Abstract Objective comparison and evaluation of paclitaxel plus cisplatin Fortnight and three weeks in the treatment of advanced non-small cell lung cancer (NSCLC) term efficacy and toxicity. Method has been pathology and cytology confirmed 60 cases of Ⅲ Ⅳ NSCLC were randomly divided into two groups. Biweekly therapy group (n = 30 patients) paclitaxel 80 mg/m2, cisplatin 40 mg/m2ivgtt d1, 8, 21 days repeat; three weeks therapy (n = 30 patients) paclitaxel 140 mg/m2 and cisplatin 60 mg / m2ivgtt d1, repeated in 21 days. 3,12,24 h after administration plasma concentration was measured, and to evaluate the efficacy and toxicity after two cycles of chemotherapy. Results biweekly therapy and three weeks of therapy efficiency of 40.0% and 33.3%, respectively, the difference was not statistically significant, but a lower incidence of biweekly therapy toxicity. The biweekly regimen conclusion paclitaxel plus cisplatin treatment of advanced NSCLC than three weeks more safe and effective therapy, patients are easy to accept, suitable for clinical application, it is worth to increase the number of cases to do in-depth research.

Three weeks therapy 【Key Words】 non-small cell lung cancer; paclitaxel; cisplatin; biweekly therapy;

    Double and Three  week Regime of Paclitaxel Combined with Cisplatin in Treatment of Advanced Non  small Cell Lung Cancer

    ZHAO Wen  yan, SHAO Huan, ZHONG Jiao, CAO Hong  fu, WANG Li  ping, MIAO Jian  hua

    Depart ment of Pharmacy, The Second People’s Hospital of Wuxi, Wuxi 214002, ChinaAbstract: Objective To evaluate the efficacy and toxicity of paclitaxel combined with cisplatin in the treatment of advanced non  small cell lung cancer (NSCLC) by double and three  week regime . Methods Sixty patients with locally advanced (stage Ⅲ) or metastatic (stage Ⅳ) NSCLC were enrolled into the study and divided to two groups. Double week regime (n = 30): paclitaxel 80 mg/m2, cisplatin 40 mg/m2 ivgtt d1 , 8, and it was repeated at d 21. Three  week regime (n = 30): paclitaxel 140 mg/m2, cisplatin 60 mg/m2 ivgtt d1 and it was repeated at d 21. A HPLC method was established for the determination of paclitaxel at 3,12, 24 h after administration, and evaluate the efficacy and toxicity after two chemotherapy cycles.Results The overall response rate of double week regime and three  week regime were 40.0% and 36.7%, respectively, there was no statistic difference, but the main toxicities of double week regime were lower.Conclusion Double week regime is a better method for the treatment of advanced NSCLC, it could increase patients for further study.

    Key words: NSCLC; Paclitaxel; Cisplatin; double  week regime; three  week regime

 Lung cancer is the most common tumor in the world today, and in recent years in the morbidity and mortality increase accounted for malignancy death of the first one. About 70% of non-small cell lung cancer treatment when 70% to 80% for advanced disease, and most patients visit advanced stage, comprehensive treatment of chemotherapy. Unsatisfactory due to the effect of chemotherapy, it is looking for efficiency and low toxicity of chemotherapy is one of the Journal of Clinical Oncology sector has been a subject of concern.

    Paclitaxel and cisplatin in the treatment of advanced NSCLC clinical chemotherapy. Generally 3 weeks 1 dose, 21 days repeated three weeks of therapy, but the high incidence of toxicity, the patient’s body injury. Therefore, we tried paclitaxel and cisplatin on day 8, repeated on day 21, composed of a biweekly regimen in advanced NSCLC compared with three weeks of the program.

    1 Materials and methods

    1.1 Materials

    1.1.1 Selection of cases

    (1) were required to sign an informed consent form;

    (2) Age: 18 to 75 years old;

    (3) with histologically or cytologically confirmed (local system) non-small cell bronchial carcinoma (adenocarcinoma or are not classified in non-small cell lung cancer) cell specimens by bronchoscopy brush cytology or biopsy obtained if measurable or evaluable lesions, pleural effusion cell samples.

    (4) in patients with lung should be X-ray or CT measurable or evaluable lesions.

