Conventional Paclitaxel Research Articles

KRAS-dependent cancer cells promote survival by producing exosomes enriched in Survivin.

Mutations in KRAS frequently occur in human cancer and are especially prevalent in pancreatic ductal adenocarcinoma (PDAC), where they have been shown to promote aggressive phenotypes. However, targeting this onco-protein has proven to be challenging, highlighting the need to further identify the various mechanisms used by KRAS to drive cancer progression. Here, we considered the role played by exosomes, a specific class of extracellular vesicles (EVs) derived from the endocytic cellular trafficking machinery, in mediating the ability of KRAS to promote cell survival. We found that exosomes isolated from the serum of PDAC patients, as well as from KRAS-transformed fibroblasts and pancreatic cancer cells, were all highly enriched in the cell survival protein Survivin. Exosomes containing Survivin, upon engaging serum-starved cells, strongly enhanced their survival. Moreover, they significantly compromised the effectiveness of the conventional chemotherapy drug paclitaxel, as well as a novel therapy that combines an ERK inhibitor with chloroquine, which is currently in clinical trials for PDAC. The survival benefits provided by oncogenic KRAS-derived exosomes were markedly reduced when depleted of Survivin using siRNA or upon treatment with the Survivin inhibitor YM155. Taken together, these findings demonstrate how KRAS mutations give rise to exosomes that provide a unique form of intercellular communication to promote cancer cell survival and therapy resistance, as well as raise interesting possibilities regarding their potential for serving as therapeutic targets and diagnostic markers for KRAS-dependent cancers.

A randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311): Primary analysis

ObjectiveTo assess the efficacy and safety of dose-dense weekly paclitaxel plus carboplatin (ddTC) with or without bevacizumab compared to conventional, tri-weekly paclitaxel plus carboplatin (cTC) with or without bevacizumab, in metastatic or recurrent cervical carcinoma not amenable to curative local therapy. MethodsPatients were randomly assigned to either the cTC or ddTC arm. The cTC regimen was paclitaxel 175 mg/m2 and carboplatin at an area under the curve (AUC) of 5 on day 1. The ddTC regimen was paclitaxel 80 mg/m2 on day 1, 8, 15 and carboplatin at AUC of 5 on day 1. Both cTC and ddTC treatments were repeated every 3 weeks for up to 9 cycles. After bevacizumab was approved in Japan, patients in both arms received bevacizumab 15 mg/kg if not contraindicated. The primary endpoint of phase II part was response rate (RR). If the RR of ddTC+bevacizumab was found to be at least 5% better than to cTC + bevacizumab, the study would proceed to phase III part, which had overall survival as its primary endpoint. Clinical trial information: jRCTs031180007. ResultsIn total, 122 patients were randomly assigned to either the cTC arm (cTC + bevacizumab: 32; cTC:29) or the ddTC arm (ddTC+bevacizumab: 30; ddTC:31). The RR for patients on cTC + bevacizumab was 67.9%, and for patients on ddTC+bevacizumab 60.7%, cTC: 55.2%, and ddTC: 50.0%. ConclusionsThe study did not meet the primary endpoint of phase II portion. Dose-dense, weekly paclitaxel plus carboplatin is not promising for metastatic or recurrent cervical carcinoma.

ESMO 2020: highlights in breast cancer.

Despite the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, results of several pertinent studies in the field of breast cancer (BC) were presented in a virtual format at the 2020 European Society of Medical Oncology (ESMO) Congress. Early results of the MonarchE trial investigating the addition of the cyclin-dependent kinase (CDK) 4/6 inhibitor abemaciclib to standard adjuvant endocrine therapy indicated a lower recurrence rate in the combination group in a high-risk population of patients with early stage hormone receptor (HR)-positive/HER2-negative BC. In contrast, the PALLAS study evaluating adjuvant palbociclib could not confirm these results. Subtle differences in the respective trial populations, a higher discontinuation rate in PALLAS, or substance-specific differences may be responsible. In HER2-positive early stage BC, long-term results of the ADAPT-TP trial support the notion that chemotherapy-free treatment may be possible in a subset of patients with favourable response to HER2-directed therapy without compromising long-term outcome. The phase III IMpassion031 trial evaluated the addition of atezolizumab to neoadjuvant anthracycline/taxane-containing chemotherapy in triple-negative BC (TNBC). A significant improvement in terms of pathologic complete remission rate was observed but data concerning long-term outcome must be awaited. Final overall survival (OS) analysis of IMpassion130 confirmed the clinically relevant OS improvement observed with the addition of atezolizumab to first-line nab-paclitaxel in metastatic PD-L1 positive TNBC. In contrast, no benefit was observed with the addition of atezolizumab to solvent-based paclitaxel in a similar population. This contradiction is commonly explained by the need for corticosteroid co-medication with conventional paclitaxel, but the exact reason remains poorly understood. Antibody–drug conjugates (ADCs) have been successfully established in HER2-positive breast cancer; in TNBC, the phase III ASCENT trial compared the ADC sacituzumab govitecan with chemotherapy by physician’s choice in pretreated metastatic patients. A significant improvement in terms of progression-free survival and OS was observed rendering this drug a potential novel standard in this patient population.

