Taxane Toxicity Research Articles

Using maximum plasma concentration (Cmax) to personalize taxane treatment and reduce toxicity.

Taxanes are a widely used class of anticancer agents that play a vital role in the treatment of a variety of cancers. However, toxicity remains a major concern of using taxane drugs as some toxicities are highly prevalent, they can not only adversely affect patient prognosis but also compromise the overall treatment plan. Among all kinds of factors that associated with taxane toxicity, taxane exposure has been extensively studied, with different pharmacokinetic (PK) parameters being used as toxicity predictors. Compared to other widely used predictors such as the area under the drug plasma concentration curve versus time (AUC) and time above threshold plasma drug concentration, maximum plasma concentration (Cmax) is easier to collect and shows promise for use in clinical practice. In this article, we review the previous research on using Cmax to predict taxane treatment outcomes. While Cmax and toxicity have been extensively studied, research on the relationship between Cmax and efficacy is lacking. Most of the articles find a positive relationship between Cmax and toxicity but several articles have contradictory findings. Future clinical trials are needed to validate the relationship between Cmax and treatment outcome and determine whether Cmax can serve as a useful surrogate endpoint of taxane treatment efficacy.

Abstract 7173: Animal pharmacokinetics of an anti-Her2+ immunoliposome of docetaxel

Abstract Despite the success of docetaxel in combination with trastuzumab in HER2+ breast cancer, docetaxel still has serious limitations, including poor water solubility and the canonical systemic toxicity of taxanes. These side effects of taxanes need to be overcome to improve patient management. In this context, we have developed a nanoparticle drug delivery system. We have developed an immunoliposome loaded with docetaxel and grafted with trastuzumab using a microfluidic method by mixing an aqueous phase (KH2PO4 buffer) and an organic phase composed of phosphatidylcholine, cholesterol and PEGmal in a molar ratio of 50:31:1, to which docetaxel is added at a rate of 1.8% of the total lipid. We perform a thiolation reaction to graft the trastuzumab onto the polyethylene glycol chain. Resulting immunoliposomes were characterized by a mean diameter of 140 nm, a docetaxel encapsulation rate of 73% and a trastuzumab uptake rate of 400 units of trastuzumab by nanoparticle. C57BL/6 mice were administered with docetaxel 1.9 mg/kg and trastuzumab 160 ng/kg or a mixture of free drugs or as liposomes at the same dose by intraperitoneal injection. Blood was collected 1h, 2h, 3h, 6h, 8h and 24h after injection and plasma was analyzed by HPLC-UV with Paclitaxel as internal standard. For each treatment group, pharmacokinetic parameters and exposure metrics were calculated using PKanalix®: half-life T1/2, elimination rate constant Kel and area under the curve AUC at the end points (AUCtlast) and infinity (AUCinfinity). Statistical tests were performed with Sigmastats®. The results showed a marked change in pharmacokinetics with increased plasma exposure with liposomal docetaxel. Preliminary results show a longer half-life for liposomal docetaxel (40.76 h VS. 4.33 h, i.e., a 9.4-fold increase). The concentration of docetaxel appeared to decrease more rapidly between T1h and T6h with free docetaxel (Kel 0.16h-1) than with liposomal docetaxel (Kel 0.017h-1). The concentration of docetaxel reached a plateau over time, up to 24 hours (52.72± 9.45 ng/ml) in mice treated with immunoliposomes whereas Docetaxel was undetectable at T24h when treated with free drugs. There was a statistical difference in PK at T6h between liposomal docetaxel and free docetaxel, 69.86 ± 15.25 ng/ml and 53.67 ± 4.92 ng/ml, respectively (p < 0.001, non-paired t-test). Liposomal docetaxel showed higher AUC0-t (x3.75) and AUC0-∞ values (x5.9) compared to non-liposomal docetaxel. In conclusion, these preliminary results suggest that we have developed a promising immunoliposome for the systemic delivery of docetaxel in HER2+ breast cancer with sustained exposure. Citation Format: Mathilde Dacos, Erwan Diroff, Sarah Giacometti, Joseph Ciccolini, Raphaelle Fanciullino. Animal pharmacokinetics of an anti-Her2+ immunoliposome of docetaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7173.

