Management of Non-Small-Cell Lung Cancer Patients Initially Diagnosed With 1 to 3 Synchronous Brain-Only Metastases: A Retrospective Study.

BACKGROUND: The treatment options for newly diagnosed non-small-cell lung cancer (NSCLC) patients with 1 to 3 synchronous brain metastases (BM) remain controversial. The current study aimed to comprehensively analyze the characteristics, local treatment paradigms, and survival outcomes in these populations. PATIENTS AND METHODS: A total of 252 NSCLC patients initially diagnosed with 1 to 3 synchronous brain-only metastases were enrolled onto this study. Local therapy (LT) to primary lung tumors (PLT) and BM included surgery, radiotherapy, or both. Median overall survival (mOS) was measured among patients who received LT to both PLT and BM (all-LT group), patients who were treated with LT to either PLT or BM (part-LT group), and patients who did not receive any LT (non-LT group). RESULTS: The mOS for all-LT (n = 70), part-LT (n = 113), and non-LT (n = 69) groups was 33.2, 18.5, and 16.8 months, respectively (P = .002). The OS rates at 5 years for the all-LT, part-LT, and non-LT groups were 25.5%, 16.2%, and 0, respectively. Multivariable analysis revealed that all-LT versus non-LT, pretreatment Karnofsky performance status > 70, histology of adenocarcinoma, thoracic stage I-II, EGFR mutation, ALK positive, and second-line systemic therapies were independent prognostic factors for improved mOS. CONCLUSIONS: The current study showed that LT for both PLT and BM is associated with superior OS in appropriately selected NSCLC patients initially diagnosed with 1 to 3 synchronous BM. Prospective trials are urgently needed to confirm this finding.

Treatment Patterns and Survival Outcomes of Non-Small Cell Lung Cancer Patients Initially Diagnosed With Brain Metastases in Real-World Clinical Practice.

BACKGROUND: This study aimed to comprehensively analyze the characteristics, treatment patterns, and survival outcomes of non-small-cell lung cancer (NSCLC) patients initially diagnosed with brain metastases (BMs) in real-world practice. METHODS: We enrolled NSCLC patients initially diagnosed with BMs between Jan 2004 and Jan 2018 in our institution. Patient demographics, treatment modalities, and survival outcomes were then analyzed. Brain localized treatment (BLT) included early brain radiotherapy (EBR), deferred brain radiotherapy (DBR), and surgery. RESULTS: A total of 954 patients were identified. Concerning initial treatment, 525 patients (55.0%) received systemic medication (SM)+BLT, 400 patients (41.9%) received SM only, and 29 patients received BLT only (3.0%). SM+BLT cohort was associated with longer median overall survival (mOS) than the SM only and the BLT only cohorts both in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-negative/unknown patients (15.3 months, 95% confidence interval [CI], 14.2-16.4; 11.1 months, 9.0-13.2; 7.0 months, 5.4-8.6; p<0.001) and in EGFR/ALK-positive patients (33.7 months, 28.5-38.9; 22.1 months, 17.8-26.4; 4.0 months, 3.6-4.4; p < 0.001). As for timing of radiotherapy, SM+EBR (14.1 months, 12.7-15.5) was associated with inferior mOS than SM+DBR (19.4 months, 14.2-24.6) in EGFR/ALK-negative/unknown patients. No significant difference was found in EGFR/ALK-positive patients (28.3 months, 19.1-37.5; 33.3 months, 28.1-38.5). Patients in the EGFR/ALK-negative/unknown cohort treated with first-line pemetrexed with platinum (PP) (15.8 months, 14.0-17.6, p<0.001) had longer mOS than those received non-PP regimens (13.1 months, 11.6-14.6). However, no difference was observed among EGFR/ALK-positive patients who were treated with tyrosine kinase inhibitors (TKIs) (29.5 months, 21.1-37.9; p = 0.140), PP (27.2 months, 21.6-32.8) and non-PP regimens (25.0 months, 16.0-34.0). CONCLUSIONS: Our study confirmed that the use of SM+BLT is associated with superior mOS than those treated with SM only and BLT only. SM+DBR might be a better radiotherapeutic strategy for this patient population. EGFR/ALK-negative/unknown patients showed a survival benefit with PP treatment.

miR-200b regulates epithelial-mesenchymal transition of chemo-resistant breast cancer cells by targeting FN1.

