PATIENTS AND METHODS: Patients ≥18 years old with histologically/cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and Eastern Cooperative Oncology Group performance status 0-2 were randomized 1:1 to receive erlotinib (oral; 150 mg once daily until progression/unacceptable toxicity) or GP [G 1250 mg/m(2) i.v. days 1 and 8 (3-weekly cycle); P 75 mg/m(2) i.v. day 1, (3-weekly cycle) for up to four cycles]. Primary end point: investigator-assessed progression-free survival (PFS). Other end points include objective response rate (ORR), overall survival (OS), and safety.
RESULTS: A total of 217 patients were randomized: 110 to erlotinib and 107 to GP. Investigator-assessed median PFS was 11.0 months versus 5.5 months, erlotinib versus GP, respectively [hazard ratio (HR), 0.34, 95% confidence interval (CI) 0.22-0.51; log-rank P < 0.0001]. Independent Review Committee-assessed median PFS was consistent (HR, 0.42). Median OS was 26.3 versus 25.5 months, erlotinib versus GP, respectively (HR, 0.91, 95% CI 0.63-1.31; log-rank P = .607). ORR was 62.7% for erlotinib and 33.6% for GP. Treatment-related serious adverse events (AEs) occurred in 2.7% versus 10.6% of erlotinib and GP patients, respectively. The most common grade ≥3 AEs were rash (6.4%) with erlotinib, and neutropenia (25.0%), leukopenia (14.4%), and anemia (12.5%) with GP.
CONCLUSION: These analyses demonstrate that first-line erlotinib provides a statistically significant improvement in PFS versus GP in Asian patients with EGFR mutation-positive NSCLC (NCT01342965).
MATERIALS AND METHODS: Patients who were treated with first line palliative chemotherapy for de novo MBC from 2002-2011 in UMMC were identified from the UMMC Breast Cancer Registry. Information collected included patient demographics, histopathological features, treatment received, including the different chemotherapy regimens, and presence of FN and TRD. FN was defined as an oral temperature >38.5° or two consecutive readings of >38.0° for 2 hours and an absolute neutrophil count <0.5x109/L, or expected to fall below 0.5x109/L (de Naurois et al, 2010). TRD was defined as death occurring during or within 30 days of the last chemotherapy treatment, as a consequence of the chemotherapy treatment. Statistical analysis was performed using the SPSS version 18.0 software. Survival probabilities were estimated using the Kaplan-Meier method and differences in survival compared using log-rank test.
RESULTS: Between 1st January 2002 and 31st December 2011, 424 patients with MBC were treated in UMMC. A total of 186 out of 221 patients with de novo MBC who received first line palliative chemotherapy were analyzed. The mean age of patients in this study was 49.5 years (range 24 to 74 years). Biologically, ER status was negative in 54.4% of patients and Her-2 status was positive in 31.1%. A 5-flourouracil, epirubicin and cyclophosphamide (FEC) chemotherapy regimen was chosen for 86.6% of the cases. Most patients had multiple metastatic sites (58.6%). The main result of this study showed a FN rate of 5.9% and TRD rate of 3.2%. The median survival (MS) for the entire cohort was 19 months. For those with multiple metastatic sites, liver only, lung only, bone only and brain only metastatic sites, the MS was 18, 24, 19, 24 and 8 months respectively (p-value= 0.319).
CONCLUSIONS: In conclusion, we surmise that FEC is a safe regimen with acceptable FN and TRD rates for de novo MBC.
METHODS: We carried a review of medical records of breast and lung cancer patients hospitalized in years 2003 and 2009 at Penang General Hospital, a public tertiary care center in Penang Island, north of Malaysia. Patients with hypercalcemia (defined as a calcium level above 10.5 mg/dl) at the time of cancer diagnosis or during cancer treatment had their medical history abstracted, including presence of metastasis, chemotherapy types and doses, calcium levels throughout cancer treatment, and other co-morbidity. The mean calcium levels at first hospitalization before chemotherapy were compared with calcium levels at the end of or at the latest chemotherapy treatment. Statistical analysis was conducted using the Chi-square test for categorical data, logistic regression test for categorical variables, and Spearman correlation test, linear regression and the paired sample t tests for continuous data.
RESULTS: Of a total 1,023 of breast cancer and 814 lung cancer patients identified, 292 had hypercalcemia at first hospitalization or during cancer treatment (174 breast and 118 lung cancer patients). About a quarter of these patients had advanced stage cancers: 26.4% had mild hypercalcemia (10.5-11.9 mg/dl), 55.5% had moderate (12-12.9 mg/dl), and 18.2% severe hypercalcemia (13-13.9; 14-16 mg/dl). Chemotherapy lowered calcium levels significantly both in breast and lung cancer patients with hypercalcemia; in particular with chemotherapy type 5-flurouracil+epirubicin+cyclophosphamide (FEC) for breast cancer, and gemcitabine+cisplatin in lung cancer.
CONCLUSION: Chemotherapy decreases calcium levels in breast and lung cancer cases with hypercalcemia at cancer diagnosis, probably by reducing PTHrP levels.