Breast Cancer: Clinical-Epidemiological Profile and Toxicities of Women Receiving Treatment with Taxanes in the Amazon Region.

Breast cancer is the most common malignant disease and the leading cause of mortality among women worldwide. Antineoplastic chemotherapy is one of its primary treatments, typically based on the class of drugs known as taxanes. Despite their proven therapeutic efficacy, these drugs can induce severe toxicities, leading to dose limitations or even treatment discontinuation. The objective of this study was to describe the clinical-epidemiological profile, risk factors, and toxicities of taxane-based chemotherapy treatment in women with breast cancer in the Amazon region. This is a cross-sectional, quantitative, and descriptive study conducted with 300 women diagnosed with breast cancer undergoing taxane treatment. Most patients were in the 40-49 age range, of brown ethnicity, and had completed elementary school. The majority of patients had risk factors such as alcoholism and a sedentary lifestyles. Most women had their first pregnancy between the ages of 18 and 21, breastfed their children, had menarche between the ages of 12 and 13, and were pre-menopausal and with a family history of cancer. The most frequent histological type was non-special invasive carcinoma and the Luminal B subtype. Most participants in this study showed taxane toxicity, with neurotoxicity being the most frequent. These findings reveal the importance of early detection, comprehensive risk factors, and effective management of treatment toxicities to improve patient outcomes in breast cancer care in the Amazon region.

Identification of a SNP cluster associated with taxane-induced peripheral neuropathy risk in patients being treated for breast cancer using GWAS data derived from a large cooperative group trial.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity of taxanes for which there is no effective intervention. Genomic CIPN risk determination has yielded promising, but inconsistent results. The present study assessed the utility of a collective SNP cluster identified using novel analytics to describe taxane-associated CIPN risk. We analyzed GWAS data derived from ECOG-5103, first identifying SNPs that were most strongly associated with CIPN using Fisher's ratio (FR). We then ranked ordered those SNPs which discriminated CIPN-positive (CIPN +) from CIPN-negative phenotypes based on their discriminatory power and developed the cluster of SNPs which provided the highest predictive accuracy using leave-one-out cross-validation (LOOCV). Using aggregated genotype data obtained from the previously reported ECOG-5103 clinical trial (in which two different arrays were used, HumanOmniExpress (727,227 SNPs) and HumanOmni1-Quad1 (1,131,857 SNPs)), we identified a 267 SNP cluster which was associated with a CIPN + phenotype with an accuracy of 96.1%. A cluster of SNPs was identified which prospectively discriminated patients most likely to develop symptomatic CIPN following taxane exposure as part of a breast cancer chemotherapy regimen. Validation using an independent patient cohort should be performed.

The effects and mechanism of taxanes on chemotherapy-associated ovarian damage: A review of current evidence.

Chemotherapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to the effects of chemotherapeutic agents. Different chemotherapeutic agents with varying mechanisms of action may damage ovarian function differently. Taxanes are widely used in clinical cancer treatment, but the specific reproductive toxicological information is still controversial. This review described the impact and duration of taxanes on ovarian function in women and analyzed the possible reasons for different conclusions. Furthermore, the toxicity of taxanes on ovarian function and its possible mechanisms were discussed. The potential protective strategies and agents against ovarian damage induced by taxanes are also reviewed.

Relative Risk of Peripheral Neuropathy With Ado-Trastuzumab Emtansine (T-DM1) Compared to Taxane-Based Regimens in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Cancers: A Systematic Review and Meta-Analysis.

