Zhonghan Zhang

Neurokinin-1 Receptor Antagonist-Based Triple Regimens in Preventing Chemotherapy-Induced Nausea and Vomiting: A Network Meta-Analysis

Background: Neurokinin‐1 receptor antagonists (NK‐1RAs) are widely used for chemotherapy‐induced nausea and vomiting (CINV) control in patients with highly emetogenic chemotherapy (HEC) and/or moderately emetogenic chemotherapy (MEC). Whether the efficacy and toxicity of antiemesis are different among various NK‐1RA‐based triple regimens is unknown. Methods: Data of complete responses (CRs) in the acute, delayed, and overall phases and treatment‐related adverse events (TRAEs) were extracted from electronic databases. Efficacy and toxicity were integrated by pairwise and network meta‐analyses. Results: Thirty‐six trials involving 18 889 patients using triple regimens (NK‐1RA+serotonin receptor antagonists [5HT3RA] + dexamethasone) or duplex regimen (5HT3RA+dexamethasone) to control CINV were included in the analysis. Different NK‐1RA‐based triple regimens shared equivalent effect on CRs. In patients with HEC, almost all triple regimens showed statistically significantly higher CRs than duplex regimen (odds ratio [OR]duplex/triple = 0.47‐0.66). However, in patients with MEC, only aprepitant‐based triple regimen showed better effect than duplex regimen statistically significantly in CRs (ORduplex/triple = 0.52, 95% confidence interval [CI] = 0.34 to 0.68). No statistically significant difference of TRAEs was found among different triple regimens. Palonosetron‐based triple regimens were equivalent to first‐generation 5HT3RAs‐based triple regimens for CRs. Moreover, different doses of dexamethasone plus NK‐1RA and 5HT3RA showed no statistically significant difference in CRs. Conclusions: Different NK‐1RAs‐based triple regimens shared equivalent effect on CINV control. Various triple regimens had superior antiemetic effect than duplex regimen in patients with HEC. Only aprepitant‐based triple regimen showed better CINV control compared with duplex regimen in patients receiving MEC. Palonosetron and first‐generation 5HT3RAs might share equivalent CINV control in the combination of NK‐1RAs and dexamethasone. Lower doses of dexamethasone might be applied when used with NK‐1RAs and 5HT3RAs.

Nomogram to Predict Cause-Specific Mortality in Patients With Surgically Resected Stage I Non-Small-Cell Lung Cancer: A Competing Risk Analysis

Micro‐Abstract It is important to consider the competing risks when evaluating prognosis. We evaluated the cumulative incidence function of cause‐specific death in 20,850 patients with surgically resected stage I non–small‐cell lung cancer. We also built the first competing risk nomogram to predict prognosis. Our nomograms show a relatively good performance and can be a convenient individualized predictive tool for prognosis. Background: The objective of this study was to evaluate the probability of cause‐specific death and other causes of death in patients with stage I non–small‐cell lung cancer (NSCLC) who underwent surgery. We also built competing risk nomograms to predict the prognosis of patients with NSCLC. Patients and Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We identified patients who underwent surgery with stage I NSCLC between 2004 and 2013. We estimated the cumulative incidence function (CIF) for cause‐specific death and other causes of death, and tested the differences using Gray’s test. The Fine and Gray proportional subdistribution hazard approach was applied to model CIF. We also built competing risk nomograms on the basis of Fine and Gray’s model. Results: We identified 20,850 stage I NSCLC patients from 2004 to 2013 in the SEER database. The 5‐year cumulative incidence of cause‐specific death for stage I NSCLC was 21.9% and 14.2% for other causes of death. Variables associated with cause‐specific mortality included age, sex, marital status, histological grade, TNM stage, and surgery. The nomograms were well calibrated, and had good discriminative ability, with a c‐index of 0.64 for the cancer‐specific mortality model and 0.66 for the competing mortality model. Conclusion: We evaluated the CIF of cause‐specific death and competing risk death in patients with surgically resected stage I NSCLC using the SEER database. We also built proportional subdistribution models and the first competing risk nomogram to predict prognosis. Our nomograms show a relatively good performance and can be a convenient individualized predictive tool for prognosis.

