Administration Of Taxanes Research Articles

Safety and Efficacy of Compression Therapy to Prevent Chemotherapy-Induced Peripheral Neuropathy in Lower Extremities of Breast Cancer Patients: A Pilot Study.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a problematic adverse event for breast cancer patients receiving taxane antimitotic agents. We evaluated the effectiveness of compression therapy against CIPN in the lower extremities of breast cancer patients receiving taxanes. Methods Eligible patients scheduled for perioperative treatment with taxanes for early-stage breast cancer were enrolled. Each patient wore latex-free surgical gloves and compression socks, putting on two layers of each 15 minutes before the administration of taxanes and removing them 15 minutes after administration. Peripheral neuropathy (PN) was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire (PNQ). The primary endpoint was the incidence of CTCAE version 4.0 grade 2 or higher CIPN in the lower extremities during the entire period of perioperative chemotherapy with taxanes. Results PN assessment by CTCAE in the lower extremities, the primary outcome, showed that 13.3% developed grade 2 sensory disturbances, and 8.3% developed grade 2 motor disturbances. The incidence of CTCAE grade 2 or higher PN in the hands was 26.7% for sensory disturbances and 13.3% for motor disturbances during the entire study period. No patient had grade 3 or higher PN. No adverse events due to compression therapy were observed. Conclusion Compression of the lower extremities with compression socks tended to reduce the incidence of CIPN compared to the general incidence. Compression therapy may help prevent the development of CIPN.

Abstract PO2-12-07: Risk of anaphylaxis associated with the use of pertuzumab or other biologics with potential for use outside the hospital

Abstract BACKGROUND Intravenous (IV) pertuzumab (P) and trastuzumab (H) are approved in the US for the treatment of HER2-positive breast cancer. P and H are also approved as a fixed-dose combination for SC injection (pertuzumab, trastuzumab, and hyaluronidase-zzxf; PH FDC SC). PH FDC SC may offer the possibility of treatment outside a hospital setting by a healthcare professional. Anaphylactic reactions can be a concern with the use of biologics. PH is also frequently initiated with six to eight cycles of taxanes, which can also be associated with anaphylaxis. We used administrative claims data to evaluate the risk of anaphylaxis associated with the real-world administration of PH or other biologic drugs in the real world. Our objective was to evaluate the risk of anaphylaxis associated with the administration of P and to contextualize the risk estimate by using other biologics that can be used outside the hospital as a benchmark. METHODS Cohorts of incident users were selected using retrospective records from a US healthcare claims database (IQVIA). Patients included were privately insured in the US, aged 16 to 65 years, and initiated a treatment of interest between 2012 and 2021. Possible and severe anaphylactic events (PAEs) were identified using the algorithm developed by the US Food and Drug Administration (FDA) Sentinel Initiative and updated with ICD10 codes (PMID: 34181291). PAEs were attributed to a drug if it occurred on the day of administration or the day after. The prevalence proportion (PP) of PAE was used to approximate the risk of anaphylaxis at each cycle. A sensitivity analysis using the proportion of prior P use amongst the cases of PAE beyond cycle 1 in the H cohort was conducted to approximate how many cases of PAE could have been missed at cycle 1 of P due to a depletion of susceptibles (as P IV and H may be administered sequentially in any order, patients with a PAE from H would not receive scheduled P and thus be excluded from the P cohort). RESULTS A total of 1,919,748 patients constituted 27 cohorts. Of them, 184,414 patients initiated monoclonal antibodies (mAbs) in 12 cohorts of which 12,264 and 184 initiated P IV and PH FDC SC, respectively. In the P IV cohort, seven PAE events were observed up to cycle 6 and none after. The PP at cycle 1 of P was 1.63 per 10,000 patients (95% confidence interval [CI] = 0.45, 5.94). The risk was comparable to that of other mAbs where anaphylaxis risk is described as uncommon/rare (Table). Accounting for a potential depletion of susceptibles increased the PP at cycle 1 of P to 2.45/10,000 (95% CI = 0.83, 7.19). No PAEs were reported in patients treated with PH FDC SC. CONCLUSIONS Using one of the largest datasets available, results suggest the risk of PAE with P administration could be within the range of what is observed with other mAbs that can be administered outside of the hospital. All events were observed when patients are expected to receive treatment at the hospital due to taxane administration. No PAE events were identified for PH FDC SC, but there were few patients in this cohort. Efforts are ongoing to identify a larger cohort treated with PH FDC SC. Risk of anaphylaxis by mAb * According to summary of product characteristics. † ≥1/1,000 to <1/100. ‡ ≥1/10,000 to <1/1,000. CI = confidence interval; H = trastuzumab; IV = intravenous; P = pertuzumab; PH FDC SC = pertuzumab, trastuzumab, and hyaluronidase-zzxf. Citation Format: Thibaut Sanglier, Tom Chambers, Joanna Harton, Laurentia Wahyudi, Magali Genevray, Eleonora Restuccia, Cécile Droz-Perroteau, Chau Dang. Risk of anaphylaxis associated with the use of pertuzumab or other biologics with potential for use outside the hospital [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-07.

