Docetaxel Group Research Articles

Impact of docetaxel plus ramucirumab in a second-line setting after chemoimmunotherapy in patients with non-small-cell lung cancer: A retrospective study.

BackgroundChemoimmunotherapy has become a standard treatment option for patients with untreated advanced non‐small‐cell lung cancer (NSCLC). However, numerous patients with advanced NSCLC develop disease progression. Therefore, the selection of second‐line treatment after chemoimmunotherapy is crucial for improving clinical outcomes.MethodsOf 88 enrolled patients with advanced NSCLC who received chemoimmunotherapy, we retrospectively evaluated 33 who received second‐line chemotherapy after progression of chemoimmunotherapy at six centers in Japan. Among them, 18 patients received docetaxel plus ramucirumab and 15 patients received single‐agent chemotherapy.ResultsThe objective response rate in patients treated with docetaxel plus ramucirumab was significantly higher than that in patients treated with a single‐agent chemotherapy regimen (55.6% vs. 0%, p < 0.001). The median progression‐free survival (PFS) of patients who received docetaxel plus ramucirumab and single‐agent chemotherapy was 5.8 months and 5.0 months, respectively (log‐rank test p = 0.17). In the docetaxel plus ramucirumab regimen group, patients who responded to chemoimmunotherapy for ≥8.8 months had a significantly longer response to docetaxel plus ramucirumab than those who responded for <8.8 months (not reached vs. 4.1 months, log‐rank test p = 0.003). In contrast, in the single‐agent chemotherapy group, there was no significant difference in PFS between the ≥8.8‐ and <8.8‐month PFS groups with chemoimmunotherapy (5.0 vs. 1.6 months, log‐rank test p = 0.66).ConclusionOur retrospective observations suggest that the group with longer PFS with chemoimmunotherapy might be expected to benefit from docetaxel plus ramucirumab treatment in second‐line settings for patients with advanced NSCLC.

Comparative Effectiveness of Atezolizumab, Nivolumab, and Docetaxel in Patients With Previously Treated Non–Small Cell Lung Cancer

Evidence regarding real-world effectiveness of therapies for patients with advanced non-small cell lung cancer (NSCLC) whose tumors are resistant to platinum-based chemotherapy is lacking. To compare the effectiveness of the immune checkpoint inhibitors atezolizumab (programmed cell death ligand 1 inhibitor) and nivolumab (programmed cell death 1 inhibitor) and the chemotherapy drug docetaxel in patients with advanced NSCLC resistant to platinum-based chemotherapy. This comparative effectiveness study compared patients aged 18 years or older with advanced NSCLC who initiated atezolizumab, docetaxel, or nivolumab and who had previously been exposed to platinum-based chemotherapy using nationally representative real-world data from more than 280 US cancer clinics. Patients were followed-up from May 2011 to March 2020. Data analysis was performed between April and June 2021. Comparisons of interest were between atezolizumab vs docetaxel and atezolizumab vs nivolumab. Initiation of atezolizumab, nivolumab, or docetaxel monotherapy. The main outcome was overall survival (OS). A total of 3336 patients (mean [SD] age, 67.1 [9.49] years; 1820 [54.6%] men and 1516 [45.4%] women) were assessed in the main analysis, including 206 patients receiving atezolizumab, 500 receiving docetaxel, and 2630 receiving nivolumab. Patients receiving atezolizumab were older than those treated with docetaxel (mean age [SD], 68.3 [9.4] years vs 65.6 [9.5] years), and were more likely to have been treated in an academic setting (39 patients [18.9%]) than those receiving docetaxel (49 patients [9.8%]) and nivolumab (128 patients [4.9%]). After adjustment for baseline characteristics, atezolizumab was associated with a significantly longer OS compared with docetaxel (adjusted hazard ratio [aHR], 0.79; 95% CI, 0.64-0.97). No significant difference in OS was observed between atezolizumab and nivolumab (aHR, 1.07; 95% CI, 0.89-1.28). These findings were consistent across all patient subgroups tested, and robust to plausible deviations from random missingness for Eastern Cooperative Oncology Group performance status in real-world data (eg, the tipping point for loss of a significantly beneficial effect for atezolizumab vs docetaxel was achieved if patients in the docetaxel group missing baseline Eastern Cooperative Oncology Group performance status had a mean performance status of 1.43 higher than expected). In this comparative effectiveness study, atezolizumab was superior to docetaxel and matched nivolumab in prolonging OS in a real-world cohort of patients with advanced NSCLC who previously received platinum-based chemotherapy.

Curcuma zedoaria petroleum ether extract reverses the resistance of triple-negative breast cancer to docetaxel via pregnane X receptor.

