Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis.

BACKGROUND: It remains controversial whether the addition of a second cytotoxic agent can further improve the therapeutic effect of gemcitabine monotherapy in advanced or metastatic pancreatic cancer (LA/MPC). OBJECTIVE: The objective of the present systematic review and meta-analysis was to investigate the efficacy and safety of gemcitabine-based doublet chemotherapy regimens compared to single-agent gemcitabine in the first-line treatment of unresectable LA/MPC. METHODS: We searched for randomized controlled trials (RCTs) of gemcitabine monotherapy versus gemcitabine in combination with a second cytotoxic agent in patients with LA/MPC. The last search date was December 31, 2016. RESULTS: Twenty-seven RCTs were identified and included in the present systematic review and meta-analysis, involving a total of 7343 patients. The meta-analysis showed that gemcitabine-based combination therapy significantly improved overall survival (OS) (HR: 0.89; 95% confidence interval (CI): 0.85-0.94; P < 0.0001), progression-free survival (PFS) (HR: 0.80; 95% CI: 0.73-0.88; P < 0.0001), and overall response rate (ORR) (RR: 1.83; 95% CI: 1.62-2.07; P < 0.0001) in comparison to single-agent gemcitabine. Subgroup analysis suggested that the antitumor activity differed between gemcitabine-based combination regimens: doublet regimens of gemcitabine plus a taxoid, and gemcitabine plus a fluoropyrimidine, in particular an oral fluoropyrimidine, resulted in a significant OS benefit for the patients. However, the combination of gemcitabine with other cytotoxic agents, such as platinum compounds or topoisomerase inhibitors failed to reduce the mortality risk. Combination therapy caused more grade 3/4 toxicities, including neutropenia, thrombocytopenia, vomiting, diarrhea, and fatigue. CONCLUSIONS: Gemcitabine-based doublet regimens demonstrated superiority over gemcitabine monotherapy in overall efficacy, but were associated with increased toxicity. Different gemcitabine-based combinations showed different antitumor activity, and doublet regimens of gemcitabine in combination with a taxoid or a fluoropyrimidine, in particular an oral fluoropyrimidine provided significant survival benefits in the first-line treatment of unresectable LA/MPC.

[A meta analysis of doublets versus single-agent chemotherapy for elderly patients with advanced non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: It remains disputed whether doublets are more effective than single-agent chemotherapy for elderly patients with advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the efficacy and safety of doublets and single-agent chemotherapy for elderly patients with NSCLC. METHODS: Data from all published, randomized trials that compared doublets and single-agent chemotherapy in elderly patients were collected from electronic databases (PubMed, EMBASE, Cochrane Library, CNKI and the CBMdice). Meta-analysis was completed using software Stata 11.0. RESULTS: The results of the meta-analysis, including 12 eligible trials (2,306 patients), showed that the doublets significantly increased the overall response rate (OR=1.80, 95%CI:1.50-2.17, P<0.000,1) and one-year survival rate (OR=1.45, 95%CI: 1.22-1.72, P<0.000,1) compared with single-agent chemotherapy. The results of one-year survival rate in platinum-based doublet chemotherapy arms (OR=1.55, 95%CI: 1.18-2.03, P=0.001) and non platinum-based ones (OR=1.38, 95%CI: 1.10-1.73, P=0.006) were both significantly higher than that of single-agent chemotherapy. However, grade 3/4 anemia, neutropenia, thrombocytopenia and neurotoxicity (P<0.05) were significantly associated with doublet chemotherapy. The incidence of toxicity effect in non platinum-based chemotherapy was similar to that of single-agent chemotherapy. CONCLUSIONS: Compared with single-agent chemotherapy, doublet chemotherapy could increase the overall response rate and one-year survival rate significantly. Therefore, doublet chemotherapy would be more appropriate for elderly patients with advanced NSCLC as the first-line chemotherapy regimen. However, further prospective randomized controlled trials in elderly NSCLC patients is needed to verify the findings in this study.

Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells.