Time-Dependent Changes of Extremity Volume and Tissue Alterations in Swollen Arms Caused by Taxanes.

Background: We aimed to determine the course of arm swelling caused by the use of taxanes and to identify valid predictors of persistent swelling. Methods and Results: A total of 15 patients with unilateral arm swelling that developed during the course, or within 3 months after termination, of postoperative taxane-based chemotherapy were included in the present study. The patients attended follow-up appointments every 3-6 months for 24 months after their initial visit. Their arm circumference was measured at each follow-up appointment, while ultrasonography of the skin and subcutaneous tissues was performed at the 0-, 6-, 12-, and 24-month follow-ups. Of the 15 patients, 12 (80%) saw their taxane-induced arm swelling resolved within a median of 12 months (range, 3-29 months) after their final taxane administration. Of the 12 patients whose swelling resolved, 9 did not use compression sleeves; however, their course of resolution did not differ from the other 3 patients who regularly used compression sleeves. In the three patients with persistent swelling, the excess subcutaneous thickness in the medial upper arm (median, 283%) was significantly greater than that in the patients whose swelling resolved (120%; p < 0.05) during their initial visits. Conclusions: Of the 15 patients included in the present study, 80% saw their taxane-induced arm swelling resolve within a median of 12 months after their final taxane administration, independent of the use of compression therapy. Persistent swelling may be predicted during the initial visit based on subcutaneous thickening of the medial upper arm.

Predictive factors for response to neoadjuvant chemotherapy: inflammatory and immune markers in triple-negative breast cancer.

Tumor-infiltrating lymphocytes (TILs) predict response to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients. However, the TIL level can be determined at a few facilities. By contrast, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are easily and objectively determined from the results of full blood counts. We conducted a retrospective study to investigate whether TILs, NLR, and PLR predict NAC efficacy and whether NLR and PLR could be surrogate markers for TILs in TNBC. Of the 266 patients diagnosed with TNBC between 2013 and 2019, 66 who underwent radical surgery after sequential administration of anthracycline and taxane as NAC were included in the study. TILs, NLR, and PLR were evaluated as predictors of pathologic complete response (pCR) using cutoff values determined from receiver operating characteristic curves. The cutoff values of TILs, NLR, and PLR were 20%, 2.6, and 180, respectively. High TIL level was associated with low NLR (P = 0.01) and low PLR (P = 0.01). High TIL level (odds ratio [OR] 4.28 [95% CI 1.40-13.1]; P = 0.01), low NLR (OR 5.51 [95% CI 1.60-18.9]; P = 0.01), and low PLR (OR 3.29 [95% CI 1.13-9.57]; P = 0.03) were associated with pCR. Low NLR predicted pCR independently (OR 6.59 [95% CI 1.45-30.0]; P = 0.01). TILs, NLR, and PLR predicted NAC efficacy against TNBC. TIL level was associated with NLR and PLR. NLR was an independent predictive factor and may be a useful surrogate marker for TILs when predicting pCR.

Taxane-induced scleroderma-like skin changes – review of the literature and case report

Abstract: Taxanes (paclitaxel, docetaxel) are antineoplastic agents used in advanced ovarian, breast, lung, head and neck cancer. Diverse cutaneous adverse reactions associated with taxane administration have been reported such as bullous eruption, onycholysis, acral erythema, erythema multiforme, pustular eruption, scleroderma-like skin changes of both upper and lower extremities. Here, we report a case of 48-year-old female patient, who presented for consultation with rheumatologist with complaints of hand and finger oedema and stiffness. Oedema and mild skin thickening of the fingers and hands were evident at physical examination. Inflammatory joint pain, synovitis, Raynaud’s phenomenon and trophic changes were not present. Standard laboratory tests i.e., complete blood count and biochemistry tests were within normal values. The patient was euthyroid. Immunological tests were negative (antinuclear antibodies; antibodies against extractable nuclear antigens – dsDNA, Sm, RNP, Scl-70; antiphospholipid antibodies – anticardiolipin, anti-beta-2-glycoprotein; anti-CCP antibody and rheumatoid factor). Capillaroscopic examination did not reveal signs of microangiopathy. Skin biopsy was perfomed in the area of a proximal phalanx and the histological examination revealed dermal oedema and superficial scant perivascular infiltrate containing lymphocytes and histiocytes. The patient had undergone an operation for breast cancer 13 years ago and subsequent second operation because of cancer recurrence 7 years ago. After the second operation chemotherapy was performed that included 1 cycle with paclitaxel and 4 cycles with docetaxel. The analysis of the case led to the conclusion that the scleroderma-like skin changes of the fingers and hands are induced by taxane administration in the past. The patient received corticosteroid treatment for 7 months with gradual resolution of symptoms.

