Long noncoding RNAs (lncRNAs) have been identified as oncogenes or tumor suppressors that are involved in tumorigenesis and chemotherapy drug resistance. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes an lncRNA, and decreased MEG3 expression plays an important role in multiple cancers. However, its biological role in the development of the chemoresistance phenotype of human lung adenocarcinoma (LAD) is unknown. This study aimed to observe the expression of MEG3 in LAD and to evaluate its biological role and clinical significance in the resistance of LAD cells to cisplatin. MEG3 expression was markedly decreased in cisplatin-resistant A549/DDP cells compared with parental A549 cells as shown by an lncRNA microarray. MEG3 overexpression in A549/DDP cells increased their chemosensitivity to cisplatin both in vitro and in vivo by inhibiting cell proliferation and inducing apoptosis. By contrast, MEG3 knockdown in A549 cells decreased the chemosensitivity. Moreover, MEG3 was decreased in cisplatin-insensitive LAD tissues while p53 protein levels were decreased and Bcl-xl protein levels increased. Furthermore, patients with lower levels of MEG3 expression showed worse responses to cisplatin-based chemotherapy. These findings demonstrate that MEG3 is significantly downregulated in LAD and partially regulates the cisplatin resistance of LAD cells through the control of p53 and Bcl-xl expression. Thus, MEG3 may represent a new marker of poor response to cisplatin and could be a potential therapeutic target for LAD chemotherapy.

/pdf/the-long-noncoding-rna-meg3-contributes-to-cisplatin-4cwv6ba2m5.pdf

The Long Noncoding RNA MEG3 Contributes to Cisplatin Resistance of Human Lung Adenocarcinoma.

Background
Approximately 50% of patients with newly diagnosed non-small cell lung cancer (NSCLC) are over 70 years of age at diagnosis. Despite this fact, these patients are underrepresented in randomized controlled trials (RCTs). As a consequence, the most appropriate regimens for these patients are controversial, and the role of single-agent or combination therapy is unclear. In this setting, a critical systematic review of RCTs in this group of patients is warranted.

Objectives
To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced (stage IIIB and IV) NSCLC. To also assess the impact of cytotoxic chemotherapy on quality of life.

Search methods
We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (1966 to 31 October 2014), EMBASE (1974 to 31 October 2014), and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 31 October 2014). In addition, we handsearched the proceedings of major conferences, reference lists from relevant resources, and the ClinicalTrial.gov database.

Selection criteria
We included only RCTs that compared non-platinum single-agent therapy versus non-platinum combination therapy, or non-platinum therapy versus platinum combination therapy in patients over 70 years of age with advanced NSCLC. We allowed inclusion of RCTs specifically designed for the elderly population and those designed for elderly subgroup analyses.

Data collection and analysis
Two review authors independently assessed search results, and a third review author resolved disagreements. We analyzed the following endpoints: overall survival (OS), one-year survival rate (1yOS), progression-free survival (PFS), objective response rate (ORR), major adverse events, and quality of life (QoL).

Main results
We included 51 trials in the review: non-platinum single-agent therapy versus non-platinum combination therapy (seven trials) and non-platinum combination therapy versus platinum combination therapy (44 trials).

Non-platinum single-agent versus non-platinum combination therapy

Low-quality evidence suggests that these treatments have similar effects on overall survival (hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.72 to 1.17; participants = 1062; five RCTs), 1yOS (risk ratio (RR) 0.88, 95% CI 0.73 to 1.07; participants = 992; four RCTs), and PFS (HR 0.94, 95% CI 0.83 to 1.07; participants = 942; four RCTs). Non-platinum combination therapy may better improve ORR compared with non-platinum single-agent therapy (RR 1.79, 95% CI 1.41 to 2.26; participants = 1014; five RCTs; low-quality evidence).

Differences in effects on major adverse events between treatment groups were as follows: anemia: RR 1.10, 95% 0.53 to 2.31; participants = 983; four RCTs; very low-quality evidence; neutropenia: RR 1.26, 95% CI 0.96 to 1.65; participants = 983; four RCTs; low-quality evidence; and thrombocytopenia: RR 1.45, 95% CI 0.73 to 2.89; participants = 914; three RCTs; very low-quality evidence. Only two RCTs assessed quality of life; however, we were unable to perform a meta-analysis because of the paucity of available data.

Non-platinum therapy versus platinum combination therapy

Platinum combination therapy probably improves OS (HR 0.76, 95% CI 0.69 to 0.85; participants = 1705; 13 RCTs; moderate-quality evidence), 1yOS (RR 0.89, 95% CI 0.82 to 0.96; participants = 813; 13 RCTs; moderate-quality evidence), and ORR (RR 1.57, 95% CI 1.32 to 1.85; participants = 1432; 11 RCTs; moderate-quality evidence) compared with non-platinum therapies. Platinum combination therapy may also improve PFS, although our confidence in this finding is limited because the quality of evidence was low (HR 0.76, 95% CI 0.61 to 0.93; participants = 1273; nine RCTs).

