Administration Of Taxanes Research Articles

A pharmacogenetic analysis of peripheral sensory neuropathy related to administration of taxanes in breast cancer patients.

e13133 Background: Commonly used in the treatment of breast cancer, the taxane class includes paclitaxel and docetaxel. Both medications are primarily metabolized by cytochrome P450 enzymes and transporters mediate drug membrane influx and efflux. Variability in metabolizing enzymes and drug transporter function can affect drug clearance. This study sought to determine if the presence of pharmacogenetic changes in metabolizing enzymes and transporters resulted in a patient experiencing peripheral sensory neuropathy. Methods: In this case-control study, patients were enrolled between April 13, 2018 and April 30, 2018. Electronic medical records of patients with current appointments at Cone Health Cancer Center- Wesley Long were reviewed to identify patients who completed treatment with taxanes for breast cancer after January 1, 2017 for evaluation for inclusion in the study. Buccal swabs for pharmacogenetics testing were collected. Genes of interest, ABCB1, CYP3A4, CYP3A5, and SLCO1B1, were evaluated and data was categorized by phenotype. Baseline characteristics and phenotype results were compared using Fisher's exact test for categorical variables and Wilcoxon Rank Sum for numeric variables as appropriate. Results: Thirty-three patients were included in the final analysis. The population was mainly white at 72% and all patients in the study were female. The average patient age was 57 years old. Most patients had stage 1 breast cancer. Most patients received docetaxel. Among patients with peripheral sensory neuropathy, nine were grade 1, five were grade 2, and seven were grade 3. Resulting phenotypes: CYP3A5, all patients were normal metabolizers. CYP3A5, 7 normal metabolizer, 4 intermediate, and 22 poor. SLCO1B1, 25 normal function, 8 intermediate, and no low. ABCB1, 13 normal function, 7 intermediate, and 13 low. For all genes, there was no statistically significant difference in phenotype between the neuropathy and no neuropathy study arms, CYP3A5 (p = 0.075) SLCO1B1 (p = 0.106), ABCB1 (p = 0.902). Conclusions: The findings of our study indicate that having pharmacogenetics changes in the genes, ABCB1, CYP3A4, CYP3A5, and SLCO1B1 did not influence the patients experience with peripheral sensory neuropathy.

Evaluation of Therapeutic Efficacy and Health Related Quality of Life of Anthracyclines Regimen and Taxanes with Anthracyclines Regimen in Node Positive Breast Cancer

Background: Chemotherapy with anthracyclines/taxanes is considered as an effective treatment option for breast cancer. Adjuvant chemotherapeutic options with anthracyclines or taxanes have improved disease free survival and overall survival rates in early breast cancer. The study is aimed to compare the therapeutic efficacy of anthracyclines containing regimen and sequential administration of taxanes with anthracyclines regimen for NODE positive breast cancer patients and to assess the Health-Related Quality of Life (HRQOL) of treated patients. Methods: This prospective open label study involved 14 patients who were treated with 6 cycles of 5-Fluorouracil (500mg/m2 ), Doxorubicin (50mg/m2 ), Cyclophosphamide (500mg/m2 ) [FAC] and 10 patients with 6 cycles of FAC plus 4 cycles of Paclitaxel (225mg/m2 ) [PAC]. Paired sample T test was used to assess the disease-free survival and reoccurrence rate. Time to progression was assessed by Kaplan Meir analysis and independent sample T test was used for assessing all the HRQOL parameters. Results: The disease-free survival was evaluated between the baseline and after 2 months of the chemotherapy which showed significant difference (p Key words: Anthracyclines, Adjuvant therapy, Breast cancer, Disease free survival, HRQOL, Taxanes.

Sequencing of anthracyclines and taxanes in neoadjuvant and adjuvant therapy for early breast cancer.