Hypersensitivity Reactions to Taxanes: A Comprehensive and Systematic Review of the Efficacy and Safety of Desensitization.

Taxanes in the treatment of cancer are associated with a significant incidence of hypersensitivity reactions, which may preclude their use in patients in need of first line therapy. Drug desensitization induces transient immunological tolerance and has allowed the reintroduction of taxanes in highly allergic patients. Increase the knowledge of hypersensitivity reactions (HSR) during the administration of taxanes. A systematic review regarding the safety and efficacy of rapid drug desensitization (RDD) for taxanes HSR. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was registered in PROSPERO(CRD42021242324) and a comprehensive search was conducted in Medline, Embase, Web of Science and Scopus databases. 25 studies encompassing 10 countries were identified and 976 patients with initial HSR to paclitaxel (n = 707) and docetaxel (n = 284), that underwent a total of 2,396 desensitizations. The most common symptoms were cutaneous (74.6%) with paclitaxel and respiratory (72.6%) with docetaxel. Severe initial hypersensitivity reactions including anaphylaxis occurred in 39.6% and 13% of paclitaxel and docetaxel cases respectively and during the first (87.4%) or second exposure (81.5%). Patients tolerated well RDD and breakthrough reactions (BTR) occurred in 32.2% of paclitaxel-treated patients and in 20.6% of docetaxel treated patients. Premedications included corticosteroids, antihistamines and leukotriene receptor antagonists. The most commonly used protocol was the BWH 3 bags 12 steps, all protocols showed a success rate between 95-100%, with no reported deaths. RDD is a safe and effective procedure in patients with HSR to taxanes and protocols should be standardized for wide range implementation.

Early taxane-induced neurotoxicity and quality of life in patients with breast cancer: A single center, retrospective study.

e12533 Background: Taxane administration in breast cancer patients relates to significant chemotherapy-induced peripheral neuropathy (CIPN). In our four years retrospective observational study, we aimed to evaluate early onset of neuropathy and its influence in patients’ quality of life, assessed through certified questionnaires. Methods: We retrospectively collected data from stage I-III breast cancer patients treated with taxane-based therapy between 2018 and 2022 at the Medical Oncology Unit of the University Hospital of Cagliari. We included 300 patients. The median age was 57 years (range, 32-85). All patients followed a schedule of PCT 80mg/m2 ± 30 weekly; they received up to a maximal cumulative dose of PCT 960 ± 30 mg/m2. Peripheral neuropathy was evaluated by the NCI-CTC scale (national cancer institute, common toxicity criteria for adverse events) at every drug administration. Patient-reported EORTC QLQ-CIPN20 and FACT-TAXANE questionnaires were collected at baseline, at 4 and 12 weeks of treatment. We used the Kruskal-Wallis test for the association between the neurotoxicity grade and quality of life. Difference in the questionnaire score at the different timing was assessed by ANOVA test for repeated measures. To assess the strength of the correlation between the different quality-of-life questionnaires, we used Spearmann's Rho test. Statistical analysis was performed with the MedCalc Statistical Software Version 14.10.2. Results: Our analysis revealed that neurotoxicity influences the quality of life assessed with the QLQ at cycle IV (p = 0.000001) and cycle XII (p = 0.008). With just a cumulative dose of 320 mg/m2 (cycle IV), patients without neurotoxicity achieved a median value of 32 in the QLQ, compared to a median value of 34 in patients with grade 1 toxicity and 43 in the group of patients with grade 2 toxicity. Similarly, at cycle XII and with cumulative dose of 960 mg/m2, patients without neurotoxicity achieved a median value of 27 at the QLQ, compared to a median value of 33 in patients with grade 1 toxicity and 34 in the group of patients with grade 2 toxicity. The ANOVA test showed a significant increase (worsening) in the CIPN20 questionnaire at 4 and 12 weeks versus baseline (p &lt; 0.001 for both). The score remained significantly higher in comparison to baseline also at the evaluation at 3 (p &lt; 0.001), 6 (p &lt; 0.001) and 12 months (p &lt; 0.0001). Similarly, the FACT-TAXANE questionnaire showed a significant worsening at 4 (p &lt; 0.001) and 12 (p &lt; 0.001) weeks in comparison to baseline. Conclusions: The majority of women who received a taxane based chemotherapy regimen for breast cancer reported neurotoxicity. In our study, the use of specific questionnaires (EORTC QLQ-CIPN20 and FACT-TAXANE) allowed to identify early neurotoxicity onset and its correlation to quality of life, yet at an initial phase of treatment (after a cumulative dose of 320 mg/m2 of paclitaxel at IV cycle).