Chemotherapy is a cornerstone treatment for early and advanced stage breast cancer patients. However, resistance to chemotherapy remains a major obstacle, resulting in disease relapse and progression. Emerging studies demonstrated that miRNAs regulate chemotherapy-induced epithelial-mesenchymal transition (EMT) and drug resistance, but the underlying mechanisms remain unclear. Here we established a doxorubicin-resistant breast cancer cell line MCF-7/Adr, and found these cells exhibited an EMT phenotype featured by a fibroblast-like morphology, increased the capacity of migration and invasion, and underwent the changes of molecular markers of EMT including E-cadherin, N-cadherin, and vimentin. We then compared the miRNA expression profiles between MCF-7/Adr and parental MCF-7 by miRNA microarray, and identified miR-200b as the most dramatically down-regulated miRNA. Overexpression of miR-200b in chemo-resistant cells reversed the EMT phenotype and increased sensitivity to doxorubicin. Inhibition of miR-200b in parental cells induced EMT and resistance to doxorubicin. Furthermore, we characterized the target gene of miR-200b, and showed that overexpression of miR-200b down-regulated FN1 expression and the luciferase activity. Compared with the parental cells, FN1 was significantly elevated in MCF-7/Adr cells. Knockdown of FN1 reversed mesenchymal morphology, inhibited cell migration and invasion, and sensitized cells to doxorubicin. Our data suggest that miR-200b regulates EMT of chemo-resistant breast cancer cells by targeting FN1. miR-200b-based therapy may be an effective strategy in treating advanced breast cancer patients.

Establishment of an Adjusted Prognosis Analysis Model for Initially Diagnosed Non-Small-Cell Lung Cancer With Brain Metastases From Sun Yat-Sen University Cancer Center.

BACKGROUND: The current published prognosis models for brain metastases (BMs) from cancer have not addressed the issue of either newly diagnosed non-small-cell lung cancer (NSCLC) with BMs or the lung cancer genotype. We sought to build an adjusted prognosis analysis (APA) model, a new prognosis model specifically for NSCLC patients with BMs at the initial diagnosis using adjusted prognosis analysis (APA). PATIENTS AND METHODS: The model was derived using data from 1158 consecutive patients, with 837 in the derivation cohort and 321 in the validation cohort. The patients had initially received a diagnosis of BMs from NSCLC at Sun Yat-Sen University Cancer Center from 1994 to 2015. The prognostic factors analyzed included patient characteristics, disease characteristics, and treatments. The APA model was built according to the numerical score derived from the hazard ratio of each independent prognostic variable. The predictive accuracy of the APA model was determined using a concordance index and was compared with current prognosis models. The results were validated using bootstrap resampling and a validation cohort. RESULTS: We established 2 prognostic models (APA 1 and 2) for the whole group of patients and for those with known epidermal growth factor receptor (EGFR) genotype, respectively. Six factors were independently associated with survival time: Karnofsky performance status, age, smoking history (replaced by EGFR mutation in APA 2), local treatment of intracranial metastases, EGFR-tyrosine kinase inhibitor treatment, and chemotherapy. Patients in the derivation cohort were stratified into low- (score, 0-2), moderate- (score, 3-5), and high-risk (score 6-7) groups according to the median survival time (16.6, 10.3, and 5.2 months, respectively; P < .001). The results were further confirmed in the validation cohort. CONCLUSION: Compared with recursive partition analysis and graded prognostic assessment, APA seems to be more suitable for initially diagnosed NSCLC with BMs.

Comparing single-agent with doublet chemotherapy in first-line treatment of advanced non-small cell lung cancer with performance status 2: a meta-analysis.