BackgroundTriple-negative breast cancer (TNBC) is characterized by its aggressiveness and poor prognosis. Docetaxel is the common chemotherapeutic drug used in the treatment of TNBC. However, resistance to docetaxel has limited the effectiveness of TNBC treatment. Petroleum ether extracts of Curcuma zedoaria (PECZ) can inhibit the proliferation of MDA-MB-231 cells. However, the effect of PECZ on docetaxel resistance is not clear.MethodsA docetaxel-resistant MDA-MB-231 (MDA-MB-231/docetaxel) cell line was established, and Cell Counting Kit-8 (CCK-8), quantitative real-time PCR (qRT-PCR), and western blotting assays were used to evaluate the effect of docetaxel resistance in MDA-MB-231 cells. Next, CCK-8 was also performed to detect the effect of docetaxel or the combination treatment of docetaxel and PECZ on the proliferation of MDA-MB-231/docetaxel cells. Thereafter, MDA-MB-231/docetaxel cells were subcutaneously injected into nude mice to induce a TNBC xenograft model, and the mice were divided into a model group, docetaxel group, PECZ group, and combination of docetaxel and PECZ group. Subsequently, hematoxylin and eosin (HE) staining, immunohistochemical, qRT-PCR, and western blotting were used to estimate the effect of pre-treatment with PECZ on docetaxel tolerance reversal.ResultsPECZ significantly inhibited the expression of pregnane X receptor (PXR), multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP), and cytochrome P-450 (CYP3A4) in MDA-MB-231/docetaxel cells. Only higher concentrations of docetaxel could inhibit the viability of MDA-MB-231/docetaxel cells. When pre-treated with PECZ, lower concentrations of docetaxel could significantly inhibit cell viability. Meanwhile, combination treatment also reduced the tumor volume, ameliorated the pathological change of tumor tissues, and down-regulated the expressions of PXR, MDR1, BCRP, and CYP3A4 (according to HE staining, immunohistochemical, qRT-PCR and western blotting results in vivo).ConclusionsOur research showed that PECZ reversed docetaxel resistance in TNBC by PXR both in vitro and in vivo, which provides the basis for further investigations into the potential therapeutic impact of docetaxel resistance in TNBC.

Randomized phase II study of docetaxel versus paclitaxel in patients with esophageal squamous cell carcinoma refractory to fluoropyrimidine- and platinum-based chemotherapy: OGSG1201

BackgroundThere is no standard chemotherapy for esophageal squamous cell carcinoma (ESCC) refractory to first-line fluoropyrimidine- and platinum-based chemotherapy. We therefore performed a randomized, selection-design phase II trial to compare docetaxel (DTX) and paclitaxel (PTX) in this setting. Patients and methodsEligible patients were randomly assigned to receive either DTX (70 mg/m2 on day 1 of each 21-day cycle) or PTX (100 mg/m2 on days 1, 8, 15, 22, 29 and 36 of each 49-day cycle). The primary end-point was overall survival (OS), and secondary end-points included progression-free survival (PFS), time to treatment failure (TTF), response rate (RR) and safety. ResultsSeventy-eight eligible patients (N = 39 in each group) were included for efficacy analysis. OS was significantly longer in the PTX group than in the DTX group (median, 8.8 versus 7.3 months; hazard ratio [HR], 0.62; P = 0.047). A significant benefit of PTX over DTX was also apparent in PFS (median, 4.4 versus 2.1 months; HR, 0.49; P = 0.002) and TTF (median, 3.8 versus 2.1 months; HR, 0.45; P < 0.001). RR (25.6% versus 7.7%, P = 0.065) were higher in the PTX group than in the DTX group. Compared to the PTX group, neutropenia (28% versus 80%) and leukopenia (28% versus 76%) of grade ≥3 as well as febrile neutropenia (0% vs. 46%, P < 0.0001) occurred more frequently in the DTX group. ConclusionPTX showed a significantly better efficacy as well as a more manageable toxicity compared with DTX. Clinical trial registrationUMIN000007940.

Prognostic significance of third-line treatment for patients with metastatic castration-resistant prostate cancer: comparative assessments between cabazitaxel and other agents.

Cabazitaxel has played an important role in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC); however, several types of sequential therapy against mCRPC have been performed in routine clinical practice. The objective of this study was to investigate the impact of third-line treatment on prognostic outcomes of mCRPC patients. This study retrospectively analyzed the clinical outcomes of 166 patients who received 3 agents following the diagnosis of mCRPC, consisting of 81 sequentially treated with either abiraterone or enzalutamide and then docetaxel, followed by third-line cabazitaxel (group A) and 85 treated with 3 agents, including abiraterone, enzalutamide, and docetaxel (group B). There were no significant differences in major characteristics at the introduction of the third-line agent between these 2 groups. The proportion of patients with prostate-specific antigen (PSA) reduction > 50% by cabazitaxel in group A was significantly greater than that by either third-line agent in group B. Both PSA progression-free survival (PFS) and overall survival (OS) following third-line therapy in group A were significantly longer than those in group B. Furthermore, OS after the diagnosis of mCRPC in group A was significantly longer than that in group B. Multivariate analysis identified independent predictors of favorable prognostic outcomes after third-line therapy as follows: high-performance status (PS), low PSA level and third-line cabazitaxel for PSA PFS, and high PS, low lactate dehydrogenase level and third-line cabazitaxel for OS. The introduction of cabazitaxel as a third-line agent could markedly improve the prognostic outcomes of mCRPC patients.

Abstract 1439: Increasing potency of anticancer drugs through SORT1+ technology: A new targeted approach for the treatment of ovarian and endometrial cancers