Abstract P1-03-01: Eribulin versus S-1 as first- or second- line chemotherapy to assess Health-related Quality of Life and overall survival in HER2-negative metastatic breast cancer (RESQ study): a non-inferiority, randomized controlled trial

Abstract Background Eribulin is a chemotherapeutic drug that prolongs overall survival (OS) in patients with HER2-negative metastatic breast cancer (MBC), mainly in third-line or later chemotherapy (ChT) [1]. However, health-related quality of life (HRQOL) and efficacy in patients who receive eribulin as first- or second-line therapy is not well known. In contrast, S-1, an oral 5-fluorouracil derivative, shows similar OS to taxanes as first-line ChT and better HRQOL, based on a large phase III trial conducted in Japan [2]. Here, we compared the effect on HRQOL and efficacy of eribulin and S-1 in MBC patients in a first- or second-line ChT setting. Methods We planned an open-label, multicenter, randomized controlled phase III study at 50 hospitals in Japan. We enrolled patients with HER2-negative MBC who had no or one previous ChT for MBC regardless of prior administration of anthracyclines and taxanes. Patients were randomly assigned (1:1) to either eribulin (1.4 mg/m² administered on days 1 and 8 of a 21-day) or S-1 (40–60 mg twice daily for 14 consecutive days, followed by a 7-day break). Randomization was stratified by institution, age, treatment line, hormone receptor status, and time from surgery to recurrence. HRQOL assessment was conducted using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 questions (QLQ-C30) every six weeks until week 24, and then every nine weeks until week 42 after baseline assessment. The primary outcome measure was the global health status (GHS) score of EORTC QLQ-C30, with a prespecified non-inferiority margin of 10% for a difference in the proportion of patients experiencing deterioration at one year. Clinically meaningful deterioration was defined as a ≥ 10-point decrease from baseline GHS score or death. Secondary outcomes were OS, progression-free survival (PFS), and adverse events. We estimated that the study needed 330 patients to obtain 80% power for non-inferiority. This trial was registered with the University Hospital Medical Information Network, Japan (protocol ID 000021398). Results Between June 2016 and October 2019, 302 patients were enrolled, with 152 assigned to eribulin and 148 to S-1. The full analysis set for HRQOL assessment included 134 and 136 patients, while that for efficacy consisted of 141 and 144 patients, respectively. Overall compliance with the questionnaire was 85.6 %. Among the full analysis set for efficacy, 28 (19.9%) and 31 (21.5%) cases were triple negative, respectively. Eribulin and S-1 were administered as first-line ChT in 99 (70.2%) and 101 (70.1%) patients, respectively. Risk difference of GHS deterioration through one year for the eribulin versus S1 group was -0.66% (95% CI -12.47 to 11.16; P non-inferiority =0.077). Median time to first deterioration in GHS score was 5.64 months (95% CI 3.51–8.00) and 5.28 months (95% CI 3.28-7.80) (HR 1.07 [95% CI 0.79–1.45]; P =0.667); median OS was 35.0 months (95% CI 27.2-41.0) and 27.8 months (95% CI 24.6-33.5) (HR 0.69 [95% CI 0.50-0.95]; P=0.023); and median PFS was 6.07 months (95% CI 5.48-7.80) and 6.66 months (95% CI 5.48-7.77), respectively (HR 0.90 [95% CI 0.68-1.18]; P=0.427). No previously unrecognized adverse events were observed. Conclusions We found a marginal non-inferiority in HRQOL for eribulin, albeit that the difference was not statistically significant owing to the smaller than planned sample size. Time to first clinically meaningful deterioration was almost identical between the two arms, whereas OS was significantly extended with eribulin. These findings indicate that eribulin in first- or second-line ChT is acceptable as a standard regimen in this patient population. [1] Lancet 2011; 377: 914–23 [2] Lancet Oncol 2016; 17: 90–98 Citation Format: Yuichiro Kikawa, Kosuke Kashiwabara, Naruto Taira, Tsuguo Iwatani, Kojiro Shimozuma, Shoichiro Ohtani, Tetsuhiro Yoshinami, Junichiro Watanabe, Masahiro Kashiwaba, Ken-ichi Watanabe, Masahiro Kitada, Koichi Sakaguchi, Yuko Tanabe, Tomohiko Aihara, Hirofumi Mukai, Masato Takahashi. Eribulin versus S-1 as first- or second- line chemotherapy to assess Health-related Quality of Life and overall survival in HER2-negative metastatic breast cancer (RESQ study): a non-inferiority, randomized controlled trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-03-01.