Bevacizumab in combination with different platinum‐based doublets in the first‐line treatment for advanced nonsquamous non‐small‐cell lung cancer: A network meta‐analysis

Platinum‐based doublet chemotherapy with or without bevacizumab is the standard treatment for untreated advanced nonsquamous non‐small‐cell lung cancer (NS‐NSCLC). However, adding bevacizumab to chemotherapies other than paclitaxel–carboplatin is, though widely applied clinically, largely unjustified due to the lack of head‐to‐head data. We performed a Bayesian network meta‐analysis (NMA) to address this important issue. Data of 8,548 patients from 18 randomized controlled trials (RCTs) receiving six treatments, including taxane–platinum (Taxane–Pt), gemcitabine–platinum (Gem–Pt), pemetrexed–platinum (Pem–Pt), taxane–platinum + bevacizumab (Taxane–Pt + B), gemcitabine–platinum + bevacizumab (Gem–Pt + B) and pemetrexed–platinum + bevacizumab (Pem–Pt + B), were incorporated into the analyses. Direct and indirect evidence of overall survival (OS) and progression‐free survival (PFS) were synthesized at the hazard ratio (HR) scale and evidence of objective response rate (ORR) and serious adverse events (SAE) were synthesized at the odds ratio (OR) scale. Taxane–Pt + B showed significant advantages in OS (HR = 0.79, p < 0.001), PFS (HR = 0.54, p < 0.001) and ORR (OR = 2.7, p < 0.001) over Taxane–Pt with comparable tolerability (OR = 3.1, p = 0.08). Gem–Pt + B showed no OS benefit compared to any other treatment. No significant differences were detected between Pem–Pt + B and Pem–Pt in four outcomes. In terms of the benefit‐risk ratio, Pem–Pt and Taxane–Pt + B were ranked the first and second, respectively. In conclusion, in the first‐line treatment for advanced NS‐NSCLC, Taxane–Pt and Gem–Pt are the most and least preferable regimens to be used with bevacizumab, respectively. Adding bevacizumab to Pem–Pt remains unjustified because it fails to improve efficacy or tolerability. In terms of the benefit‐risk ratio, Pem–Pt and Taxane–Pt + B are the best and second‐best treatment for this population.

The comparison of EGFR-TKI failure modes and subsequent management between exon 19 deletion and exon 21 L858R mutation in advanced non-small-cell lung cancer

Background: Advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion (19 Del) and exon 21 L858R mutation (L858R) might be distinct diseases. Therefore, it is necessary to take EGFR mutation subgroups into consideration for making choices of subsequent treatment after tyrosine kinase inhibitors (TKIs) failure. Patients and methods: 174 patients who developed to EGFR-TKI failure were categorized into three cohorts of dramatic progression, gradual progression and local progression. Chi-square was used to compare the distribution of failure modes between 19 Del and L858R. Kaplan-Meier method and Cox Regression were performed for analyses of survival in different subsequent treatments. Results: The distribution of EGFR-TKI failure modes showed no significant difference between 19 Del and L858R. Patients in gradual progression had a longer progression-free survival (PFS) and overall survival (OS) compared with other failure modes in whole population, 19 Del cohort and L858R cohort. 19 Del patients with dramatic progression would obtain survival benefit from chemotherapy, while those with gradual progression got no survival benefit neither from chemotherapy nor previous TKI continuation. However, patients with dramatic or gradual progression would benefit from previous TKI continuation in L858R cohort. Conclusion: For advanced EGFR-positive NSCLC patients with acquired resistance to EGFR-TKI, subsequent treatment should be personalized according to EGFR-TKI failure modes & EGFR mutation subtypes.

Olanzapine‐Based Triple Regimens Versus Neurokinin‐1 Receptor Antagonist‐Based Triple Regimens in Preventing Chemotherapy‐Induced Nausea and Vomiting Associated with Highly Emetogenic Chemotherapy: A Network Meta‐Analysis

BACKGROUND The current antiemetic prophylaxis for patients treated with highly emetogenic chemotherapy (HEC) included the olanzapine-based triplet and neurokinin-1 receptor antagonists (NK-1RAs)-based triplet. However, which one shows better antiemetic effect remained unclear. MATERIALS AND METHODS We systematically reviewed 43 trials, involving 16,609 patients with HEC, which compared the following antiemetics at therapeutic dose range for the treatment of chemotherapy-induced nausea and vomiting: olanzapine, aprepitant, casopitant, fosaprepitant, netupitant, and rolapitant. The main outcomes were the proportion of patients who achieved no nausea, complete response (CR), and drug-related adverse events. A Bayesian network meta-analysis was performed. RESULTS Olanzapine-based triple regimens showed significantly better no-nausea rate in overall phase and delayed phase than aprepitant-based triplet (odds ratios 3.18, 3.00, respectively), casopitant-based triplet (3.78, 4.12, respectively), fosaprepitant-based triplet (3.08, 4.10, respectively), rolapitant-based triplet (3.45, 3.20, respectively), and conventional duplex regimens (4.66, 4.38, respectively). CRs of olanzapine-based triplet were roughly equal to different NK-1RAs-based triplet but better than the conventional duplet. Moreover, no significant drug-related adverse events were observed in olanzapine-based triple regimens when compared with NK-1RAs-based triple regimens and duplex regimens. Additionally, the costs of olanzapine-based regimens were obviously much lower than the NK-1RA-based regimens. CONCLUSION Olanzapine-based triplet stood out in terms of nausea control and drug price but represented no significant difference of CRs in comparison with NK-1RAs-based triplet. Olanzapine-based triple regimens should be an optional antiemetic choice for patients with HEC, especially those suffering from delayed phase nausea. IMPLICATIONS FOR PRACTICE According to the results of this study, olanzapine-based triple antiemetic regimens were superior in both overall and delayed-phase nausea control when compared with various neurokinin-1 receptor antagonists-based triple regimens in patients with highly emetogenic chemotherapy (HEC). Olanzapine-based triplet was outstanding in terms of nausea control and drug price. For cancer patients with HEC, especially those suffering from delayed-phase nausea, olanzapine-based triple regimens should be an optional antiemetic choice.

Trends in incidence and associated risk factors of suicide mortality in patients with non-small cell lung cancer

Lung cancer patients have an increased risk for committing suicide. But no comprehensive study about the suicide issues among non‐small‐cell lung cancer (NSCLC) patients has been published. We aimed to estimate the trend of suicide rate and identify the high‐risk group of NSCLC patients. Patients diagnosed with primary NSCLC were identified from Surveillance, Epidemiology, and End Results (SEER) database (1973‐2013). Suicide mortality rate (SMR) were calculated. Multivariable logistic regression was employed to find out independent risk factors for suicide. Among 495 889 NSCLC patients, 694 (0.14%) of them died from suicide. The suicide mortality rates have significantly decreased (before 1993: 0.21%, 1994‐2003: 0.16%, after 2004: 0.09%, P < .001). Male (OR 6.22, 95% CI: 4.96‐7.98, P < .001), white (OR 3.89, 95% CI: 2.66‐5.97, P < .001), being unmarried (OR 1.43, 95% CI: 1.22‐1.67, P < .001), the elderly (60‐74 vs <60: OR 1.24, 95% CI: 1.03‐1.50, P = .024, >75 vs <60: OR 1.31, 95% CI: 1.05‐1.63, P = .018) were independently associated with higher risk of suicide mortality. Surgery (OR: 1.44, 95% CI: 1.19‐1.73, P < .001) was also relative with higher risk of suicide. Our study observed significant decrease in suicide mortality among NSCLC patients in US over past decades. Older age, male sex, unmarried status, and surgery were risk factors of committing suicide. Clinicians should be aware of these high‐risk groups.

Effects of thoracic radiotherapy timing and duration on progression-free survival in limited-stage small cell lung cancer

Concurrent chemoradiotherapy (CRT) has been recommended and applied widely as the standard treatment for limited‐stage small cell lung cancer (LS‐SCLC). However, controversies remain regarding the optimal timing and treatment duration of thoracic radiotherapy (TRT), and their effects on patient survival. To evaluate prognostic values of TRT timing and duration on progression‐free survival (PFS) in LS‐SCLC and their dependence on TRT fractionation and clinicopathological characteristics, we retrospectively analyzed 197 LS‐SCLC patients receiving CRT from 2000 to 2016 at Sun Yat‐sen University Cancer Center. Based on the optimal cut‐off values of TRT timing and duration generated by Cutoff Finder, patients were divided into early TRT/late TRT group and short TRT/long TRT group respectively. Univariate and multivariate Cox analysis were performed to assess correlations of TRT timing, duration, fractionation, and clinicopathological characteristics with PFS. Univariate analysis revealed that early‐initiated TRT (P = 2.54 × 10−4) and short TRT (P = .001) significantly correlated with longer PFS. Their PFS benefits persisted in patients receiving hyperfractionated TRT and etoposide‐cisplatin (EP) chemotherapy, but were less prominent in those receiving once‐daily TRT and non‐EP chemotherapy. Multivariate analysis further identified early initiated TRT (P = .004) and short TRT (P = .017) as independent prognostic factors for longer PFS in LS‐SCLC. Our study confirmed that early‐initiated TRT and short TRT had positive prognostic roles in LS‐SCLC, especially in patients receiving hyperfractionated TRT and etoposide‐cisplatin chemotherapy. TRT fractionation was not an independent prognostic factor in LS‐SCLC.

p300 promotes proliferation, migration, and invasion via inducing epithelial-mesenchymal transition in non-small cell lung cancer cells