METHODS: This is a multicenter observational study of first-line afatinib in Malaysian patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC). Patients' demographic, clinical and treatment data, as well as resistance mechanisms to afatinib were retrospectively captured. The statistical methods included Chi-squared test and independent t-test for variables, Kaplan-Meier curve and log-rank test for survival, and Cox regression model for multivariate analysis.
RESULTS: Eighty-five patients on first-line afatinib from 1st October 2014 to 30th April 2018 were eligible for the study. EGFR mutations detected in tumors included exon 19 deletion in 80.0%, exon 21 L858R point mutation in 12.9%, and rare or complex EGFR mutations in 7.1% of patients. Among these patients, 18.8% had Eastern Cooperative Oncology Group performance status of 2-4, 29.4% had symptomatic brain metastases and 17.6% had abnormal organ function. Afatinib 40 mg or 30 mg once daily were the most common starting and maintenance doses. Only one-tenth of patients experienced severe side-effects with none having grade 4 toxicities. The objective response rate was 76.5% while the disease control rate was 95.3%. At the time of analysis, 56 (65.9%) patients had progression of disease (PD) with a median progression-free survival (mPFS) of 14.2 months (95% CI, 11.85-16.55 months). Only 12.5% of the progressed patients developed new symptomatic brain metastases. The overall survival (OS) data was not mature. Thirty-three (38.8%) patients had died with a median OS of 28.9 months (95% CI, 19.82-37.99 months). The median follow-up period for the survivors was 20.0 months (95% CI, 17.49-22.51 months). Of patients with PD while on afatinib, 55.3% were investigated for resistance mechanisms with exon 20 T790 M mutation detected in 42.0% of them.
CONCLUSIONS: Afatinib is an effective first-line treatment for patients with EGFR-mutant advanced NSCLC with a good response rate and long survival, even in patients with unfavorable clinical characteristics. The side-effects of afatinib were manageable and T790 M mutation was the most common resistance mechanism causing treatment failure.
METHODS: Cancer 10-pathway reporter array was performed to screen the pathways affected by Phyllanthus in lung carcinoma cell line (A549) to exert its antimetastatic effects. Results from this array were then confirmed with western blotting, cell cycle analysis, zymography technique, and cell based ELISA assay for human total iNOS. Two-dimensional gel electrophoresis was subsequently carried out to study the differential protein expressions in A549 after treatment with Phyllanthus.
RESULTS: Phyllanthus was observed to cause antimetastatic activities by inhibiting ERK1/2 pathway via suppression of Raf protein. Inhibition of this pathway resulted in the suppression of MMP2, MMP7, and MMP9 expression to stop A549 metastasis. Phyllanthus also inhibits hypoxia pathway via inhibition of HIF-1α that led to reduced VEGF and iNOS expressions. Proteomic analysis revealed a number of proteins downregulated by Phyllanthus that were involved in metastatic processes, including invasion and mobility proteins (cytoskeletal proteins), transcriptional proteins (proliferating cell nuclear antigen; zinc finger protein), antiapoptotic protein (Bcl2) and various glycolytic enzymes. Among the four Phyllanthus species tested, P. urinaria showed the greatest antimetastatic activity.
CONCLUSIONS: Phyllanthus inhibits A549 metastasis by suppressing ERK1/2 and hypoxia pathways that led to suppression of various critical proteins for A549 invasion and migration.
METHODS: The effect of AMEAE on cell proliferation of different cell lines was analyzed by MTT assay. High content screening (HCS) was applied to investigate the suppression of NF-κB translocation, cell membrane permeability, mitochondrial membrane potential (MMP) and cytochrome c translocation from mitochondria to cytosol. Reactive oxygen species (ROS) formation, lactate dehydrogenase (LDH) release and activation of caspase-3/7, -8 and -9 were measured while treatment. The western blot analysis also carried out to determine the protein expression of cleaved caspase-3 and -9. Flow cytometry analysis was used to determine the cell cycle distribution and phosphatidylserine externalization. Quantitative PCR analysis was performed to measure the gene expression of Bax and Bcl-2 proteins.
RESULTS: Cell viability analysis revealed the selective cytotoxic effect of AMEAE towards lung cancer cells, A549, with an IC50 value of 5.09 ± 0.41 μg/mL after 72 h of treatment. Significant LDH leakage and phosphatidylserine externalization were observed in AMEAE treated cells by fluorescence analysis. Treatment of A549 cells with AMEAE significantly elevated ROS formation, followed by attenuation of MMP via upregulation of Bax and downregulation of Bcl-2, accompanied by cytochrome c release to the cytosol. The incubation of A549 cells with superoxide dismutase and catalase significantly attenuated the cytotoxicity caused by AMEAE, indicating that intracellular ROS plays a pivotal role in cell death. The released cytochrome c triggered the activation of caspase-9 followed by caspase-3. In addition, AMEAE-induced apoptosis was accompanied by cell cycle arrest at G0/G1 phase. Moreover, AMEAE suppressed the induced translocation of NF-κB from cytoplasm to nucleus.
CONCLUSIONS: Our data showed for the first time that the ethyl acetate extract of Annona muricata inhibited the proliferation of A549 cells, leading to cell cycle arrest and programmed cell death through activation of the mitochondrial-mediated signaling pathway with the involvement of the NF-kB signalling pathway.