Aroma lymphatic massage (Aroma lymphatic tressage) for symptom relief in breast cancer patients with taxane acute pain syndrome: A randomized controlled crossover trial

Taxane acute pain syndrome (TAPS) is a common complication of taxane; however, no standard of care has been established yet. This study aimed to evaluate the efficacy of aroma lymphatic tressage (ALT) on TAPS. We conducted a phase II randomized crossover trial on breast cancer patients who were to receive taxane-based chemotherapy. The participants were randomly assigned to receive standard care only (group A) or ALT in addition to standard care for pain (group B) in the first cycle. The patients in each group were then crossed over in the next cycle. ALT was applied on 4 consecutive days from the day after taxane administration. There were 2 weeks of wash-out period between cycles. Daily pain scores and analgesic dose requirements were self-reported by the participants. 65 patients were analysed: 32 and 33 patients in groups A and B, respectively. Average age was significantly lower in group B. The mean pain score of cycle 1 was higher in group B, which received ALT, but the analgesic dose requirement was lower in group B (12.69 vs. 8.09, effect size 0.21). The pain score in the chemotherapy cycle with ALT was lower than that in the standard care only period (1.92 vs. 1.73, effect size -0.09). There was no severe toxicity regarding additive ALT. There were no significant difference in pain score between additive ALT and standard-of-care. Short-course ALT added to standard care may help reduce the analgesic dose requirement in breast cancer patients with TAPS. KCT0005758.

A Randomized Controlled Phase 2 Study of Neoadjuvant Eribulin Versus Paclitaxel in Women with Operable Breast Cancer: The JONIE-3 Study

ObjectiveNeoadjuvant chemotherapy (NAC) is essential for surgical downstaging of early-stage breast cancer, but taxane administration is associated with neuropathy. We investigated whether eribulin induces less neuropathy than paclitaxel. MethodsIn this multicentre, randomised study (UMIN000012817), patients diagnosed with invasive breast cancer between December 2013 and April 2016 were randomly assigned to group E (eribulin followed by fluorouracil, epirubicin, and cyclophosphamide; FEC) or group P (paclitaxel followed by FEC). The primary endpoint was incidence of grade 1 or higher peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints were pathological complete response (pCR), clinical response, breast-conserving surgery, adverse events, disease-free survival (DFS), and patient neurotoxicity questionnaire (PNQ) analysis. ResultsOne hundred and eighteen cases were analyzed for safety and 115 were evaluated for efficacy. Peripheral sensory neuropathy was significantly lower in group E after week 6, while peripheral motor neuropathy in group E was significantly lower at weeks 9, 12, and 15. pCR in groups E and P was 20.7% and 29.8% (P = .289), respectively, and clinical response was 55.2% and 77.2% (P = .017), respectively. Three-year DFS was 89.7% in group E and 86.0% in group P (P = .561). Neutropenia was more frequent and more severe in group E. PNQ was evaluated for 4 years, and item 1 (sensory) was consistently lower in group E. ConclusionNeuropathy was significantly less frequent and less severe in patients who received eribulin compared with paclitaxel. Thus, eribulin could be a good alternative to paclitaxel in patients suffering severe neuropathy.