Effects on major adverse events between treatment groups were as follows: anemia: RR 2.53, 95% CI 1.70 to 3.76; participants = 1437; 11 RCTs; low-quality evidence; thrombocytopenia: RR 3.59, 95% CI 2.22 to 5.82; participants = 1260; nine RCTs; low-quality evidence; fatigue: RR 1.56, 95% CI 1.02 to 2.38; participants = 1150; seven RCTs; emesis: RR 3.64, 95% CI 1.82 to 7.29; participants = 1193; eight RCTs; and peripheral neuropathy: RR 7.02, 95% CI 2.42 to 20.41; participants = 776; five RCTs; low-quality evidence. Only five RCTs assessed QoL; however, we were unable to perform a meta-analysis because of the paucity of available data.

Authors' conclusions
In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities, increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy. For people who are not suitable candidates for platinum treatment, we have found low-quality evidence suggesting that non-platinum combination and single-agent therapy regimens have similar effects on survival. We are uncertain as to the comparability of their adverse event profiles. Additional evidence on quality of life gathered from additional studies is needed to help inform decision making.

/pdf/chemotherapy-for-advanced-non-small-cell-lung-cancer-in-the-3l88kzs4op.pdf

Chemotherapy for advanced non-small cell lung cancer in the elderly population.

Lung cancer remains the most significant contributor of cancer-related mortality globally. Despite the significant progress over the last decade with the introduction of targeted and immunotherapeutic agents in the treatment of advanced non-small cell lung cancer (NSCLC), chemotherapy is still the appropriate treatment for the majority of patients. Based on clinical evidence, platinum-containing regimens have been established as the cornerstone of treatment as of today. Research efforts to optimize chemotherapy outcomes have led to novel chemotherapy regimens such as the combination of platinum plus pemetrexed as well as the addition of bevacizumab in patients with advanced non squamous NSCLC, and the combination of carboplatin with nanoparticle-albumin bound paclitaxel regardless of histology. In this article, we review clinical data regarding the recent evolution of chemotherapy in the advanced NSCLC setting, and critically evaluate the progress in therapeutic efficacy in terms of survival. We conclusively state that chemotherapy alone has reached a therapeutic plateau and report the current trends in clinical research combining chemotherapy with novel systemic therapies.

Novel chemotherapy regimens for advanced lung cancer: have we reached a plateau?

The development of effective agents for overcoming platinum chemoresistance in lung carcinoma continues to have high priority. We have demonstrated recently that β-elemene, a novel antitumor compound, enhances cisplatin activity by triggering lung cancer cell death via apoptosis. Here, we investigated whether β-elemene acts synergistically with cisplatin to inhibit non-small cell lung cancer (NSCLC) cell proliferation by blocking cell cycle progression. β-Elemene substantially increased the suppressive effect of cisplatin on cell growth and proliferation in the NSCLC cell lines H460 and A549. Furthermore, β-elemene augmented cisplatin in the cell cycle arrest of NSCLC cells at G2/M. This was associated with upregulated checkpoint kinase (CHK2) expression and reduced CDC2 activity (i.e., increased phosphorylation of CDC2 on Tyr-15 and decreased phosphorylation of CDC2 on Thr-161). Moreover, β-elemene and cisplatin in combination clearly decreased the protein levels of cyclin B1 and CDC25C and increased the levels of p21Cip1/Waf1, p27Kip1, and GADD45 in these cells, compared with the effects of either agent alone at the same concentration. These results suggest that the β-elemene-enhanced inhibitory effect of cisplatin on lung carcinoma cell proliferation is regulated by a CHK2-mediated CDC25C/CDC2/cyclin B1 signaling pathway and leads to the blockade of cell cycle progression at G2/M. A comparison of the cytotoxic efficacies of β-elemene and three synthetic analogs (β-elemenol, β-elemenal, and β-elemene fluoride) in the two lung cancer cell lines revealed that β-elemenol and β-elemene fluoride had the same antitumor efficacy as β-elemene, whereas β-elemenal was appreciably more potent than β-elemene. Thus, although all three synthetic analogs of β-elemene considerably suppressed NSCLC cell growth and proliferation, β-elemenal may have greater potential as an anticancer alternative to β-elemene in treating lung cancer and other tumors.

Sensitization of lung cancer cells to cisplatin by β-elemene is mediated through blockade of cell cycle progression: antitumor efficacies of β-elemene and its synthetic analogs

CV247 (CV), an aqueous mixture of copper (Cu) and manganese (Mn) gluconates, vitamin C and sodium salicylate increased the antitumour effects of cisplatin (CDPP; cis-diamminedichloroplatinum) in vi...

/pdf/protective-effect-of-cv247-against-cisplatin-nephrotoxicity-2hod767lkx.pdf

Protective effect of CV247 against cisplatin nephrotoxicity in rats.

The FAST is a 2 × 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G). A total of 433 stage IIIB–IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine–cisplatin (GP), gemcitabine–vinorelbine, gemcitabine–ifosfamide-cisplatin or gemcitabine–ifosfamide–vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets. For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression-free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3–4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3–4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3–4 nausea-vomiting was significantly increased in P-containing regimens. This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G-based doublet does not improve treatment outcome.

/pdf/triplets-versus-doublets-with-or-without-cisplatin-in-the-kftx06szfz.pdf

Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB–IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST)

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Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB–IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST)