Albumin-stabilized layered double hydroxide nanoparticles synergized combination chemotherapy for colorectal cancer treatment.

Combination chemotherapy with two or more complimentary drugs has been widely used for clinical cancer treatment. However, the efficacy and side effects of combination chemotherapy still remain a challenge. Here, we constructed an albumin-stabilized layered double hydroxide nanoparticle (BLDH) system to simultaneously load and deliver two widely used anti-tumor drugs, i.e. 5-fluorouracil (5FU) and albumin-bound PTX (Abraxane, ABX) for colorectal cancer treatment. The cellular uptake test has revealed that 5FU-ABX encapsulated BLDH (BLDH/5FU-ABX) nanoparticles were efficiently internalized by the colorectal cancer cell (HCT-116), synergistically inducing apoptosis of colon cancer cells. The in vivo test has demonstrated that BLDH/5FU-ABX nanomedicine significantly inhibited the tumor growth after three intravenous injections, without any detectable side effects. The enhanced therapeutic effectiveness is attributed to efficient accumulation of BLDH/5FU-ABX at tumor sites and acid-sensitive release of co-loaded drugs. Thus, combination chemotherapy based on BLDH/5FU-ABX nanomedicine would be a new strategy for colorectal cancer treatment.

Nonlinear response to cancer nanotherapy due to macrophage interactions revealed by mathematical modeling and evaluated in a murine model via CRISPR-modulated macrophage polarization.

Tumor-associated macrophages (TAMs) have been shown to both aid and hinder tumor growth, with patient outcomes potentially hinging on the proportion of M1, pro-inflammatory/growth-inhibiting, to M2, growth-supporting, phenotypes. Strategies to stimulate tumor regression by promoting polarization to M1 are a novel approach that harnesses the immune system to enhance therapeutic outcomes, including chemotherapy. We recently found that nanotherapy with mesoporous particles loaded with albumin-bound paclitaxel (MSV-nab-PTX) promotes macrophage polarization towards M1 in breast cancer liver metastases (BCLM). However, it remains unclear to what extent tumor regression can be maximized based on modulation of the macrophage phenotype, especially for poorly perfused tumors such as BCLM. Here, for the first time, a CRISPR system is employed to permanently modulate macrophage polarization in a controlled in vitro setting. This enables the design of 3D co-culture experiments mimicking the BCLM hypovascularized environment with various ratios of polarized macrophages. We implement a mathematical framework to evaluate nanoparticle-mediated chemotherapy in conjunction with TAM polarization. The response is predicted to be not linearly dependent on the M1:M2 ratio. To investigate this phenomenon, the response is simulated via the model for a variety of M1:M2 ratios. The modeling indicates that polarization to an all-M1 population may be less effective than a combination of both M1 and M2. Experimental results with the CRISPR system confirm this model-driven hypothesis. Altogether, this study indicates that response to nanoparticle-mediated chemotherapy targeting poorly perfused tumors may benefit from a fine-tuned M1:M2 ratio that maintains both phenotypes in the tumor microenvironment during treatment.

Retrospective cohort study of nanoparticle albumin-bound paclitaxel plus ramucirumab versus paclitaxel plus ramucirumab as second-line treatment in patients with advanced gastric cancer.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX) has shown non-inferiority to paclitaxel (PTX) as second-line therapy for advanced gastric cancer (AGC) with fewer infusion-related reactions. The efficacy and safety of nab-PTX plus ramucirumab (RAM) was reported in a phase II trial; however, there is no randomized trial comparing this regimen with PTX plus RAM in patients with AGC. This retrospective study aimed to investigate the efficacy and safety of nab-PTX plus RAM versus PTX plus RAM in patients with AGC. METHODS: This study included patients with AGC who received nab-PTX plus RAM from September 2017 to January 2019 or PTX plus RAM from June 2015 to August 2017 as second-line chemotherapy in our hospital. RESULTS: A total of 113 and 138 patients who received nab-PTX plus RAM and PTX plus RAM, respectively, were analyzed. Median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI]: 3.4-4.3) in the nab-PTX plus RAM group and 3.9 months (95% CI: 3.1-4.7) in the PTX plus RAM group (hazard ratio [HR]: 1.08; 95% CI: 0.83-1.40; P = 0.573). Median overall survival (OS) was 10.9 months (95% CI: 9.3-12.7) in the nab-PTX plus RAM group and 10.3 months (95% CI: 8.5-12.0) in the PTX plus RAM group (hazard ratio: 0.82; 95% CI: 0.61-1.10; P = 0.188). In patients with moderate/massive ascites, favorable outcomes for progression-free survival were observed in the nab-PTX plus RAM group compared with the PTX plus RAM group. Although anemia and fatigue (any grade) were more frequent in the nab-PTX plus RAM group, discontinuation of study treatment was not increased in the nab-PTX plus RAM group. There was no occurrence of hypersensitivity reaction in the nab-PTX plus RAM group, while two patients (1.4%) experienced grade 3 hypersensitivity reactions in the PTX plus RAM group. CONCLUSIONS: The combination of nab-PTX plus RAM showed a similar efficacy and safety profile to PTX plus RAM as second-line treatment for patients with AGC.