Anthracyclines and taxanes are chemotherapeutic agents widely used in a sequential regimen in the adjuvant and neoadjuvant treatment of early breast cancer to reduce the risk of cancer recurrence. Standard practice is to administer anthracycline-based chemotherapy followed by a taxane. Anthracyclines tend to be administered first as they were established before taxanes for treatment of early breast cancer. To assess whether the sequence in which anthracyclines and taxanes are administered affects outcomes for people with early breast cancer receiving adjuvant or neoadjuvant therapy. We searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 1 February 2018. Randomised controlled trials comparing administering a taxane prior to an anthracycline with taxane following anthracycline to people with early breast cancer receiving chemotherapy. The studies needed to have reported on at least one of our outcomes of interest, which included overall survival, disease-free survival, pathological response, treatment adherence, toxicity and quality of life. Two review authors independently extracted data, assessed risk of bias and quality of the evidence. The primary outcome measure was overall survival. Secondary outcomes included disease-free survival, pathological response (in the neoadjuvant setting only), adverse events, treatment adherence and quality of life. For time-to-event outcomes of overall survival and disease-free survival, we derived hazard ratios (HRs) with 95% confidence intervals (CI) where possible. For dichotomous outcomes of pathological complete response, treatment adherence and adverse events, we reported the treatment effect as a risk ratio (RR) with 95% CI where possible. We used GRADE to assess the certainty of the evidence separately for the neoadjuvant and adjuvant settings. There were 1415 participants in five neoadjuvant studies and 280 participants in four adjuvant studies involving five treatment comparisons. Four of the five neoadjuvant studies collected data for the primary outcome (overall survival) and two studies had data available; one of the four adjuvant studies collected overall survival data.The neoadjuvant studies suggested that the administration of taxanes first probably resulted in little to no difference in overall survival (HR 0.80, 95% CI 0.60 to 1.08; 947 participants; 2 studies; moderate-certainty evidence) and disease-free survival (HR 0.84, 95% CI 0.65 to 1.09; 828 participants; 1 study; moderate-certainty evidence). Administration of taxanes first also resulted in little to no difference in pathological complete response (absence of cancer in the breast and axilla: RR 1.15, 95% CI 0.96 to 1.38; 1280 participants; 4 studies; high-certainty evidence). However, there appeared to be a trend in favour of taxanes first. Studies reported treatment adherence using a range of measures. Administration of taxanes first probably did not increase the likelihood of requiring dose reductions compared to administration of anthracyclines first (RR 0.81, 95% CI 0.59 to 1.11; 280 participants; 1 study; moderate-certainty evidence). There was probably little to no difference in the risk of grade 3/4 neutropenia (RR 1.25, 95% CI 0.86 to 1.82; 280 participants, 1 study; moderate-certainty evidence) or grade 3/4 neurotoxicity (RR 0.95, 95% CI 0.55 to 1.65; 1108 participants; 2 studies; low-certainty evidence) when taxanes were given first. There were no data on quality of life.Only one adjuvant study collected data on overall survival and disease-free survival but did not report data. Administration of taxanes first reduced the risk of grade 3/4 neutropenia (RR 0.62, 95% CI 0.40 to 0.97; 279 participants; 4 studies, 5 treatment comparisons; high-certainty evidence) and appeared to result in little to no difference in grade 3/4 neurotoxicity (RR 0.78, 95% CI 0.25 to 2.46; 162 participants; 3 studies; low-certainty evidence). There was probably little to no difference in the proportions experiencing dose delays when taxanes are given first compared to anthracyclines given first (RR 0.76, 95% CI 0.52 to 1.12; 238 participants; 3 studies, 4 treatment comparisons; moderate-certainty evidence). One study reported on quality of life and indicated that scores (using the Functional Assessment of Cancer Therapy - Breast Cancer (FACT-B) validated questionnaire) were similar in both groups though did not provide numerical data. In the neoadjuvant setting, there is high- to low-certainty evidence of equivalent outcomes for the sequence in which taxanes are delivered. In the adjuvant setting, none of the studies reported on overall survival or disease-free survival. In most institutions, standard practice would be to deliver anthracycline followed by taxane, and currently available data do not support a change in this practice. We wait for the full-text publication of a relevant neoadjuvant study for women with HER2-negative breast cancer for inclusion in an update of this review.

Role of clustered HER2/neu amplification as a marker for a special sensitivity to neoadjuvant anti-HER2 therapy with trastuzumab in patients with stage II-III breast cancer

To evaluate the influence of clinical and morphological factors and HER2 copy numbers on pathologic complete response (pCR) rates in patients with HER2-positive stage II-III breast cancer (BC). Treatment results were studied in 73 patients with HER2-positive Stage II-III BC, who received treatment at the N.N. Blokhin National Medical Research Center of Oncology in 2015 to 2018. Treatment included neoadjuvant chemotherapy (NACT) with HER2-blockade and radical surgery followed by the evaluation of a pathologic response in the primary tumor and regional lymph nodes. The patients` age varied from 29 to 71; its median was 51.5; 45.2% of patients had primary operable stages (T1-3N0-1) and 54.8% had locally advanced tumors. All the patients had grade 2-3 anaplasia; luminal HER2-positive BC was diagnosed in 41.4% of patients; hormone-negative tumors were seen in 58.9%; 91.5% of patients had Ki-67 ≥20% in 75.3% of patients, preoperative systemic therapy included anthracycline-containing regimens (4AC + 4 x paclitaxel 175 mg/m2/12 × weekly administrations of paclitaxel 80 mg/m2; trastuzumab therapy was simultaneously performed with the administration of taxanes in the standard regimen) and anthracycline-free regimen TCH ± Pertuzumab regimen in 24.7% of cases. After NACT patients underwent surgery (radical mastectomy in 78.1%, breast-sparing treatment in 21.9%) with the assessment of morphological findings. Biopsy specimens obtained before the treatment was restudied; HER2 amplification was detected using a Dako HER2 IQFISH pharmDx kit according to its instruction and the 2018 ASCO/CAP guidelines. In 87.1% of cases, the HER2-positive status corresponded to the first category of the 2018 ASCO/CAP criteria for HER2-positive BC; clustered HER2 amplification was found in 30.1% of cases. The authors analyzed the frequency of bpCR and tpCR attainment by various clinical and morphological factors, as well as the impact of a HER2 amplification level on pCR rates. A breast pCR (bpCR) was achieved in 57.4% patients; bpCR and lymph node CR (lnCR) were noted in 48.9% patients. The rates of bpCR significantly depended on female age, chemotherapy regimen, addition of Pertuzumab, and HER2 copy number. That of bpCR in women less than 35 years of age, in those aged 36-50 years, and in those aged older than 50 years was 22.2, 57.7 and 71.9%, respectively (p=0.026). The maximum bpCR rate observed with the TCH±P regimen was 80.0%, that with anthracycline-containing regimes was 52.8% (p=0.045), and the addition of Pertuzumab increased complete response rates up to 88.9% (that with Trastuzumab was 54.2% (p=0.049). The relationship of bpCR rates to the detection of cluster amplification turned out to be highly significant (81% in its detection and 48.9% in its absence (p=0.013). In addition, clustered HER2 amplification was the only significant predictive factor for complete regression in the primary tumor and lymph nodes: in its presence, the tpCR rate reached 68.8% versus 38.7%. Clustered amplification of the HER2 gene is the most significant factor of sensitivity to anti-HER2 therapy for Stage II-III BC, and is associated with the maximum rate of both bpCR and total pCR. Further study of this factor may assist in optimizing the treatment algorithm for HER2 + BC.

SUCCESSFUL DESENSITIZATION TO PACLITAXEL: A CASE REPORT

Introduction Antineoplastics are the third leading cause of death due to drug-induced anaphylaxis. Taxanes are an integral part of the chemotherapeutic regimen used in gynecological malignancies. Drug desensitization is a therapeutic technique that induces a temporary state of tolerance to a drug responsible for a hypersensitivity reaction. Case Description A 48 year old female diagnosed with stage IV mixed epithelial ovarian cancer and arterial hypertension. Chemotherapy with carboplatin + paclitaxel is indicated, during the first cycle. She presents within the first 5 minutes of application of paclitaxel: lipotimia and wheals, without hypotension, hypoxemia, or wheezing. Skin tests are performed, resulting positive to paclitaxel at dilution 1:1000, a protocol of desensitization was performed based on 6 bags of sodium chloride, and paclitaxel in different concentrations. The desensitization doses were administered within six hours of preparation, and there was no reaction to the administration of the medication. Discussion Hypersensitivity reactions are common with the administration of taxanes. A desensitization protocol was performed, considering it successful since the patient was able to continue her treatment without adverse reactions. Antineoplastics are the third leading cause of death due to drug-induced anaphylaxis. Taxanes are an integral part of the chemotherapeutic regimen used in gynecological malignancies. Drug desensitization is a therapeutic technique that induces a temporary state of tolerance to a drug responsible for a hypersensitivity reaction. A 48 year old female diagnosed with stage IV mixed epithelial ovarian cancer and arterial hypertension. Chemotherapy with carboplatin + paclitaxel is indicated, during the first cycle. She presents within the first 5 minutes of application of paclitaxel: lipotimia and wheals, without hypotension, hypoxemia, or wheezing. Skin tests are performed, resulting positive to paclitaxel at dilution 1:1000, a protocol of desensitization was performed based on 6 bags of sodium chloride, and paclitaxel in different concentrations. The desensitization doses were administered within six hours of preparation, and there was no reaction to the administration of the medication. Hypersensitivity reactions are common with the administration of taxanes. A desensitization protocol was performed, considering it successful since the patient was able to continue her treatment without adverse reactions.

Oral Administration of Prunella vulgaris L Improves the Effect of Taxane on Preventing the Progression of Breast Cancer and Reduces Its Side Effects.