    (5) ECOG score of 0 to 2.

    12周。">(6) the expected survival time of> 12 weeks.

    (7) hematology, liver and kidney function is normal. 1 500/mm3,血小板>100 000/mm3,血红蛋白>8 g/mm3,转氨酶< 3×正常值上限,胆红素<1.5×正常值上限,肌酐<1.5 mg/dl。">Neutrophil count> 500/mm3, platelets> 100 000/mm3 hemoglobin> 8 g/mm3, transaminase❤ × upper limit of normal, bilirubin <1.5 × upper limit of normal, creatinine <1.5 mg / dl.

    1.1.2 General pathology or needle aspiration cytology diagnosis of inoperable advanced NSCLC 60 patients were randomly divided into biweekly therapy group (A) and three weeks therapy group (B). A group of 30 patients, 22 males and 8 females; aged 36 to 68 years, mean age 60.4 ± 4.6 years; 16 cases of adenocarcinoma, squamous cell carcinoma, 11 cases, 2 cases of adenosquamous carcinoma, alveolar cell carcinoma 1 cases; Ⅲ 21 cases, Ⅳ 9 cases; initial treatment of 17 cases, 13 cases of retreatment. B group of 30 patients, 20 males and 10 females; aged 45 to 75 years old, with an average of 62.2 ± 5.2 years, 17 cases of adenocarcinoma, 10 cases of squamous cell carcinoma, adenosquamous carcinoma, alveolar cell carcinoma in two cases; Ⅲ of 18 cases, Ⅳ 12 cases; initial treatment of 16 cases, 14 cases of retreatment. No statistically significant differences in the clinical characteristics of the two groups of patients.

    All patients had efficacy evaluation of measurable lesions, not previously containing paclitaxel chemotherapy not radiotherapy; Karnofsky score ≥ 60 points; hemogram, liver and kidney function, heart function without significant exception, no chemotherapy taboo.

    1.2 Methods

    1.2.1 Treatment Group A: paclitaxel 80 mg/m2, cisplatin the 40 mg/m2ivgtt d1, 8, 21 days repeat. Group B: paclitaxel 140 mg/m2, cisplatin 60 mg/m2ivgtt d1, repeated on day 21.

    3 hours before paclitaxel for cisplatin infusion, the routine use of dexamethasone before chemotherapy, anti-allergy, diphenhydramine and granisetron antiemetic; blood toxicity colony stimulating factor treatment of severe thrombocytopenia and anemia, given the ingredients blood transfusion.

    1.2.2 plasma concentrations were measured in patients stop after intravenous infusion of paclitaxel, 4 ml (heparin), 3,12,24 h depicting blood plasma samples were measured by HPLC after extraction processing its plasma concentration [1] .

    1.2.3 evaluation of the efficacy and toxicity of WHO Solid Tumors Common Criteria is divided into complete remission (CR), partial remission (PR), no change (NC) and progress (PD), the CR, PR effectively. The toxicity evaluation of toxic reactions the indexing (0-4 degrees) the unified standard to be assessed according to the WHO anti-cancer drugs. Both groups were first chemotherapy cycle made efficacy evaluation, no tumor increase the performance of those who continue chemotherapy; later evaluate the efficacy of once every 2 cycles; to tumor progression terminate observed.

    1.2.4 Statistical methods χ2 test (Fisher’s exact method), SAS 8.1 software processing, P ≤ 0.05 difference was statistically significant.

    2 Results

    2.1 blood concentrations are shown in Table 1. Fortnight in Table 1 Table 2 paclitaxel and cisplatin Fortnight three weeks therapy in the treatment of advanced non-small cell carcinoma of the efficacy with the plasma concentration of the three time points after administration of three weeks therapy programs

    2.2 The short-term effect

    All patients completed 2 cycles of chemotherapy, could be evaluated. Group A total response rate (RR) 40.0% (12/30). Group B, the total response rate (RR) 33.3% (10/30). RR was no significant difference between the two groups. -Naïve patients in group A 17 cases, the CR 2 cases, PR 6, RR = 47.1% (8/17); B group, 16 patients, CR 1, PR in 5 cases, RR = 37.5% (6/16). Two sets of previously untreated patients with no tumor progression, no statistically significant difference between the groups. Retreatment in patients with non-CR, A group of 13 patients, PR 4 cases, RR = 30.8% (4/13); B group (14 cases), PR 4 cases, RR = 28.6% (4/14), the difference between the groups was not statistically significance.

