Gemcitabine Plus Paclitaxel as Second-line Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality and the incidence is increasing among women (Kosmidis et al., 2008). The American Cancer Society has estimated that the number of new lung cancer cases in the United States will be 114,690 in men and 100,330 in women for 2008. Among them, 161,840 are expected to die from this disease (Shepherd et al., 1993; Huang et al., 2008; Kosmidis et al., 2008; De et al., 2011). Most patients (>80%) have locally advanced stage III or metastatic stage IV NSCLC at the time of diagnosis and are ineligible for potentially curative surgery, and 5-year survival is <10% in this patient population (Shepherd et al., 1993; Walling et al., 1994; Caponi et al., 2010; De et al., 2011). Platinum-based chemotherapy offers a

Only a few agents including docetaxel, pemetrexed, gefitinib and erlotinib have shown to be effective in the second-line and third-line chemotherapy for advanced NSCLC (Shepherd et al., 2005;Thatcher et al., 2005;Barlesi et al., 2006;Cullen et al., 2008;Kim et al., 2008;Scagliotti et al., 2009;Cappuzzo et al., 2010;Douillard et al., 2010;Reck et al., 2010;Vamvakas et al., 2010).Despite an increasing proportion of patients with advanced NSCLC derive prolonged survival with novel chemotherapy regimens; many of them will require salvage chemotherapy after relapse (Kosmas et al., 2007).Despite the improvement in treating advanced or metastatic NSCLC responses to modern platinum or non-platinum-based chemotherapy are still rarely results in long-term tumor control.For these reason development of effective second-line treatments is very important for advanced or metastatic NCSLC who have progressive disease after first-line treatment.
In this study we retrospectively evaluated response rates, progression-free survival (PFS), overall survival (OS) and toxicity of gemcitabine plus paclitaxel combination among patients with advanced or metastatic NSCLC patients who have progressive disease after the platinum-based first-line chemoterapy.

Materials and Methods
We retrospectively evaluated file records of 48 patients (45 male, 3 female) treated with gemcitabine plus paclitaxel in advanced or metastatic NSCLC who have progressive disease after the first-line chemoterapy in February 2008 from June 2010 in five centers in Turkey.Gemcitabine and paclitaxel schedule as follows: gemcitabine 1500 mg/m 2 infused >30 min and paclitaxel 150 mg/m 2 infused >3 h, both administered bi-weekly.Patients were pretreated with dexamethasone 16 mg i.v.before receiving paclitaxel.Patients were also premedicated with diphenhydramine 50 mg i.v. and a histamine H2-receptor antagonist before receiving paclitaxel.All of patients had recieved first-line chemoterapy (Table 1).
Toxic effects were graded according to World Health Organisation (WHO) criteria, and the worst score registered during treatment by each patient was recorded.Responses to treatment were evaluated after every four cycles by computed tomography of the chest, abdomen  or the radiological examinations that detected the disease at other sites.Standard RECIST criteria were used for classifying tumor response.Complete response was as the disappearance of all known disease (target and non-target lesions).A partial response (PR) was defined as a 30% reduction from baseline in the sum of maximal diameters of the target lesions and a lack of disease progression in non-target lesions.Progressive disease (PD) was defined as the development of any new lesions or an increase of 20% in the maximal diameters of target lesions.Patients with stable disease (SD) did not meet the criteria for PR or PD.Duration of response was calculated from the date of initial therapy to the date of documented tumour progression, clinical deterioration, or death.

Discussion
In the recently several studies investigated the role of second-line therapies in advanced NSCLC.Based on these trials, docetaxel or pemetrexed suggested the main chemotherapeutic options, and erlotinib is the biological alternative to chemotherapy, mainly in non-smoker females with adenocarcinoma (Hana et al., 2004;Barlesi et al., 2006;Cullen et al., 2006;De et al., 2008;Gridelli et al., 2008;Stinchombe et al., 2008;Scagliotti et al., 2009).
Many other trials comparing a combined chemotherapy versus single-agent chemotherapy as second-line treatment in NCSLC.These trials showed that combined chemotherapy significantly increases response rate and progression-free survival, but is more toxic and does not improve overall survival compared to single-agent chemotherapy (Georgoulias et al., 2004;Georgoulias et al., 2005;Pectasides et al., 2005;Wachters et al., 2005;Smit et al., 2008;Di et al., 2009;Gebbia et al., 2009;Takeda et al., 2009;Tucker, 2010) A number of studies single-agent chemotherapy with gemcitabine as second-line treatment in advanced NSCLC have been showed that median OS, 22 weeks to 8.3 months, RR 3-25% (Androulakis et al., 1998;Crino et al., 1999;Gridelli et al., 1999).Coskun et al. study,21 patients treated with single agent gemcitabine as a secondline treatment and reported a partial response rate 19%, stabil disease rate 29%, median OS was 36 weeks.Only one patients experienced grade ¾ hemathologic toxicity in this study (Coskun et al., 2008).
Single-agent chemotherapy with paclitaxel as secondline treatment in advanced NSCLC have been showed elapsed from the date of diagnosis to the date of death or the last visit.Statistical analyses were carried out using SPSS 15.0 program.
Mori et al.'s study, patients treated with paclitaxel and gemcitabine as second-line treatment for advanced NSCLC after treatment with platinum-based chemotherapy.Partial response rate was 37.5%, SD rate was 65%, PD rate was 12.5%.The median OS was 41.7 weeks, the median PFS was 19 weeks, grade 3 / 4 hematologic toxicities included neutropenia (60%), anemia (15%), and thrombocytopenia (12.5%) were observed (Mori et al., 2007).In our study partial response rate was 12.5%, SD rate was 27%, PD was 56.3%, median PFS was 2.7 months (95%CI 1.8-3.6)and median OS was 6.63 months (95%CI 4.0-9.2).Grade 3 / 4 hematologic events, including neutropenia (8.4%), and anemia (6.3%) were occurred.There wasn't grade 3 / 4 thrombocytopenia.These consequencies were shorter and worse than Mori et al.'s study.When we looked at patients characterictics in our study a greater number of patients had stage 4 disease and had liver metastasis unlike the study of Mori et al. and we observed significantly less hemathologic toxicities than Mori's study.Androulakis et al. (1998) gemcitabine and paclitaxel were administered as a second-line setting patients with NSCLC and reported that the median survival was 11 months, the median TTP 8 months; CR rate was 2% (1/49); PR rate was 16% (8/4); SD rate was 29% (14/49), PD rate was 53% (26/49).The toxicity profile was grade 3/4 neutropenia and thrombocytopenia occurring in 12% and 2% respectively (Androulakis et al., 1998).In our study we detected median PFS and median OS was shorter than this study; and we found similar PR, SD and PD rates.We thought that these results due to poor performance status of our patients and also high incidence of liver and brain metastasis in our patients.Grade 3/4 hematologic and nonhemathologic toxicities were aproximately similar.
In conclusion, the combination of gemcitabine and paclitaxel is an effective and well-tolerated secondline chemotherapy regimen for advanced or metastatic NSCLC patients who previously treated with platinumcontaining chemotherapy.The most common and dose limiting toxicities were neutropenia and neuropathy and an unexpected toxicity wasn't observed.In our study two-weekly gemcitabine plus paclitaxel therapy was tolareted well by the patients whose performance status was relatively worse.The treatment schema which causes the least toxicity and effects the performance status minimally is not well known; but the two-weekly schema may be suitable relevant for these patients.Conflict of interest disclousores: All authors have agreed there is no conflict of interest.