Abstract Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer.Whereas little therapy advances have been made in recent years, precise anticancer drug targeting modalities could be achieve by incorporating a peptide ligand that has the ability to specifically recognize cancer cells. High expression of sortilin (SORT1), a scavenging receptor, was observed in ovarian and endometrial cancers. In light of this, we developed a SORT1-targeted technology to increase both selectivity and efficacy of anticancer drug delivery. Docetaxel was conjugated to a sortilin-binding peptide (TH19P01 peptide). In vitro, high and saturable intracellular delivery of the fluorescent Alexa488-TH19P01 was confirmed in different SORT1+ cancer cell models, whereas internalization was reduced by 70-80% when SORT1 was silenced using siRNA, or by 50-70% upon competition with the SORT1 ligands neurotensin and progranulin. Sortilin expression level was assessed in tissue micro-arrays of biopsies from patients with high grade serous ovarian carcinoma (HGSC), from endometrial cancers, and from healthy tissues. A strong sortilin staining was effectively observed in more than 90% of the tumor biopsies and remained high in those from HGSC patients that received neoadjuvant chemotherapy. Immunoblotting also revealed high levels of SORT1 in a wide variety of human cancer cell lines including ovarian and endometrial cancer cells. In vivo, tumor xenografts were generated from two of the sortilin-expressing ovarian cancer cell lines (ES-2 and SKOV-3/Luc). Administration of TH1902, a docetaxel-TH19P01 conjugate, impeded ES-2 ovarian tumor xenograft growth when administered for three cycles at 35 mg/kg/week, versus unconjugated docetaxel at 15 mg/kg/week. A 78% decrease in tumor growth was observed in TH1902-treated animals, though docetaxel-treated tumor volumes were indistinguishable from either of the other groups. In contrast, administration of either docetaxel or TH1902 completely prevented tumor growth in SKOV-3/Luc ovarian tumor xenografts and even led to tumor regression. When TH1902 and docetaxel were administered to mice bearing AN3-CA endometrial tumor xenografts at an equivalent of docetaxel dose (3.75 mg/kg/week), a decrease in the rate of tumor growth by 73% was apparent in TH1902 group whereas docetaxel lacked any observable effect. In addition, higher equivalent dose of both TH1902 and docetaxel (15 mg/kg/week) inhibited tumor growth, however and in contrast to docetaxel group, TH1902-treated mice showed sustained tumor regression. These results strongly support the clinical development of this SORT1+ technology for both endometrial and ovarian cancers. Citation Format: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Larocque, Alain Zgheib, Richard Béliveau, Christian Marsolais, Borhane Annabi. Increasing potency of anticancer drugs through SORT1+ technology: A new targeted approach for the treatment of ovarian and endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1439.

A Comparative Study on Anticancer Effects of the Alhagi maurorum and Amygdalus haussknechtii Extracts Alone and in Combination with Docetaxel on 4T1 Breast Cancer Cells.

Medicinal plants have long been studied due to their anticancer effects and use of them is commonly increased as a complementary and alternative medicine (CAM therapies) among patients with cancer. In this study, Alhagi maurorum (A.m) and Amygdalus haussknechtii (A.h) extracts were evaluated for their effects on inhibiting the growth of 4T1 breast cancer cells. Based on MTT assay results, the IC50s of A.m and A.h extracts were 57 µg/ml and 85 µg/ml, respectively. Then the cell migration, gene expression, and degree of apoptosis after 48 hours in each treated group with A.m and A.h extracts alone or in combination with docetaxel (DTX) on 4T1 cells were evaluated. A.m had a synergistic behavior with DTX (CI < 1). A.h reduced DTX IC50 but presented CI > 1. Cell migration assay showed that each extract alone or in combination with DTX prevented the migration of 4T1 cells. The Ao/EB staining and flowcytometry results confirmed that, in combination therapy, A.m + DTX and A.h + DTX induced apoptosis close to the level of DTX. Real-time PCR analysis showed that A.m + DTX (IC50 + IC25) downregulated the mRNA expression of HIF-1α and FZD7. A.m + DTX (IC50 + IC10) group decreased the expression of HIF-1α. Moreover, in A.h + DTX (IC50 + IC25) group, β-Catenin and FZD7 were downregulated and upregulated, respectively. Generally, our findings suggest that the combination of A.m and DTX possesses synergistic antitumor effects on 4T1 cells, which may be a valuable choice for CAM therapies. A.h has an acceptable antitumor activity but not in combination with DTX.

Randomized phase II study comparing docetaxel versus paclitaxel in patients with esophageal squamous cell carcinoma who are refractory to fluoropyrimidine and platinum-based chemotherapy: OGSG1201.

4037 Background: Fluoropyrimidine and platinum-based chemotherapy are considered first-line therapy options for patients with unresectable advanced or recurrent metastatic esophageal squamous cell carcinoma(ESCC). After fluoropyrimidine and platinum-based chemotherapy is failed, taxanes (docetaxel(DTX) and paclitaxel(PTX)) was mainly used as a second-line treatment for ESCC. Therefore, we conducted a trial to compare DTX and PTX in patients with unresectable advanced or recurrent ESCC who were failed to previous fluoropyrimidine and platinum-based chemotherapy. Methods: We did a randomized, an open-labeled and multicentre phase 2 study. Inclusion criteria included age 20 to 80 years with unresectable advanced or recurrent ESCC, Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Patients who were refractory to fluoropyrimidine and platinum-based chemotherapy. Treatment consisted of DTX 70 mg/m2 repeated every 21 days or PTX 100 mg/m2 once weekly on days 1, 8, 15, 22, 29, and 36 of a 49-day cycle. Results: 80 patients were enrolled between May 2012 and April 2019. 41 patients received DTX and 39 patients received PTX. After assessment of eligibility, two patients proved uneligible (one for double cancer, one for contraindication to DTX) and were excluded from the analysis. But, 80 patients were evaluable for the toxicity analyses. A median follow-up time was 32 months. Overall survival was significantly longer in the PTX group than in the DTX group (median, 8.8 months vs. 7.3 months; hazard ratio, 0.62; 95% CI, 0.38 to 0.9998; P = 0.047). The median progression-free survival was significantly longer in the PTX group than in the DTX group (median, 4.4 months vs. 2.1 months; hazard ratio, 0.49; 95% CI, 0.30 to 0.78; P = 0.002). The median time to treatment failure was significantly longer in the PTX group than in the DTX group (median, 3.8 months vs. 2.1 months; hazard ratio, 0.45; 95% CI, 0.28 to 0.73; P＜0.001). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 28% of the PTX group and in 80% of the DTX group). Febrile neutropenia was also more frequent in the DTX group than the PTX group (46％ vs. 0%). There was one death from sudden death in which treatment-related mortality could not be ruled out. Conclusions: Secound-line treatment with PTX, as compared with DTX, reduced the risk of ESCC. Clinical trial information: UMIN000007940.

