Abstract Objective To compare paclitaxel albumin particles and to polyoxyethylene castor oil solvent paclitaxel treatment of advanced breast cancer, the efficacy and adverse reactions. Were treated 21 cases of advanced breast cancer, were randomly divided into a treatment group and a control group. Treatment group paclitaxel albumin particles each dose of 260mg / m2, the control group, polyoxyethylene castor oil solvent paclitaxel each dose of 175mg / m2, were repeated every 3 weeks. The control group before chemotherapy routinely given dexamethasone, cimetidine small and benzene Diphenhydramine prevention of allergic reactions. The two groups of patients each received at least four cycles of treatment, once every two cycle assessment efficacy. 9/9 patients of the treatment group CR + PR, the control group, 7/12 cases. The two groups were not an allergic reaction occurs, major adverse neurotoxicity and neutropenia. Conclusion paclitaxel albumin particles to polyoxyethylene castor oil solvent paclitaxel compared to treatment, the treatment group in the prevention of allergic reactions to deal with the case, and no case of allergic reactions.

Key words】 paclitaxel albumin particles; advanced breast cancer; efficacy; adverse reactions

 Albumin  Bound Particles in Treatment with Advanced Breast Cancer

    ZHAO Jing, YU Shi  ying

    Tongji Hospital Cancer Centre, Tongji Medical College Affiliated Huazhong University of Science & Technology, Wuhan 430030, ChinaAbstract: Objective To compare the efficacy and the adverse reactions between albumin  bound particles and polyethylated castor oil  based paclitaxel in treatment of advanced breast cancer. Methods Twenty  one patients were randomly divided into treatment and control groups with 3  week cycles. The dose of treatment group was 260mg/m2, which was 175mg/m2 in control group. In control group, dexamethasone, cimetidine and diphenhydramine were given before chemotherapy to prevent allergic reactions. Two groups of patients received at least four cycles of treatment, with assessment of every two cycles.Results

    In treatment group, 9/9 cases were CR or PR, and in control group was 7/12 cases. No allergic reactions in two groups. The main adverse reactions were neurotoxicity and neutropenia. Conclusion By compare albumin  bound particles and polyethylated castor oil  based paclitaxel, the efficacy was similar, and in treatment group, allergic reactions didn’t occur without any preventive treatments of allergic reactions.

    Key words: Albumin  bound particles; Advanced breast cancer; Efficacy; Adverse reactions

Taxol is used clinically in the 90s of the 20th century, a new generation of broad-spectrum anti-cancer drug. It water soluble Terrible. The current clinical use of paclitaxel formulations to polyoxyethylene castor oil (Cremophor EL) and absolute ethanol (1:1) mixture as a cosolvent. These co-solvents may be used to cause a variety of adverse reactions, including a relatively clear Allergies and neurotoxicity. Further, the polyoxyethylene castor oil of the formation of small particles in the blood circulation can paclitaxel molecules wrapped hindered drugs.

    Paclitaxel albumin particles are a novel paclitaxel formulation. , Because it does not contain cosolvents can cause allergic reactions in the United States, Europe and India Ⅰ, Ⅱ, Ⅲ clinical studies have shown that, prior to administration without pretreatment, and security enhanced paclitaxel dose. From July 2005 to November 2006, we were for advanced breast cancer Phase II open label, randomized controlled clinical studies, mainly to observe the efficacy and adverse effects, the results reported below.

    1 Materials and Methods

    1.1 patient inclusion criteria

    Non-pregnant, non-lactating women, aged 18 to 70 years, patients with histologically or cytologically confirmed breast cancer, and CT measurable recurrent or metastatic lesions. ECOG performance status ≤ 1, the expected survival of> 12 weeks. Before treatment, blood tests must satisfy the following requirements: ANC ≥ 1.5 × 109 / L, PLT ≥ 100 × 109 / L, Hb ≥ 90g / L, ALT, AST ≤ 2.5 times the upper limit of normal (without liver metastasis cases) or ≤ 5 times normal value ceiling (liver metastases cases), creatinine ≤ 1.5 times the upper limit of normal, total bilirubin properly. All patients enrolled before January did not receive anti-cancer therapy.

    1.2 study drug

    Treatment groups: paclitaxel albumin particles (Kay prime), a bottle of 100mg; control group: paclitaxel injection, each bottle of 30mg.

