Clinical Investigation of Efficacy of Albumin Bound Paclitaxel plus Platinum Compounds as First-line Chemotherapy for Stage III / IV Squamous Non-small Cell Lung Cancer

Recently, great progression have been made on the research of pulmonary adenocarcinoma. Pemetrexed, a third-generation chemotherapeutic agent, has showed its favorable efficacy and tolerable toxicity both in first-line, second-line and maintenance treatment of pulmonary adenocarcinoma (Hanna et al., 2004; Scagliotti et al., 2008; Ciuleanu et a1., 2009), so the combination chemotherapy of pemetrexed and platinum compounds is recommended as first-line standard therapy for advanced non-small cell lung cancer (NSCLC) by NCCN. Targeted drugs, such as bevacizumab, combined with chemotherapy, are also quitely effective treatment for pulmonary adenocarcinoma (Barlesi et al., 2013). There are various therapeutic treatments of targeted EGFR-TKI inhibiter owing to the 50~60% EGFR mutation rate in Asiatic pulmonary adenocarcinoma patients (Shi et al., 2014). In contrast, there is no breakthrough in treatment of pulmonary adenocarcinoma and the treatment options are also limited. Nanoparticle albumin bound paclitaxel


Clinical Investigation of Efficacy of Albumin Bound Paclitaxel plus Platinum Compounds as First-line Chemotherapy for Stage Ⅲ/IV Squamous Non-small Cell Lung Cancer
Ying Fang, Li Wang, Guo-Hao Xia, Mei-Qi Shi* (nab-paclitaxel), a new type of paclitaxel praeparatum, has many advantages like high efficiency, low toxicity and convenience.Our department applied nanoparticle albumin bound paclitaxel (nab-paclitaxel) combinded platinum agents (cisplatin, DPP or carboplatin, CBP) as first-line treatment in 40 lung squamous carcinoma patients between February, 2011 to October, 2013, and the results are as follows.

Clinical data
Eligible adults had histologically/cytologically confirmed nonresectable stage III or IV squamous carcinoma from February 2011 to October 2013.All patients were naive cases, including 36 males and 4 females, aged between 30 to 79 years, the median age was 61. 26 cases in stage III including 24 cases in III A period and 2 cases in III B ; 14 cases in IV ; 19 cases receiving nanoparticle albumin bound paclitaxel plus cisplatin, 21 cases in combination with carboplatin.All patients were confirmed the presence of measurable lesions by CT scan and the Eastern Cooperative Oncology Group (ECOG) score was 0~2, and a life expectancy of more than 3 months.Their routine blood test and electrocardiogram were generally normal before treatment, meanwhile liver and kidney functions ≤1.5 times the normal range.All patients signed consent form before treatment.Table 1 gives general situation of 40 cases.

Methods
Albumin-bound paclitaxel was used at a dose of 125 mg/m 2 (injection for over 30 minutes).The drug was administered on a day 1 and day 8 schedule every three weeks.Cisplatin was administered at 75 mg/m 2 on day 1 every three weeks.Carboplatin was administered at an area under the curve (AUC) of 6 calculated according to the Calvert formula on day 1 every three weeks.The efficacy was evaluated every two cycles.Hematologic and imaging examinations were routinely performed during the medication.The original protocol would be kept for 2~4 cycles if it was effective.

Assessment of efficacy and adverse reactions
The objective efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.The observation indicators included complete remission (CR), partial response (PR), stable disease (SD), disease progression (PD), objective response rate (ORR), and disease control rate (DCR).Progression-free survival (PFS) is defined as the time from first medication to the first objective progression of disease.The evaluation of adverse reactions was based on the NCI Common Toxicity Criteria (CTC) Version 3.0.

Statistics analysis
Statistical analysis was done by SPSS 13.0 software.Correlation between clinical features and curative effects was valued by using χ 2 test.PFS was analyzed using Kaplan-Meier methods.A value of p < 0.05 was considered to be statistically significant.

Survival analysis
We kept following up by clinic service or telephone from the beginning of treatment to October 31st, 2013.PFS of the 20 patients who had no surgery or radiotherapy was 1.4~17.9months, and median-PFS was 5 months in which PFS of patients on stage III was 4.3 months and 5.3 of stage IV.PFS of patients received cisplatin was 4.5 months and that received carboplatin was 5.4 months.The PFS of 19 cases on stage III and 1 case on stage IV was censored values because of their treatment of surgery or radiotherapy (Table 4, Figure 1~3).