Evidence for Delivery of Abraxane via a Denatured-Albumin Transport System.

Abraxane, an albumin-bound paclitaxel nanoparticle formulation, is superior to conventional paclitaxel preparations because it has better efficacy against unresectable pancreatic cancer. Previous reports suggest that this better efficacy of Abraxane than conventional paclitaxel preparation is probably due to its transport through Gp60, an albumin receptor on the surface of vascular endothelial cells. The increased tumor accumulation of Abraxane is also caused by the secreted protein acid and rich in cysteine in the tumor stroma. However, the uptake mechanism of Abraxane remains poorly understood. In this study, we demonstrated that the delivery of Abraxane occurred via different receptor pathways from that of endogenous albumin. Our results showed that the uptake of endogenous albumin was inhibited by a Gp60 pathway inhibitor in the process of endocytosis through endothelial cells or tumor cells. In contrast, the uptake of Abraxane-derived HSA was less affected by the Gp60 pathway inhibitor but significantly reduced by denatured albumin receptor inhibitors. In conclusion, these data indicate that Abraxane-derived HSA was taken up into endothelial cells or tumor cells by a mechanism different from normal endogenous albumin. These new data on distinct cellular transport pathways of denatured albumin via gp family proteins different from those of innate albumin shed light on the mechanisms of tumor delivery and antitumor activity of Abraxane and provide new scientific rationale for the development of a novel albumin drug delivery strategy via a denatured albumin receptor.

Reprogramming Cancer Stem-like Cells with Nanoforskolin Enhances the Efficacy of Paclitaxel in Targeting Breast Cancer.

Cancer stem-like cells (CSCs) have emerged as an important target for breast cancer therapy owing to their self-renewability, proliferation, and elevated chemoresistance properties. Here, we present a strategy of eliminating CSCs by differentiation therapy where "forced differentiation" reprograms CSCs so that they lose their intrinsic properties and become susceptible for conventional chemotherapeutic drugs. In this study, we report that a conventional chemotherapeutic paclitaxel enhances the stemness of CSCs, while a phytochemical forskolin being essentially nontoxic to CSCs possesses the intrinsic ability to reprogram them. To achieve simultaneous targeting of CSCs and bulk tumor cells, we used a co-delivery system where liquid crystal nanoparticles (LCN) were co-encapsulated with both paclitaxel and forskolin. LCN showed higher uptake, retention, and penetration potential in CSCs overcoming their high drug efflux property. Moreover, LCN improved the pharmacokinetic parameters of forskolin, which otherwise had very low retention and bioavailability. Forskolin-loaded LCN forced CSCs to exit from their mesenchymal state, which reduced their stemness and chemosensitized them while inhibiting E-cadherin-mediated survival and tumor-initiating potential as well as reversing paclitaxel-induced stemness. We further showed that upon administration of paclitaxel and forskolin co-loaded LCN to an orthotropic xenograft mouse model, the nanomedicine showed enhanced passive tumor targeting capability with very potent antitumor activity that eradicated small solid tumor in a single dose and showed no sign of tumor relapse or systemic toxicity over a long period. Overall, these findings give a proof of concept that co-delivery of forskolin and paclitaxel in a single nanoformulation can achieve overall tumor targeting where forskolin can efficiently reprogram/differentiate CSCs and paclitaxel can induce cytotoxicity in both differentiated CSCs and bulk tumor cells simultaneously. Hence, this study can provide a nanoformulation that can offer an efficient strategy for cancer therapy.

Acupuncture for Paclitaxel-Induced Peripheral Neuropathy: A Review of Clinical and Basic Studies.

Paclitaxel-induced peripheral neuropathy (PIPN) is a common and intractable side effect of the conventional chemotherapeutic agent paclitaxel. Acupuncture has been reported as an effective alternative therapy in treatment of PIPN in both basic studies and clinical trials. However, there is a lack of comprehensive surveys to summarize the action of acupuncture in management of PIPN. In this review, we briefly demonstrate the basic pathology of PIPN, which includes the activation of ion channels, mitochondrial dysfunction, disruption of axonal transport and also neuro-inflammatory involvement. Meanwhile, we review both the clinical and basic studies as an emphasis to give a general overview of the therapeutic effect of acupuncture against PIPN. Finally, we summarize the current known mechanisms underlying the action of acupuncture against PIPN mainly at peripheral and spinal levels, which include various neurotransmitters, multiple receptors, different types of enzymes and molecules. In conclusion, acupuncture could be considered as a potential alternative therapy in treatment of PIPN, and further clinical and experimental studies are called for in the future.

Nanoparticle albumin-bound paclitaxel versus solvent-based paclitaxel in breast cancer: A protocol for systemic review and meta-analysis.

Background:Nanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel in breast cancer patients of all stages.Method:Pubmed, EMBASE, Cochrane Library, Chinese Biomedical database, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical database, and WangFang database were searched for head-to-head randomized controlled trials of nab-PTX and solvent-based paclitaxel in breast cancer. Other sources will also be searched like Google Scholar and gray literatures. Two researchers will independently search the database and extract data from the articles. Risk of bias will be assessed using the Cochrane Collaboration's tool. Objective tumor response rate, chemotherapy completion rate after 4 or 6 cycles, and toxicity will be primary outcomes. Disease control rate, overall survival, and progression-free survival/disease-free survival will be included in secondary outcomes. Risk ratio with 95% confidence interval was used for dichotomous variables while hazard ratio was used for time-to-event outcomes. The following 3 data sets will all be considered when synthesizing the data: intention-to-treat population, those who actually received taxanes treatment, and those who were actually assessed. All the analyses were done using Review Manager Software 5.3. Any disagreements in study selection, data collection, and analysis will be resolved by a third investigator.Results and conclusion:This study is aim to evaluate the efficacy and safety of nab-PTX compared with PTX in breast cancer treatment as well as to find the best dose or schedule and identify the benefit population. This meta-analysis could provide evidence for clinicians to make a better choice between nab-PTX and PTX in different specific contexts.Prospero registration number:CRD42019117912.

Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death.

α/β-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhibitors has not been reported yet. In this study, we verified the antitumor activity of gatastatin, a γ-tubulin specific inhibitor. The cytotoxicity of gatastatin was relatively weak compared with that of the conventional MT inhibitors, paclitaxel and vinblastine. To improve the cytotoxicity, we screened the chemicals that improve the effects of gatastatin and found that BI 2536, a Plk1 inhibitor, greatly increases the cytotoxicity of gatastatin. Co-treatment with gatastatin and BI 2536 arrested cell cycle progression at mitosis with abnormal spindles. Moreover, mitotic cell death induced by the combined treatment was suppressed by the Mps1 inhibitor, reversine. These findings suggest that co-treatment with Plk1 and γ-tubulin inhibitors causes spindle assembly checkpoint-dependent mitotic cell death by impairing centrosome functions. These results raise the possibility of Plk1 and γ-tubulin inhibitor co-treatment as a novel cancer chemotherapy.

Potentially Overestimated Efficacy of Nanoparticle Albumin-bound Paclitaxel compared with Solvent-based Paclitaxel in Breast Cancer: A Systemic Review and Meta-analysis.

Background: Nanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel (sb-PTX) in breast cancer patients of all stages.Method: Pubmed, Embase and Cochrane Library were searched for head-to-head randomized controlled trials of nab-PTX and sb-PTX in breast cancer. Risk ratio (RR) with 95% confidence interval was used for dichotomous variables while Hazard ratio (HR) was used for time-to-event outcomes.Results: Our review finally included 9 studies with 3508 patients. Nab-PTX showed a benefit on objective response rate (ORR) (RR=1.22 [1.04-1.43], P=0.01) as well as non-inferiority compared with sb-PTX in disease control rate (DCR) (RR=1.01 [0.98-1.04], P=0.44), overall survival (OS) (HR=0.99 [0.93-1.05], P=0.81) and disease free survival/progression free survival (DFS/PFS) (HR=0.92 [0.81-1.05], P=0.21). However, when it comes to toxicities (fatigue, nausea or vomiting, peripheral sensory neuropathy and adverse event related discontinuation), results favored sb-PTX (RR=2.89 [1.07-7.8], 3.15 [1.78-5.59], 2.11 [1.32-3.37], 2.02 [1.61-2.53]; P<0.05). Patients with metastatic tumors or undergoing conventional schedule responses better to nab-PTX than the compared groups (RR of ORR in metastatic vs early or locally advanced patients: 1.46 [1.09-1.96] vs 1.01 [0.94-1.08]; conventional vs dose dense group: 1.59 [1.23-2.06] vs 1.01 [0.91-1.12]).Conclusions: Nab-PTX can improve ORR compared with paclitaxel and should be given priority to when aiming to reduce tumor load in breast cancer. Sb-PTX of dose dense schedule is recommended when toxicity of nab-PTX is hard to bear for breast cancer patients.

Observation on the Clinical Effect of Apatinib Combined with Chemotherapy in the Treatment of Advanced Non-Small Cell Lung Cancer.

Objectives:To evaluate the clinical effect of apatinib combined with chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC).Methods:Eighty patients with advanced NSCLC treated in Hebei General Hospital from January 2017 to July 2020 were randomly divided into two groups: the experimental group and the control group, each with 40 cases. Patients in the control group were treated with conventional paclitaxel combined with cisplatin chemotherapy, while patients in the experimental group were treated with apatinib mesylate tablets based on the treatment of the control group. After treatment, tumor efficacy evaluation was conducted on all patients every two cycles, and the therapeutic effect, adverse drug reactions, improvement of quality-of-life scores prior to and after treatment, and changes of indicators such as tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 153(CA153) were compared and analyzed between the two groups.Results:The total effective rate of the experimental group was 67.5%, which was significantly better than the 45% of the control group (p=0.04); The incidence of adverse drug reactions in the experimental group was 25%, while that in the control group was 37.5%, with no significant difference (p=0.23); Moreover, the improvement rate of quality of life scores in the experimental group was significantly higher than that in the control group (p=0.03), and the levels of CEA and CA153 in the experimental group were significantly lower after treatment than those in the control group, with a statistically significant difference (p=0.01).Conclusion:Apatinib combined with conventional chemotherapy is effective in the treatment of advanced non-small cell lung cancer, the quality of life can be significantly improved, tumor markers can be significantly reduced, and adverse reactions will not be significantly increased.

Encapsulating paclitaxel in polymeric nanomicelles increases antitumor activity and prevents peripheral neuropathy

Paclitaxel (PTX) has a great clinical significance as an antitumor drug, although several side effects are strongly dose-limiting. In this way, we prepared a PTX-loaded 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] polymeric micelles (PM/PTX) in an attempt to improve safety and effectiveness of conventional PTX formulation (CrEL/EtOH/PTX). In this study, we evaluated from both formulations: stability after dilution, hemocompatibility, cellular uptake, acute toxicity in healthy mice, antitumor activity, and toxicity after multiple-dose treatment. PM/PTX appeared to be more stable than CrEL/EtOH/PTX after dilution. PM/PTX did not exhibit hemolytic activity (values <1%), even at high concentrations. In vitro cellular uptake study indicated that polymeric micelles were able to deliver more PTX (5.8 %) than CrEL/EtOH (2.7 %) to 4T1 cells. In the acute toxicity evaluation in healthy mice, CrEL/EtOH/PTX (single dose of 20 mg/kg) induced peripheral neuropathy, which was not observed in PM/PTX group. Similar results were observed after tumor-bearing mice received a multiple-dose regimen (seven doses of 10 mg/kg). Worth mentioning, we also evaluated vehicles, and CrEL/EtOH alone was not capable of inducing neuropathic pain. Besides, PM/PTX exhibited a higher antitumor activity with an inhibition ratio approximately 1.5-fold higher than CrEL/EtOH/PTX group. This study suggested that PM/PTX is safer than CrEL/EtOH/PTX, and was able to improve the antitumor effectiveness in a 4T1 breast cancer model.

Abstract 2622: Paclitaxel directed screening to identify novel anti-cancer drugs

Abstract Among the main challenges for the treatment of breast cancers is disease spread which is often coupled with resistance to chemotherapy. Furthermore, patients with late stage breast cancer go through first- and second-line therapies before they are candidates for new and/or experimental therapies. At such late stages, tumors that might have responded to new therapies have evolved to express multi-drug resistance - conceivably as a consequence of exposure to the initial therapies. Many mechanisms have been proposed to contribute to drug resistance, ranging from (but not limited to) reduced drug penetration and the activity of drug efflux pumps through to cell-adhesion mediated resistance to cell death. To address these challenges we sought to determine whether; a) tumor metastasis to different secondary sites generates location-specific tumor phenotypes that alter sensitivity to chemotherapy and, b) whether pre-treatment of tumors to conventional paclitaxel (PTX) chemotherapy alters their sensitivity to new drugs. First, we implanted 2x10(5) human luciferase-positive LM2-4 human breast cancer cells intracardiacally into SCID mice (n=15), which resulted 2 weeks later in the development of widespread metastases to the lungs, liver, spleen, and bone. For some of the mice bearing such metastases, PTX therapy (20mg/kg, i.p.) was administered 24 hours before the mice were euthanized. Next, we used RNA sequencing of isolated LM2-4 metastatic nodules to determine the impact of the location of metastases on transcriptome profiles (assessed by 40 million reads per each total RNA sample, followed by Principal Component Analysis). This study revealed that lung metastases have similar signatures to metastases to spleen and ovary, and to metastases in those organs following PTX therapy, while such transcriptome profiles are all quite distinct from those of metastases of the same tumor to the liver. These changes presumably are due to different cell-cell interactions of tumor cells in the different organs, as well as a consequence of the different microenvironments. Second, we set up a drug screen of LM2-4 breast cancer cells recovering from 1nM paclitaxel 24hr exposure in vitro to test for drugs that are toxic to the tumor cells following PTX pre-exposure. A screen of 30,000 small molecule drugs thus far identified 7 hit compounds. Our results serve a proof of concept that the location of metastases can alter the tumor cell phenotype, as can pre-treatment with PTX, and suggest that in some cases therapy ought to be tailored to the location of metastasis. Based on those results we identified drugs that may be useful in hampering the tumor cell recovery from PTX chemotherapy. Our work serves as a test ground for stratifying tumors based on their tissue of tumor spread, and provide a rationale for identifying drugs that hamper recovery of tumor cells to chemotherapy agents often incorporated into first and second line therapies, such as paclitaxel. Citation Format: Joseph Wingate, Diana Gonzalez Garcia, Karla Parra, Serina Batson, Joel Martinez, Ivan Sosa Ontiveros, Renato Aguilera, Armando Varela, Paloma Valenzuela, Marcos Armendariz, Chloe Clifton, Arlene Levario, Angelica Chacon, Andres Villagrana, Emmanuel Sanchez, Guido Bocci, Giulio Francia. Paclitaxel directed screening to identify novel anti-cancer drugs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2622.

Clinical outcomes of neoadjuvant chemotherapy for patients with breast cancer: Tri-weekly nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide: a retrospective observational study.

ABSTRACTNeoadjuvant chemotherapy (NAC) using the combination of anthracycline and taxanes is the standard regimen for patients with primary breast cancer. Among the taxanes, conventional paclitaxel (PTX) and docetaxel have usually been adopted in the neoadjuvant or adjuvant setting. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a solvent-free formulation that can be delivered to cancer cells at higher doses than conventional PTX. This study is a retrospective observational study in a single institution. We evaluated the efficacy and safety of nab-PTX followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) in the neoadjuvant setting. In this study, 50 patients with primary breast cancer received nab-PTX (q3w, 260 mg/m2 ± trastuzumab 6 mg/kg) followed by FEC (q3w, 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) prior to surgery. The efficacy was evaluated using the clinical response rate (CRR), pathological complete response (pCR) rate, and Ki67 labeling index. Safety was evaluated using the frequency of treatment-related adverse events and relative dose intensity (RDI). All patients received at least one course of chemotherapy. The CRR and pCR rate were 88.0% and 40.0%, respectively. The mean Ki67 labeling index was significantly decreased from 47.7% to 24.6% after NAC. The safety profiles were comparable with previously reported regimens, and high RDIs were obtained (97.2% for nab-PTX and 95.5% for FEC). This study illustrated the efficacy and tolerability of a neoadjuvant regimen of nab-PTX followed by FEC.

Dose-dense carboplatin and paclitaxel versus three weekly regimen in the first-line treatment of ovarian carcinoma.

e18059 Background: The benefit of dose dense chemotherapy (ddCT) in the adjuvant treatment of ovarian carcinoma (OC) is not clear. There is one positive Japanese trial and two negative trials in non-Asian patients, which differed from the JGOG 3016 trial for the use of bevacizumab in one of them and the use of neoadjuvant CT (NCT) in half the patients in the other. In this study, we aimed to compare progression free survival (PFS) of ddCT to conventional regimen. Methods: We did a retrospective review of medical records from patients with OC treated in a Brazilian cancer center from 2007 to 2018. All patients treated with ddCT or conventional carboplatin and paclitaxel regimen (3wCT) in the first line setting were included. PFS and overall survival (OS) were compared. To address selection bias we performed a second analysis in a propensity score matched cohort. Patients were matched according to age, ECOG performance status, CA 125, stage, residual disease and histological subtype, in a 1:2 ratio. Results: A total of 615 cases were enrolled for analysis, 62 were treated with ddCT. Patients treated with ddCT presented better ECOG and more frequently presented advanced stage, high-grade serous carcinoma and residual disease ≤ 1cm. Only 10% of patients were treated with NCT in both groups. In the multivariate analysis ddCT showed a non-significant benefit over conventional CT (PFS HR 0.646, 95% CI 0.384–1.087, p = 0.10). In the propensity score matched cohort 186 patients were included, 62 treated with ddCT and 124 3wCT. Groups were well balanced. After a median follow-up of 48.1 months, median PFS was 32 (18-45.9) versus 22.7 (18.8-26.6) months, favoring dose dense treatment (p = 0.059). In the multivariate cox regression ddCT showed a 45% lower risk of progression (HR 0.55, 95% CI 0.35–0.88, p = 0.01). Overall survival data is immature, but suggested better outcomes for ddCT (NR versus 76.1 months; p = 0.02). Conclusions: There is no prospective study in a Western population with the same design as the JGOG 3016 trial. In our study, in a population with the same treatment schedules of the Japanese trial, ddCT was associated with longer PFS. This finding suggests that a weekly regimen of paclitaxel might still be a reasonable option for first-line treatment for women with advanced ovarian cancer, and should be further prospectively evaluated.

A randomized phase II/III trial of conventional paclitaxel and carboplatin with/without bevacizumab versus dose-dense paclitaxel and carboplatin with/without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311): Results of the phase II part.

6027 Background: A randomized controlled trial was conducted to assess the efficacy and safety of dose-dense, weekly paclitaxel plus carboplatin (ddTC) with or without bevacizumab (Bmab) compared to conventional, tri-weekly paclitaxel plus carboplatin (cTC) with or without Bmab, in metastatic or recurrent cervical carcinoma not amenable to curative treatments with local therapy. Methods: Patients were randomly assigned to either a cTC or a ddTC regimen. After Bmab was approved in Japan (in May 2016) the protocol was amended, and patients on both arms received Bmab if not contraindicated. The cTC was paclitaxel 175 mg/m2 intravenously (IV) for 3 h on day 1 followed by carboplatin at an area under the curve of five IV for 1 h on day 1. The ddTC was paclitaxel 80 mg/m2 IV for 1 h on day 1 followed by carboplatin at an area under the curve of five IV for 1 h on day 1 and paclitaxel 80 mg/m2 IV for 1 h on day 8 and day 15. Both cTC and ddTC treatments were repeated every three weeks, for up to nine cycles. Bmab 15 mg/kg IV was repeated until progression or unacceptable toxicity. The primary endpoint of phase II was the response rate (RR) in patients with measurable lesion, who had received Bmab. If the RR of the ddTC + Bmab arm was greater than that of the cTC + Bmab arm for more than 5%, the study would proceed to phase III, which had overall survival (OS) as its primary endpoint. The planned sample size in the phase II part was 56 to select the ddTC arm with a probability of at least 75% if the difference of RR was 15% or more (45% vs. 60%). Results: Patient accrual started in October 2015. It was suspended in May 2019 because the number of Bmab-treated patients with measurable lesions reached 56. In total, 122 patients were enrolled and randomly assigned to either the cTC arm (cTC: 29 patients; cTC + Bmab: 32 patients) or the ddTC arm (ddTC: 30 patients; ddTC + Bmab: 31 patients). The primary analysis of the phase II part was conducted in November 2019. The RRs of each regimen were 67.9% [95% CI, 47.7-84.1] (19/28, cTC + Bmab), 60.7% [40.6-78.5] (17/28, ddTC + Bmab), 55.2% [35.7-73.6] (16/29, cTC), and 50.0% [29.9-70.1] (13/26, ddTC). Conclusions: The study did not meet the primary endpoint of phase II. Dose-dense, weekly paclitaxel plus carboplatin is not promising for metastatic or recurrent cervical carcinoma. Clinical trial information: jRCTs031180007.

Abstract P2-15-04: Patient-reported outcomes in a randomized, optimal dose finding, phase II study of triweekly nab-paclitaxel in patients with metastatic breast cancer (the ABROAD study)

Abstract OBJECTIVE: Nab-paclitaxel (nab-PTX) has superior efficacy compared to conventional paclitaxel in metastatic breast cancer (MBC), but chemotherapy-induced peripheral neuropathy (CIPN) is more frequent with nab-PTX. In a single arm phase 2 trial (CA002-0LD), low dose nab-PTX (175 mg/m2) every 3 weeks (q3w) resulted in a good objective response rate (39.5%) without CIPN of grade 3 or higher. Therefore, we conducted a randomized controlled study to evaluate the optimal dose of nab-PTX by comparing a low dose (LD) and a medium dose (MD) to the standard dose (SD). Here, we evaluate the patients-reported outcomes (PROs) and health-related quality of life (HRQoL) in the ABROAD study. PATIENTS AND METHODS: Three different doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2) were administered in patients with HER2-negative metastatic breast cancer. The primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates with the three doses were estimated by logistic regression. The optimal dose was selected by 2-step selection. First, if the hazard ratio (HR) for PFS was &amp;lt;0.75 or &amp;gt;1.33, the inferior dose was dropped. Then, a dose with an estimated incidence of grade 3/4 neurotoxicity &amp;gt;10% was also dropped. PROs and HRQoL were assessed as secondary endpoints at baseline, and during the 2nd, 4th and 6th courses of protocol treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Patient Neurotoxicity Questionnaire (PNQ), Cancer Fatigue Scale (CFS) and EuroQol 5 Dimension (EQ-5D). The primary outcome for PROs and HRQoL was the FACT-Taxane trial outcome index (TOI), and inter-group comparison was performed using a mixed effect model for repeated measures (MMRM). This trial was registered with the University Hospital Medical Information Network (UMIN), Japan (protocol ID C000012429). RESULTS: A total of 141 patients were randomly assigned to SD (n=47), MD (n=46) or LD (n=48) nab-PTX. PFS analysis showed that LD nab-PTX at 180 mg/m2/3 weeks was the optimal dose with good clinical efficacy and tolerability for patients with MBC (reported by Hara at ASCO2019). Longitudinal analysis (MMRM) showed that the difference from the baseline FACT-Taxane TOI score at MD and LD were significantly better than that at SD (MD vs. SD p&amp;lt;0.001, LD vs. SD p&amp;lt;0.001). Differences from baseline for the FACT-Taxane total score, physical well-being sub-score, and emotional well-being sub-score at MD and LD were also better than at SD. The difference from baseline for the CFS score at LD was better than that at SD (p=0.013) and those for EQ-5D utility scores at MD and LD were better than that at SD (MD vs. SD p=0.011, LD vs. SD p&amp;lt;0.001). There were no significant differences for the PNQ. CONCLUSION: Our results show that low dose nab-PTX at 180 mg/m2/3 weeks could be an optimal dose for PFS and from the perspectives of PROs and HRQoL. Citation Format: Hiroaki Kato, Fumikata Hara, Masahiro Kitada, Masato Takahashi, Yuichiro Kikawa Yuichiro Kikawa, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Junji Tsurutani, Naruto Taira, Tsutomu Takashima, Kosuke Kashiwabara, Tomohiko Aihara Tomohiko Aihara, Hirofumi Mukai. Patient-reported outcomes in a randomized, optimal dose finding, phase II study of triweekly nab-paclitaxel in patients with metastatic breast cancer (the ABROAD study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-04.

Abstract P2-15-11: A phase II trial of genexol-PM and doxorubicin in patients with advanced Her-2 negative breast cancer

Abstract Background: Genexol PM is a lyophilized polymeric micellar formulation of paclitaxel that delivers a higher paclitaxel dose with lower vehicle-related toxicities than conventional paclitaxel formulations. This study was designed to evaluate the efficacy and safety of genexol- PM and doxorubicin combination in advanced Her-2 negative Breast cancer as first line treatment. Methods: Patients with advanced Her-2 negative Breast cancer received Genexol-PM at 260mg/m2 on day 1 and doxorubicin 50mg/m2 on day 1 of 3-week interval cycle. Six to nine cycles of combination chemotherapy were planned unless there was disease progression. The primary endpoint was objective response rate. Results: Thirty patients received this combination chemotherapy with a median 6cycles per patient (range 1-9). The objective response rate was 67% with disease control rate 87%, Median duration of response was 5.5months (95%CI 3.0-8.1months). Median progression free survival was 7.4 months (95%CI 5.3-9.6months) and overall survival 38.7months (95%CI 21.4-55.9months). The common toxicities were alopecia(93%), peripheral neuropathy(60%), nausea(57%), neutropenia(47%). The most common G3/4 toxicities were neutropenia(43%) and neutropenic fever(27%). There was no treatment related mortality. Conclusion: Genexol-PM, CrEL-free paclitaxel, in combination with doxorubicin demonstrated favorable antitumor activity in advanced Her-2 negative breast cancer. The most common G3/4 toxicities was neutropenia but it was manageable. Citation Format: Eun Kyung Cho, Hyo Yeon Yun, Yun Yeong Kim, Yong Soon Jeon, Heungkyu Park. A phase II trial of genexol-PM and doxorubicin in patients with advanced Her-2 negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-11.

Micellar paclitaxel in the treatment of patients with tumors of the female reproductive system

Background. Treatment of patients with advanced cancers of the female reproductive system is very challenging. The most common treatment scheme for such patients includes paclitaxel 135—175 mg/m 2 + carboplatin AUC 5—6 or cisplatin 75 mg/m 2 . However, lengthy treatment with this regimen is limited by adverse events, such as neuropathy, allergic reactions, nephropathy, etc. The new micellar form of paclitaxel has demonstrated better tolerability compared to conventional paclitaxel and, considering the increased safe effective dose (up to 250 mg/m 2 ) it should ensure higher efficacy and better progression-free survival. The use of cremophor EL free paclitaxel is recommended in patients with concomitant extragenital diseases (including diabetes and neurological deficit), in elderly patients, and in patients with allergic reactions, as well as in cases when additional steroids should be avoided. Objective : to summarize the experience of using the new form of paclitaxel in patients with tumors of the female reproductive system and concomitant diseases. Materials and methods . We analyzed both world and our own experience in using micellar paclitaxel at a dose of200—250 mg/m 2 administered as a 1-hour intravenous infusion every 21 days for 3—6 treatment cycles in patients with solid tumors of the female reproductive system. Results. The polymeric micellar composition of cremophor EL free paclitaxel can be used in higher therapeutic doses with a lower risk of hypersensitivity and peripheral neurotoxicity. Fatigue and neuropathy were the most common dose-dependent adverse events of this drug. Nonew adverse reactions unknown for paclitaxel have been registered. Conclusions. The possibility of administration of micellar paclitaxel without premedication with steroids or at a minimum dose* makes it a promising candidate for further studies in combination with new targeted drugs and immunotherapy.

Dose-dense paclitaxel and carboplatin vs. conventional paclitaxel and carboplatin as neoadjuvant chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: a retrospective study.

The purpose of this study was to determine the optimal regimen of neoadjuvant chemotherapy (NAC) for advanced epithelial ovarian, fallopian tube, and peritoneal cancers. A clinical information survey involving 171 patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer was conducted. These patients underwent NAC followed by interval debulking surgery at the Hyogo Cancer Center (Hyogo, Japan) between January 2006 and December 2015. The median observation period was 41 (range 4-138) months. Dose-dense paclitaxel and carboplatin (TC) was administered in 101 patients (59%); tri-weekly TC was administered 70 patients (41%). Median progression-free survival was 21 [95% confidence interval (CI) 18-23] months and 15 (95% CI 13-17) months in the dose-dense TC and conventional-TC group [hazard ratio (HR) = 0.69, 95% CI 0.46-0.96; p = 0.02], respectively. The median overall survival was 59 (95% CI 46-72) and 40 (95% CI 32-57) months in the dose-dense TC group and conventional-TC group (HR = 0.72, 95% CI 0.48-1.06; p = 0.09). Multivariate analysis for progression-free survival demonstrated that dose-dense TC represented an independent prognostic factor (HR = 0.70, 95% CI 0.50-0.99; p = 0.04). Dose-dense TC is a promising regimen of NAC for advanced epithelial ovarian cancer.

KRAS pathway expression changes in pancreatic cancer models by conventional and experimental taxanes.

The KRAS signalling pathway is pivotal for pancreatic ductal adenocarcinoma (PDAC) development. After the failure of most conventional cytotoxic and targeted therapeutics tested so far, the combination of taxane nab-paclitaxel (Abraxane) with gemcitabine recently demonstrated promising improvements in the survival of PDAC patients. This study aimed to explore interactions of conventional paclitaxel and experimental taxane SB-T-1216 with the KRAS signalling pathway expression in in vivo and in vitro PDAC models in order to decipher potential predictive biomarkers or targets for future individualised therapy. Mouse PDAC PaCa-44 xenograft model was used for evaluation of changes in transcript and protein levels of the KRAS signalling pathway caused by administration of experimental taxane SB-T-1216 in vivo. Subsequently, KRAS wild-type (BxPc-3) and mutated (MiaPaCa-2 and PaCa-44) cell line models were treated with paclitaxel to verify dysregulation of the KRAS signalling pathway gene expression profile in vitro and investigate the role of KRAS mutation status. By comparing the gene expression profiles, this study observed for the first time that in vitro cell models differ in the basal transcriptional profile of the KRAS signalling pathway, but there were no differences between KRAS mutated and wild-type cells in sensitivity to taxanes. Generally, the taxane administration caused a downregulation of the KRAS signalling pathway both in vitro and in vivo, but this effect was not dependent on the KRAS mutation status. In conclusion, putative biomarkers for prediction of taxane activity or targets for stimulation of taxane anticancer effects were not discovered by the KRAS signalling pathway profiling in various PDAC models.