    1.3 The method of administration

    The study was an open-label, randomized controlled clinical trial. Enrolled patients were randomly divided into a treatment group and a control group. The treatment group starting dose of 260mg / m2, intravenous infusion, 30min to complete, not pre-treatment before medication. The control group, the starting dose of 175mg / m2, the intravenous infusion 3h completed, be 12,6 h before treatment with dexamethasone 20mg orally, half an hour before the administration be diphenhydramine 50mg oral cimetidine small 0.4g intravenous drip . Two groups of drugs were repeated every 3 weeks. Addition to hair loss, III, grade IV hematologic or non-hematologic toxicity, the next cycle to reduce a dose level administered. A dose level in the treatment group, 40mg/m2, 30mg/m2 control group.

    1.4 efficacy and adverse reactions assessed

    Once every two cycle assessment efficacy. Assessment standards of Solid Tumors (RECIST), divided into complete remission (CR), partial remission (PR), stable (SD), progress (PD). Adverse reactions assessed by WHO chemotherapy drugs acute and subacute toxicity grading criteria, divided into 0 ~ Ⅳ degrees.

    2 Results

    2.1 general information of the selected cases

    27 patients signed informed consent for screening, 21 patients met the criteria of the patients received at least four cycles of treatment, as shown in Table 1, 2. Table 1, the subgroup of patients in Table 2 patients with general information

    In November 2006, 21 patients completed a total of 120 cycles of treatment. During adverse events (AEs) reported a total of 136 times, serious adverse events (SAE) 11 times. The AEs in hematologic toxicity accounted for 59.6%, the majority of the I and II. SAE reduce neutrophils are Ⅳ degree. Four patients with a total of six cycles due to hematological toxicity of grade Ⅲ, Ⅳ, reduction of administration, the treatment group and the control group, 2 cases each.

    2.2 efficacy analysis

    The two groups recently efficacy analysis, the number of cases of CR + PR 7/12 patients in the treatment group, 9/9 patients in the control group, as shown in Table 3. Table 3 groups term efficacy comparison

    2.3 Adverse reactions

    Taxanes major adverse reactions include allergic reactions, neutropenia, and neurotoxicity. In this study, the two groups were not seen allergic reactions. Treatment group, 9 cases of 52 cycles of treatment, neutropenia was 75.0% in the control group, 12 cases of 68 cycles of treatment neutropenia incidence rate of 83.8%, neutropenia was 13.5% in the treatment group Ⅳ degree of control 5.9%, the difference was not statistically significant (P> 0.05), are shown in Table 4. Table 4 hematologic toxicity
    3 Discussion

    3.1 The effect of

    Taxol is an anticancer broad spectrum of new anti-microtubule drug, can promote tubulin assembly into microtubules, but inhibition of microtubule depolymerization, leading to the arrangement of microtubules abnormal microtubule bundle formation of stable non-functional, spindle loss of normal function and lead to cell death [1], is most active in breast cancer chemotherapy drugs one. Jiang Zefei et al [2] reported breast cancer to initial treatment and retreatment rate was 60% and 33.3%, Wada Y, etc. [3] the treatment of recurrent or metastatic breast cancer 37 cases, an effective rate of 35.1%.

    Early paclitaxel clinical study found that paclitaxel clinical correlation exists dose  efficacy [4  5], but to help solvent polyoxyethylene castor oil paclitaxel molecule can be wrapped, hinder the role of the drug. To solve this problem, it has conducted a large number of Exploration. Qiu Airlines [6] found that serum albumin modified paclitaxel has a higher absorption peak. Compared with the absorption peaks of pure albumin or Taxol, there are significant differences. Thuringia et al [7] developed doxorubicin the star magnetic albumin particles, was found with a single drug doxorubicin comparison, both tumor suppression was similar at the same concentration. Schnitzer [8] found that the cell membrane, the presence of albumin receptor by Gp60 and sugar-based protein expression of caveolin-1 is directly involved in the transshipment of drugs through the membrane cell. The albumin-containing drugs can be transported through the membrane to the tumor cells, so that the increased local concentration of the drug within the tumor cells, thereby enhancing efficacy.