Albumin Nanoparticle of Paclitaxel (Abraxane) Decreases while Taxol Increases Breast Cancer Stem Cells in Treatment of Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has a high rate of metastasis, which is associated with breast cancer stem-like cells (CSCs). Although Taxol (micelle formulation of paclitaxel) is the first line chemotherapy to treat TNBC, it increases CSCs in residual tumors. Abraxane, albumin nanoparticle of paclitaxel, showed lower plasma concentration compared to Taxol in both human and animal models, but it is not clear why Abraxane showed superior efficacy to Taxol in treatment of metastatic breast cancer in humans. In this study, we intend to investigate if Abraxane eliminates CSCs for its better efficacy. The results showed that Abraxane showed similar cytotoxicity in SUM149 cells in comparison with Taxol. Although Abraxane showed 3- to 5-fold lower blood drug concentration compared to Taxol, it achieved similar tumor drug concentration and 10-fold higher tumor/plasma ratio in SUM149 xenograft NOD/SCID mouse model. In addition, Abraxane and Taxol showed similar efficacy to shrink the tumor size in orthotopic breast cancer NOD/SCID mouse model. However, Abraxane decreased breast CSCs frequency by 3- to 9-fold, while Taxol increased breast CSCs frequency in an orthotopic breast cancer NOD/SCID mouse model. Furthermore, Abraxane increased 3- to 15-fold intracellular uptake in both ALDH+ CSCs and differentiated ALDH- cells in comparison with Taxol, which provides a mechanism for Abraxane's superior efficacy to eliminate CSCs in comparison with Taxol. Our data suggest albumin nanoparticle Abraxane may have a broad implication to enhance drug's efficacy by eliminating breast cancer stem cells for treatment of metastatic diseases.

Phase II clinical trial of S-1 plus nanoparticle albumin-bound paclitaxel in untreated patients with metastatic gastric cancer.

The present study is the first phase II clinical trial aimed to evaluate the efficacy and safety of S-1 plus nanoparticle albumin-bound paclitaxel (Nab-PTX) as first-line chemotherapy for advanced gastric cancer (AGC). Previously untreated patients with metastatic gastric adenocarcinoma received S-1 in oral doses of 40 mg (BSA <1.25 m2 ), 50 mg (1.25 ≤ BSA < 1.50 m2 ) and 60 mg (BSA ≥1.50 m2 ) b.i.d. on days 1-14 in combination with Nab-PTX (120 mg/m2 , on days 1 and 8) for each 21-day cycle. Primary endpoint was progression-free survival (PFS), and secondary endpoints were overall response rate (ORR), overall survival (OS), disease control rate (DCR), and toxicity. A total of 73 gastric cancer patients with metastatic and measurable lesions were enrolled in the first-line setting. Median PFS and OS were 9.63 months and 14.60 months, respectively. Four (5.5%) patients had complete responses, 39 (53.4%) had partial responses (PRs), 21 (28.8%) had stable disease, four (5.5%) progressed and five (6.8%) were not evaluable. ORR and DCR were 58.9% and 87.7%, respectively. Most toxicities were mild, and no treatment-related deaths occurred. Grade 3 to 4 toxicities occurred in 22 patients (30.1%) as follows: leukopenia (13.7%), neutropenia (12.3%), anemia (5.5%), thrombocytopenia (1.4%), diarrhea (6.8%), vomiting (2.7%), stomatitis (1.4%), peripheral neuropathy (1.4%), and hand-foot syndrome (1.4%). Seven patients achieved good responses and underwent gastrectomy plus metastasectomy. Thirty (41.1%) patients had S-1 maintenance with a median of four cycles. S-1 plus Nab-PTX is an efficient and safe regimen as first-line treatment for patients with AGC.