AIM: This systematic review and meta-analysis was performed to assess the efficacy and side effects between single-agent and doublet chemotherapy in first-line treatment of advanced non-small cell lung cancer with performance status 2 (PS2). METHODS: We searched for randomized controlled trials in online electronic databases and extracted data from eligible studies for meta-analysis. Pooled hazard ratio (HR) for overall survival (OS), pooled risk difference (RD) for 1-year survival, pooled risk ratio (RR) for objective response rate (ORR) and adverse effects were calculated using a fixed-effect model. RESULTS: Six trials with 386 participants in the single-agent group and 389 participants in the doublet group were included in this review. Compared with single-agent chemotherapy, doublet significantly improved OS (HR 0.72; 95% CI 0.61-0.84; P < 0.0001) and significantly increased 1-year survival rate (RD -0.09; 95% CI -0.14 to -0.03; P = 0.004) and ORR (RR 0.4; 95% CI 0.30-0.69; P = 0.0002). Doublet chemotherapy also significantly increased the risk of grade 3/4 neutropenia (RR = 4.97; 95% CI 2.93-8.43; P < 0.00001), thrombocytopenia (RR = 10.29; 95% CI 3.80-27.85; P < 0.00001) and anemia (RR = 2.50; 95% CI 1.27-4.90; P = 0.008). CONCLUSIONS: Our study implies that carboplatin-containing doublet chemotherapy improved OS, 1-year survival rate and ORR, but increased the risk of grade 3/4 hematotoxicity. Carboplatin-containing doublet may well be superior to non-carboplatin-containing treatment.

Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy.

INTRODUCTION: To explore the ability of gefitinib to penetrate blood brain barrier (BBB) during whole brain radiation therapy (WBRT). PATIENTS AND METHODS: Enrolled in this study were eligible patients who were diagnosed with BM from NSCLC. Gefitinib was given at 250 mg/day for 30 days, then concurrently with WBRT (40 Gy/20 F/4 w), followed by maintenance. Serial CSF and blood samples were collected on 30 day after gefitinib administration, and at the time of 10, 20, 30 and 40 Gy following WBRT. CSF and plasma samples of 13 patients without BM who were treated with gefitinib were collected as control. CSF and plasma gefitinib levels were measured by LC-MS/MS. RESULTS: Fifteen BM patients completed gefitinib plus WBRT. The CSF-to-plasma ratio of gefitinib in patients with BM was higher than that in patients without BM (1.34% vs. 0.36%, P < 0.001). The CSF-to-plasma ratio of gefitinib increased with the increased dose of WBRT and reached the peak (1.87 ± 0.72%) at 30 Gy, which was significantly higher than that 1.34 ± 0.49% at 0 Gy (P = 0.01). The median time to progression of brain lesions and the median overall survival were 7.07 and 15.4 months, respectively. CONCLUSION: The BBB permeability of gefitinib increased in accordance with escalated dose of WBRT.

Toxic epidermal necrolysis related to AP (pemetrexed plus cisplatin) and gefitinib combination therapy in a patient with metastatic non-small cell lung cancer.

Toxic epidermal necrolysis (TEN) is a rare acute life-threatening mucocutaneous disorder that is mostly drug-related (80%-95%). It is clinically characterized as a widespread sloughing of the skin and mucosa. AP regimen (pemetrexed plus cisplatin) has been the preferred first-line chemotherapy for metastatic non-squamous non-small cell lung cancer (NSCLC). Gefitinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has already been recommended as a first-line treatment in EGFR-mutant metastatic NSCLC. We report rare presentation of TEN involving adverse effects of AP and gefitinib combination treatment in a 42-year-old woman diagnosed with metastatic NSCLC harboring an EGFR mutation. On the 21st day after administration of the first cycle of AP regimen and the 8th day after the initiation of gefitinib treatment, she developed an acne-like rash, oral ulcer, and conjunctivitis, which later became blisters and ultimately denuded. The characteristic clinical courses were decisive for the diagnosis of TEN. Treatment with systemic steroids and immunoglobulin as well as supportive treatment led to an improvement of her general condition and a remarkable recovery.

Effects of an oral allosteric AKT inhibitor (MK-2206) on human nasopharyngeal cancer in vitro and in vivo.