    In September 2004, the the paclitaxel albumin particles (Kay prime) Phase I clinical trials done in our country [9], the test dose range is 135 ~ 350mg/m2, the maximum tolerated dose of 300mg/m2. The study shows the total effective rate of 38%, the disease control rate was 81%. In the clinical study, the treatment group, the amount of Phase I clinical trials recommended 260 mg / m2, 9 patients were all effective, which achieved CR and PR, respectively, for the two cases and 7 cases. 20-month follow-up, the treatment group of disease-free survival time of 6 to 20 months, with a median time of 13 months. Gradishar et al [10] conducted a Phase III clinical trial, were randomly divided into the ABI  007 (paclitaxel albumin particles) consistent with the study group of 229 cases and traditional the paclitaxel group of 225 cases, dose. The results show that the two sets of clinical remission rate of 33% and 19%, respectively (P = 0.001). The tumor median time to progression was 23 weeks and 16.9 weeks, and median overall survival time of 65 months and 55.7 months, respectively.

    3.2 allergic reactions

    Paclitaxel allergic reaction mechanism is the body’s anti-cholesterol antibodies with poly (ethylene oxide) castor oil micelle surface combined with the large number of hydroxyl groups, the activation of the complement C3 particles cause mast cells to release histamine, produce the type Ⅰ immediate allergic reactions. In this study, the treatment group because without poly (ethylene oxide) castor oil, and thus not pretreatment did not occur allergic reactions, makes administration more safe and convenient, easier to accept patients. Incidence of allergic reactions is not observed in the control group, with adequate precautions are taken before treatment relevant.

    , Jiang Zefei [2] compared a the domestic several traditional paclitaxel product of allergic reactions. Mild allergic reaction manifested as itching, flushing, rash, chest tightness, chills, hypotension incidence of 41% to 56%, severe allergic reactions tend to be more rare, hypotension, nausea, bronchospasm, diffuse urticaria measles and angioedema and shock, with an incidence of 0.5% to 2%.

    Paclitaxel hypersensitivity reactions and infusion techniques. Paclitaxel infusion, can not use PVC containers, infusion pipe can not contain polyvinyl chloride, should be used glass container or polypropylene, polyolefin-based container, the diameter of the microporous membrane of the filter must not exceed 0.22μm. Using saline diluted slow infusion, the total administered at least 3h.

    3.3 neurotoxicity

    Neurotoxicity is another common use of taxanes toxicity. Including peripheral neurotoxicity, movement neurotoxicity and autonomic nervous system toxicity, myopathy, central nervous system toxicity [11]. Peripheral nerve toxicity manifested as numbness, paresthesia, tingling, burning sensation, common in the fingers and toes. Motor nerve toxicity manifested as distal toe extensor mild weakness. The most common manifestation is mild numbness and paresthesia.

    Nabholtz et al [4] reported that paclitaxel single drug dose of 135 ~ 175mg/m2 sensory neuropathy was 46% to 70%, while the of Ⅲ degree or Ⅳ degree sensory neuropathy incidence of 3% to 7%. This may be related to the organic solvent poly (ethylene oxide) castor oil induced demyelination and neuronal degeneration, and there is a dose-dependent dose of paclitaxel dose increased to 200 ~ 250mg/m2, Ⅳ degree sensory neuropathy rate of 9% to 12%.

    In this study, the use of a control group of patients, occurred Ⅰ, Ⅱ degree of neurotoxicity six cases, two cases of Ⅲ degree of neurotoxicity, the overall incidence of 66.7%. In the treatment group, only one case occurred Ⅲ degree of neurotoxicity, the total incidence compared with the control group, accounting for 77.8%, but the difference was not statistically significant. Neurotoxicity occurred in the two groups of patients to return to normal required median time to treatment group in April, the control group in May. Neurotoxicity after treatment group patients, and more able to quickly recover, and no cases cause the administration to delay.

    4 summarizes

    Paclitaxel albumin particles is a new paclitaxel formulation, it has a good anti-cancer activity, and the effects of not less than traditional paclitaxel; former without polyoxyethylene castor oil, and thus reduce an allergic reaction, and the incidence of severe neurotoxicity these have been reported in the pre-clinical trials of foreign as well as domestic. Also observed in the trial, both treatment and paclitaxel albumin particles before treatment did not prevent allergic reactions treatment, no cases of allergic reactions. Deserves further attention in future clinical applications.