BackgroundPeripheral neuropathy (PN), especially peripheral sensory neuropathy (PSN), is significant toxicity of taxanes, the most used class of microtubule inhibitors for human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Ado-trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate, consisting of trastuzumab and a microtubule inhibitor DM1, which has been approved for HER2-positive breast cancer. T-DM1 has also been found to cause significant PN, including PSN.MethodsWe conducted a systematic review and meta-analysis of phase 3 randomized controlled trials using T-DM1 in the experimental arm and a taxane-based regimen in the control arm to determine the relative risk of PN and PSN associated with T-DM1 as compared to taxanes. A total of 1,857 patients were included in the analysis. The Cochran-Mantel-Haenszel method and the random-effects model were used to calculate the pooled risk ratio (RR) with a 95% confidence interval (CI) for all-grade and grade ≥3 PN and PSN. ResultsThe relative risks of all-grade PN and all-grade PSN were lower with T-DM1 compared to taxanes. The pooled RR of all-grade PN was 0.59, 95% CI: 0.39-0.89, P = 0.01, and the pooled RR of all-grade PSN was 0.58, 95% CI: 0.46-0.74, P < 0.0001.ConclusionsOur meta-analysis demonstrated that T-DM1 is associated with a relatively lower risk of all-grade PN and PSN than the taxane-based regimens for HER2-positive cancers. It could be an area of consideration in selecting therapy for HER2-positive breast cancer patients at high risk of developing or having pre-existing PN and PSN.

2-methoxyestradiol sensitizes breast cancer cells to taxanes by targeting centrosomes.

Centrosomes amplification is a hallmark of cancer. We hypothesize that 2-methoxyestradiol (2-ME) sensitizes breast cancer (BC) cells to taxanes by targeting amplified centrosomes. We assessed the extent by which 2-ME together with paclitaxel (PTX) induces centrosome alterations with subsequent mitotic catastrophe in different BC subtypes. 2-ME induced a significant reduction in PTX IC50 values in all cells tested ranging from 28–44% (P < 0.05). Treatment with both PTX and 2-ME significantly increased the number of misaligned metaphases compared to PTX alone (34%, 100% and 52% for MCF7, MDA-MB231 and SUM149, respectively; P < 0.05). The number of cells with multipolar spindle formation was significantly increased (81%, 220% and 285% for MCF7, MDA-MB231 and SUM 149, respectively; P < 0.05). PTX and 2-ME treatment significantly increased interphase declustering in cancer cells (56% for MCF7, 208% for MDA-MB231 and 218% for SUM149, respectively; P < 0.05) and metaphase declustering (1.4-fold, 1.56-fold and 2.48-fold increase for MCF7, MDA-MB231 and SUM149, respectively; P < 0.05). This report is the first to document centrosome declustering as a mechanism of action of 2-ME and provides a potential approach for reducing taxane toxicity in cancer treated patients.

A pilot study of oncology massage to treat chemotherapy-induced peripheral neuropathy (CIPN).

111 Background: Short- and long-term toxicity of platinum compounds and taxanes includes development of CIPN. With an increased interest regarding the role of complementary approaches for symptom control, we investigated massage therapy for symptomatic relief of chronic CIPN. Methods: This pilot study evaluated the optimum treatment schedule and initial efficacy of a standardized Swedish massage technique to treat lower extremity (LE) CIPN. Inclusion criteria: LE neuropathy attributed to oxaliplatin, paclitaxel, or docetaxel, no other history of attributable causes; self-reported neuropathy score ≥3, 0-10 scale; ≥ 6 months since last chemotherapy treatment; age ≥ 18. Patients (pts) were randomized to one of four groups: 1) LE massage 3 times (3X) week for 4 weeks; LE massage 2X week for 6 weeks; 3) head/neck/shoulder (control) massage 3X week for 4 weeks; or 4) control massage 2X week for 6 weeks. Massage completion rate was examined and symptoms of CIPN measured with the Pain Quality Assessment Scale [PQAS (Range: 0-10); subscales of SP (surface pain), DP (deep pain), and PP (paroxysmal pain)] at baseline and at 10 weeks. Results: 71 pts fulfilled inclusion criteria: 77.5% women; 57.7% (breast cancer), and 42.3% (GI cancer); mean age 60.3 y/o (range: 40-77). Average length of time since the end of chemotherapy was &gt; 3 yrs. Mean massage completion rates (max = 12) were 8.9 (SD 4.2) for 3X week and 9.8 (4.0) for 2X week with no statistical differences. There were no statistically significant differences in PQAS scores at follow-up between site-specific massage groups (lower extremity vs controls). Pts who had massage 3X week reported statistically and clinically significantly improved PQAS scores versus those who had massage 2X week (change scores: PQAS-SP: -2.3 vs. -0.6, p = 0.001; PQAS-DP: -2.1 vs. -0.9, p = 0.008; PQAS-PP: -2.3 vs. -1.0, p = 0.025), with sustained improvement in the 3X week group, but minimal change in the 2X week group. Conclusions: We observed sustained reduction in pts with long-term CIPN up to 6 weeks after treatment completion for the more intensive 3X week massage group, regardless of treatment site. A large-scale efficacy trial is warranted to validate the role of oncology massage therapy for CIPN. Clinical trial information: NCT02221700.

CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane‐induced alopecia

Taxanes are a leading cause of severe and often permanent chemotherapy‐induced alopecia. As the underlying pathobiology of taxane chemotherapy‐induced alopecia remains poorly understood, we investigated how paclitaxel and docetaxel damage human scalp hair follicles in a clinically relevant ex vivo organ culture model. Paclitaxel and docetaxel induced massive mitotic defects and apoptosis in transit amplifying hair matrix keratinocytes and within epithelial stem/progenitor cell‐rich outer root sheath compartments, including within Keratin 15+ cell populations, thus implicating direct damage to stem/progenitor cells as an explanation for the severity and permanence of taxane chemotherapy‐induced alopecia. Moreover, by administering the CDK4/6 inhibitor palbociclib, we show that transit amplifying and stem/progenitor cells can be protected from paclitaxel cytotoxicity through G1 arrest, without premature catagen induction and additional hair follicle damage. Thus, the current study elucidates the pathobiology of taxane chemotherapy‐induced alopecia, highlights the paramount importance of epithelial stem/progenitor cell‐protective therapy in taxane‐based oncotherapy, and provides preclinical proof‐of‐principle in a healthy human (mini‐) organ that G1 arrest therapy can limit taxane‐induced tissue damage.

A pilot study of oncology massage to treat chemotherapy-induced peripheral neuropathy (CIPN).

e23067 Background: Short- and long-term toxicity of platinum compounds and taxanes includes development of CIPN. Although anti-neuropathic medications are available, there is increased interest by health care providers and patients (pts) regarding the role of complementary approaches for symptom control. Therefore, we explored the role of massage therapy for symptomatic relief of chronic CIPN. Methods: This pilot study evaluated the optimum treatment schedule and initial efficacy of two treatment schedules of a standardized Swedish massage technique to treat lower extremity (LE) CIPN. Inclusion criteria: LE neuropathy attributed to oxaliplatin, paclitaxel, or docetaxel, no other history of attributable causes (concurrent upper extremity neuropathy allowed); self-reported neuropathy score ≥3, 0-10 scale; ≥ 6 months since last chemotherapy treatment; age ≥ 18. Pts were randomized to one of four groups: 1) LE massage 3 times (3X) week for 4 weeks; LE massage 2X week for 6 weeks; 3) head/neck/shoulder (control) massage 3X week for 4 weeks; or 4) control massage 2X week for 6 weeks. Massage completion rate was examined and symptoms of CIPN measured with the Pain Quality Assessment Scale [PQAS (Range: 0-10); subscales of PQAS-SP (surface pain), PQAS-DP (deep pain), and PQAS-PP (paroxysmal pain)] at baseline and at 10 weeks. Results: 71 pts fulfilled inclusion criteria: 77.5% women; 57.7% (breast cancer), and 42.3% (GI cancer); mean age 60.3 y/o (range: 40-77). Average length of time since the end of chemotherapy was &gt; 3 yrs. Mean massage completion rates (max = 12) were 8.9 (SD 4.2) for 3X week and 9.8 (4.0) for 2X week with no statistical differences. There were no statistically significant differences in PQAS scores at follow-up between site-specific massage groups (lower extremity vs controls). Pts who had massage 3X week reported statistically and clinically significantly improved PQAS scores versus those who had massage 2X week (change scores: PQAS-SP: -2.3 vs. -0.6, p = 0.001; PQAS-DP: -2.1 vs. -0.9, p = 0.008; PQAS-PP: -2.3 vs. -1.0, p = 0.025), with sustained improvement maintained in the 3X week group, but minimal change in the 2X week group. Conclusions: We observed sustained reduction in pts with long-term CIPN up to 6 weeks after treatment completion for the more intensive 3X week massage group, regardless of massage treatment site. A large-scale efficacy trial is warranted to validate the role of oncology massage therapy for CIPN. Clinical trial information: NCT02221700.

Taxanes in the treatment of breast cancer: Have we better defined their role in older patients? A position paper from a SIOG Task Force.

Along with anthracyclines, taxanes are the most active cytotoxics in breast cancer (BC). Balancing efficacy against toxicity in older patients with reduced physiological reserves and significant comorbidities is both important and difficult. This is especially so given the under-representation of elderly patients in major trials and a consequent lack of evidence for drug, dose and schedule. However, BC is frequent in elderly women, who are a growing proportion of the population. Careful consideration of their care is therefore imperative. Treatment that can cure or extend the duration and quality of life should not be restricted by age, but needs to be tailored to the circumstances of elderly patients. In adjuvant use, taxane toxicity in older women is greater than in their younger counterparts, limiting its sequential combination with anthracyclines for high-risk disease unless patients are in very good health. More frequently taxanes are used alone (weekly paclitaxel, three-weekly docetaxel) or combined with cytotoxics other than anthracyclines (e.g. docetaxel plus cyclophosphamide) to reduce cardiac risk, especially in HER-2-positive patients who may develop additional trastuzumab-related cardiac events. In elderly patients with metastases, weekly paclitaxel and three-weekly docetaxel are among the cornerstones of treatment, with generally acceptable toxicity. Three-weekly docetaxel at the approved dose of 100mg/m(2) is not appropriate for the elderly. Nab-paclitaxel has efficacy comparable with solvent-based taxanes without need for steroid premedication but has been little studied in older BC patients. A head-to-head comparison with weekly paclitaxel favoured the solvent-free formulation for pathologic response, but those studied were a general adult population. Compared with early stage disease, choice of taxane and regimen in the metastatic setting relies even more on availability and preferences with regard to schedule, toxicity profile and cost, especially for recently developed formulations.

Are pharmacogenomic biomarkers an effective tool to predict taxane toxicity and outcome in breast cancer patients? Literature review.

Breast cancer is a heterogeneous disease, characterized by various molecular phenotypes that correlate with different prognosis and response to treatments. Taxanes are some of the most active chemotherapeutic agents for breast cancer; however, their utilization is limited, due to hematologic and cumulative neurotoxicity on treated patients. To understand why only some patients experience severe adverse effects and why patients respond and develop resistance with different rates to taxane therapy, the metabolic pathways of these drugs should be completely unraveled. The variant forms of several genes, related to taxane pharmacokinetics, can be indicative markers of clinical parameters, such as toxicity or outcome. The search of the data has been conducted through PubMed database, presenting clinical data, clinical trials and basic research restricted to English language until June 2015. We studied the literature in order to find any possible association between the major pharmacogenomic variants and specific taxane-related toxicity and patient outcome. We found that the data of these studies are sometimes discordant, due to both the small number of enrolled patients and the heterogeneity of the examined population. Among all analyzed genes, only CYP1B1 and ABCB1 resulted the strongest candidates to become biomarkers of clinical response to taxane therapy in breast cancer, although their utilization still remains an experimental procedure. In the future, greater studies on genetic polymorphisms should be performed in order to identify differentiating signatures for patients with higher toxicity and with resistant or responsive outcome, before the administration of taxanes.