Effect of radiotherapy sequence on long-term outcome in patients with node-positive breast cancer: a retrospective study

The optimal sequence of chemotherapy (CT) and radiotherapy (RT) after surgery in breast cancer patients is unclear. There is a lack of literature on RT given between anthracycline and taxane administration. We evaluated the effect of RT sequence on long-term outcome in breast cancer. Two hundred patients who underwent surgery between January 2009 and December 2012 for node-positive breast cancers were evaluated retrospectively. All patients were treated with doxorubicin and cyclophosphamide (AC) followed by taxane. Sandwich RT group that received RT between AC and taxane was compared to the group that received RT after CT. The mean follow-up period was 105.4 months. The locoregional recurrence (LRR) rate was lower in sandwich RT group (P = 0.012) and there was no significant difference in distant metastasis between the two groups. The RT sequence was an important predictor for LRR in multivariable analysis (P = 0.017). For luminal A subtype, disease-free survival (DFS) was better in sandwich RT group than in CT followed by RT group (P = 0.001). The overall survival did not correlated with RT sequence regardless of subtype. Sandwich RT can offer DFS benefit in luminal A subtype breast cancer. A tailored approach of sequencing chemotherapy and radiotherapy would be needed considering the factors that can influence outcome.

Probing the new strategy for the oral formulations of taxanes: changing the method with the situation.

The first-generation taxanes (including paclitaxel and docetaxel) are widely used for the treatment of various cancers in clinical settings. In the past decade, a series of new-generation taxanes have been developed which are effective in the inhibition of tumor resistance. However, intravenous (i.v.) infusion is still the only route of administration, and may result in serious adverse reactions with respect to the utilization of Cremophor EL or Tween-80 as solvent. Besides, the dosing schedule is also limited. Therefore, oral administration of taxanes is urgently needed to avoid the adverse reactionss and increase dosing frequency. In this review, we first outlined the discovery and development of taxane-based anticancer agents. Furthermore, we summarized the research progress on the oral formulations of taxanes and proposed some thoughts on the future development of oral taxane formulations.

Effects of Chronic Oral Probiotic Treatment in Paclitaxel-Induced Neuropathic Pain.

Chemotherapy-induced peripheral neuropathy (CIPN) represents one of the most prevalent and potentially disabling side effects due to the use of anticancer drugs, one of the primary neuropathies detected is peripheral neuropathy induced by administration of taxanes, including paclitaxel. It has been demonstrated that gut microbiota is crucial for the therapeutic effect of chemotherapeutic drugs for inhibiting tumor growth and contributed to the pathogenesis of the CIPN. The use of nutraceuticals has receiving growing attention from the research community due to their phytochemical, biological, and pharmacological properties. It has been demonstrated that probiotic formulations may both reduce inflammation and modulate the expression of pain receptors. Our studies tested the efficacy of a probiotic formulation, SLAB51, in preventing paclitaxel-induced neuropathy. Interestingly, our probiotic formulation was able to keep the gut integrity, preserving its functionality, in CIPN-mice, moreover, it prevented the mechanical and cold hypersensitivity induced in paclitaxel-mice. Additionally, ex-vivo analysis showed that in CIPN-mice the pro-biotic treatment increased the expression of opioid and cannabinoid receptors in spinal cord, it prevented in the reduction in nerve fiber damage in the paws and modulated the serum proinflammatory cytokines concentration. On basis of these data, the use of this specific probiotic formulation may represent a valid adjuvant agent to paclitaxel, useful and not toxic for long-lasting therapies.

Current Perspectives on Taxanes: Focus on Their Bioactivity, Delivery and Combination Therapy.

Taxanes, mainly paclitaxel and docetaxel, the microtubule stabilizers, have been well known for being the first-line therapy for breast cancer for more than the last thirty years. Moreover, they have been also used for the treatment of ovarian, hormone-refractory prostate, head and neck, and non-small cell lung carcinomas. Even though paclitaxel and docetaxel significantly enhance the overall survival rate of cancer patients, there are some limitations of their use, such as very poor water solubility and the occurrence of severe side effects. However, this is what pushes the research on these microtubule-stabilizing agents further and yields novel taxane derivatives with significantly improved properties. Therefore, this review article brings recent advances reported in taxane research mainly in the last two years. We focused especially on recent methods of taxane isolation, their mechanism of action, development of their novel derivatives, formulations, and improved tumor-targeted drug delivery. Since cancer cell chemoresistance can be an unsurpassable hurdle in taxane administration, a significant part of this review article has been also devoted to combination therapy of taxanes in cancer treatment. Last but not least, we summarize ongoing clinical trials on these compounds and bring a perspective of advancements in this field.

Characterization of circulating tumor cells in early breast cancer patients receiving neoadjuvant chemotherapy.