Facile Deposition of Manganese Dioxide to Albumin-Bound Paclitaxel Nanoparticles for Modulation of Hypoxic Tumor Microenvironment To Improve Chemoradiation Therapy.

Tumor microenvironment with hypoxia and excess hydrogen peroxide (H2O2) tremendously limits the effect of chemoradiation therapy of colorectal cancer. For the first time, we developed a facile method to deposit manganese dioxide (MnO2) on the surface of albumin bound paclitaxel nanoparticles (ANPs-PTX) to obtain MnO2-functioned ANPs-PTX (MANPs-PTX). In the tumor microenvironment, MANPs-PTX could consume excess hydrogen peroxide (H2O2) to produce abundant oxygen for tumor oxygenation and improve chemoradiation therapy. Meanwhile, the released Mn2+ from MANPs-PTX had excellent T1 magnetic resonance imaging (MRI) performances for tumor detection. Notably, the obtained MANPs-PTX would be a promising theranostic agent and have potential clinical application prospects.

Pharmacokinetics and safety of paclitaxel delivery into porcine airway walls by a new endobronchial drug delivery catheter.

BACKGROUND AND OBJECTIVE: Intratumoral administration of chemotherapeutic agents is a treatment modality that has proven efficacious in reducing the recurrence of tumours and increases specificity of treatment while minimizing systemic side effects. Direct intratumoral injection of malignant airway obstruction has potential therapeutic benefits but tissue drug concentrations and side-effect profiles are poorly understood. METHODS: Bronchial wall injection of generic paclitaxel (PTX) (102 injections of 0.05, 0.5, 1.5 or 2.5 mg/mL in 10 healthy pigs), saline (14 injections in 2 healthy pigs) or Abraxane (ABX) (24 injections of 0.5 mg/mL in 4 healthy pigs) was performed with a microneedle infusion catheter. Local histopathology, plasma and tissue PTX concentrations were evaluated at 7, 20 or 28 days post-injection. RESULTS: Injection of generic PTX directly into the bronchial wall at doses up to 1.5 mg/mL only caused minimal tissue injury. Dose-limiting tissue reaction was observed at 2.5 mg/mL. Plasma PTX was detectable for up to 5 days but not at 28 days, with area under the curve (AUC)(0-5d) 20- to 50-fold lower than the AUC(0-∞) of 6300 ng h/mL for the approved intravenous dose. At 7 and 28 days post-injection, bronchial PTX tissue concentrations were above a 10-nmol/L cancer therapeutic level. PTX was not found in peripheral tissues. Similar results were observed between ABX and generic PTX. CONCLUSION: Results of these studies confirm the administration of PTX directly into the bronchial wall is safe and feasible. PTX was detectable in plasma for <7 days but tissue concentrations remained therapeutic throughout the follow-up period.

[A Case in Which Good Control of Carcinomatous Serositis Was Achieved Using Chemotherapy Including Albumin-Bound Paclitaxel(Nab-PTX)for Advanced-Stage Pulmonary Adenocarcinoma Exhibiting Carcinomatous Pleurisy and Carcinomatous Pericarditis].

The subject was a 63-year-old man. The patient was transported by ambulance to the hospital because of dyspnea caused by carcinomatous pleurisy and carcinomatous pericarditis, after which pericardial drainage was performed; however, Staphylococcus aureus bacteremia arose as a complication. Adequate control of carcinomatous serositis was achieved usingchemotherapy, includingalbumin -bound paclitaxel(nab-PTX), which is a nanoparticle formulation bindinghuman serum albumin and paclitaxel, in combination with 1 course of antibiotics. For cancerous serositis cases, platinum combination chemotherapy usingnab -PTX is believed to be 1 treatment option in which good disease control can be expected along with bevacizumab, whose efficacy has already been confirmed.

Neoadjuvant Therapy with Weekly Nanoparticle Albumin-Bound Paclitaxel for Luminal Early Breast Cancer Patients: Results from the NABRAX Study (GEICAM/2011-02), a Multicenter, Non-Randomized, Phase II Trial, with a Companion Biomarker Analysis.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) is an alternative to standard taxanes for breast cancer (BC) treatment. We evaluated nab-Paclitaxel efficacy as neoadjuvant treatment for early estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) disease. MATERIALS AND METHODS: Women with ER+, HER2-, stage II-III BC were treated preoperatively with four cycles of weekly nab-Paclitaxel (150 mg/m2), 3 weeks on and 1 week off. We hypothesized that poor pathological response rate (residual cancer burden [RCB] III; Symmans criteria) would be ≤16%. RESULTS: Eighty-one patients with a median age of 47 years were treated; 64.2% were premenopausal, and 69% of tumors were stage II. Residual cancer burden III rate was 28.4% (95% confidence interval [CI]: 18.6%-38.2%), RCB 0+I (good response) rate was 24.7% (95% CI: 15.3%-34.1%) and RCB 0 (complete response) rate was 7.4% (95% CI: 1.7%-13.1%). Objective response rate by magnetic resonance imaging was 76.5% and rate of conversion to breast conserving surgery was 40.0%. The most frequent grade 3 and 4 toxicity was neutropenia (12.3% and 3.7% of patients, respectively), without any febrile neutropenia. Sensory neuropathy grade 2 and 3 were seen in 25.9% and 2.5% of patients, respectively. Tumor secreted protein, acidic, cysteine-rich (SPARC) overexpression was significantly associated with RCB 0 (odds ratio: 0.079; 95% CI: 0.009-0.689; p = .0216). CONCLUSION: Despite failing to confirm an RCB III rate ≤16% in nab-Paclitaxel-treated patients, the RCB 0+I rate indicates a significant drug antitumor activity with low rates of grade 3-4 toxicity. Our exploratory biomarker analysis suggests a potential predictive role of complete response for SPARC. Confirmatory analyses are warranted, adapting dose and schedule to decrease peripheral neurotoxicity. (Trial registration: European Clinical Trials Database study number: 2011-004476-10; ClinicalTrials.gov: NCT01565499). IMPLICATIONS FOR PRACTICE: The pathological response rate (residual cancer burden [RCB]; Symmans criteria) of nanoparticle albumin-bound paclitaxel administered as neoadjuvant treatment for early estrogen receptor-positive, human epidermal growth factor receptor 2-negative disease was evaluated. Whereas poor response (RCB III) was 24.7%, similar to that for docetaxel, good response (RCB 0+I) reached 23.0%, far superior to the 13% for docetaxel, while keeping toxicity low. Exploratory biomarker analysis suggests secreted protein, acidic, cysteine-rich overexpression in tumor cells as a potential predictor of complete response (RCB 0). Findings point to an encouraging single-agent neoadjuvant treatment with low toxicity, which warrants future research and development.

[A Case of Albumin-Bound Paclitaxel-Induced Peripheral Neuropathy without Exacerbation].

Albumin-bound paclitaxel(nab-PTX)-associated neuropathy decreases the quality of life of cancer patients and leads to dose modification, discontinuation of chemotherapy, and occasionally dose-limiting toxicity. In the present case study, a 92- year-old female patient with peritoneal cancer of carcinomatous peritonitis and carcinomatous ascites was treated with carboplatin plus nab-PTX every 4 weeks as first-line chemotherapy, and a good response was achieved following 4 cycles of this regimen. However, the patient developed Grade 3 peripheral neuropathy and stopped the therapy. As a result, the peripheral neuropathy gradually improved. After 1 year, ascites appeared, and tumor marker(CA125)levels increased. We tried an 8-h infusion of nab-PTX to avoid peripheralneuropathy. After 4 cycles, a positive response was achieved without exacerbation of the peripheralneuropathy. Administering nab-PTX over shorter periods of time has generally led to increased peripheral neuropathy. The severity of peripheralneuropathy can be reduced with a longer infusion time.

[A Case of Shock Due to nabPTX Administration Successfully Treated with Cytokine Adsorption Therapy].