Discussion
Paclitaxel, with broad-spectrum antitumor activity, is approved for the treatment of advanced non-small-cell lung cancer (Li et al., 2013;Natukula et al., 2013;Gurses et al., 2013;Ozdemir et al., 2013;Cui et al., 2014).With the vector of albumin, it can reduce risk of hypersensitivity reactions and blood toxicity induced by organic solvent.It exploits the natural properties of album into increase of uptake and causes accumulation of paclitaxel in the tumor through gp 60-mediated endothelial transcytosis (Aapro et al., 2008), and interaction with the album inbinding protein SPARC (secreted protein, acidic and rich in cysteine).Nab-paclitaxel has greater antitumor activity with increased intratumoral concentrations (Trieu et al., 2006;Desai et al., 2009).Socinski et al. ( 2013) conducted a major international multicenter randomized phase III clinical study of nab-paclitaxel compared solvent-based paclitaxel.1052 patients in the phase III/IV NSCLC was enrolled and randomly assigned to carboplatin and either nab-paclitaxel or solvent-based paclitaxel for the firstline treatment.the ORR was higher with nab-P/C versus sb-P/C (34% versus 25%, P=0.005).further histologic subgroup analysis for squamous histology indicated the ORR was 67% higher with nab-paclitaxel than solvent-based paclitaxel (24%).There was no survival difference between nab-paclitaxel and solvent-based paclitaxel.This is the best efficacy of lung squamous carcinoma data reported in literatures.According to the analysis by investigator, the treatment nab-paclitaxel demonstrated greater short-term efficacy with potentially increasing uptake and accumulation of paclitaxel in the tumor through gp60-CAV1 mediated endothelial transcytosis induced by abnormal higher expressions of CAV-1.
In this study we enrolled 40 patients with lung squamous carcinoma took nab-paclitaxel with cisplatin or carboplatin.The ORR was 62.5% and the DCR was 92.5%.The ORR was up to 73.7% in patients with nab-paclitaxel combined with cisplatin, and was better than the data reported in the literature.In Socinski's study, the ORR was 44.4% in lung squamous carcinoma patients.The treatment of nab-paclitaxel showed better effective compared with solvent-based paclitaxel in western countries, for instance, the efficacy of the general third generation platinum-based two drugs combination chemotherapy was 17% to 22% ( Schiller et al., 2002).The reason for the efficacy in this study was superior to the results reported maybe related to the race.The previous research revealed the efficacy of chemotherapy or targeted therapy of East Asian patients was better than that on Western patients.The median PFS in the patients without surgery or radiotherapy was 5 months, the phase III patients 4.3 months and the phase IV patients 5.3 moths.The reason for the higher efficacy seemingly did not translate to the median PFS extention compared with 5.6 months median PFS reported in Socinski's study in lung squamous carcinoma, it is probably attributed to that the patients abandon the initial therapy without disease progression, such as, turned to surgery or radiotherapy.The continuity of chemotherapy was effected because that the patients who was older, with poor lung functions and suffering diseases could not receive the further surgery or radiotherapy.the prolong of median PFS was effected with some patients who was in phase IV and discontinued the therapy because of the economy or un-tolerance adverse drug reaction.The ORR in the treatment combined with cisplatin (100%) was tremendously higher than that with carboplatin (63.6%) in the patients with surgery or radiotherapy.The treatment of nab-paclitaxel plus platinum-based chemotherapy may be a optimal protocol for the patients with good physical situation and tolerance because that it could alleviate the tumor load rapidly and strengthen the efficacy of local tumor especially to make a chance of the surgery for the potential patients and maximized reduction of the volume of the tumor.
Finally, the nab-PC showed a better safety and tolerability with neutropenia, sensory nerve toxicity, the incidence of myalgia obviously reduced, except anemia and thrombocytopenia increased.Nab-PC was approved chemotherapy agent for the patients with advanced or metastatic NSCLC in the first-line treatment.
I n g e n e r a l , t h e m o s t c o m m o n A E s w e r e myelosuppression, gastrointestinal reaction and baldness, and secondary AEs neurovirulence.The most AEs were I/II degree, except 4 myelosuppression with IV degree which eased after symptomatic therapy.And there was no treatment-related deaths occurred.In sum, the nabpaclitaxel combined with cisplatin or carboplatin has a good tolerance for lung squamous carcinoma with the first-line treatment.
In summary, the combination of nab-paclitaxel and cisplatin or carboplatin indicated better short-term efficacy, less AEs, and well tolerated.The protocol of nab-paclitaxel combined with platinum-based make a chance for the treatment of the lung squamous carcinoma especially multidisciplinary synthetic therapy of locally advanced lung squamous carcinoma to improve the efficacy and prolong survival with currently less selectable chemotherapy and no precise efficacy of targeted-therapy.This study was a retrospective analysis with small sample size.The efficacy and toxicity of the treatment of nabpaclitaxel combined with platinum-based for Asian or Chinese patients needed a prospective, large sample, multi-center clinical study.

Figure
Figure 1.Progression-free Survival (PFS) of Allpatients without Surgery or Radiotherapy.The median PFS were 5 months