Background and Aims:The aim of this study was to characterize circulating tumor cells (CTCs) during neoadjuvant chemotherapy (NACT) in early and locally advanced breast cancer (LABC) patients. Using ultrasound, tumor volume measurement was compared with the presence and the molecular nature of CTCs over multiple time intervals corresponding to treatment periods.Methods:A total of 20 patients diagnosed with breast cancer (BC) of different histotypes were monitored during the NACT period and in the follow-up period (~5 years). Peripheral blood for CTCs (n = 115) was taken prior to NACT, after two to three chemotherapy cycles, after the completion of NACT (before surgery) and at some time points during adjuvant therapy. CTCs were enriched using a size-based filtration method (MetaCell®) capturing viable cells, which enabled vital fluorescence microscopy. A set of tumor-associated (TA) genes and chemoresistance-associated (CA) genes was analyzed by qPCR in the enriched CTC fractions.Results:The analysis of tumor volume reduction after administration of anthracyclines (AC) and taxanes (TAX) during NACT showed that AC therapy was responsive in 60% (12/20) of tumors, whereas TAX therapy was responsive in 30% (6/20; n.s.). After NACT, CTCs were still present in 70.5% (12/17) of patients (responders versus non-responders, 61.5% versus 100%; not significant).In triple-negative BC (TNBC) patients (n = 8), tumor volume reduction was observed in 75% cases. CTCs were significantly reduced in 42.9% of all HER2-negative BC patients. In HER2+ tumors, CTC reduction was reported in 16.6% only. Relapses were also more prevalent in the HER2-positive patient group (28.5 versus 66.6%).During NACT, the presence of CTCs (three tests for each patient) identified patients with relapses and indicated significantly shorter progression-free survival (PFS) rates (p = 0.03). Differentiation between progressive disease and non-progressive disease was obtained when the occurrence of excessive expression for CA genes in CTCs was compared (p = 0.024). Absence of tumor volume reduction was also significantly indicative for progressive disease (p = 0.0224).Disseminated CTCs in HER2-negative tumors expressed HER2 in 29% of samples collected during the overall follow-up period (16/55), and in 32% of samples during the follow-up of NACT (10/31). The change accounted for 78.5% of HER2-negative patients (11/14) in total, and 63.6% of the conversion cases occurred during NACT (7/11). For the remaining four patients (36.3%), conversion to HER2+ CTCs occurred later during adjuvant therapy. We believe there is the possibility of preventing further progression by identifying less responsive tumors during NACT using CTC monitoring, which could also be used effectively during adjuvant therapy.

Phase II study of liposomal doxorubicin, docetaxel and trastuzumab in combination with metformin as neoadjuvant therapy for HER2-positive breast cancer.

Background:The aim of this study was to improve activity over single human epidermal growth factor receptor 2 (HER2)-blockade sequential neaodjuvant regimens for HER2-positive breast cancer, by exploiting the concomitant administration of trastuzumab, taxane and anthracycline, while restraining cardiac toxicity with use of liposomal doxorubicin, and by adding metformin, based on preliminary evidence of antitumor activity.Patients and methods:This multi-center, single-arm, two-stage phase II trial, assessed the safety and the activity of a new treatment regimen for HER2-positive, early or locally advanced breast cancer. Patients received six 21-day cycles of non-pegylated liposomal doxorubicin, 50 mg/m2 intravenously (i.v.) on day 1, docetaxel, 30 mg/m2 i.v. on days 2 and 9, trastuzumab, 2 mg/kg/week i.v. on days 2, 9, and 16 (with 4 mg/kg loading dose), in association with metformin 1000 mg orally twice daily. The primary endpoint was the rate of pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). A subgroup of patients performed a 3-deoxy-3-18F-fluorothymidine positron emission tomography (FLT-PET) at baseline and after one cycle.Results:Among 47 evaluable patients, there were 18 pCR [38.3%, 95% confidence interval (CI) 24.5–53.6%]. A negative estrogen-receptor status, high Ki67, and histological grade 3 were related with pCR, although only grade reached statistical significance. FLT-PET maximum standardized uptake value after one cycle was inversely related to pCR in the breast (odds ratio 0.29, 95% CI 0.06–1.30, p = 0.11). Toxicity included grade 3–4 neutropenia in 70% and febrile neutropenia in 4% of patients, grade 1–2 nausea/vomiting in 60%/38%, and grade 3 in 4%/2%, respectively, grade 1–2 diarrhea in 72%, and grade 3 in 6%. There were two cases of reversible grade 2 left-ventricular ejection-fraction decrease, and one case of sharp troponin-T increase.Conclusions:The concomitant administration of trastuzumab, liposomal doxorubicin, docetaxel, and metformin is safe and shows good activity, but does not appear to improve activity over conventional sequential regimens.