AIM: Protein kinase B (AKT) signaling frequently is deregulated in human cancers and plays an important role in nasopharyngeal carcinoma (NPC). This preclinical study investigated the effect of MK-2206, a potent allosteric AKT inhibitor, on human NPC cells in vitro and in vivo. METHODS: The effect of MK-2206 on the growth and proliferation of CNE-1, CNE-2, HONE-1, and SUNE-1 cells was assessed by Cell Counting Kit 8 and colony formation assay. Flow cytometry was performed to analyze cell cycle and apoptosis. The effects of MK-2206 on the AKT pathway were analyzed by Western blotting. Autophagy induction was evaluated via electron microscopy and Western blot. To test the effects of MK-2206 in vivo, CNE-2 cells were subcutaneously implanted into nude mice. Tumor-bearing mice were treated orally with MK-2206 or placebo. Tumors were harvested for immunohistochemical analysis. RESULTS: In vitro, MK-2206 inhibited the four NPC cell line growths and reduced the sizes of the colonies in a dose-dependent manner. At 72 and 96 hours, the half maximal inhibitory concentration (IC50) values of MK-2206 in CNE-1, CNE-2, and HONE-1 cell lines were 3-5 µM, whereas in SUNE-1, IC50 was less than 1 µM, and MK-2206 induced cell cycle arrest at the G1 phase. However, our study found no evidence of apoptosis. MK-2206 induced autophagy in NPC cells, as evidenced by electron microscopy and Western blot, and inhibited the growth of tumors that were subcutaneously implanted in mice. Inhibition of downstream phosphorylation through the PRAS40 and S6 pathways seems to be the main mechanism for the MK-2206-induced growth inhibition. CONCLUSION: Our preclinical study suggests that MK-2206's antiproliferative effect may be useful for NPC treatment; however, strategies for reinforcing this effect are needed to maximize clinical benefit.

A systematic review of gemcitabine and taxanes combination therapy randomized trials for metastatic breast cancer.

PURPOSE: Gemcitabine/taxanes-based combination shows anti-tumor activity for the treatment of metastatic breast cancer, but there is a debate regarding the advantages of gemcitabine and taxanes regimens as a first-line or second-line treatment for metastatic breast cancer. Here we conducted a systematic review and meta-analysis to compare the efficacy and toxicity for patients receiving chemotherapy with or without GT-based regimens. METHODS: The randomized controlled trials were performed by searching Pubmed, MEDLINE, EMBASE, and conference proceedings. We identified eight randomized controlled trials and then extracted and combined the data using to calculate hazard ratios (HR). The primary outcomes were progression-free survival (PFS) and time to progression (TTP). The secondary outcomes were overall survival (OS) and acute toxicity. A meta-analysis was performed using Review Manager Version 4.2. RESULTS: Eight eligible trails were identified. These studies involved 2234 patients with metastatic breast cancer, (1122 patients received GT-based combination regimen and 1112 patients received a regimen without the combination). A fixed-effects model meta-analysis showed that ORR and TTP are superior for GT-treated patients ORR (OR = 1.28, 95% CI 1.07-1.53), TTP (HR = 0.80; 95% CI 0.71-0.89). And GT-based combination significantly improved OS in the first-line subgroup (HR = 0.84; 95% CI 0.71-0.99). However, there were significant differences regarding acute hematological toxicity, particularly thrombocytopenia. CONCLUSION: Gemcitabine/taxanes-treated patients with metastatic breast cancer showed a significant improvement in the ORR, TTP and OS (first-line background) compared to patients not treated with the combination regimen.

Pemetrexed and cisplatin combination with concurrent whole brain radiotherapy in patients with brain metastases of lung adenocarcinoma: a single-arm phase II clinical trial.

