Systemic therapy of advanced non-small cell lung cancer: Major-developments of the last 5-years

doi:10.1016/j.ejca.2012.11.021

European Journal of Cancer

Volume 49, Issue 6, April 2013, Pages 1216-1225

https://doi.org/10.1016/j.ejca.2012.11.021 Get rights and content

Abstract

The standard palliative treatment for advanced stage NSCLC remains a platinum doublet but by tailoring chemotherapy according to tumour histology the results can be improved through using pemetrexed-containing schemas in non-squamous-cell disease. In addition, maintenance chemotherapy appears to be effective in patients achieving clinical benefit by induction therapy. Targeted therapy based on the presence of activating epidermal growth factor receptor (EGFR) activating mutations or EML4–ALK gene rearrangement is becoming standard practice with high median survival rates, up to 30 months. There are still numerous other molecular targeted drugs in development. This review presents the most recent relevant progress in systemic anti-cancer therapy of advanced NSCLC in the past 5 years and delineates today’s new treatment options.

Introduction

Lung cancer is the second most common cancer in men and women and a leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) representing approximately 85% of all cases.¹ More than half of the patients are still diagnosed with advanced metastatic, disease and have a poor prognosis.² Platinum-based palliative chemotherapy is considered a standard therapy for advanced disease, resulting in a median survival of 8–10 months with only 5% patients alive at 2 years.³ A recent randomised trial⁴ highlighted the importance of early palliative care given these poor outcomes. Patients assigned to early palliative care had a better quality of life (QoL) and lived longer compared to patients on standard care (which in most of the patients includes chemotherapy) alone.

Even though, some patients benefit from chemotherapy, the result of the ‘one size fits all’ approach to treatment in NCSLC is finally changing. During the last few years we have learnt that by tailoring chemotherapy according to tumour histology and/or the response to the first four cycles of chemotherapy, the results obtained by standard chemotherapy can be improved upon. Recent improved understanding of the molecular biology of NSCLC has been followed by new, targeted therapies, and represents a major step forward in the treatment of this disease. This review presents the most recent relevant progress in systemic anti-cancer therapy of advanced NSCLC and delineates today’s new treatment options.

Section snippets

Platinum-based chemotherapy

The meta-analysis published in 1995 established the benefit of chemotherapy compared with supportive care alone (without chemotherapy) for advanced NSCLC.⁵ The updated meta-analysis, published in 2008 assessing newer platinum-based regimens incorporating third-generation cytotoxic drugs (gemcitabine, vinorelbine and paclitaxel), showed a further chemotherapy benefit (23% reduction of risk of death, 1-year survival gain of 9% and 1.5 months absolute increase in median survival).⁶ The results

Epidermal growth factor receptor (EGFR)-directed therapy

The major advances in the treatment of NSCLC during the last 5 years are due to the discovery of activating EGFR mutations as well as the introduction of reversible tyrosine kinase inhibitors (TKIs) of EGFR in all lines of treatment of EGFR mutated disease. First-generation EGFR TKIs, gefitinib and erlotinib, were initially studied in unselected populations of NSCLC patients in which they have demonstrated modest activity in second- and third-line treatment.36, 37, 38 The predictive value of

Conclusions

During the last 5 years major advances have been made in individualising systemic therapy for advanced NSCLC. The standard chemotherapy can already be tailored based on tumour histology, with pemetrexed being effective mainly in patients with non-squamous-cell histology. Overall survival benefits in maintenance chemotherapy are dominated by pemetrexed results in the switch or continuing maintenance setting. Major developments in NSCLC biology and identification of druggable targets, such as EGFR

Conflict of interest statement

None declared.

References (70)

J. Ferlay et al.
Estimates of cancer incidence and mortality in Europe in 2008
Eur J Cancer
(2010)
J.A. Roth et al.
Prognostic role of ERCC1 in advanced non-small-cell lung cancer: a systematic review and meta-analysis
Clin Lung Cancer
(2011)
E. Quoix et al.
Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small cell lung cancer. IFCT 0501 randomized phase 3 trial
Lancet
(2011)
M. Reck et al.
Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL)
Ann Oncol
(2010)
T. Brodowicz et al.
Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial
Lung Cancer
(2006)
T. Ciuleanu et al.
Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study
Lancet
(2009)
C.P. Belani et al.
Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study
Lancet Oncol
(2012)
L. Paz-Ares et al.
Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomized controlled trial
Lancet Oncol
(2012)
M.J. Edelman et al.
Maintenance therapy and advanced non-small-cell lung cancer: a skeptic’s view
J Thorac Oncol
(2012)
G.M. Clark et al.
Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21
Clin Lung Cancer
(2006)

J.S. Temel et al.

Early palliative care for patients with metastatic non-small-cell lung cancer

N Engl J Med

(2010)

Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group

BMJ

(1995)

NSCLC Meta-analyses Collaborative Group

Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials

J Clin Oncol

(2008)

A. Ardizzoni et al.

Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis

J Natl Cancer Inst

(2007)

Ferry D, Billingham L, Jarrett H. British Thoracic Oncology Group Trial. BTOG2: randomised phase III clinical trial of...

G.V. Scagliotti et al.

Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non-small cell lung cancer

J Clin Oncol

(2008)

G. Scagliotti et al.

The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies

Oncologist

(2009)

P. Ceppi et al.

Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase

Cancer

(2006)

R.A. Hubner et al.

Excision repair cross-complementation group 1 (ERCC1) status and lung cancer outcomes: a meta-analysis of published studies and recommendations

PLoS One

(2011)

J. Jiang et al.

ERCC1 expression as a prognostic and predictive factor in patients with non-small cell lung cancer: a meta-analysis

Mol Biol Rep

(2012)

Cited by (98)

Inhibition effect of miR-150 on the progression of oral squamous cell carcinoma by data analysis model based on independent sample T-test
2020, Saudi Journal of Biological Sciences
To explore the influence of mir-150 (M-150) ornithine decarboxylase (ODC) or inhibition in the development of oral squamous cell carcinoma (OSCC), the malignant tumor (MT) textures removed by surgical resection of maxillofacial tumors in patients with OSCC and the normal neighbor oral textures were collected. Then human OSCC cal-27 cell line was cultivated in vitro. The expression differences of M-150 in MT textures, neighbor textures and cal-27 cells were explored by fluorescence polymerase chain reaction (PCR). Cal-27 cells were transfected with M-150 mimic, M-150 inhibitor (M-150-I) and negative control of different concentrations, respectively, to test the transfection rate. After transfection (AF) with the optimum transfection concentration, the migration rate of transfected cells was explored by cell scratch test. Transwell assay was used to detect the change of aggression rate of transfected cells. Finally, independent sample t-test model was used to explore and compare the results between groups. The results manifested that the expression of M-150 (Eom) in MT textures and cal-27 cells was obviously less than that in neighbor normal textures (P < 0.05). Transfection rate results manifested that M-150 mimic of 100 nmol/L and M-150-I of 50 noml/L had the best efficiency. AF, cell migration and aggression (M&A) rates in the M-150 mimic group were obviously less than those in the negative control group (CP) (P < 0.05), while those in the M-150-I group were obviously upper (P < 0.05), which indicates that the over Eom could inhibit the M&A of OSCC cells, and thus play an effect in inhibiting the development of OSCC.
Value of serum tumor markers for predicting EGFR mutations and positive ALK expression in 1089 Chinese non-small-cell lung cancer patients: A retrospective analysis
2020, European Journal of Cancer
Citation Excerpt :
Over the past two decades, tyrosine kinase inhibitors (TKIs) matched to targetable oncogenic drivers have shown remarkable efficacy and have become a mainstay in the treatment of lung cancer. TKIs targeting EGFR and ALK have dramatically improved the progression-free survival (PFS) and overall survival (OS) of NSCLC patients, especially those with advanced lung adenocarcinoma (ADC) [10–12]. The frequency of EGFR mutations among Asian NSCLC populations with ADC (51.4%) is significantly higher than that among Caucasians (approximately 20%), and among the former cohort, the mutation rate is shockingly high in females (61.1%) and never-smokers (60.7%) [13–16].
The role of serum tumor markers (STMs) in the modern management of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in lung cancer remains poorly described. In this study, we investigated whether STMs could be a valuable noninvasive tool to predict EGFR mutations and ALK positivity in non-small-cell lung cancer (NSCLC) patients.
We retrospectively reviewed and included 1089 NSCLC patients who underwent EGFR or ALK mutation testing and STMs measurement prior to treatment. The differences in several clinical characteristics and STMs between the subgroups were analyzed. Multivariate logistic regression analysis was performed to identify predictors of EGFR mutations and ALK positivity.
EGFR mutations were found more frequently in females (63.11%), never-smokers (59.69%), and those with lung adenocarcinoma (ADC) (53.87%). Negative carbohydrate antigen (CA) 125, ferritin (FERR), squamous cell carcinoma antigen (SCC), and soluble fragment of cytokeratin 19 (CYFRA 21-1) levels were significantly associated with EGFR mutations (p < 0.05). Multivariate analysis demonstrated that ADC, never-smoker status, and negative CA 125 and SCC results were predictors of EGFR mutations (p < 0.05). The receiver operating characteristic (ROC) curve yielded an area under the curve (AUC) of 0.715 (95% confidence interval [CI]: 0.673–0.758) for the combination of the four factors. Positive ALK expression was found more frequently in younger patients (median age: 49 years), females (8.40%), never-smokers (8.82%), and those negative for carcinoembryonic antigen (CEA) (8.02%). Multivariate analysis demonstrated that younger age and never-smoker status were the only independent predictors of ALK positivity (p < 0.05). The ROC curve yielded an AUC of 0.760 (95% CI: 0.677–0.844) for the combination of these two factors.
STMs are associated with mutant EGFR status and could be integrated with other clinical factors to enhance the ability to distinguish EGFR mutation status among NSCLC patients. For ALK-positive patients, younger age and never-smoker status could predict the mutation status, whereas STMs could not.
Long Non-coding RNA PVT1 Competitively Binds MicroRNA-424-5p to Regulate CARM1 in Radiosensitivity of Non-Small-Cell Lung Cancer
2019, Molecular Therapy Nucleic Acids
Accumulating evidence revealed that dysregulated long non-coding RNAs (lncRNAs) were involved in tumorigenesis and progression. This study is supposed to reveal the effects of lncRNA PVT1 on the radiosensitivity of non-small-cell lung cancer (NSCLC) via the microRNA (miR)-424-5p/lncRNA PVT1/CARM1 signaling pathway. Differentially expressed lncRNA was filtrated. The co-expressed gene of lncRNA was predicted, and gene ontology analysis was performed to find out the genes associated with NSCLC radiosensitivity. The miR that was combined with lncRNA and mRNA was filtrated. Two cell lines with the highest expressed PVT1 were selected, followed by transfection with a series of different mimic, inhibitor, or siRNA. RIP assay was employed for the interaction between PVT1 and CARM1. The regulatory effect of miR-424-5p on cell proliferation, migration, invasion, cycle, and apoptosis was investigated. PVT1 was the most remarkable lncRNA that upregulated in NSCLC. CARM1 co-expressed with lncRNA PVT1 and associated with NSCLC radiosensitivity. Both lncRNA PVT1 and CARM1 can combine with miR-424-5p. Increased PVT1, CARM1, MMP-2, MMP-9, and Bcl-2 and decreased miR-424-5p and Bax were found in NSCLC tissues. PVT1 was targeted by miR-424-5p. After silencing of PVT1 or overexpressed miR-424-5p, decreased PVT1, CARM1, MMP-2, MMP-9, and Bcl-2 inhibited cell proliferation, migration, and invasion but promoted miR-424-5p, Bax, and cell apoptosis. The present study confirms the radiosensitivity of NSCLC radiotherapy can be increased by siRNA-PVT1 and overexpressed miR-424-5p.
MUC1-EGFR crosstalk with IL-6 by activating NF-κB and MAPK pathways to regulate the stemness and paclitaxel-resistance of lung adenocarcinoma
2024, Annals of Medicine
Characterization of stemness features and construction of a stemness subtype classifier to predict survival and treatment responses in lung squamous cell carcinoma
2023, BMC Cancer
A retrospective study on immune-related pneumonitis in patients with non-small-cell lung cancer undergoing treatment with PD-1/PD-L1 inhibitors
2023, European Clinical Respiratory Journal

View all citing articles on Scopus

View full text

Systemic therapy of advanced non-small cell lung cancer: Major-developments of the last 5-years

Abstract

Introduction

Section snippets

Platinum-based chemotherapy

Epidermal growth factor receptor (EGFR)-directed therapy

Conclusions

Conflict of interest statement

Eur J Cancer

Clin Lung Cancer

Lancet

Ann Oncol

Lung Cancer

Lancet

Lancet Oncol

Lancet Oncol

J Thorac Oncol

Clin Lung Cancer

Lancet

Lancet Oncol

Lancet Oncol

Lancet Oncol

Lancet Oncol

Lancet

Lancet Oncol

Lancet Oncol

Lancet Oncol

Lancet Oncol

Lancet Oncol

Eur J Cancer

Eur J Cancer

Lung cancer in Slovenia

Endoscopic Rev

Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer

N Engl J Med

Early palliative care for patients with metastatic non-small-cell lung cancer

N Engl J Med

Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group

BMJ

Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials

J Clin Oncol

Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis

J Natl Cancer Inst

Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non-small cell lung cancer

J Clin Oncol

The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies

Oncologist

Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase

Cancer

Excision repair cross-complementation group 1 (ERCC1) status and lung cancer outcomes: a meta-analysis of published studies and recommendations

PLoS One

ERCC1 expression as a prognostic and predictive factor in patients with non-small cell lung cancer: a meta-analysis

Mol Biol Rep