The Evolution of Non-Small Cell Lung Cancer Treatment Through Bibliometric Analysis
Lung cancer remains the most devastating oncological disease worldwide, responsible for approximately 1.8 million deaths annually – more than breast, prostate, and colorectal cancers combined. Among these cases, non-small cell lung cancer (NSCLC) constitutes approximately 85% of all diagnoses, making it the most prevalent form of this deadly disease 1 .
Annual deaths from lung cancer worldwide
For decades, treatment options were limited primarily to surgery, chemotherapy, and radiation therapy, with disappointing outcomes for patients with advanced disease. The five-year survival rate for metastatic NSCLC hovered around a dismal 5%, creating an urgent need for more effective approaches 9 .
The past two decades have witnessed nothing short of a revolution in NSCLC management, transforming it from a virtually uniform approach to a highly personalized precision medicine paradigm. This extraordinary transformation has been documented in a comprehensive bibliometric analysis of the 100 most impactful scientific papers in the field, revealing how research trends have evolved from basic chemotherapy to sophisticated targeted therapies and immunotherapies 1 .
Bibliometric analysis is a powerful tool that allows researchers to quantitatively assess the development of a scientific field by analyzing publication patterns, citation networks, and research trends. Think of it as creating a "map of scientific knowledge" that reveals which directions have proven most fruitful and which territories remain unexplored 1 7 .
Top 100 most-cited papers on NSCLC treatment published between 2000 and 2021 from Web of Science Core Collection database.
VOSviewer, CiteSpace, and R-bibliometrix for analyzing citation patterns and research trends.
| Journal Name | Number of Papers | Total Citations | Impact Factor (2020) |
|---|---|---|---|
| New England Journal of Medicine | 33 | 80,427 | 74.7 |
| Journal of Clinical Oncology | 28 | 32,408 | 32.9 |
| Lancet | 12 | 15,642 | 60.4 |
| Lancet Oncology | 9 | 8,745 | 33.8 |
| Journal of Thoracic Oncology | 7 | 5,218 | 15.6 |
Source: Bibliometric analysis of top 100 NSCLC papers 1
For much of the late 20th century, platinum-based chemotherapy represented the standard of care for advanced NSCLC. The bibliometric analysis revealed that "chemotherapy" was the keyword with the greatest frequency of co-occurrence in the historical literature (appearing in 36 of the top 100 papers), reflecting its former dominance in the field 1 .
The discovery that specific genetic mutations drive certain NSCLC subtypes fundamentally transformed treatment paradigms. Researchers identified that tumors could harbor mutations in genes such as EGFR, ALK, ROS1, BRAF, MET, RET, NTRK, and others, each potentially targetable with specific inhibitors 3 5 .
Perhaps the most dramatic shift documented in the bibliometric analysis is the recent explosion of immunotherapy research. The analysis identified "nivolumab" as the keyword with the second-strongest burst strength (3.85), followed by "blockade" (2.86) and "efficacy" (2.85), reflecting the immense research interest in immune checkpoint inhibitors 1 .
| Molecular Target | Approximate Prevalence in NSCLC | First Generation Targeted Therapies | Next-Generation Therapies |
|---|---|---|---|
| EGFR | 10-15% (Western), 30-50% (Asian) | Gefitinib, Erlotinib | Osimertinib, Amivantamab |
| ALK | 3-7% | Crizotinib | Alectinib, Lorlatinib |
| KRAS | 20-30% | None (historically) | Sotorasib, Adagrasib |
| ROS1 | 1-2% | Crizotinib | Entrectinib, Repotrectinib |
| BRAF V600E | 1-2% | Dabrafenib + Trametinib | - |
One of the most influential studies in the bibliometric analysis is the CheckMate 816 trial, which exemplifies the modern approach to NSCLC treatment 2 . This groundbreaking study investigated the use of neoadjuvant (pre-surgical) immunotherapy in patients with resectable NSCLC.
Randomized, open-label phase III study across multiple medical centers with patients having stage IB to IIIA resectable NSCLC.
| Outcome Measure | Nivolumab + Chemotherapy | Chemotherapy Alone | Hazard Ratio (95% CI) |
|---|---|---|---|
| Pathological Complete Response | 24% | 2.2% | - |
| Median EFS | 31.6 months | 20.8 months | 0.63 (0.45-0.87) |
| 24-month EFS Rate | 63.8% | 45.3% | - |
| 24-month Overall Survival | 82.7% | 70.6% | 0.57 (0.30-1.07) |
Source: 2
The CheckMate 816 trial fundamentally altered the treatment paradigm for early-stage, resectable NSCLC, establishing neoadjuvant immunotherapy plus chemotherapy as a new standard of care that received FDA approval in March 2022 2 .
Advances in NSCLC research have been propelled by sophisticated laboratory tools and reagents that enable precise molecular characterization and therapeutic targeting:
Highly sensitive blood tests that identify tumor-derived DNA fragments in circulation, enabling non-invasive diagnosis and monitoring 5 .
Immunodeficient mice implanted with patient tumor tissue, used to study tumor biology and test drug responses 3 .
Despite remarkable progress, significant challenges remain in NSCLC management. Drug resistance inevitably develops to both targeted therapies and immunotherapies, necessitating continued research into resistance mechanisms and combination strategies 3 5 .
FDA approved for NSCLC in 2024 alone, demonstrating the accelerated pace of discovery 2 4
Future directions include the development of more sophisticated biomarkers beyond PD-L1 expression, such as tumor mutational burden and immune gene signatures, to better predict immunotherapy response 5 . The integration of artificial intelligence into pathology and radiology may enhance early detection and characterization of NSCLC 9 . Additionally, novel approaches such as nanoparticle-based drug delivery systems and therapeutic cancer vaccines represent promising frontiers 6 7 .
The bibliometric analysis of the 100 most impactful papers in NSCLC management reveals a compelling story of scientific progress. From the early days of cytotoxic chemotherapy to the current era of precision medicine and immunotherapy, each evolutionary step has been documented through the collective efforts of researchers worldwide 1 .
This quantitative analysis of publication trends shows clearly how research has evolved from general cytotoxic approaches to highly specific molecular targets and immune modulation strategies. The United States has led in research output, with Memorial Sloan Kettering Cancer Center as the most prolific institution, while the New England Journal of Medicine has been the most influential journal disseminating this knowledge 1 .
As we look to the future, the field continues to evolve at a remarkable pace. With ongoing research into combination therapies, novel agents, and better biomarkers, the outlook for patients with NSCLC continues to improve—offering hope where once there was little.
The journey of NSCLC management exemplifies how sustained scientific investment, international collaboration, and methodological innovation can transform a fatal disease into a manageable condition for many patients.
Top keywords with strongest citation bursts: