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OncoTargets and Therapy 2018The development of acquired resistance to the first-line epidermal growth factor-tyrosine kinase inhibitor (EGFR-TKI) treatment in non-small-cell lung cancer (NSCLC) is...
Chemotherapy with or without pemetrexed as second-line regimens for advanced non-small-cell lung cancer patients who have progressed after first-line EGFR TKIs: a systematic review and meta-analysis.
PURPOSE
The development of acquired resistance to the first-line epidermal growth factor-tyrosine kinase inhibitor (EGFR-TKI) treatment in non-small-cell lung cancer (NSCLC) is inevitable, and most of these patients needed second-line chemotherapy. Furthermore, the optimum chemotherapeutic regimen is unclear. The aim of this meta-analysis was to evaluate the chemotherapeutic regimens "with-pemetrexed" versus "non-pemetrexed" in advanced NSCLC patients who had progressed after first-line EGFR-TKIs.
MATERIALS AND METHODS
We searched PubMed, Embase, Cochrane Library, and the Web of science for relevant clinical trials. Outcomes analyzed were response rate (RR), disease control rate (DCR), 1-year survival rate (1-year SR), progression-free survival (PFS), and overall survival (OS).
RESULTS
One randomized controlled trial (RCT) and three retrospective studies were included in this meta-analysis, covering a total of 354 patients. The results showed that there was no significant difference between with-pemetrexed arm and non-pemetrexed arm in RR (OR 1.43, 95% CI 0.85-2.41, =0.18), DCR (OR 1.5, 95% CI 0.94-2.39, =0.09), and 1-year SR (OR 1.47, 95% CI 0.79-2.74, =0.22). But the with-pemetrexed chemotherapeutic regimens significantly improved the PFS (HR 0.61, 95% CI 0.46-0.81, =0.0005) and OS (HR 0.62, 95% CI 0.42-0.90, =0.01).
CONCLUSION
The second-line with-pemetrexed chemotherapeutic regimens provided significantly longer PFS and OS than non-pemetrexed chemotherapeutic regimens. These findings indicate that the with-pemetrexed chemotherapeutic regimen may be an optimal second-line chemotherapeutic regimen for patients with advanced NSCLC following EGFR-TKI failure.
PubMed: 29983578
DOI: 10.2147/OTT.S160147 -
OncoTargets and Therapy 2018Pemetrexed-based chemotherapy regimens (pem regimens) are the standard first-line treatment option in patients with non-squamous non-small cell lung cancer (NSCLC). The... (Review)
Review
Efficacy of pemetrexed-based regimens in advanced non-small cell lung cancer patients with activating epidermal growth factor receptor mutations after tyrosine kinase inhibitor failure: a systematic review.
Pemetrexed-based chemotherapy regimens (pem regimens) are the standard first-line treatment option in patients with non-squamous non-small cell lung cancer (NSCLC). The objective of this systematic review was to assess the efficacy of pemetrexed in the context of epidermal growth factor receptor () mutation-positive NSCLC following the failure of -tyrosine kinase inhibitor (TKI) treatment. We searched biomedical literature databases (PubMed, EMBASE, and the Cochrane library) and conference proceedings for studies evaluating the efficacy of pemetrexed monotherapy or pemetrexed combined with platinum or any other chemotherapeutic agent in -mutation-positive NSCLC after -TKI failure. We extracted data of primary outcomes of interest (progression-free survival [PFS], overall survival [OS], and overall response rate [ORR]). The weighted median PFS, OS, and ORR were then calculated. Of 83 potentially relevant studies, eight (three randomized studies and five retrospective studies) were identified (involving 1,193 patients) and included in this systematic review, with 640 patients receiving pem regimens. The weighted median PFS, median OS, and ORR for patients treated with pem regimens were 5.09 months, 15.91 months, and 30.19%, respectively. Our systematic review results showed a favorable efficacy profile of pem regimens in NSCLC patients with mutation after -TKI failure.
PubMed: 29695919
DOI: 10.2147/OTT.S157370 -
BMC Medicine Oct 2017Docetaxel, pemetrexed, erlotinib, and gefitinib are recommended as second-line treatment for advanced non-small cell lung cancer (NSCLC) with wild-type or unknown status... (Comparative Study)
Comparative Study Meta-Analysis Review
Comparative efficacy and safety of second-line treatments for advanced non-small cell lung cancer with wild-type or unknown status for epidermal growth factor receptor: a systematic review and network meta-analysis.
BACKGROUND
Docetaxel, pemetrexed, erlotinib, and gefitinib are recommended as second-line treatment for advanced non-small cell lung cancer (NSCLC) with wild-type or unknown status for epidermal growth factor receptor (EGFR). However, the number of published randomized clinical trials (RCTs) on this topic is increasing. Our objective was to assess the comparative effectiveness and tolerability of all second-line treatments for advanced NSCLC with wild-type or unknown status for EGFR by a systematic review and network meta-analysis.
METHODS
MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov, and the US Food and Drug Administration website, as well as other sources, were searched for available reports up to June 6, 2017. Two reviewers independently selected published and unpublished reports of RCTs comparing any second-line treatments, extracted data and assessed the risk of bias of all included trials. We performed a Bayesian network meta-analysis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included objective response (ObR), the number of serious adverse events, and quality of life.
RESULTS
We included 102 RCTs involving 36,058 patients (62% male, median age 61 years, 81% with stage IV cancer, 80% smokers, and 92% with performance status 0-1). We revealed a differential reporting of outcomes between efficacy and safety outcomes. Half of the trials reported safety outcomes and less than 20% quality of life. For OS, nivolumab was more effective than docetaxel (hazard ratio (HR) 0.69, 95% credible interval (CrI) 0.56-0.83), pemetrexed (0.67, 0.52-0.83), erlotinib (0.68, 0.53-0.86), and gefitinib (0.66, 0.53-0.83). Pembrolizumab, atezolizumab, and pemetrexed plus erlotinib were also significantly more effective than docetaxel, pemetrexed, erlotinib, and gefitinib. For PFS, erlotinib plus cabozantinib was more effective than docetaxel (HR 0.39, 95% CrI 0.18-0.84), pemetrexed (0.38, 0.18-0.82), erlotinib (0.37, 0.18-0.78), and gefitinib (0.38, 0.18-0.82). Cabozantinib and pemetrexed plus erlotinib were also significantly more effective than the four recommended treatments. For ObR, no treatment was significantly more effective. The effectiveness of the four recommended treatments was similar and they were ranked among the 25 less-effective treatments. For safety, evidence is insufficient to draw certain conclusions.
CONCLUSIONS
Nivolumab, pembrolizumab, atezolizumab, and pemetrexed plus erlotinib may be the most effective second-line treatments for NSCLC in terms of OS. The four recommended treatments seem to have relatively poor performance. However, the impact on life expectancy of immunotherapy versus other treatments should be further explored by future analyses, and more trials comparing the novel treatments are needed to reduce uncertainty in these results.
TRIAL REGISTRATION
Registration number: PROSPERO ( CRD42015017592 ).
Topics: Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Genes, erbB-1; Humans; Lung Neoplasms; Male; Middle Aged
PubMed: 29082855
DOI: 10.1186/s12916-017-0954-x -
PeerJ 2016The benefit of maintenance therapy has been confirmed in patients with non-progressing non-small cell lung cancer (NSCLC) after first-line therapy by many trials and...
Single-agent maintenance therapy for advanced non-small cell lung cancer (NSCLC): a systematic review and Bayesian network meta-analysis of 26 randomized controlled trials.
BACKGROUND
The benefit of maintenance therapy has been confirmed in patients with non-progressing non-small cell lung cancer (NSCLC) after first-line therapy by many trials and meta-analyses. However, since few head-to-head trials between different regimens have been reported, clinicians still have little guidance on how to select the most efficacious single-agent regimen. Hence, we present a network meta-analysis to assess the comparative treatment efficacy of several single-agent maintenance therapy regimens for stage III/IV NSCLC.
METHODS
A comprehensive literature search of public databases and conference proceedings was performed. Randomized clinical trials (RCTs) meeting the eligible criteria were integrated into a Bayesian network meta-analysis. The primary outcome was overall survival (OS) and the secondary outcome was progression free survival (PFS).
RESULTS
A total of 26 trials covering 7,839 patients were identified, of which 24 trials were included in the OS analysis, while 23 trials were included in the PFS analysis. Switch-racotumomab-alum vaccine and switch-pemetrexed were identified as the most efficacious regimens based on OS (HR, 0.64; 95% CrI, 0.45-0.92) and PFS (HR, 0.54; 95% CrI, 0.26-1.04) separately. According to the rank order based on OS, switch-racotumomab-alum vaccine had the highest probability as the most effective regimen (52%), while switch-pemetrexed ranked first (34%) based on PFS.
CONCLUSIONS
Several single-agent maintenance therapy regimens can prolong OS and PFS for stage III/IV NSCLC. Switch-racotumomab-alum vaccine maintenance therapy may be the most optimal regimen, but should be confirmed by additional evidence.
PubMed: 27781159
DOI: 10.7717/peerj.2550 -
World Journal of Clinical Oncology Aug 2016To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer.
AIM
To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer.
METHODS
An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov, by using the search terms "sorafenib" and "breast cancer". Papers found were checked for further relevant publications. Overall, 21 relevant studies were found, 18 in advanced breast cancer (16 in stage IV and two in stages III-IV) and three in early breast cancer.
RESULTS
Among studies in advanced breast cancer, there were two trials with sorafenib as monotherapy, four trials of sorafenib in combination with taxanes, two in combination with capecitabine, one with gemcitabine and/or capecitabine, one with vinorelbine, one with bevacizumab, one with pemetrexed and one with ixabepilone, three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy. In addition, there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting, and two trials in the neoadjuvant setting. In general, sorafenib was well tolerated in breast cancer patients, though its dosage had to be adjusted in some trials, and discontinuation rates were high, particularly for the combination of sorafenib with anastrozole. Sorafenib monotherapy and combinations with taxanes, bevacizumab and ixabepilone showed inadequate efficacy, while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising.
CONCLUSION
At present, sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.
PubMed: 27579253
DOI: 10.5306/wjco.v7.i4.331 -
OncoTargets and Therapy 2016To assess the efficacy of pemetrexed plus platinum doublet chemotherapy as first-line treatment for advanced nonsquamous non-small-cell lung cancer (NSCLC) through a...
Efficacy of pemetrexed plus platinum doublet chemotherapy as first-line treatment for advanced nonsquamous non-small-cell-lung cancer: a systematic review and meta-analysis.
PURPOSE
To assess the efficacy of pemetrexed plus platinum doublet chemotherapy as first-line treatment for advanced nonsquamous non-small-cell lung cancer (NSCLC) through a trial-level meta-analysis.
METHODS
Trials published between 1990 and 2015 were identified by an electronic search of public databases (Medline, Embase, and Cochrane Library). All clinical studies were independently identified by two authors. Demographic data, treatment regimens, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were extracted and analyzed using comprehensive meta-analysis software (version 2.0).
RESULTS
A total of 2,551 patients with advanced nonsquamous NSCLC from ten trials were included for analysis: 1,565 patients were treated with pemetrexed plus platinum doublet chemotherapy and 986 with platinum plus other first-line chemotherapy. Pooled ORR for pemetrexed plus platinum chemotherapy was 37.8% (95% confidence interval [CI]: 31.7%-44.3%), with median PFS and OS of 5.7 and 16.05 months, respectively. When compared to other platinum-based doublet chemotherapies, the use of pemetrexed plus platinum chemotherapy significantly improved OS (hazard ratio [HR] =0.86, 95% CI: 0.77-0.97, P=0.01) but not PFS (HR =0.90, 95% CI: 0.80-1.01, P=0.084) in advanced nonsquamous NSCLC patients.
CONCLUSION
Pemetrexed plus platinum doublet regimen is an efficacious treatment for advanced nonsquamous NSCLC patients. Our findings support the use of pemetrexed plus platinum doublet regimen as first-line treatment in advanced nonsquamous NSCLC patients because of its potential survival benefits.
PubMed: 27042115
DOI: 10.2147/OTT.S96160 -
Journal of Thoracic Oncology : Official... Jul 2016Non-small cell lung cancer (NSCLC) is often diagnosed at later stages when treatment options are limited. Maintenance therapy may prolong the time to disease progression... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Non-small cell lung cancer (NSCLC) is often diagnosed at later stages when treatment options are limited. Maintenance therapy may prolong the time to disease progression and potentially increase overall survival. Secondarily, it may increase the proportion of patients eligible for second-line therapy at the time of progression. The objective of this systematic review was to examine the use of systemic treatment in the maintenance of patients with NSCLC.
METHODS
MEDLINE, EMBASE, and the Cochrane Library were searched for phase III randomized controlled trials comparing maintenance systemic treatment against another systemic treatment or placebo in patients with stage IIIB or IV NSCLC who had received a minimum of four prior cycles of platinum-based chemotherapy. Meta-analyses were conducted with clinically homogenous trials.
RESULTS
Fourteen randomized controlled trials with 22 publications were included. The overall survival benefit was strongest for maintenance therapy with pemetrexed for patients with nonsquamous NSCLC (hazard ratio = 0.74, 95% confidence interval: 0.64-0.86) but not significant for patients with squamous NSCLC. There was also an overall survival benefit with maintenance therapy with epidermal growth factor receptor tyrosine kinase inhibitors, but the magnitude of the benefit was smaller than with pemetrexed (hazard ratio = 0.84, 95% confidence interval: 0.75-0.94). Docetaxel or gemcitabine as maintenance chemotherapies did not have an impact on overall survival.
CONCLUSION
For patients with advanced, stable stage IIIB/IV NSCLC whose disease has not progressed after four to six cycles of platinum-based chemotherapy, the overall survival benefits were strongest for pemetrexed maintenance therapy followed by epidermal growth factor receptor tyrosine kinase inhibitor maintenance therapy.
Topics: Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Docetaxel; ErbB Receptors; Humans; Lung Neoplasms; Neoplasm Staging; Pemetrexed; Taxoids; Gemcitabine
PubMed: 27013406
DOI: 10.1016/j.jtho.2016.03.007 -
PloS One 2016Gemcitabine and pemetrexed have been used as maintenance therapy. However, few systematic reviews and meta-analyses have assessed their effects in the newest studies.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Gemcitabine and pemetrexed have been used as maintenance therapy. However, few systematic reviews and meta-analyses have assessed their effects in the newest studies. This systematic review and meta-analysis were conducted to assess the role of gemcitabine and pemetrexed in the maintenance treatment of non-small-cell lung carcinoma (NSCLC).
METHODS
We performed a literature search using PubMed, EMBASE and Cochrane library databases from their inceptions to September 16, 2015. We also searched the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) databases from 2008 to 2015. Two authors independently extracted the data. The Cochrane Collaboration's risk of bias graph was used to assess the risk of bias. The GRADE system was used to assess the grading of evidence, and a meta-analysis was conducted using Stata 11.0 software.
RESULTS
Eleven randomized controlled trial (RCT) studies were collected. Ten studies were included in the meta-analysis and divided into the following 4 groups: gemcitabine vs. best supportive care (BSC)/observation, pemetrexed vs. BSC/placebo, pemetrexed + bevacizumab vs. bevacizumab and pemetrexed vs. bevacizumab. Gemcitabine exhibited significantly improved progression-free survival (PFS) compared with BSC (hazard ratio (HR) = 0.62, p = 0.000). Pemetrexed exhibited significantly improved PFS (HR = 0.54, p = 0.000) and OS (HR = 0.75, p = 0.000) compared with BSC. Pemetrexed + bevacizumab almost exhibited significantly improved PFS (HR = 0.71, p = 0.051) compared with bevacizumab. Pemetrexed exhibited no improvement in PFS or overall survival (OS) compared with bevacizumab. Regarding the grade, the GRADE system indicated that the gemcitabine group was "MODERATE", the pemetrexed group was "HIGH", and both the pemetrexed + bevacizumab vs. bevacizumab groups and pemetrexed vs. B groups were "LOW".
CONCLUSIONS
Gemcitabine or pemetrexed compared with BSC/observation/placebo significantly improved PFS or OS. Whether pemetrexed + bevacizumab compared with bevacizumab alone significantly improves PFS requires further investigation.
Topics: Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Pemetrexed; Randomized Controlled Trials as Topic; Survival Rate; Gemcitabine
PubMed: 26954503
DOI: 10.1371/journal.pone.0149247 -
European Journal of Cancer (Oxford,... Nov 2015Recent trials have suggested that maintenance treatments improve outcomes for patients not progressing after first-line therapy for advanced non-small-cell lung cancer... (Meta-Analysis)
Meta-Analysis Review
Bayesian network meta-comparison of maintenance treatments for stage IIIb/IV non-small-cell lung cancer (NSCLC) patients with good performance status not progressing after first-line induction chemotherapy: results by performance status, EGFR mutation, histology and response to previous induction.
BACKGROUND
Recent trials have suggested that maintenance treatments improve outcomes for patients not progressing after first-line therapy for advanced non-small-cell lung cancer (NSCLC). However, physicians have little guidance on selecting which patients benefit the most and what drug or regimen is optimal. Here, we report a systematic review and network meta-analysis of maintenance treatments in subgroups determined by performance status (PS), epidermal growth factor receptor (EGFR) mutation, histology and response to induction.
METHODS
PubMed and conference proceedings were reviewed and individual study relative efficacy measures were meta-analysed in a Bayesian hierarchical model. The primary outcome, overall survival (OS), was evaluated in terms of (i) posterior surface under cumulative ranking curve (SUCRA), (ii) probability of being best treatment, (iii) probability of outperforming no maintenance, and (iv) posterior median hazard ratio (95% credible interval). Secondary outcomes were progression-free survival (PFS) and adverse events.
FINDINGS
Twelve trials evaluating eight maintenance treatments in 3850 patients were meta-analysed. Selected maintenance treatments showed clinically meaningful benefits of ⩾20% reduction in hazards of death with ⩾90% probability of outperforming no maintenance in terms of OS: (i) switch to or continue pemetrexed (nonsquamous), continue gemcitabine, or switch to EGFR tyrosine kinase inhibitors (TKIs) for PS 0 patients, (ii) switch to pemetrexed (nonsquamous) for PS 1 patients, (iii) switch to EGFR TKI for EGFR mutation positive patients, (iv) switch to or continue pemetrexed or switch to EGFR TKI for nonsquamous patients, (v) continue gemcitabine for squamous patients, (vi) switch to docetaxel or continue gemcitabine for responders to induction, or (vii) switch to or continue pemetrexed (nonsquamous) or switch to EGFR TKI for patients with stable disease post-induction.
INTERPRETATION
Maintenance treatments show clinically meaningful survival benefits in good performance status patients with advanced NSCLC not progressing after first-line chemotherapy. Benefits are optimised by targeting specific maintenance to individual patients guided by PS, EGFR mutation status, histology and response to induction.
Topics: Antineoplastic Agents; Bayes Theorem; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Disease Progression; Disease-Free Survival; Docetaxel; Drug Substitution; ErbB Receptors; Genetic Predisposition to Disease; Humans; Induction Chemotherapy; Lung Neoplasms; Maintenance Chemotherapy; Markov Chains; Monte Carlo Method; Mutation; Neoplasm Staging; Pemetrexed; Phenotype; Protein Kinase Inhibitors; Risk Factors; Survival Analysis; Taxoids; Time Factors; Treatment Outcome; Gemcitabine
PubMed: 26364517
DOI: 10.1016/j.ejca.2015.07.007 -
ClinicoEconomics and Outcomes Research... 2015During these last years, there have been an increased number of new drugs for non-small cell lung cancer (NSCLC), with a growing financial effect on patients and... (Review)
Review
During these last years, there have been an increased number of new drugs for non-small cell lung cancer (NSCLC), with a growing financial effect on patients and society. The purpose of this article was to review the economics of first-line and maintenance NSCLC treatments. We reviewed economic analyses of NSCLC therapies published between 2004 and 2014. In first-line settings, in unselected patients with advanced NSCLC, the cisplatin gemcitabine doublet appears to be cost-saving compared with other platinum doublets. In patients with nonsquamous NSCLC, the incremental cost-effectiveness ratios (ICERs) per life-year gained (LYG) were $83,537, $178,613, and more than $300,000 for cisplatin-pemetrexed compared with, respectively, cisplatin-gemcitabine, cisplatin-carboplatin-paclitaxel, and carboplatin-paclitaxel-bevacizumab. For all primary chemotherapy agents, use of carboplatin is associated with slightly higher costs than cisplatin. In all the analysis, bevacizumab had an ICER greater than $150,000 per quality-adjusted life-year (QALY). In epidermal growth factor receptor mutated advanced NSCLC, compared with carboplatin-paclitaxel doublet, targeted therapy based on testing available tissue yielded an ICER of $110,644 per QALY, and the rebiopsy strategy yielded an ICER of $122,219 per QALY. Compared with the triplet carboplatin-paclitaxel-bevacizumab, testing and rebiopsy strategies had ICERs of $25,547 and $44,036 per QALY, respectively. In an indirect comparison, ICERs per LYG and QALY of erlotinib versus gefitinib were $39,431 and $62,419, respectively. In anaplastic lymphoma kinase-positive nonsquamous advanced NSCLC, the ICER of first-line crizotinib compared with that of chemotherapy was $255,970 per QALY. For maintenance therapy, gefitinib had an ICER of $19,214 per QALY, erlotinib had an ICER of $127,343 per LYG, and pemetrexed had an ICER varying between $183,589 and $205,597 per LYG. Most recent NSCLC strategies are based on apparently no cost-effective strategies if we consider an ICER below $50,000 per QALY an acceptable threshold. We need, probably on a countrywide level, to have a debate involving public health organizations and pharmaceutical companies, as well as clinicians and patients, to challenge the rising costs of managing lung cancer.
PubMed: 25548525
DOI: 10.2147/CEOR.S43328