PURPOSE: TNF-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic agent that preferentially induces apoptosis in cancer cells. However, breast cancer cells are generally resistant to TRAIL. Bufalin is a major active ingredient of the traditional Chinese medicine ChanSu. The present study aimed to assess the synergistic effect of bufalin and TRAIL and elucidate the underlying mechanisms in breast cancer cells. METHODS: Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. The expression of proteins was assayed by flow cytometry and/or Western blotting. Transfection studies were used to determine the involvement of DR4, DR5 and Cbl-b in the synergistic effect of bufalin and TRAIL. RESULTS: MCF-7 and MDA-MB-231 cells were resistant to TRAIL. Both cell lines were dramatically sensitized to TRAIL-induced apoptosis by bufalin. Further experiments indicated that bufalin up-regulated DR4 and DR5, activated ERK, JNK and p38 MAPK and down-regulated Cbl-b. Blocking the up-regulation of DR4 and DR5 by siRNA rendered cells less sensitive to apoptosis induced by the combination of bufalin and TRAIL. Inhibition of the activation of ERK, JNK and p38 MAPK by specific inhibitors attenuated DR4 and DR5 up-regulation. Moreover, down-regulation of Cbl-b by shRNA led to stronger activation of ERK, JNK and p38 MAPK, more up-regulation of DR4 and DR5, and a stronger synergistic effect of bufalin and TRAIL. CONCLUSIONS: Bufalin enhanced TRAIL-induced apoptosis by up-regulating the expression of DR4 and DR5. Bufalin-induced down-regulation of Cbl-b contributed to the up-regulation of DR4 and DR5, which might be partially mediated by the activation of ERK, JNK and p38 MAPK.

[Effect of the XRCC1 and XRCC3 genetic polymorphisms on the efficacy of platinum-based chemotherapy in patients with advanced non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: DNA repair gene polymorphisms can be used to predict the sensitivity of platinum-based chemotherapy. Thus, such polymorphisms are important for the individual treatment of non-small cell lung cancer (NSCLC). The aim of this study is to investigate the relationship between X-ray repair cross complementing protein 1 (XRCC1) and X-ray repair cross complementing protein 3 (XRCC3) gene polymorphisms and the chemosensitivity of platinum-based chemotherapy in patients with advanced NSCLC. METHODS: Genomic DNA were extracted from the sera of a total of 130 patients with advanced NSCLC who received platinum-based chemotherapy. XRCC1 Arg194 Trp, Arg399 Gln, and XRCC3 Thr241 Met were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method, and the relationship between XRCC1 and XRCC3 polymorphisms and chemotherapy sensitivity was analyzed. RESULTS: A total of 130 patients with advanced NSCLC received platinum-based chemotherapy, with an overall response rate of 33.8% after two chemotherapy cycles. The XRCC1 194 and 399 genetic polymorphisms, but not XRCC3 241, were found to be related to the chemosensitivity. The objective response rate of the patients with at least one XRCC1 194 Trp allele was 2.5 times higher than that of Arg/Arg genotype carriers (42.1% vs 22.2%, OR=2.545, 95%CI: 1.159-5.590, P=0.020). The objective response rate of the XRCC1 399 Arg/Arg genotype carriers was significantly higher than that of the patients with at least one Gln allele (45.5% vs 21.9%, OR=0.336, 95%CI: 0.156-0.722, P=0.005). Combined effects between XRCC1 194 and XRCC1 399 were observed. The objective response rate of the patients with at least one XRCC1 194 Trp allele and a 399 Arg/Arg genotype was significantly higher than that of patients with 194 Arg/Arg and 399 Arg/Gln genotypes (44.4% vs 18.8%, OR=3.467, 95%CI: 1.223-9.782, P=0.019). Moreover, XRCC1 and XRCC3 have a combined effect in predicting chemosensitivity. Patients with XRCC3 241 Thr/Met, 399 Arg/Arg, and at least one XRCC1 194 Trp allele simultaneously showed an improved objective response rate. CONCLUSIONS: The combination of the XRCC1 and XRCC3 polymorphisms may be associated with patient sensitivity to platinum-based chemotherapy in advanced NSCLC.

[Value of serum carcinoembryonic antigen in prediction of chemotherapy efficacy and prognosis in patients with advanced non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitor].