Macroscopic Extramedullary Hematopoiesis Resembling Hepatic Metastases in Prostate Cancer

Extramedullary hematopoiesis is a rare entity to consider in patients with cancer and signs of bone marrow infiltration that can involve a diagnosis challenge in clinical practice. We report the case of a metastatic prostate cancer patient progressing with liver nodes and hepatic dysfunction symptoms that presented a great response to an alternative chemotherapy schedule regimen used to avoid liver toxicity of taxanes.

SNPs and taxane toxicity in breast cancer patients.

In order to identify genetic variants associated with taxanes toxicity, a panel with 47 SNPs in 20 genes involved in taxane pathways was designed. Genomic DNA of 113 breast cancer patients was analyzed (70 taking docetaxel, 43 taking paclitaxel). Two SNPs associated with docetaxel toxicity were identified: CYP3A4*1B with infusion-related reactions; and ERCC1 Gln504Lys with mucositis (p≤0.01). Regarding paclitaxel toxicity: CYP2C8 HapC and CYP2C8 rs1934951 were associated with anemia; and ERCC1 Gln504Lys with neuropathy (p≤0.01). Genes involved in DNA repair mechanisms and reactive oxygen species levels influence taxane toxicity in cancer patients treated with chemotherapy schemes not containing platinum. These findings could lead to better treatment selection for breast cancer patients.

Dendrimer–TPGS mixed micelles for enhanced solubility and cellular toxicity of taxanes

Taxanes are the most effective, efficient and broad spectrum anticancer drugs for the treatment of various cancers. However, poor aqueous solubility is the major problem in their delivery at higher concentrations in cancer cells. In this research work, poor solubility of taxanes is addressed by preparing dendrimer and d-α-tocopherol polyethylene glycol succinate (TPGS) mixed micelles by taking into consideration the advantages of TPGS such as solubility enhancement and P-glycoprotein inhibition. Dendrimer–TPGS mixed micelles were prepared by solvent casting method. Docetaxel (DTX) and paclitaxel (PTX) were chosen as model drugs representing the group of taxanes. Nanomicelles were characterized by DLS, FTIR, PXRD, in vitro drug release and hemolytic studies. Effects of pH and dendrimer to TPGS ratio on the solubility of taxanes were also studied. Solubility of DTX and PTX were increased by 20.36 and 34.95 folds, respectively, when formulated in dendrimer–TPGS mixed micelles. Drug release studies exhibited better release profile of encapsulated drug at acidic pH which is advantageous in enhanced intracellular drug release in cancer cells. Formulations were found to be biocompatible in hemolytic toxicity assay. Cytotoxicity studies revealed that anticancer activities of both drugs were enhanced after encapsulation in micelles against cancer cells while caused very low toxicity to normal cells. Thus, dendrimer–TPGS mixed micelles are promising alternate for delivery of poorly water-soluble drugs taxanes.

Synergistic effect of cyclodextrins and methyl jasmonate on taxane production in Taxus x media cell cultures.

Methyl jasmonate and cyclodextrins are proven effective inducers of secondary metabolism in plant cell cultures. Cyclodextrins, which are cyclic oligosaccharides, can form inclusion complexes with nonhydrophilic secondary products, thus increasing their excretion from the producer cells to the culture medium. In the present work, using a selected Taxus x media cell line cultured in a two-stage system, the relationship between taxane production and the transcript profiles of several genes involved in taxol metabolism was studied to gain more insight into the mechanism by which these two elicitors regulate the biosynthesis and excretion of taxol and related taxanes. Gene expression was not clearly enhanced by the presence of cyclodextrins in the culture medium and variably induced by methyl jasmonate, but when the culture was supplemented with both elicitors, a synergistic effect on transcript accumulation was observed. The BAPT and DBTNBT genes, which encode the last two transferases involved in the taxol pathway, appeared to control limiting biosynthetic steps. In the cell cultures treated with both elicitors, the produced taxanes were found mainly in the culture medium, which limited retroinhibition processes and taxane toxicity for the producer cells. The expression level of a putative ABC gene was found to have increased, suggesting it played a role in the taxane excretion. Taxol biosynthesis was clearly increased by the joint action of methyl jasmonate and cyclodextrins, reaching production levels 55 times higher than in nonelicited cultures.