We aimed to explore the efficacy and safety of Prunella vulgaris L (PVL) combined with taxane for treatment of patients with breast cancer (BC). The main ingredients of PVL were analyzed by high-performance liquid chromatography (HPLC). In the experiment, 424 patients with BC were evenly assigned into two groups: experimental group (EG, oral administration of PVL and taxane) and control group (CG, oral administration of placebo and taxane). The primary endpoint was pathologic complete response (pCR), which was evaluated using Miller and Payne system. The secondary endpoints included adverse events (AE) and overall survival (OS), which were evaluated by Common Terminology Criteria for Adverse Event version and Kaplan–Meier curves, respectively. Response Evaluation Criteria in Solid Tumors was used to evaluate the clinical efficacy of PVL. Estrogen receptor (ER) status was also measured. The main side effects were compared between the two groups. The main ingredients of PVL were caffeic acid and rosmarinic acid, which both exert anti-tumor properties. The average follow-up time was 41 months. Eighteen and 31 patients dropped out from EG and CG, respectively. Overall, pCRs were detected in 94 cases (25.1%), comprising 61 cases (31.4%) from EG and 33 cases (18.2%) from CG (P < 0.05). PVL treatment improved the pCR rate and OS time compared with those in CG (P < 0.05). The 3-year OS rates were 86.5 and 77.2% in patients from EG and CG, respectively (P < 0.05). Moreover, ER status was associated with pCR rate and could be an independent prognostic factor in BC. Moreover, treatment with PVL prevented side effects, namely, neutrophil-reduced fever and anemia caused by chemotherapy. Hence, chemotherapy using PVL and taxane could be a safe and effective treatment for patients with BC. PVL may be a potential adjuvant medicine for BC treatment.

Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer

ImportanceA blood test to determine whether to treat patients with metastatic castration-resistant prostate cancer (mCRPC) with an androgen receptor signaling (ARS) inhibitor or taxane is an unmet medical need.ObjectiveTo determine whether a validated assay for the nuclear-localized androgen receptor splice variant 7 (AR-V7) protein in circulating tumor cells can determine differential overall survival among patients with mCRPC treated with taxanes vs ARS inhibitors.Design, Setting, and ParticipantsThis blinded correlative study conducted from December 31, 2012, to September 1, 2016, included 142 patients with histologically confirmed mCRPC and who were treated at Memorial Sloan Kettering Cancer Center, The Royal Marsden, or the London Health Sciences Centre. Blood samples were obtained prior to administration of ARS inhibitors or taxanes as a second-line or greater systemic therapy for progressing mCRPC.Main Outcomes and MeasuresOverall survival after treatment with an ARS inhibitor or taxane in relation to pretherapy AR-V7 status.ResultsAmong the 142 patients in the study (mean [SD] age, 69.5 [9.6] years), 70 were designated as high risk by conventional prognostic factors. In this high-risk group, patients positive for AR-V7 who were treated with taxanes had superior overall survival relative to those treated with ARS inhibitors (median overall survival, 14.3 vs 7.3 months; hazard ratio, 0.62; 95% CI, 0.28-1.39; P = .25). Patients negative for AR-V7 who were treated with ARS inhibitors had superior overall survival relative to those treated with taxanes (median overall survival, 19.8 vs 12.8 months; hazard ratio, 1.67; 95% CI, 1.00-2.81; P = .05).Conclusions and RelevanceThis study suggests that nuclear-localized AR-V7 protein in circulating tumor cells can identify patients who may live longer with taxane chemotherapy vs ARS inhibitor treatment.

Could the Combined Administration of Bone Antiresorptive Drug, Taxanes, and Corticosteroids Worsen Medication Related Osteonecrosis of the Jaws in Cancer Patients?

The study presents a report of 58 metastatic cancer patients who developed osteonecrosis of the jaws after being treated with zoledronic acid and taxanes, plus corticosteroids. A retrospective analysis of data registered in the archives of two Italian osteonecrosis of the jaws treatment centers, who are based at the University of Messina and at the University of Palermo, was performed in order to study, in these patients, demographic data and characteristics such as frequency of cancer location, lines of therapy, frequency of cancer drugs, presence/absence of oral trigger, number, location, and stage of jaw osteonecrosis. It was found that the majority of patients developed advanced stages of osteonecrosis, frequently complicated with infection. It was hypothesized that the concurrent administration of chemotherapeutic agents could be eventually considered as a factor able to allow a faster worsening of the clinical manifestation through the exacerbation of soft tissue defects, due to chemotherapy drugs.

5-year overall survival after early breast cancer diagnosed during pregnancy: A retrospective case-control multicentre French study

BackgroundBreast cancer diagnosed during pregnancy (BCP) is rare, but the prevalence is expected to rise. Long-term follow-up data regarding this clinically challenging condition are scarce. The main objective of this multicentre case-control French study was to compare the survival between pregnant patients and matched controls. MethodsPatients from 27 centres diagnosed between 2000 and 2009 with histologically proven invasive breast cancer occurring during pregnancy were retrospectively included. Controls were matched to BCP patients on age, clinical T stage, hormone receptor, HER2, administration of neo-adjuvant chemotherapy and pathological node involvement in the absence of neo-adjuvant chemotherapy. Five-year overall survival (OS), disease-free survival (DFS) and metastasis-free survival (MFS) rates were estimated using the Kaplan–Meier method. ResultsOne hundred and eleven BCP patients and 253 controls were included. Median age was 33 and 35 years, respectively. Both populations were managed similarly, except for less frequent sentinel node dissection (p = 0.026) and taxane administration (p = 0.03) among BCP patients. Median follow-up was 7.5 years. Survival rates were similar between both BCP and control patients: 5-year OS rates were 83.1% (95% CI: 74.5–89.0) vs 85.5% (95% CI: 80.4–89.4), respectively, p = 0.31; 5-year DFS rates 60.0% (95% CI: 50.1–68.6) vs 68.5% (95% CI: 62.3–73.9), respectively, p = 0.12 and 5-year MFS rates 71.0% (95% CI: 61.3–78.6) and 74.5% (95% CI: 68.6–79.5), respectively, p = 0.21. ConclusionOur study showed that the survival outcomes of patients diagnosed with BCP were not significantly different as compared to those of matched non-pregnant controls. A proper management of women diagnosed with BCP is crucial.

Incidence of infusion hypersensitivity reaction after withholding dexamethasone premedication in early breast cancer patients not experiencing two previous cycles of infusion hypersensitivity reaction for weekly paclitaxel chemotherapy.

Premedication with dexamethasone is an essential part of the prevention of hypersensitivity reaction (HSR) associated with taxane administration. However, the possibility of stopping dexamethasone premedication has been investigated in previous studies to reduce the steroid's adverse events; however, either the result or the particular protocol was limited. Thus, our study aimed to evaluate the incidence of HSR after dexamethasone premedication discontinuation after lack of HSR in two previous weekly paclitaxel infusions. Early breast cancer patients who received adjuvant weekly paclitaxel in a retrospective cohort from January 2012 through February 2016 at the King Chulalongkorn Memorial Hospital were reviewed. All patients received a standard premedication protocol prior to the first and second paclitaxel infusion. Dexamethasone was omitted in later cycles in all patients who did not undergo infusion HSR. Patients who developed HSR during the first or second cycles of paclitaxel infusion were excluded. The incidence of HSR during the later cycle of paclitaxel administration and factors associated with this adverse reaction were collected. Eighty-one of 85 patients who did not undergo infusion HSR after 2cycles of weekly paclitaxel administration were retrospectively reviewed. The median age was 51years (range 27-74years). Only 16% of the patients had a BMI greater than 30kg/m2, 57.8% were premenopausal, 67.9% had no comorbidity, none had a history of allergy or asthma, 65.4% received weekly paclitaxel as a single agent, and 34.6% received weekly paclitaxel in combination with trastuzumab. Five of 81 patients reported grade I-II HSR (6.25%), which occurred mostly during the first 6cycles (60%). Temporary discontinuation of paclitaxel infusion was observed in all HSR patients. No differences regarding age, BMI, menopausal status, and underlying disease between the HSR and no HSR groups were identified. Concerning the safety profile, peripheral neuropathy (gr I 60%, gr II 13.5%, and gr III 2.4%), myalgia (43.4%), and edema (10.5%) were commonly reported, whereas dyspepsia (5.3%) and insomnia (14.5%) were rarely described in withholding patients. Withholding dexamethasone premedication in non-experiencing HSR patients after two previous cycles of weekly paclitaxel administration was safe and did not impact the higher incidence of HSR. A discontinuing dexamethasone protocol should be recommended generally in these patients, especially those with a high risk for steroid-induced side effects.

Assessment of Antihistamines and Corticosteroids as Premedication in Rapid Drug Desensitization to Paclitaxel: Outcomes in 155 Procedures

In early clinical trials, infusion reactions during the administration of taxanes were managed using systematic premedication with antihistamines and corticosteroids before standard infusions. Consequently, these premedications are also administered before rapid drug desensitization (RDD) with taxanes. However, their role in RDD has not been studied. To assess the need for premedication with antihistamines and corticosteroids to prevent hypersensitivity reactions in RDD to paclitaxel. Over a 4-year period, we selected patients with confirmed hypersensitivity to paclitaxel (positive skin testing and/or drug provocation testing results) who had received paclitaxel through RDD. These patients were assigned to 2 prospective noninception cohorts: one cohort premedicated with antihistamine and corticosteroids and another cohort that was not. We assessed 66 paclitaxel-reactive patients, of whom 22 met the inclusion criteria. A total of 155 RDDs to paclitaxel were performed. There were no significant differences in tolerance to RDD between the cohorts. Administering systematic premedication with corticosteroids and antihistamines had no significant effect on the effectiveness or safety of RDD in patients with confirmed hypersensitivity to paclitaxel in the study population. Moreover, these premedications can mask early signs of hypersensitivity and delay treatment. We believe that systematic premedication with these drugs for patients undergoing RDD should be carefully and individually assessed if their only purpose is to prevent breakthrough reactions during RDD.