Phase 3 Randomized Controlled Trial of Androgen Deprivation Therapy with or Without Docetaxel in High-risk Biochemically Recurrent Prostate Cancer After Surgery (TAX3503)

BackgroundNo standard of care exists for patients with high-risk biochemical recurrence (BCR) after prostatectomy. ObjectiveTo evaluate whether addition of docetaxel to androgen deprivation therapy (ADT) improved progression-free survival (PFS) in high-risk BCR patients. Design, setting, and participantsTAX3503 was a multicenter phase 3 trial that randomized patients with high-risk BCR to ADT for 18 mo ± docetaxel (75 mg/m2 q3w for ten cycles). Eligibility included prostate-specific antigen (PSA) ≥1.0 ng/ml after prostatectomy alone or after postoperative radiation therapy, PSA doubling time ≤9 mo, and absence of metastases on computed tomography and bone scintigraphy. Outcome measurements and statistical analysisThe primary endpoint was PFS following testosterone recovery to noncastrate levels (testosterone >50 ng/dl). Secondary endpoints included time to testosterone recovery, overall survival (OS), quality of life, and safety. Results and limitationsBetween September 2007 and May 2011, 413 patients were assigned to ADT ± docetaxel. In 2012, following completion of accrual and treatment, the sponsor withdrew support of the study, and in 2013, a registry was created to secure the primary endpoint. The final analysis included data from the original trial and registry. At a median follow-up of 33.6 mo, 260 patients demonstrated testosterone recovery, which occurred similarly between groups. ADT plus docetaxel trended toward a nonclinically meaningful improvement in PFS (median 26.2 vs 24.7 mo) for the testosterone-recovered population (218 events, hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61–1.04) and in OS for the intention-to-treat population (medians not reached, HR 0.51, 95% CI 0.23–1.10). Grade ≥3 adverse events occurred more frequently in the ADT plus docetaxel group (48.0% vs 10.8%). ConclusionsTAX3503 did not demonstrate a meaningful benefit of adding docetaxel to ADT in patients with high-risk BCR. Testosterone recovery was unaffected by addition of docetaxel to ADT. Patient summaryAddition of docetaxel to androgen deprivation therapy did not meaningfully improve outcomes for men with high-risk biochemically recurrent prostate cancer.

Population-Based Study of Docetaxel or Abiraterone Effectiveness and Predictive Markers of Progression Free Survival in Metastatic Castration-Sensitive Prostate Cancer.

BackgroundBoth Docetaxel (DOC) and Abiraterone (ABI) improve the survival of men with metastatic, castration sensitive prostate cancer (mCSPC). However, the outcome among mCSPC patients is highly variable, while there is a lack of predictive markers of therapeutic benefit. Furthermore, there is limited data on the comparative real-world effectiveness of adding DOC or ABI to androgen deprivation therapy (ADT).MethodsWe conducted a retrospective analysis of 121 mCSPC patients treated at Odette Cancer Centre (Toronto, ON, Canada) between Dec 2014 and Mar 2021 (DOC n = 79, ABI n = 42). The primary endpoint studied was progression free survival (PFS), defined as the interval from start of ADT to either (i) biochemical, radiological, or symptomatic progression, (ii) start of first-line systemic therapy for castration-resistant prostate cancer (CRPC), or (iii) death, whichever occurred first. To identify independent predictive factors for PFS in the entire cohort, a Cox proportional hazard model (stepwise selection) was applied. Overall survival (OS) was among secondary endpoints.ResultsAfter a median follow-up of 39.6 and 25.1 months in the DOC and ABI cohorts, respectively, 79.7% of men in the DOC and 40.5% in the ABI group experienced a progression event. PFS favored the ABI cohort (p = 0.0038, log-rank test), with 78.0% (95%CI 66.4–91.8%) of ABI versus 67.1% (57.5–78.3%) of DOC patients being free of progression at 12 months. In univariate analysis superior PFS was significantly related to older age at diagnosis of mCSPC, metachronous metastatic presentation, low-volume (CHAARTED), and low-risk (LATITUDE) disease, ≥90% PSA decrease at 3 months (PSA90), and PSA nadir ≤0.2 at 6 months. Age (HR = 0.955), PSA90 (HR = 0.462), and LATITUDE risk stratification (HR = 1.965) remained significantly associated with PFS in multivariable analysis. OS at 12 months was 98.7% (96.3–100%) and 92.7% (85.0–100%) in the DOC and ABI groups (p = 0.97), respectively.ConclusionsIn this real-world group of men undergoing treatment intensification with DOC or ABI for mCSPC, we did not find a significant difference in OS, but PFS was favoring ABI. Age at diagnosis of mCSPC, PSA90 at 3 months and LATITUDE risk classification are predictive factors of PFS in men with mCSPC.