The patient was a 71-year-old woman with ER(+), PgR(-), HER2(3+), and Ki-674 2% breast cancer. After surgery for left breast cancer(Bt+Ax), epirubicin, cyclophosphamide therapy was administered as postoperative adjuvant chemotherapy, and nabPTX plus trastuzumab therapy was started sequentially. The patient was hospitalized due to severe neutrope- nia(neutrophils 0/mm3)from nabPTX, but her condition stabilized after admission. However, the patient suddenly went into shock after 3 days and was thus transferred to the ICU. Her general condition was rapidly improved through cytokine adsorption therapy in the ICU. After 5 days, she was extubated and wheeled back to a general ward. She was discharged without problems in the succeeding months. In this case, FN or cardiovascular diseases was ruled out, and engraftment syndrome was considered given that cytokine adsorption therapy significantly improved the patient's condition. Considering the risk for severe neutropenia in nabPTX administration, clinicians should exercise caution when administering the drug.

Phase I/II dose-finding study of nanoparticle albumin-bound paclitaxel (nab®-Paclitaxel) plus Cisplatin as Treatment for Metastatic Nasopharyngeal Carcinoma.

BACKGROUND: This phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab (®)-paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC). METHODS: Patients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m(2) on day 1; 2) IV nab-paclitaxel 140 mg/m(2) on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m(2) on day 1. Treatment continued for 4-6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining. RESULTS: Sixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6-12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC. CONCLUSIONS: Our findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study. TRIAL REGISTRATIONS: ClinicalTrials.gov ID: NCT01735409 . The trial was registered on November 20th, 2012.

A randomized phase II study of carboplatin with weekly or every-3-week nanoparticle albumin-bound paclitaxel (abraxane) in patients with extensive-stage small cell lung cancer.

BACKGROUND: Platinum plus etoposide is the standard therapy for extensive-stage small cell lung cancer (ES-SCLC) and is associated with significant myelosuppression. We hypothesized that the combination of carboplatin and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) would be better tolerated. We investigated carboplatin with nab-paclitaxel on every-3-week and weekly schedules. METHODS: This noncomparative randomized phase II trial used a two-stage design. The primary objective was objective response rate, and secondary objectives were progression-free survival, overall survival, and toxicity. Patients with ES-SCLC and an Eastern Cooperative Oncology Group performance status ≤2 and no prior chemotherapy were randomized in a 1:1 ratio to arm A (carboplatin area under the curve [AUC] of 6 on day 1 and nab-paclitaxel of 300 mg/m(2) on day 1 every 3 weeks) or arm B (carboplatin AUC of 6 on day 1 and nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15 every 21 days). Response was assessed after every two cycles. RESULTS: Patients required frequent dose reductions, treatment delays, and omission of the weekly therapy. The trial was closed because of slow accrual. CONCLUSION: Carboplatin and nab-paclitaxel demonstrated activity in ES-SCLC but required frequent dose adjustments.

Impact of perioperative chemotherapy on survival in patients with advanced primary urethral cancer: results of the international collaboration on primary urethral carcinoma.

BACKGROUND: To investigate the impact of perioperative chemo(radio)therapy in advanced primary urethral carcinoma (PUC). PATIENTS AND METHODS: A series of 124 patients (86 men, 38 women) were diagnosed with and underwent surgery for PUC in 10 referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank testing was used to investigate the impact of perioperative chemo(radio)therapy on overall survival (OS). The median follow-up was 21 months (mean: 32 months; interquartile range: 5-48). RESULTS: Neoadjuvant chemotherapy (NAC), neoadjuvant chemoradiotherapy (N-CRT) plus adjuvant chemotherapy (ACH), and ACH was delivered in 12 (31%), 6 (15%) and 21 (54%) of these patients, respectively. Receipt of NAC/N-CRT was associated with clinically node-positive disease (cN+; P = 0.033) and lower utilization of cystectomy at surgery (P = 0.015). The objective response rate to NAC and N-CRT was 25% and 33%, respectively. The 3-year OS for patients with objective response to neoadjuvant treatment (complete/partial response) was 100% and 58.3% for those with stable or progressive disease (P = 0.30). Of the 26 patients staged ≥cT3 and/or cN+ disease, 16 (62%) received perioperative chemo(radio)therapy and 10 upfront surgery without perioperative chemotherapy (38%). The 3-year OS for this locally advanced subset of patients (≥cT3 and/or cN+) who received NAC (N = 5), N-CRT (N = 3), surgery-only (N = 10) and surgery plus ACH (N = 8) was 100%, 100%, 50% and 20%, respectively (P = 0.016). Among these 26 patients, receipt of neoadjuvant treatment was significantly associated with improved 3-year relapse-free survival (RFS) (P = 0.022) and OS (P = 0.022). Proximal tumor location correlated with inferior 3-year RFS and OS (P = 0.056/0.005). CONCLUSION: In this series, patients who received NAC/N-CRT for cT3 and/or cN+ PUC appeared to demonstrate improved survival compared with those who underwent upfront surgery with or without ACH.