OBJECTIVE: The aim of this study was to detect the pre- and post-treatment serum carcinoembryonic antigen (CEA) levels after 4 weeks of EGFR-TKIs treatment in advanced non-small cell lung cancer (NSCLC) patients to evaluate the clinical value of CEA in the prediction of chemotherapy response and prognosis in those patients. METHODS: Pre- and post-treatment serum CEA levels of the patients were measured with immunoradiometric kits after 4 weeks of EGFR-TKIs treatment to evaluate the relationship between chemotherapy response and prognosis. RESULTS: After 4 weeks of EGFR-TKIs treatment, one patient in the total of 75 patients (1.3%) achieved complete response (CR), 17 patients (22.7%) achieved partial response (PR), 31 patients (41.3%) achieved disease stable (SD) and 26 patients had progressive disease (PD). The radiological objective response rate(ORR) and disease control rate (DCR) were 24.0% and 65.3%, respectively. The median survival time (MST) of all patients was 8.1 months. The MST of SD patients was similar to that in the OR patients (P = 0.06), but both longer than that in the PD patients (P < 0.001). The MST of DC patients was similar to that in OR patients (P = 0.358), but longer than that in PD patients (P < 0.001). Serum CEA levels decreased ≥ 32% and ≥ 61% were closely related with the objective response and disease control. The median survival time (MST) of patients with serum CEA decreased ≥ 32% was longer than those with CEA decreased < 32% (9.5 months vs 6.7 months, P < 0.0001). The MST of patients with serum CEA decreased ≥ 32% was similar to those with CEA decreased ≥ 61% (9.5 months vs 10.5 months, P = 0.370), but both longer than those with CEA decreased < 32% (6.7 months, P < 0.001). Cox multivariate survival analysis confirmed that serum CEA level decreased ≥ 32%, CEA level decreased ≥ 61%, PS score, and DC are independent prognostic factor, but not OR. CONCLUSIONS: To advanced NSCLC patients, the disease control rate (DCR) may be more suitable than objective response rate (ORR) as an indicator in predicting the efficacy and prognosis in advanced NSCLC patients. Serum CEA levels decreased ≥ 32% may be a reliable indicator to determine the therapeutic efficacy of EGFR-TKIs.

[Clinical significance of serum cytokeratin 19 fragment in the prediction of chemotherapy efficacy and prognosis in patients with advanced non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: RECIST (Response Evaluation Criteria in Solid Tumors) criteria could not be used to detect viable tumor tissue and is not an accurate tool for evaluation of objective response (OR) in non-small cell lung cancer (NSCLC) patients without measurable lesions. The aim of this study is to detect the pre- and post-chemotherapy serum cytokeratin 19 fragment (CYFRA21-1) expression levels in advanced NSCLC patients to evaluate the clinical value of CYFRA21-1 in the prediction of chemotherapy response and prognosis in NSCLC patients. METHODS: A automatic electrochemiluminescence immunoassay analyzer was applied to detect the pre- and post-chemotherapy serum CYFRA21-1 expression levels in 112 cases of initial treatment patients with NSCLC. Application of receiver operating characteristics curve (ROC) curve in evaluation the significance of serum CYFRA21-1 response in the diagnosis of OR and its correlation with prognosis. RESULTS: After 2 cycles of platinum-based combined chemotherapy, post-chemotherapy serum CYFRA21-1 significantly decreased compared with baseline levels. 80 patients were evaluable for radiological and serological efficacy, and 26.3% (21/80) patients achieved radiological OR. The decrease ratio of post-chemotherapy serum CYFRA21-1 with CYFRA21-1 response was 40.0% (32/80). There was significant correlation between serum CYFRA21-1 response and OR (P < 0.001). The median survival time of all patients was 9.9 months; the survival of patients with CYFRA21-1 response were significantly longer than those without CYFRA21-1 responders (12.3 months vs 8.9 months, P < 0.001). Univariate survival analysis showed that PS score, OR, baseline serum CYFRA21-1 level and CYFRA21-1 response were important prognostic factors. Cox multivariate survival analysis confirmed that only the PS score, serum CYFRA21-1 baseline levels and CYFRA21-1 response were independent prognostic factors of NSCLC patients; OR was not an independent prognostic factor. CONCLUSIONS: Serum CYFRA21-1 level can be sensitive to reflect changes in tumor volume, which may be a reliable substitution index for evaluation the chemotherapy efficacy in advanced NSCLC patients and a good indicator for prediction the prognosis of survival.