Phase 3 Trial Comparing Nanoparticle Albumin-Bound Paclitaxel With Docetaxel for Previously Treated Advanced NSCLC

IntroductionWe aimed to evaluate the efficacy and safety of nanoparticle albumin-bound (nab-) paclitaxel for previously treated patients with advanced NSCLC. MethodsIn this randomized, open-label, noninferiority phase 3 trial, we enrolled patients with advanced NSCLC previously treated with cytotoxic chemotherapy. Patients were randomly allocated (1:1) to receive docetaxel (60 mg/m2) on day 1 or nab-paclitaxel (100 mg/m2) on days 1, 8, and 15 of a 21-day cycle. The primary end point was overall survival (OS) analyzed on an intention-to-treat basis. ResultsBetween May 22, 2015, and March 12, 2018, a total of 503 patients were randomly allocated to the treatment. Median OS was 16.2 months (95% confidence interval [CI]: 14.4–19.0) for the 252 patients allocated to nab-paclitaxel and 13.6 months (95% CI: 10.9–16.5) for the 251 patients allocated to docetaxel (hazard ratio = 0.85, 95.2% CI: 0.68–1.07). Median progression-free survival was 4.2 months (95% CI: 3.9–5.0) for the nab-paclitaxel group versus 3.4 months (95% CI: 2.9–4.1) for the docetaxel group (hazard ratio = 0.76, 95% CI: 0.63–0.92, p = 0.0042). The objective response rate was 29.9% (95% CI: 24.0–36.2) for the nab-paclitaxel group and 15.4% (95% CI: 10.9–20.7) for the docetaxel group (p = 0.0002). Adverse events of grade greater than or equal to 3 included febrile neutropenia (5 of 245 patients [2%] in the nab-paclitaxel group versus 55 of 249 patients [22%] in the docetaxel group) and peripheral sensory neuropathy (24 [10%] versus 2 [1%], respectively). ConclusionsNab-paclitaxel was noninferior to docetaxel in terms of OS. It should, thus, be considered a standard treatment option for previously treated patients with advanced NSCLC.

Haemopoietic Potential of Tannin Fractionates of Vitex doniana Leaf on Nitrosobis (2-Oxopropyl) Amine Comobidity in Docetaxel-Induced Myelosuppression in Wistar Rat

Aim: This study investigated the haemopoietic potential of tannin fractionate of Vitex doniana leaf against nitosobis (2-oxopropyl) amine comorbidity in docetaxel-induced bone marrow suppression.&#x0D; Study Design: This is an experimental research.&#x0D; Place of Research: University of Nigeria, Enugu campus.&#x0D; Methodology: The male Wistar rats used in this experiment were twenty-eight in number, and they were grouped into 7, with each group having four rats. Group 1 served as control, and received 1ml of normal saline, while groups 2-7 were treated with Nitrosobis (2-oxopropyl) amine 5 mg/kg daily for 2 weeks. Then groups 3-7 were treated with 8 mg/Kg of docetaxel weekly for 2 weeks. And groups 4, 5 and 6 also received 250 mg/Kg and 500 mg/Kg and 1000 mg/kg of tannin, respectively, daily for 2 weeks. Group 7 received 40 mg/Kg of fesolate daily for 2 weeks.&#x0D; Results: The haemoglobin concentration and white blood cell count of rats in the groups treated with Nitrosobis (2-oxopropyl) amine alone (group 2) and Nitrosobis (2-oxopropyl) amine plus Docetaxel (group 3) showed statistically significant reduction (p=.05) in number when compared with the group treated with normal saline (group 1). The haemoglobin concentration and white blood cell count of the rats in the groups treated with 250 mg/kg, 500 mg/kg, and 1000 mg/kg of the tannin fractionate, in addition to the Nitrosobis (2-oxopropyl) amine and Docetxel (i.e. groups 4, 5, and 6, respectively) showed statistically significant dose dependent increase in number, with the group treated with 1000mg/kg showing the highest increment (p=.05). The cells in the bone marrow show significant reduction in number in the rats treated with Nitrosobis (2-oxopropyl) amine (group 2) and Nitrosobis (2-oxopropyl) amine plus docetaxel (group 3) when compared with the rats in group 1 (treated with normal saline). With the addition of graded doses of the tannin fractionate, 250 mg/kg, 500 mg/kg, and 1000mg/kg (i.e. groups 4, 5, and 6, respectively), the number of cells in the bone marrow showed statistically significant increase when compared to group 3 (treated with Nitrosobis (2-oxopropyl) amine plus docetxel), with the rats in the group treated with 1000 mg/kg of tannin fractionate (group 6) having the highest increment (p=.05).&#x0D; Conclusion: Tannin obtained from Vitex doniana leaf extract increases the haemoglobin concentration in dose dependent manner. It also increases the white blood cell count, and number of proliferating bone marrow cells, following suppression by Nitrosobis (2-oxopropyl) amine and Docetaxel. So, this tannin obtained from Vitex doniana leaf extract may be useful in clinical practice to cushion the myelosupression, anaemia and leukopenia that are associated with use of docetaxel in treatment of malignancies.

Short-term outcomes of risk-adapted upfront docetaxel administration in patients with metastatic hormone-sensitive prostate cancer: a multicenter prospective study in Japan.