Reinvention of chemotherapy: drug conjugates and nanoparticles.

PURPOSE OF REVIEW: Recent advances in nanotechnology have addressed some of the issues related to lack of selectivity and nonspecific toxicities associated with conventional chemotherapy. Nanoparticles are therapeutic carriers that can be fine tuned for specific application and for passive or active tumor targeting. RECENT FINDINGS: Although the nanoparticle field is rapidly expanding, there are to date only six nanoparticle-based drug delivery platforms and two antibody-drug conjugates that are clinically approved for cancer therapy. Here, we review the clinical data of liposomal anthracyclines, nanoparticle formulations of paclitaxel and trastuzumab emtansine. We then briefly comment on efficacy and safety issues of nanoparticles, as well as on the next-generation nanoparticles for cancer therapy. SUMMARY: The emerging development of cancer nanotechnology offers the opportunity of reinvestigating the potential of cytotoxic agents, improving tumor targeting and drug delivery, leading to better safety profile and antitumor activity. Adding specificity to nanoparticles may allow personalization of cancer therapy using chemotherapy.

A phase I study of combination therapy with nanoparticle albumin-bound paclitaxel and cyclophosphamide in patients with metastatic or recurrent breast cancer.

BACKGROUND: The objective of the present clinical study is to determine the maximum tolerated dose (MTD)/recommended dose (RD) of combination therapy with nanoparticle albumin-bound paclitaxel (nab-PTX) and cyclophosphamide (CPA) in patients with metastatic or recurrent breast cancer. METHODS: nab-PTX and CPA were administered on the first day of each 21-day treatment cycle. The dose of CPA was fixed at 600 mg/m(2), while the dose of nab-PTX was increased from 180 mg/m(2) (Level 1) to 220 mg/m(2) (Level 2) and then to 260 mg/m(2) (Level 3). RESULTS: A total of 11 patients from two institutions were enrolled in the present study. At Level 3, a dose-limiting toxicity (DLT) was observed in 1 patient. Considering treatment continuity and the risk of adverse events in Cycle 2 and thereafter at this level, further subject enrollment at Level 3 was discontinued after two patients had been enrolled. Since the doses used at Level 3 were considered the MTD of nab-PTX and CPA and the doses used at Level 2 were considered the RD of nab-PTX and CPA, three additional subjects were enrolled at Level 2. No DLTs were observed at Level 2. CONCLUSION: The RD of combination therapy with nab-PTX and CPA was 220 mg/m(2) and 600 mg/m(2), respectively, in patients with metastatic or recurrent breast cancer.

Short-Term Safety Evaluation of Albumin-Bound Paclitaxel in Intraoperative and Postoperative Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer.

PURPOSE: To evaluate the short-term safety of albumin-bound paclitaxel in hyperthermic intraperitoneal chemotherapy (HIPEC) during and after gastric cancer (GC) surgery. METHODS: A retrospective analysis of clinical data was conducted for GC surgery patients at Zhongnan Hospital of Wuhan University, from January 2020 to September 2022. The study group (n = 120) received HIPEC and the control group (n = 268) did not receive albumin-bound paclitaxel. Short-term safety indicators including intraoperative complications, hematological toxicity, liver and kidney function, and gastrointestinal function recovery were compared between the two groups. RESULTS: There were no statistically significant differences between the two groups regarding intraoperative complications, hematological toxicity, liver and kidney function, and gastrointestinal function recovery time (P > 0.05 for all). In the study group, patients were further divided into subgroups based on dose and timing. Subgroup analysis revealed no significant differences among the different dose subgroups. However, when focusing on timing subgroups, the postoperative subgroup exhibited significantly higher white blood cell counts and bilirubin levels compared to the intraoperative subgroup, while the intraoperative subgroup had significantly higher bilirubin levels compared to both postoperative and intraoperative plus postoperative subgroups. CONCLUSION: Albumin-bound paclitaxel demonstrates good safety and tolerability in HIPEC during and after GC surgery, without increasing the risk of intraoperative complications.