BackgroundHistone acetyltransferase p300 is a crucial transcriptional coactivator and has been implicated as a poor prognostic factor in human cancers. However, little is known about the substantial functions and mechanisms of p300 in NSCLC proliferation and distant metastasis.MethodsWe constructed p300 down-regulated and up-regulated cell lines through RNAi and recombinant plasmid transfection. Cell Counting Kit-8 assays were used to test the cell proliferation and confirmed by colony formation assays. Wound healing assays and transwell chamber assays were used to test the migration and invasion ability. Based upon these results, we measured the epithelial markers and mesenchymal markers after regulating p300 expression to explore epithelial-mesenchymal transition as a potential mechanism of p300 promoting NSCLC metastasis.ResultsIn NSCLC cells NCI-H1975 and NCI-H1993, down-regulation of p300 leads to inhibition of cell proliferation and colony formation. Cells with reduced p300 expression also demonstrate inhibited migration and invasion ability. Contrarily, up-regulation of p300 significantly enhanced the proliferation, colony formation, migration and invasion ability of NCI-H460. Importantly, further investigation shows that decreased p300 expression is associated with reduced expression of mesenchymal markers and increased expression of epithelial markers, while up-regulated p300 expression correlated with decreased expression of epithelial markers and increased expression of mesenchymal markers.ConclusionsAs a crucial tumor promoter, p300 promotes cell proliferation, migration, and invasion in NSCLC cells. Epithelial-mesenchymal transition is a potential mechanism of p300 promoting NSCLC metastasis.

Therapeutic Efficacy Comparison of 5 Major EGFR-TKIs in Advanced EGFR-positive Non–Small-cell Lung Cancer: A Network Meta-analysis Based on Head-to-Head Trials

BACKGROUND Five major first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, icotinib, afatinib, and dacomitinib, are currently optional for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, there was no head-to-head-based network meta-analysis among all the TKIs in EGFR-mutated populations. METHODS Eligible literature was searched from an electronic database. Data of objective response rate, disease control rate, progression-free survival, and overall survival were extracted from enrolled studies. Multiple treatment comparisons based on Bayesian network integrated the efficacy of all included treatments. RESULTS Six phase III randomized trials involving 1055 EGFR-mutated patients with advanced NSCLC were enrolled. Multiple treatment comparisons showed that 5 different EGFR-TKIs shared equivalent therapeutic efficacy in terms of all outcome measures. Rank probabilities indicated that dacomitinib and afatinib had potentially better efficacy compared with erlotinib, gefitinib, and icotinib in the EGFR-mutated patients. When compared with other agents, potential survival benefits (progression-free and overall survival) were observed in dacomitinib, whereas afatinib showed a better rank probability in overall response rate and disease control rate. CONCLUSION Our study indicated a preferable therapeutic efficacy in the second-generation TKIs (dacomitinib and afatinib) when compared with the first-generation TKIs (erlotinib, gefitinib, and icotinib).

Optimal tumor shrinkage predicts long-term outcome in advanced nonsmall cell lung cancer (NSCLC) treated with target therapy: Result from 3 clinical trials of advanced NSCLC by 1 institution

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as standard therapies for advanced nonsmall cell lung cancer (NSCLC) patients with EGFR mutation positive. Because these targeted therapies could cause tumor necrosis and shrinkage, the purpose of the study is to search for a value of optimal tumor shrinkage as an appropriate indicator of outcome for advanced NSCLC. A total of 88 NSCLC enrollees of 3 clinical trials (IRESSA registration clinical trial, TRUST study and ZD6474 study), who received Gefitinib (250 mg, QD), Erlotinib (150 mg, QD), and ZD6474 (100 mg, QD), respectively, during December 2003 and October 2007, were retrospectively analyzed. The response evaluation criteria in solid tumors (RECIST) were used to identify responders, who had complete response (CR) or partial responses (PR) and nonresponders who had stable disease (SD) or progressive disease (PD). Receiver operating characteristics (ROC) analysis was used to find the optimal tumor shrinkage as an indicator for tumor therapeutic outcome. Univariate and multivariate Cox regression analyses were performed to compare the progression-free survival (PFS) and overall survival (OS) between responders and nonresponders stratified based on radiologic criteria. Among the 88 NSCLC patients, 26 were responders and 62 were nonresponders based on RECIST 1.0. ROC indicated that 8.32% tumor diameter shrinkage in the sum of the longest tumor diameter (SLD) was the cutoff point of tumor shrinkage outcomes, resulting in 46 responders (⩽8.32%) and 42 nonresponders (≥8.32%). Univariate and multivariate Cox regression analyses indicated that (1) the responders (⩽8.32%) and nonresponders (≥ −8.32%) were significantly different in median PFS (13.40 vs 1.17 months, P < 0.001) and OS (19.80 vs 7.90 months, P < 0.001) and (2) –8.32% in SLD could be used as the optimal threshold for PFS (hazard ratio [HR], 8.11, 95% CI, 3.75 to 17.51, P < 0.001) and OS (HR, 2.36, 95% CI, 1.41 to 3.96, P = 0.001). However, 8.32% tumor diameter shrinkage is validated as a reliable outcome predictor of advanced NSCLC patients receiving EGFR-TKIs therapies and may provide a practical measure to guide therapeutic decisions.