We conducted a risk-adapted upfront docetaxel (DOC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Here, we reported an interim analysis of the study. The study enrolled 68 patients with newly diagnosed mHSPC between 2016 and 2018. According to the presence of visceral metastasis, an EOD score ≥ 3, or prostate-specific antigen (PSA) level at 3months of ≥ 1ng/mL, patients were divided into low- and high-risk groups. Patients were treated with androgen deprivation therapy (ADT) with or without bicalutamide; those in the high-risk group received upfront treatment involving six cycles of DOC (70mg/m2). Short-term treatment effect, adverse events, and quality of life (QOL) were evaluated. Fifty (73.5%) were classified in the high-risk group, and 46 (67%) received upfront ADT + DOC. In the ADT + DOC group, 43.5% (20/46) patients achieved a PSA level ≤ 0.2ng/mL. PSA nadir and time to PSA nadir were 0.291ng/mL and 288days, respectively. In the ADT + DOC group, 76.1% (35/42) patients had adverse events (AEs) of grade ≥ 3. During a median follow-up of 18.5months, 36.4% (8/22) patients in the ADT group and 43.5% (20/46) in the ADT + DOC group had CRPC. Two QOL scores including the physical status and appetite loss at 6months significantly worsened in the ADT + DOC group but was resolved by 12months. Upfront DOC achieved high PSA responses without long-term QOL deterioration. However, the short-term outcomes were limited. Longer follow-up is needed to determine the survival advantage.

OA03.05 Phase III Study Comparing Nab-Paclitaxel With Docetaxel in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer

Nanoparticle albumin-bound (nab-) paclitaxel showed promising efficacy for treatment of advanced non–small cell lung cancer (NSCLC) in a phase 2 study. We aimed to assess the efficacy and safety of nab-paclitaxel for previously treated patients with advanced NSCLC. In this multicenter, randomized, open-label, noninferiority phase 3 trial, we enrolled patients with advanced NSCLC previously treated with cytotoxic chemotherapy. Patients were randomly allocated (1:1) to receive docetaxel (60 mg/m2) on day 1 or nab-paclitaxel (100 mg/m2) on days 1, 8, and 15 of a 21-day cycle. The primary end point was overall survival analyzed on an intention-to-treat basis. Adverse events were assessed according to treatment received. Between 22 May 2015 and 12 March 2018, 503 patients were randomly allocated to treatment. Median overall survival was 13.6 months (95% CI, 10.9–16.5) for the 251 patients allocated to docetaxel and 16.2 months (95% CI, 14.4–19.0) for the 252 patients allocated to nab-paclitaxel (hazard ratio, 0.85; 95.2% CI, 0.68–1.07). Median progression-free survival was 4.2 months (95% CI, 3.9–5.0) for the nab-paclitaxel group versus 3.4 months (95% CI, 2.9–4.1) for the docetaxel group (hazard ratio, 0.76; 95% CI, 0.63–0.92; p=0.0042). The objective response rate was 29.9% (95% CI, 24.0–36.2) for the nab-paclitaxel group and 15.4% (95% CI, 10.9–20.7) for the docetaxel group (p=0.0002), and it showed a significant improvement for nab-paclitaxel versus docetaxel regardless of tumor histology. Adverse events of grade ≥3 included febrile neutropenia (55 [22%] of 249 patients in the docetaxel group versus 5 [2%] of 245 patients in the nab-paclitaxel group) and peripheral sensory neuropathy (2 [1%] versus 24 [10%], respectively). The trial showed that nab-paclitaxel was noninferior to docetaxel in terms of overall survival. Nab-paclitaxel should thus be considered a standard treatment option for previously treated patients with advanced NSCLC.

Abstract PS18-44: Simvastatin induces ferroptosis in breast cancer cells by inhibiting GPX4 and sensitizes chemotherapy

Abstract Background The incidence of breast cancer ranks the first among female malignant tumors. Although the effect of breast cancer treatment strategies has been very ideal and the mortality rate of breast cancer has decreased, some patients are still not sensitive to these, which eventually leads to rapid recurrence, metastasis and poor prognosis. Ferroptosis is a kind of Regulated cell death, which induced by accumulation of lipid peroxidation products and Reactive Oxygen Species (ROS). It is quite different from apoptosis and autophagy in cell morphological characteristics and biochemical indicators. According to the latest studies, ferroptosis can reduce the activity of GPX4 (Gutathione Peroxidase 4) in cells and accumulate ROS and lipid Peroxidase products through iron metabolism, ROS metabolism, amino acid metabolism and lipid metabolism, etc., thus causing ferroptosis. Ferroptosis is a hotspot in the study of drug resistance and metastasis of breast cancer. Simvastatin is a kind of commonly used oral cholesterol-lowering drugs, belongs to the HMG CoA reductase inhibitors. Some clinical studies have shown that statins can reduce the risk of a variety of cancers, including breast cancer, and the risk of recurrence. Other basic experiment show lipophilic statins have anti-cancer effect. Simvastatin is the most lipophilic of all statins in use. Recent studies have found that simvastatin can be used in combination with docetaxel to enhance the effect of chemotherapy in prostate cancer, but has not been reported in breast cancer. In this study, we investigated whether simvastatin could induce ferroptosis in breast cancer by inhibiting GPX4 and play the role of chemotherapy sensitization in combination with docetaxel. Methods (1) CCK8 assay was used for cell proliferation in vitro by simvastatin and docetaxel in breast cancer cells MDA-MB-231 and MCF-7. (2) The anti-cancer effect of simvastatin in vivo was verified by xenograft experiments in nude mice. (3) GPX4 mRNA and protein levels were detected by qPCR and Western blot. (4) GPXs activity test, ROS level test and MDA level test were used for ferroptosis detection.(5) the expression of ferroptosis-related genes ACSL4, PTGS2 and NOX1 was detected by qPCR.(6) anti-tumor effect of simvastatin combined with docetaxel in breast cancer cells mda-mb-231 and McF-7 was detected in vitro by CCK8 method.(7) By MDA-MB-231 tumor xenograft models surveyed anti-tumor activity of simvastatin and docetaxel. Results CCK8 results showed that simvastatin significantly inhibited cell proliferation in breast cancer cells MDA-MB-231 and MCF-7 (P&amp;lt;0.001), with the IC50 values of MDA-MB-231 was 4.67um and MCF-7 was 81.53um,. In the xenograft experiments of nude mice, it was found that compared with the control group, the tumor volume of the simvastatin group was significantly reduced. In qPCR and Western blot, simvastatin was found to significantly inhibit GPX4 mRNA and protein expression. Compared with the control group, in breast cancer cells MDA-MB-231 and MCF-7, simvastatin can reduce the activity of GPXs and increase the level of ROS and MDA, thus causing ferroptosis in breast cancer cells. qPCR showed that ferroptosis -related gene ACSL4 and PTGS2, which are related to lipid metabolism, and ROS metabolism were significantly increased. In the xenograft experiments of nude mice, it was found that compared with the control group and the single drug group, the tumor volume of simvastatin combined with docetaxel group was significantly reduced. Conclusion Simvastatin can inhibit the proliferation of breast cancer cells both in vivo and in vitro, inhibit the expression of breast cancer cell MDA-MB-231 and MCF-7 GPX4, and induce ferroptosis. Besides, simvastatin sensitizes the effect of docetaxel. Citation Format: Sihong Lu, Nan Shao, Jong Bi, Ying Lin. Simvastatin induces ferroptosis in breast cancer cells by inhibiting GPX4 and sensitizes chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-44.