[Impact of anemia on chemotherapy efficacy and prognosis in patients with advanced non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: Cancer-related anemia is the common complication of non-small cell lung cancer (NSCLC), which affects the quality of life (QOL), chemotherapy efficacy and prognosis in patients with NSCLC. In this study, we statistically analysed the incidence of anemia in NSCLC patients before and after chemotherapy and related risk factors, and investigated the impact of anemia on QOL, chemotherapy efficacy and prognosis in patients with NSCLC. METHODS: Clinical data of 140 patients with NSCLC from January 2007 to December 2008 were collected and retrospectively analysed for the changes in hemoglobin levels before and after chemotherapy, the risk factors of anemia, and the relationship with chemotherapy efficacy and prognosis. Application of QOL scale (EORTCQLQ-C30, Chinese version) to evaluate the impact of anemia on QOL in patients with advanced NSCLC. RESULTS: Total 140 cases of NSCLC patients, the incidence of anemia after two cycles of chemotherapy was significantly higher than that before chemotherapy (71.4% vs 47.1%, P < 0.001), and the severity of anemia increased simultaneously with the cycles of chemotherapy. According to univariete and multivariate Logstic regression analysis, age, clinical stage, PS score and albumin levels were closely related to pre-treatment cancerrelated anemia. However, multivariate Logistic regression analysis confirmed that only albumin levels was the risk factors of anemia. QOL scores on physical function, symptoms and overall quality of life were significantly different in anemia and nonanemic patients (P < 0.05). Anemia occurred before and after chemotherapy were significantly lower chemotherapy efficacy in patients with advanced NSCLC. Cancer-related anemia obviously impacted on the prognosis of patients, the median survival of cancer-related anemia patients was significantly shorter than those without anemia (7 months vs 13 months, P < 0.001), and the median survival of cancer-related anemia patients before chemotherapy was significantly longer than those with anemia (7 months vs 11 months, P < 0.001). Cox multivariate regression analysis confirmed that anemia, clinical stage, PS score, albumin level were the independent prognostic factors in advanced NSCLC. CONCLUSIONS: NSCLC patients had a higher incidence of anemia, especially the incidence of chemotherapy-related anemia, age, clinical stage, PS score, albumin levels were the risk factors of pre-treatment cancer-related anemia. NSCLC patients with anemia had lower QOL and chemotherapy efficacy, and shorter lifetime. Anemia was an independent prognostic factor in NSCLC patients.

[The expression and prognostic significance of ERCC1 and GST-pi in lung cancer].

BACKGROUND AND OBJECTIVE: It has been known that the expression levels of ERCC1 and GST-pi were correlated with tumorigenesis and prognosis. The aim of this study is to investigate the relationship between expression levels of ERCC1 and GST-pi, and clinicopathologic parameters and survival in patients with lung cancer. METHODS: The expression levels of ERCC1 and GST-pi were detected by immunohistochemical staining on tissue micro-array sections made of 148 cases of lung cancer and 7 cases of normal lung samples. The results were compared with relevant clinical and pathologic data. RESULTS: Positive rates of ERCC1 and GST-pi were 36.2% and 73.6%, respectively. None of normal lung samples was positive staining. Positive expression of ERCC1 was significantly higher in group of non-small cell lung cancer (NSCLC), highly differentiated and the smokers less than 400 (P < 0.05), positive expression of GST-pi was significantly higher in group of non-smokers and NSCLC (P < 0.05). There were significant correlations between expression of ERCC1 and GST-pi (r = 0.253, P = 0.001). The 5 years survival rate was higher in positive expression of ERCC1. There was significant correlations between expression of ERCC1 and survival (P = 0.037). There was no significant correlations between expression of GST-pi and survival (P = 0.614). Multivariate analysis using Cox regression model showed that expression levels of ERCC1 and GST-pi were not the important independent prognostic factors for survival. CONCLUSION: ERCC1 and GST-pi are aberrant highly expressed in NSCLC with positive correlation, which indicate they might act synergistically in tumorigenesis of NSCLC. The positive expression of ERCC1 have better survival and may have effect on prognosis.