A retrospective study of adjuvant albumin-bound paclitaxel plus S-1 after D2 gastrectomy versus oxaliplatin plus S-1 in gastric cancer.

Adjuvant oxaliplatin plus S-1 (SOX) chemotherapy for gastric cancer (GC) after D2 gastrectomy has been proven effective. There has yet to be a study that evaluates adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus S-1. In this single-center, retrospective study, GC patients after D2 gastrectomy received either nab-paclitaxel plus S-1 (AS group) or SOX group were recruited between January 2018 and December 2020 in The First Affiliated Hospital of Zhejiang University. Intravenous nab-paclitaxel 120 mg/m2 or 260 mg/m2 and oxaliplatin 130 mg/m2 were administered as eight 3 week cycle, especially in the AS and SOX group. Patients received S-1 twice daily with a dose of 40 mg/m2 in the two groups on days 1-14 of each cycle. The end points were disease-free survival (DFS) rate at 3 years and adverse events (AEs). There were 56 eligible patients, 28 in the AS group and 35 in the SOX group. The 3 year DFS rate was 78.0% in AS group versus 70.7% in SOX group (p = 0.46). Subgroup analysis showed that the patients with signet-ring positive in the AS group had a prolonged DFS compared with the SOX group (40.0 vs. 13.8 m, p = 0.02). The diffuse-type GC or low differentiation in the AS group was associated with numerically prolonged DFS compared with the SOX group, but the association was not statistically significant (p = 0.27 and p = 0.15 especially). Leukopenia (14.3%) were the most prevalent AEs in the AS group, while thrombocytopenia (28.5%) in the SOX group. Neutropenia (7.1% in AS group) and thrombocytopenia (22.8% in SOX group) were the most common grade 3 or 4 AEs. In this study analyzing past data, a tendency towards a greater 3 year DFS was observed when using AS regimen in signet-ring positive patients. AS group had fewer thrombocytopenia compared to SOX group. More studies should be conducted with larger sample sizes.

Dose-dense doxorubicin and cyclophosphamide followed by dose-dense albumin-bound paclitaxel plus bevacizumab is safe as adjuvant therapy in patients with early stage breast cancer.

UNLABELLED: Every-2-week (dose-dense) adjuvant doxorubicin (A) plus cyclophosphamide (C) followed by cremophor-formulated paclitaxel (cf-P) was efficacious in metastatic breast cancer (BC). Albumin-bound paclitaxel (ab-P) was safe and more effective than cf-P, and the addition of bevacizumab to cf-P improved efficacy. This study compared the safety of dose-dense ab-P vs cf-P plus bevacizumab following dose-dense adjuvant AC for early-stage BC. PATIENTS AND METHODS: Women with operable, histologically confirmed BC were randomized to 4 cycles of dose-dense A 60 mg/m(2) plus C 600 mg/m(2) IV with SC pegfilgrastim, followed by 4 cycles of either dose-dense IV ab-P 260 mg/m(2) or cf-P 175 mg/m(2). Bevacizumab was given during and following chemotherapy. 97 and 96% of patients completed 4 cycles of AC therapy, while 84 and 85% of patients completed 4 cycles of taxane therapy in the ab-P and cf-P arms, respectively (N = 197). Baseline patient characteristics were similar. The most common grade ≥3 taxane-related adverse events (AEs) were fatigue and neutropenia. Dose reductions were similar between the treatment arms. During AC therapy, the majority of dose reductions were due to febrile neutropenia; during taxane therapy, the majority of cases were due to neuropathy. No taxane-related dose interruption occurred in the ab-P arm, while 3 occurred in the cf-P arm due to hypersensitivity reactions. The mean cumulative paclitaxel dose was 950.5 and 660.8 mg/m(2) in the ab-P and cf-P arms, respectively. A 44% higher paclitaxel dose was delivered in the ab-P compared with the cf-P arm (P < 0.0001), while achieving a similar safety profile. ab-P plus bevacizumab following AC therapy without prophylactic premedications was tolerable in early-stage BC patients.

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

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