Icotinib versus Cisplatin Plus Docetaxel as Adjuvant Chemotherapy in Patients with Stage II (N1+) Non-Small Cell Lung Cancer Harboring Positive EGFR Mutations: A Single-Center Retrospective Study.

PurposeThe superior efficacy of first-line treatment with icotinib over that of standard chemotherapy has been well demonstrated in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation. However, whether icotinib is superior to cisplatin plus docetaxel as adjuvant chemotherapy in patients with stage II (N1+) NSCLC selected by EGFR mutation is controversial.MethodsA total of 43 patients with completely resected stage II (T1-2N1M0) NSCLC and proven sensitive EGFR mutation (19Del or L858R) between January 2010 and December 2019 were included in our study. The disease-free survival (DFS) and overall survival (OS) were analyzed in 22 patients treated with icotinib and 21 patients treated with cisplatin plus docetaxel. Factors affecting DFS and OS were assessed by the Kaplan-Meier (KM) estimator and univariate Cox regression analysis.ResultsOur cohort included 22 icotinib patients and 21 cisplatin plus docetaxel patients with a median follow-up of 35.5 months and 38 months, respectively. Survival time was significantly longer in the icotinib group than in the chemotherapy group, with a median DFS of 47 months (95% CI, not reached) versus 18 months (95% CI, 12.4–23.6; HR 0.16; 95% CI, 0.07–0.35; log-rank p<0.0001). In the icotinib group, the most common adverse effects (AEs) were skin rash (40.9%) and elevated alanine aminotransferase (22.7%), whereas in the cisplatin plus docetaxel group, the most common AEs were nausea or vomiting (90.5%), anorexia (71.4%), and fatigue (71.4%). No deaths were treatment-related.ConclusionIn this study, we demonstrated that in EGFR mutation-positive patients with completely resected stage II (T1-2N1M0) NSCLC, icotinib might provide DFS benefits, and reduced drug toxicity compared to cisplatin plus docetaxel. Thus, icotinib may be a reasonable option for adjuvant chemotherapy in patients with pathological stage II (N1+) NSCLC with EGFR mutation.

Confirmed three-year RFS and OS of the randomized trial of adjuvant S-1 versus S-1 plus docetaxel after curative resection of pStage III gastric cancer (JACCRO GC-07).

159 Background: JACCRO GC-07 is a randomized controlled trial to explore postoperative S-1/docetaxel compared to S-1 alone after D2 gastrectomy for pStage III gastric cancer (GC) patients. The second interim analysis demonstrated that the significant improvement of RFS was obtained by S-1/docetaxel compared to S-1 alone. The study was terminated by the recommendation of independent data and safety monitoring committee and the results were reported at ASCO 2018 and published in the Journal of Clinical Oncology (Yoshida K et al. 2019; 37:1296-1304). As 3 years have passed after completion of the enrollment, preplanned analysis was performed with the updated information of the patients. Methods: Patients with pStage III GC were randomly assigned to receive either S-1/docetaxel (S-1 80-120mg/body on days 1-14 with a 7-day rest followed by docetaxel 40mg/m2 on day 1 and S-1 80-120mg/body on days 1-14 every 21 days for 6 cycles followed by S-1 80-120mg/body on days 1-28 every 42 days for 4 cycles) or S-1 (80-120mg/body on days 1-28 every 42 days for 8 cycles) after D2 gastrectomy. Block randomization was performed by a central interactive computerized system stratified by the stage (IIIA, IIIB, IIIC) and histological type (differentiated or undifferentiated). The sample size of 1,100 was necessary to detect a 7% increase in the 3-year RFS. The primary endpoint was 3y RFS and the secondary endpoints were OS, TTF and safety. Results: In the present analysis, 400 recurrences and 324 deaths were confirmed among 912 patients during the median follow-up period of 42.5 months (0.3-85.16). The 3y RFS of 67.7% in the S-1/docetaxel group was significantly superior to 57.4% in the S-1 group (HR 0.715, 95% CI: 0.587-0.871, p = 0.0008) and the 3y OS was 77.7% in the S-1/docetaxel group and that of S-1 group was 71.2%, respectively (HR 0.742, 95% CI: 0.596-0.925, p = 0.0076), confirming the significant improving effect on the survival of the patient. Conclusions: Adjuvant S-1 plus docetaxel is recommended for patients with pStage III gastric cancer who underwent D2 gastrectomy without neoadjuvant chemotherapy. Clinical trial information: UMIN 000010337.