Pemetrexed-based chemotherapy presented about 40 % response rate (RR) on brain lesions of non-small cell lung cancer (NSCLC). But whole brain radiotherapy (WBRT) is still the standard treatment when surgery or radio-surgery is not feasible. This trial evaluated the efficacy and safety and efficacy of pemetrexed-cisplatin plus concurrent WBRT in this population. Forty-two patients were enrolled this study. Patients with newly diagnosed NSCLC with brain metastasis (BM) and performance status (PS) 0-2 were eligible for WBRT. Patients received up to six cycles of cisplatin and pemetrexed (75 and 500 mg/m(2), respectively) every 3 weeks. On day 1-12 during the first cycle of chemotherapy, patients received WBRT 30 Gy/10 fx/12 days. Primary end point was objective RR and progression free survival (PFS) on BM. Secondary end points included extracerebral and overall RR, survival and safety profile. Forty-one were evaluable for response. The histology was all adenocarcinoma. The objective cerebral RR (complete and partial response) in the intent-to-treat population was 68.3 % (28 of 41 patients). Extracerebral and overall RR was 34.1 and 36.6 %, respectively. Progression free survival of BM was 10.6 months, and median overall survival was 12.6 months. The combined treatment with pemetrexed-cisplatin and concurrent WBRT are effective in patients with NSCLC with newly diagnosed BM. This modality of treatment appears to be particularly favorable in RR and progression free survival of BM. Further clinical studies are warranted.

Gefitinib alone or with concomitant whole brain radiotherapy for patients with brain metastasis from non-small-cell lung cancer: a retrospective study.

BACKGROUND: Gefitinib, a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), is used both as a single drug and concurrently with whole brain radiotherapy (WBRT) the standard treatment for brain metastases (BM), and is reported to be effective in a few small studies of patients with BM from non-small-cell lung cancer (NSCLC). However, no study has compared the two treatment modalities. This retrospective analysis was conducted to compare the efficacy of gefitinib alone with gefitinib plus concomitant WBRT in treatment of BM from NSCLC. METHODS: We retrospectively reviewed 90 patients with BM from NSCLC who received gefitinib alone (250 mg/day, gefitinib group) or with concomitant WBRT (40 Gy/20 f/4 w, gefitinib-WBRT group) between September 2005 and September 2009 at Sun Yat-Sen University Cancer Center. Forty-five patients were in each group. RESULTS: The objective response rate of BM was significantly higher in gefitinib-WBRT group (64.4%) compared with gefitinib group (26.7%, P<0.001). The disease control rate of BM was 71.1% in gefitinib- WBRT group and 42.2% in gefitinib group (P=0.006). The median time to progression of BM was 10.6 months in gefitinib-WBRT group and 6.57 months in gefitinib group (P<0.001). The median overall survival (OS) of gefitinib-WBRT and gefitinib alone group was 23.40 months and 14.83 months, respectively (HR, 0.432, P=0.002). CONCLUSION: Gefitinib plus concomitant WBRT had higher response rate of BM and significant improvement in OS compared with gefitinib alone in treatment of BM from NSCLC.

Chemotherapy with concurrent brain and thoracic radiotherapy in brain-only metastases of treatment naive small-cell lung cancer: a phase II study.

To study the treatment outcomes of brain-only metastases from small-cell lung cancer (SCLC) at initial diagnose treated by chemotherapy with concurrent brain and thoracic radiotherapy (RT). From Jan 2004 to Jan 2009, 36 treatment-naïve SCLC patients with brain-only metastases in Sun yat-sen University were enrolled. Treatment contained initial EP chemotherapy with concurrent whole-brain radiotherapy (WBRT). EP regimen consisted of etoposide 100 mg/m(2) IV d1-3, cisplatin 80 mg/m(2) IV d1, repeated every 3 weeks. WBRT with total dose of 30 Gy in 10 fractions was started within 1 week from the beginning of chemotherapy followed by thoracic RT including 2 Gy once daily to a total dose of 60 Gy. Treatment responses were evaluated after 3 cycles of chemotherapy. EP regimen was given totally 6 cycles for no tumor progression. Thirty-four patients were evaluable. All of the 20 CNS symptomatic patients experienced symptoms relief. Objective responses in the brain and primary thoracic lesions were observed in 26 (76.5%, 16CR + 10PR) and 29 (85.3%, 23CR + 6PR) patients, respectively. The median survival time (MST) was 19.2 months, and the 1-and 2-year overall survival rates (OS) were 70.6 and 29.4%, respectively, in all patients. Patients with CR response had the longest MST of 21.9 months and 1-and 2-year OS of 93.8 and 43.8%, respectively. Treatment toxicity profiles were acceptable. The treatment strategy of concurrent chemotherapy with brain and thoracic RT might achieve promising survival outcomes comparable to limited-stage SCLC in initially diagnosed SCLC with brain-only metastases.