Sequencing of anthracyclines and taxanes in neoadjuvant and adjuvant therapy for early breast cancer

Background Anthracyclines and taxanes are chemotherapeutic agents widely used in a sequential regimen in the adjuvant and neoadjuvant treatment of early breast cancer to reduce the risk of cancer recurrence. Standard practice is to administer anthracycline-based chemotherapy followed by a taxane. Anthracyclines tend to be administered first as they were established before taxanes for treatment of early breast cancer. Objectives To assess whether the sequence in which anthracyclines and taxanes are administered affects outcomes for people with early breast cancer receiving adjuvant or neoadjuvant therapy. Search methods We searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 1 February 2018. Selection criteria Randomised controlled trials comparing administering a taxane prior to an anthracycline with taxane following anthracycline to people with early breast cancer receiving chemotherapy. The studies needed to have reported on at least one of our outcomes of interest, which included overall survival, disease-free survival, pathological response, treatment adherence, toxicity and quality of life. Data collection and analysis Two review authors independently extracted data, assessed risk of bias and quality of the evidence. The primary outcome measure was overall survival. Secondary outcomes included disease-free survival, pathological response (in the neoadjuvant setting only), adverse events, treatment adherence and quality of life. For time-to-event outcomes of overall survival and disease-free survival, we derived hazard ratios (HRs) with 95% confidence intervals (CI) where possible. For dichotomous outcomes of pathological complete response, treatment adherence and adverse events, we reported the treatment effect as a risk ratio (RR) with 95% CI where possible. We used GRADE to assess the certainty of the evidence separately for the neoadjuvant and adjuvant settings. Main results There were 1415 participants in five neoadjuvant studies and 280 participants in four adjuvant studies involving five treatment comparisons. Four of the five neoadjuvant studies collected data for the primary outcome (overall survival) and two studies had data available; one of the four adjuvant studies collected overall survival data.The neoadjuvant studies suggested that the administration of taxanes first probably resulted in little to no difference in overall survival (HR 0.80, 95% CI 0.60 to 1.08; 947 participants; 2 studies; moderate-certainty evidence) and disease-free survival (HR 0.84, 95% CI 0.65 to 1.09; 828 participants; 1 study; moderate-certainty evidence). Administration of taxanes first also resulted in little to no difference in pathological complete response (absence of cancer in the breast and axilla: RR 1.15, 95% CI 0.96 to 1.38; 1280 participants; 4 studies; high-certainty evidence). However, there appeared to be a trend in favour of taxanes first. Studies reported treatment adherence using a range of measures. Administration of taxanes first probably did not increase the likelihood of requiring dose reductions compared to administration of anthracyclines first (RR 0.81, 95% CI 0.59 to 1.11; 280 participants; 1 study; moderate-certainty evidence). There was probably little to no difference in the risk of grade 3/4 neutropenia (RR 1.25, 95% CI 0.86 to 1.82; 280 participants, 1 study; moderate-certainty evidence) or grade 3/4 neurotoxicity (RR 0.95, 95% CI 0.55 to 1.65; 1108 participants; 2 studies; low-certainty evidence) when taxanes were given first. There were no data on quality of life.Only one adjuvant study collected data on overall survival and disease-free survival but did not report data. Administration of taxanes first reduced the risk of grade 3/4 neutropenia (RR 0.62, 95% CI 0.40 to 0.97; 279 participants; 4 studies, 5 treatment comparisons; high-certainty evidence) and appeared to result in little to no difference in grade 3/4 neurotoxicity (RR 0.78, 95% CI 0.25 to 2.46; 162 participants; 3 studies; low-certainty evidence). There was probably little to no difference in the proportions experiencing dose delays when taxanes are given first compared to anthracyclines given first (RR 0.76, 95% CI 0.52 to 1.12; 238 participants; 3 studies, 4 treatment comparisons; moderate-certainty evidence). One study reported on quality of life and indicated that scores (using the Functional Assessment of Cancer Therapy - Breast Cancer (FACT-B) validated questionnaire) were similar in both groups though did not provide numerical data. Authors' conclusions In the neoadjuvant setting, there is high- to low-certainty evidence of equivalent outcomes for the sequence in which taxanes are delivered. In the adjuvant setting, none of the studies reported on overall survival or disease-free survival. In most institutions, standard practice would be to deliver anthracycline followed by taxane, and currently available data do not support a change in this practice. We wait for the full-text publication of a relevant neoadjuvant study for women with HER2-negative breast cancer for inclusion in an update of this review.

Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes.

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10-26, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.

Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group

Background:Sequential anthracyclines and taxanes are standard adjuvant chemotherapy for patients with high-risk axillary node-positive breast cancer. We compared a sequential to a concurrent regimen in high-risk node-negative early breast cancer.Methods:Patients were eligible if they had tumours >2 cm or T1c with two of the following characteristics: no oestrogen receptor (ER) and progesterone receptor (PR) expression, histological grade III, Ki67 >40% and vascular, lymphovascular or perineural invasion. They were randomised to receive four cycles of epirubicin 90 mg m−2 followed by four cycles of docetaxel 75 mg m−2 (sequential regimen) or six cycles of epirubicin 75 mg m−2 plus docetaxel 75 mg m−2 (concurrent regimen). All chemotherapy cycles were administered every 21 days with G-CSF prophylaxis only for the concurrent arm. The primary endpoint was disease-free survival (DFS).Results:Between 2001 and 2013, 658 women received the sequential (n=329) or the concurrent (n=329) regimen. The median age was 53 years, 43.9% of the patients were premenopausal and of the tumours 44.2% were ⩽2 cm, 52.7% histological grade 3 and 35.3% hormone receptor-negative. After a median follow-up of 70.5 months, there were 29 (8.8%) vs 42 (12.8%) disease relapses (P=0.102) and 11 (3.3%) vs 19 (5.8%) deaths (P=0.135), in the sequential and concurrent arm, respectively. The 5-year DFS rates were 92.6% vs 88.2% for sequential and concurrent arm, respectively (hazard ratio (HR): 1.591; 95% confidence interval (CI): 0.990–2.556; P=0.055). Toxicity included grade 2–4 neutropenia in 54% vs 41% (P=0.001), febrile neutropenia 2.7% vs 6.1% (P=0.06), nausea/vomiting 18.5% vs 12.4% (P=0.03) of patients in the sequential and concurrent arm. There were no toxic deaths.Conclusions:Sequential compared with the concurrent administration of anthracyclines and taxanes is associated with a non-significant but possibly clinically meaningful improvement in DFS. In the era of molecular selection of patients for adjuvant chemotherapy, this study offers valuable information for the optimal administration of anthracyclines and taxanes in patients with node-negative disease.

Feasibility of withholding dexamethasone premedication for hypersensitivity reactions associated with paclitaxel administration

Abstract Background Premedication with dexamethasone is crucial to prevent hypersensitivity reactions (HSR) associated with administration of taxanes. However, high dose and prolonged exposure to dexamethasone may cause adverse effects. Objectives To determine the incidence of HSR in patients with early breast cancer who did or did not receive dexamethasone prophylaxis for weekly paclitaxel infusions. Methods We retrospectively reviewed the records of a cohort of patients with early breast cancer who received paclitaxel weekly from January 2012 through March 2015 at King Chulalongkorn Memorial Hospital. All patients received a standard premedication protocol including dexamethasone before their first paclitaxel infusion. Dexamethasone was omitted in later cycles in some patients at the discretion of the attending physician. Data concerning the baseline characteristics of the patient, details of the premedication protocol, including dose and schedule of dexamethasone, and HSR events were collected in this observational study. Results Data were drawn from 86 breast cancer patients (median age 52.6 years) treated with a total of 984 cycles of paclitaxel chemotherapy. No patient had any history of allergy or HSR to taxanes. Dexamethasone was omitted in 617 later cycles. Six patients had grade II-III HSR (7.0%), which occurred mostly during the first 6 cycles (5/6, 83.3%). The incidence of HRS was 3/367 cycles (0.82%) with dexamethasone premedication (P = 0.99) and 5/617 (0.81%) without. Conclusions Withholding dexamethasone premedication for paclitaxel chemotherapy was feasible, and did not result in a higher incidence of HSR. However, an optimal schedule for dexamethasone warrants investigation in a prospective manner.

Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG)

Sequential administration of anthracycline and taxane is the current standard of care adjuvant regimen for node-positive early breast cancer. Due to long-term toxicity concerns, anthracycline-free regimens have been developed. We compared a sequential dose-dense anthracycline and taxane regimen with the anthracycline-free regimen of docetaxel and cyclophosphamide. In this randomized, non-inferiority, phase III trial, women with HER2-negative invasive breast cancer and at least one positive axillary lymph node were randomized to receive either epirubicin (75 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and cyclophosphamide (500 mg/m(2)) every 2 weeks for four cycles, followed by four cycles of docetaxel (75 mg/m(2)) every 2 weeks with prophylactic G-CSF support (FEC → D) or docetaxel (75 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every 21 days for six cycles (TC). The primary end point of the study was the 3-year disease-free survival (DFS) rate. Six hundred and fifty women were randomized to either FEC → D (n = 326) or TC (n = 324). After a median follow-up of 46 and 47 months, the 3-year DFS rate was 89.5% and 91.1% for the FEC → D and TC arm, respectively (hazard ratio = 1.147, 95% confidence interval 0.716-1.839, P = 0.568). Grade 3-4 neutropenia was higher in the TC arm (32.4% versus 10.5%, P = 0.0001). The incidence of neutropenic fever was low (<1%). Nausea, vomiting, hand-foot syndrome and fatigue (grade 3-4) were more common with FEC → D. Acute cardiotoxicity was rare (1 event in each group). There were no toxic deaths. This trial did not clearly demonstrate that TC is non-inferior to dose-dense FEC → D. However, 3-year DFS rates were excellent in both arms for women with node-positive, HER2-negative early breast cancer. NCT01985724.