Randomized Phase II Study to Comparing Docetaxel/Nedaplatin versus Docetaxel for 5-Fluorouracil/Cisplatin Resistant Esophageal Squamous Cell Carcinoma

Purpose: To compare efficacy and safety of dual docetaxel/nedaplatin treatment versus docetaxel alone as second-line chemotherapy for advanced esophageal cancer.Methods: In all, 36 patients with metastatic and/or recurrent esophagus squamous cell carcinoma resistant to first-line chemotherapy (fluorouracil/cisplatin) were recruited from 2011 to 2018 and randomized into two groups. Treatment response and survival were compared between the docetaxel/nedaplatin (60/80 mg/m2/day) group and docetaxel (70 mg/m2/day) group. Treatment was repeated every 3 weeks until tumor progression. Patients were followed up until March 2019 or death.Results: The frequency of Grade 3 or higher adverse events in the docetaxel/nedaplatin group (58.8%) was higher compared with the docetaxel group (26.3%) (P = 0.090). We found a treatment response rate of 52.9% and 36.8% and a median survival of 8.9 and 7.0 months in the docetaxel/nedaplatin-treated and docetaxel-treated group, respectively (P = 0.544).Conclusion: No significant survival advantage was found for docetaxel/nedaplatin-treated patients, although there was an increased frequency of high-grade adverse events compared to docetaxel-treated patients. Because of the limited cohort size, a Phase III study based on our findings is not warranted to assess the clinical impact of docetaxel/nedaplatin treatment. This trial is registered with the University Hospital Medical Information Network (UMIN 000005877).

The effect of docetaxel on survival, fertilization rate and apoptosis-related genes mRNA expression in mouse metaphase II oocytes following vitrification.

Docetaxel is beneficial in oocyte cryopreservation. The effect of docetaxel, on the survival, fertilization rate and mRNA expression of apoptosis-related genes of vitrified mature oocytes was investigated. Mature oocytes were divided into eight experimental groups, including I) control, II) docetaxel, III) docetaxel + cryoprotectant agent 1 (CPA1), IV) docetaxel + CPA2, V) docetaxel + vitrification 1 (Vit1), VI) docetaxel + Vit2, VII) Vit1, and VIII) Vit2. The survival and fertilization rates, and the mRNA expression level of Bcl-xl, Bax and caspase-3 as apoptosis-related genes were evaluated. The survival rates in Vit1, and Vit2 groups were significantly lower than in the control group (P<0.05). The fertilization rates in docetaxel + Vit1, docetaxel + Vit2, Vit1, and Vit2 were significantly lower than the control, docetaxel, and related groups using docetaxel and CPAs. Bax expression was significantly increased in groups which oocytes vitrified. Also, its expression in the Vit2 group increased significantly in comparison to the docetaxel + Vit2 group. The expression of the Bcl-xl gene was downregulated in docetaxel + CPA2, docetaxel + Vit2 and Vit2 compared to docetaxel group. The Bax/Bcl-xl ratio significantly increased in docetaxel + CPA2, docetaxel + Vit1, docetaxel + Vit2, Vit1 and Vit2 groups compared to control, docetaxel and the docetaxel + CPA1 group. Caspase-3 expression significantly increased in all six groups in comparison to the control, and docetaxel groups. Its expression significantly increased in the Vit1 and Vit2 groups in comparison with docetaxel + Vit1, and docetaxel + Vit2, respectively. Docetaxel ameliorates the damages to oocytes during vitrification by altering the expression of apoptosis-related genes and its effects are dependent on the vitrification solution used in cryopreservation of oocytes.

Atezolizumab prolongs overall survival over docetaxel in advanced non-small-cell lung cancer patients harboring STK11 or KEAP1 mutation

ABSTRACT Somatic mutations of STK11 or KEAP1 are associated with poor clinical outcomes for advanced non-small-cell lung cancer (aNSCLC) patients receiving immune checkpoint inhibitors (ICIs), chemotherapy, or targeted therapy. Which treatment regimens work better for STK11 or KEAP1 mutated (SKmut) aNSCLC patients is unknown. In this study, the efficacy of atezolizumab versus docetaxel in SKmut aNSCLC was compared. A total of 157 SKmut aNSCLC patients were identified from POPLAR and OAK trials, who were tested by blood-based FoundationOne next-generation sequencing assay. Detailed clinical data and genetic alterations were collected. Two independent cohorts were used for biomarker validation (n = 30 and 20, respectively). Median overall survival was 7.3 months (95% confidence interval [CI], 4.8 to 9.9) in the atezolizumab group versus 5.8 months (95% CI, 4.4 to 7.2) in the docetaxel group (adjusted hazard ratio [HR] for death, 0.70; 95% CI, 0.49 to 0.99; P = .042). Among atezolizumab-treated patients, objective response rate, disease control rate, and durable clinical benefit were higher when blood tumor mutation burden (bTMB) and PD-L1 being higher (biomarker 1, n = 61) or with FAT3 mutation-positive tumors (biomarker 2, n = 83) than otherwise. The interactions for survival between these two biomarkers and treatments were significant, which were further validated in two independent cohorts. In SKmut patients with aNSCLC, atezolizumab was associated with significantly longer overall survival in comparison to docetaxel. Having FAT3 mutation or high TMB and PD-L1 expression potentially predict favorable response in SKmut patients receiving atezolizumab.