    2.3 toxicity

    All cases were for toxicity assessment, and the results are shown in Table 3. Table 3 paclitaxel plus cisplatin toxicity of biweekly with three weeks regimen in advanced non-small cell carcinoma

    3 Discussion

    Paclitaxel as a new type of plant-based anticancer drugs, and its mechanism of action is aggregated into clumps and wispy and stabilize microtubules by promoting cell cancer cells to arrest in M ​​phase and G2 phase, thus preventing cell division and proliferation, reaching The purpose of anti-tumor [2]. The higher activity of paclitaxel in NSCLC, single-agent chemotherapy for advanced NSCLC effective rate of 21% to 31% [3,4].

    Is one of the more effective and widely used chemotherapy paclitaxel and cisplatin in the treatment of advanced NSCLC [5]. Generally administered three times a week, 21 days. Efficacy is far more satisfactory, but the high incidence of toxicity, in patients with bone marrow suppression common and serious, could easily lead to chemotherapy interrupt is not conducive to patients receiving long-term treatment. It has been reported [6] that paclitaxel 3 weeks of chemotherapy, patients with neutropenia than 90% up to 52%, Ⅳ degree. Domestic reports [7], leukopenia incidence of 65.1% degree of of Ⅲ ~~ IV 21.9%, 19.3% thrombocytopenia, fever 6.4%. Based on this, in order to reduce the toxicity of better clinical benefit, and our trial paclitaxel and cisplatin on day 8, repeated on day 21, composed of a biweekly regimen in advanced NSCLC compared with three weeks of the program. More satisfied with the efficacy of biweekly paclitaxel and cisplatin therapy for advanced NSCLC, the effective rate was 40.0% higher than the control group of three weeks therapy programs, though not statistically significant, but the severity of the toxicity significantly from the results in Table 2 shows reduced. Observed through the results in Table 3, three weeks therapy group and severe toxicity (Ⅲ – Ⅳ degrees) were significantly higher than biweekly therapy group, the biweekly therapy toxicity is still common, but mostly mild severe reactions occur rarely, no one cases Ⅳ degree of toxicity, patients easily accepted and well tolerated, especially in severe hematologic toxicity rarely occurs. Three weeks therapy group, eight cases have been so delayed chemotherapy biweekly therapy group therefore delay the administration, treatment progressed smoothly.

    Paclitaxel therapeutically effective blood concentration of 0.01 ~ 0.1 umol / L i.e. from 8.5 ~~ 85 ng / ml (the former for the in vitro radiosensitization concentration, the latter as bone marrow inhibition concentration). As can be seen from the results in Table 1, three weeks therapy the patient’s blood concentration at 12 h after administration is still greater than the minimum concentration of the inhibition of the bone marrow, which is easy to lead to severe bone marrow suppression, concurrent infection, limiting the smooth progress of chemotherapy, so The incidence of the three weeks of the toxicity of the therapy is significantly more than the biweekly therapy, which was positively correlated with the plasma concentration results.

    Three weeks program group toxicity incidence in this study is higher than that reported in the general condition may be associated with poor late stage of disease and related intolerance to chemotherapy in the retreatment of patients with a relatively high proportion of this study, there bone marrow dysfunction of vital organs reserves and other factors. Experimental study and clinical validation [8  11], to increase the frequency of dosing can increase the contact time of the drugs with tumor cells, to improve the anti-ratio, reduce drug; single dose while reducing the blood concentration can be reduced, thereby reducing the toxicity reaction. Biweekly therapy by reducing the single dose and increase the frequency of administration, to improve the efficacy and reduce the toxicity.

    Summary, bi-weekly dosing regimen of paclitaxel and cisplatin in patients with advanced NSCLC recent results were satisfactory, low toxicity, good security, with three weeks of therapy than to reduce the toxicity and improve the quality of life of patients, benefit to patients receiving long-term treatment. Therefore, the the biweekly therapy program is worth further expand the case to continue in-depth study to guide rational drug.