Mitochondria Participate in Chemoresistance to Cisplatin in Human Ovarian Cancer Cells

Ovarian cancer is an aggressive disease that affects about 300,000 patients worldwide, with a yearly death count of about 185,000. Following surgery, treatment involves adjuvant or neoadjuvant administration of taxane with platinum compounds cisplatin or carboplatin, which alkylate DNA through the same chemical intermediates. However, although platinum-based therapy can cure patients in a number of cases, a majority of them discontinues treatment owing to side effects and to the emergence of resistance. In this study, we focused on resistance to cisplatin and investigated whether metabolic changes could be involved. As models, we used matched pairs of cisplatin-sensitive (SKOV-3 and COV-362) and cisplatin-resistant (SKOV-3-R and COV-362-R) human ovarian carcinoma cells that were selected in vitro following exposure to increasing doses of the chemotherapy. Metabolic comparison revealed that resistant cells undergo a shift toward a more oxidative metabolism. The shift goes along with a reorganization of the mitochondrial network, with a generally increased mitochondrial compartment. More functional mitochondria in cisplatin-resistant compared with cisplatin-sensitive cells were associated to enzymatic changes affecting either the electron transport chain (SKOV-3/SKOV-3-R model) or mitochondrial coupling (COV-362/COV-362-R model). Our findings further indicate that the preservation of functional mitochondria in these cells could be due to an increased mitochondrial turnover rate, suggesting mitophagy inhibition as a potential strategy to tackle cisplatin-resistant human ovarian cancer progression. IMPLICATIONS: Besides classical mechanisms related to drug efflux and target modification, we report that preserving functional mitochondria is a strategy used by human ovarian cancer cells to resist to cisplatin chemotherapy.

Extremity Cooling: A Synthesis of Cryotherapy Interventions to Reduce Peripheral Neuropathy and Nail Changes From Taxane-Based Chemotherapy

Taxane-based chemotherapies are frequently used to treat solid tumor cancers. Two significant side effects include nail changes and/or peripheral neuropathy. These side effects can cause pain, infections, dose reductions, and treatment delays, all of which negatively affect quality of life. This article synthesizes the literature on efficacy and tolerability of extremity cryotherapy during taxane administration to identify if it is an intervention that can be provided to patients to mitigate these symptoms. A literature review was performed using PubMed®, the Cochrane Database of Systematic Reviews, Ovid, Web of Science, and CINAHL®. 46 articles were initially identified, and 10 articles were reviewed (5 related to nail changes and 5 related to neuropathy). Larger, powered studies are needed on these topics; however, existing data suggest this intervention as a promising low-risk option for mitigating the severity of nail changes and peripheral neuropathy related to taxane chemotherapy.

Incidence and Management of Diarrhea With Adjuvant Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

BackgroundThe APHINITY (BIG 4-11) study showed that pertuzumab significantly improved the rates of invasive disease-free survival among patients with human epidermal growth factor receptor 2 (HER2)-positive, operable breast cancer when added to adjuvant trastuzumab and chemotherapy. Because diarrhea was a common adverse event that could compromise treatment administration, we evaluated the incidence and management of diarrhea in the APHINITY study. Patients and MethodsThe APHINITY trial is a prospective, randomized, multicenter, multinational, double-blind, placebo-controlled trial. The eligible patients were randomly assigned to receive standard adjuvant chemotherapy and 1 year of trastuzumab combined with pertuzumab or placebo. The diarrhea incidence, severity (National Cancer Institute common terminology criteria for adverse events, version 4.0), onset, and management were analyzed. ResultsA total of 4805 patients were randomized. Diarrhea of any grade was the most common adverse event and occurred in 71% of patients in the pertuzumab arm versus 45% in the placebo arm. Diarrhea grade 3 to 4 was observed in 10% and 4% in the pertuzumab and placebo arms, respectively. The greatest incidence of diarrhea was reported during the concomitant administration of HER2-targeted therapy and taxane (61% vs. 34% of patients experienced an event with pertuzumab vs. placebo, respectively). A marked decrease was observed on chemotherapy cessation. Antidiarrheal agents were commonly used, and diarrhea rarely caused treatment dose modifications or discontinuation. ConclusionDiarrhea was a common adverse event in the APHINITY study. Most episodes were low grade and were generally manageable with common antidiarrheal agents. The incidence of diarrhea was greater with the combination of a taxane and HER2-targeted treatment and decreased once chemotherapy was stopped.

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.