Impact of Prior Use of an Androgen Receptor-Axis-Targeted (ARAT) Agent With or Without Subsequent Taxane Therapy on the Efficacy of Another ARAT Agent in Patients With Metastatic Castration-Resistant Prostate Cancer

BackgroundThe objective of this study was to investigate whether the prior use of a novel androgen receptor-axis-targeted (ARAT) agent with or without subsequent taxane therapy could affect the efficacy of another ARAT agent in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients and MethodsThis study included a total of 302 patients with mCRPC, who were treated with abiraterone acetate and/or enzalutamide. These 302 patients were classified into the following 3 groups: group A, 173 received an ARAT agent without the prior use of another ARAT agent; group B, 102 sequentially received ARAT agents without any treatment between the 2 agents; group C, 27 sequentially received ARAT agents, with taxane therapy between the 2 ARAT agents. ResultsThe response rate to the ARAT agent in group A (63.6%) was significantly higher than those to the ARAT agent introduced late-line in groups B and C (20.6% and 29.6%, respectively). In addition, prostate-specific antigen progression-free survival during the ARAT therapy in group A was significantly superior to those during the ARAT therapy conducted late-line in groups B and C. Multivariate analyses of several parameters identified the prior use of an ARAT agent, but not the administration of taxane between the ARAT therapies, as one of the independent predictors of prostate-specific antigen progression-free survival. ConclusionsCross-resistance between ARAT agents may be a common phenomenon in patients with mCRPC, irrespective of the introduction of taxane between the ARAT therapies.

Feasibility of withholding dexamethasone premedication in patients not experiencing two previous cycles of weekly paclitaxel related infusion hypersensitivity reaction.

e21634Background: Premedication with dexamethasone is an essential part in prevention of hypersensitivity reaction associated with taxane administration. However, the possibility of stopping dexame...

Chemotherapy-induced painful neuropathy: pain-like behaviours in rodent models and their response to commonly used analgesics.

Chemotherapy-induced painful neuropathy (CIPN) is a major dose-limiting side-effect of several widely used chemotherapeutics. Rodent models of CIPN have been developed using a range of dosing regimens to reproduce pain-like behaviours akin to patient-reported symptoms. This review aims to connect recent evidence-based suggestions for clinical treatment to preclinical data. We will discuss CIPN models evoked by systemic administration of taxanes (paclitaxel and docetaxel), platinum-based agents (oxaliplatin and cisplatin), and the proteasome-inhibitor - bortezomib. We present an overview of dosing regimens to produce CIPN models and their phenotype of pain-like behaviours. In addition, we will discuss how potential, clinically available treatments affect pain-like behaviours in these rodent models, relating those effects to clinical trial data wherever possible. We have focussed on antidepressants, opioids, and gabapentinoids given their broad usage. The review outlines the latest description of the most-relevant rodent models of CIPN enabling comparison between chemotherapeutics, dosing regimen, rodent strain, and sex. Preclinical data support many of the recent suggestions for clinical management of established CIPN and provides evidence for potential treatments warranting clinical investigation. Continued research using rodent CIPN models will provide much needed understanding of the causal mechanisms of CIPN, leading to new treatments for this major clinical problem.

The Sojourn from Parenteral to Oral Taxanes using Nanocarrier Systems: A Patent Review.

Natural diterpenoid taxanes and their semisynthetic analogues have already made an indelible mark in the chemotherapeutic world for treating various kinds of malignancies. However, due to the absence of any functional groups which could be ionized by pH alteration or which may participate in salt formation, these taxanes, exhibit low solubility. Parenteral administration of taxanes with solubilising agents such as Cremophor EL and Polysorbate 80 results in undesirable side effects like hypersensitivity reactions, myelosuppression and peripheral neuropathy. Nanoengineered drug delivery systems like nanoemulsions, nanocrystals, dendrimers, micelles, selfnanoemulsifying systems, liposomes, solid-lipid nanoparticles and biodegradable polymeric nanoparticles, in this regard, tend to surmount these ostensible challenges, when administered orally. The bare taxanes encounter several inadequacies, namely poor aqueous solubility, structural instability in physiological fluids, p-glycoprotein recognition, hepatic first-pass effect, gastrointestinal permeability, and Cytochrome P450 enzymatic metabolism, etc. In addition, nanoscaled oral delivery improves drug encapsulation, thus facilitating diffusion through intestinal epithelium, modification of pharmacokinetic and tissue distribution profile of the drug, eventually resulting in flexibility of dosing schedules, prevention of discomfort of the injection and hospitalization, and improved patient convenience. The current review paper endeavors to provide a bird's eye view on the significant headway made on orally-administered nanosystems of taxanes and their analogues through patent applications published till date since its discovery.