samples were obtained from 283 consented, evaluable patients with tissue (50% of trial) yielding 183 (65%) GC scores that passed quality metrics, 91 from control and 92 from the interventional arm. Median age was 66 years, median PSA was 19.3 ng/uL (IQR: 8.1-41.4), 81% had clinical stage ≥T2 and 80% had Gleason score ≥8 (47% ≥9). Median GC score was 0.55 (IQR: 0.38-0.78) and overall the arms were balanced for key covariates. With a median follow-up of 9.9 years (IQR: 9.3, 10.7), 67 MFS events including 34 distant metastases (DM) were observed. On MVA, only the GC (per 0.1 unit) was independently associated with MFS (HR 1.12, 95% CI 1.01-1.25) as well as DM (sHR 1.22, 95% CI 1.06-1.41), whereas the 4 pre-defined trial risk groups used for stratification (based on Gleason score, T-stage and PSA), randomization and patient age were not. For categorical GC, on MVA, higher-risk GC patients (65%) had worse DM (sHR 2.82, 95% CI 1.1-7.3) compared to those with lower GC. Cumulative incidence of DM at 10-years was 27% for higher GC vs 9% (95% CI 7-18%) for lower GC. No biomarker-by-treatment interaction with GC and the addition of docetaxel was detected. In pre-treatment biopsy samples from a randomized Phase 3 trial cohort, GC demonstrated its ability to further risk stratify clinically high-risk men demonstrating an independent association of GC score with DM and MFS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making. NRG-GU009/PREDICT-RT (NCT04513717) aims to determine the optimal therapy based on GC score for high-risk prostate cancer. [ABSTRACT FROM AUTHOR]