Patient-Reported Neuropathy and Taxane-Associated Symptoms in a Phase 3 Trial of nab-Paclitaxel Plus Carboplatin versus Solvent-Based Paclitaxel Plus Carboplatin for Advanced Non–Small-Cell Lung Cancer

nab-Paclitaxel (nab-P) is approved, in the United States, in combination with carboplatin for the first-line treatment of advanced non-small-cell lung cancer, based on a randomized phase 3 trial of nab-P plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C). This trial revealed a higher overall response rate (33% versus 25%; p = 0.005) and longer, but not statistically significant, overall and progression-free survival for nab-P/C versus sb-P/C. In addition, nab-P/C demonstrated lower rates of grade 3 or higher peripheral neuropathy, myalgia, arthralgia, and neutropenia but higher rates of anemia and thrombocytopenia. This report analyzes patient and physician assessment of symptoms within this trial. Patients completed the taxane subscale of the Functional Assessment of Cancer Therapy questionnaire, which focuses on taxane toxicity, including peripheral neuropathy and neurotoxicity. Mean baseline scores and changes from baseline are reported. Physicians also graded the severity of neuropathy at each patient visit using National Cancer Institute Common Toxicity Criteria. Patients receiving nab-P/C reported significantly less worsening of peripheral neuropathy (p < 0.001), pain (p < 0.001), and hearing loss (p = 0.002). Patient-reported edema was similar between the two treatment arms. In agreement with patient-reported symptoms, the results of a per-treatment cycle physician assessment of peripheral neuropathy also favored nab-P/C over sb-P/C (p < 0.001). In this trial of patients receiving first-line treatment for advanced non-small-cell lung cancer, nab-P/C was associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss compared with sb-P/C.

Abstract A269: A selective Aurora A inhibitor, TAS-119, enhanced the antitumor activity of taxanes in an intermittent dosing schedule without affecting neurotoxicity.

Abstract Background: Aurora A is a serine/threonine kinase that plays important roles in the regulation of the M phase of the mammalian cell cycle. Aberrant expression of Aurora A has been associated with spindle checkpoint dysfunction and increased resistance to the microtubule-polymerizing agents, paclitaxel and docetaxel (1). Moreover, Aurora A overexpression/ gene amplification has been reported in various types of human cancers. Previously, we have reported on the development of a highly potent and selective Aurora A inhibitor, TAS-119 (TAS-2104), which enhanced anti-proliferation activity by taxanes (2). This study was undertaken to select the optimal combination schedule of TAS-119 and taxanes both in vitro and in vivo. Additionally, we evaluated the effects of TAS-119 on peripheral neurotoxicity, a well known major toxicity of taxanes. Materials and Methods: For in vitro experiments, cells were exposed to paclitaxel and/or the Aurora A inhibitor in different order and duration. Cell viability was determined by measuring cellular ATP concentration. For an in vivo tumor efficacy study, human tumor cell lines were subcutaneously transplanted into the side flank of nude mice or rats. Dosing of taxanes and TAS-119 was started when the transplanted tumor size reached &amp;gt; ∼ 200 mm3. Peripheral neurotoxicity was evaluated in rats. Paclitaxel was dosed weekly for 8 weeks and neurotoxicity was assayed by changes of action potential (M-wave amplitude) after electrical stimuli or histopathology changes in nerve neurons. Results: In in vitro experiments, the Aurora A inhibitor enhanced paclitaxel activity in all 3 schedules tested; Aurora A inhibitor before or after paclitaxel or simultaneous treatment. However, the latter 2 schedules were better than first schedule. When different treatment duration times of the Aurora A inhibitor combined with a single dose of paclitaxel were tested, 48 hrs was found to be enough to cause maximum enhancement. Similar experiments were performed in in vivo xenograft models. Maximum enhancement by TAS-119 was observed with 2 to 4 days of treatment (dependent on the model). Moreover, the combination of TAS-119 did not exacerbate the paclitaxel-induced peripheral neurotoxicity in rats. Conclusion: In this study, intermittent dosing of TAS-119 is efficacious for combination with taxanes, and sustained exposure of TAS-119 is not required for maximal combination efficacy. These findings provide a rationale for the clinical evaluation of combination therapies of TAS-119 with taxanes under the defined optimal schedule. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A269. Citation Format: Keiko Ishihara, Hiroshi Sootome, Takamasa Suzuki, Norio Masuko, Akihiro Miura, Megumu Okada, Nobuyuki Oda, Hiroshi Hirai, Teruhiro Utsugi. A selective Aurora A inhibitor, TAS-119, enhanced the antitumor activity of taxanes in an intermittent dosing schedule without affecting neurotoxicity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A269.

934P - Efficacy and Tolerability of Taxane-Based Chemotherapy in Senior Adults with Metastatic Castration-Resistant Prostate Cancer (MCRPC): A Prospective International Registry

ABSTRACT Background Docetaxel every 3 weeks is the standard of care in mCRPC, although other chemotherapy regimens may be administered. Efficacy and toxicity of taxanes in older men (70+ y) is poorly documented. Their enrolment in randomized trials is limited by exclusion criteria related to performance status (PS) and comorbidities. This prospective international registry evaluates taxane toxicity and efficacy in such men in real life practice. Methods 333 men with mCRPC (median age 76 y) were evaluated. PS, grade 3-4 comorbidities (Cumulative Illness Scoring Rate-Geriatrics), dependence (Activity Daily Living [ADL], Instrumental ADL [IADL]), nutritional status, primary therapy received and outcomes (overall survival (OS), progression-free survival (PFS), best clinical benefit [based on pain, analgesic consumption, PS], PSA response, toxicity) were collected. Follow-up under therapy was 6 months. Results In all, 24.0% had PS ≥2, 13.5% grade 3-4 comorbidities, 21% were dependent in ≥1 IADL, 15.6% in ≥1 ADL and 12.8% had a weight loss ≥5% within the past 3 months. According to SIOG (International Society of Geriatric Oncology) algorithm, 65.2% were fit, 13.5% vulnerable, 16.8% frail and 4.5% had terminal illness. Most men (62.4%) had pain at enrolment. Primary therapy was a taxane in 58% (3-weekly, 84.4%; median, 5 months) and received another therapy (hormonal therapy alone in 23.7%, non-taxane chemotherapy in 10.6%). Clinical characteristics of men treated by taxanes and other therapies were comparable at baseline. At 6 months, 91% were still alive with taxanes vs 81% with other therapies (HR [95% CI] 0.53 [0.30-0.93] p = 0.027). Frail patients showed the greatest benefit in OS (83% vs 57%, HR 0.32 [0.11-0.91] p = 0.033). Taxanes also significantly increased PFS (66% vs 50%, HR 0.55 [0.40-0.76], p Conclusions Taxanes appear the most effective first-line therapy in older men with mCRPC and show an acceptable and manageable toxicity, including in frail patients. Droz et al. BJU Int 2010; 106: 462-69 Disclosure J. Droz: Member of Advisory Board on Prostate Cancer- SANOFI, A. Heidenreich: Advisory relationship for Astellas, Janssen Cilag, Sanofi, Ipsen, Takeda Honoraria received from Amgen, Astellas, Glaxo, Ipsen, Jansen Cilag, Pfizer, Sanofi, Takeda. All other authors have declared no conflicts of interest.

Linking Toxicity to the Target

Linking Toxicity to the Target