Volume 73, Issue 6 p. 620-652
REVIEW ARTICLE
Open Access

Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions

Zsolt Megyesfalvi MD, PhD

Zsolt Megyesfalvi MD, PhD

Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary

National Koranyi Institute of Pulmonology, Budapest, Hungary

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Carl M. Gay MD, PhD

Carl M. Gay MD, PhD

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Helmut Popper MD

Helmut Popper MD

Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria

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Robert Pirker MD

Robert Pirker MD

Department of Medicine I, Medical University of Vienna, Vienna, Austria

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Gyula Ostoros MD, PhD

Gyula Ostoros MD, PhD

National Koranyi Institute of Pulmonology, Budapest, Hungary

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Simon Heeke PhD

Simon Heeke PhD

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Christian Lang MD

Christian Lang MD

Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

Division of Pulmonology, Department of Medicine II, Medical University of Vienna, Vienna, Austria

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Konrad Hoetzenecker MD, PhD

Konrad Hoetzenecker MD, PhD

Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

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Anna Schwendenwein MSc

Anna Schwendenwein MSc

Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

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Kristiina Boettiger BSc

Kristiina Boettiger BSc

Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

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Paul A. Bunn jr MD

Paul A. Bunn jr MD

University of Colorado School of Medicine, Aurora, CO, USA

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Ferenc Renyi-Vamos MD, PhD

Ferenc Renyi-Vamos MD, PhD

Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary

National Koranyi Institute of Pulmonology, Budapest, Hungary

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Karin Schelch MSc, PhD

Karin Schelch MSc, PhD

Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

Center for Cancer Research, Medical University of Vienna, Vienna, Austria

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Helmut Prosch MD

Helmut Prosch MD

Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna General Hospital, Vienna, Austria

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Lauren A. Byers MD, MSc

Lauren A. Byers MD, MSc

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Fred R. Hirsch MD, PhD

Corresponding Author

Fred R. Hirsch MD, PhD

Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Tisch Cancer Institute, Center for Thoracic Oncology, Mount Sinai Health System, New York, NY, USA

Correspondence

Fred R. Hirsch, Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Health System, New York, NY, USA.

Email: [email protected]

Balazs Dome, Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Email: [email protected]

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Balazs Dome MD, PhD

Corresponding Author

Balazs Dome MD, PhD

Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary

National Koranyi Institute of Pulmonology, Budapest, Hungary

Department of Translational Medicine, Lund University, Lund, Sweden

Correspondence

Fred R. Hirsch, Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Health System, New York, NY, USA.

Email: [email protected]

Balazs Dome, Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Email: [email protected]

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First published: 17 June 2023
Citations: 8

The last two authors contributed equally to this work as senior authors.

Abstract

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.

INTRODUCTION

Small cell lung cancer (SCLC) represents approximately 13%–15% of all lung cancer cases and remains one of the most lethal malignancies, with a 5-year survival rate <7%.1, 2 In addition to rapid proliferation, high vascularity, and apoptotic imbalance, SCLC is also characterized by early metastatic spread.2, 3 Mirroring this high metastatic capacity, two thirds of patients already present with tumor cell dissemination outside the chest at initial diagnosis. Thus only a small fraction of patients are amenable to potentially curative-intent multimodality therapy.4 In the past decade, genotype-directed targeted therapies based on mutually exclusive subtypes defined by aberrant oncogenic drivers have dramatically improved treatment outcomes in patients with non-small cell lung cancer (NSCLC).5 Nevertheless, because SCLC is biologically and clinically different from other types of lung cancer, the progress in its therapeutic armamentarium stands in sharp contrast to that seen in NSCLC.6 However, after a nihilistic period lasting for decades, substantial progress in our understanding of SCLC biology and tumor heterogeneity has been made.6, 7 These advancements on several fronts might define new avenues in management protocols and provide renewed hope for patients with this hard-to-treat disease.

SCLC and its bronchial origin were first described by Barnard in 1926 by referring to it as an unusual mediastinal oat cell sarcoma (Figure 1).8 Some 30 years later, Azzopardi provided its light-microscopic description and distinguished SCLC from other types of lung cancer.9, 10 The finding in 1973 that SCLC cells spread through lymphatic and blood vessels earlier than malignant cells of other lung cancer histotypes receded surgical resection into the background.11 Consequently, the therapeutic focus was shifted toward radiation and chemotherapy. Indeed, SCLC tumors are tantalizingly chemosensitive in the beginning.12, 13 Yet recurrence occurs rapidly, resulting in SCLC as an extremely challenging tumor type for oncologists to treat.14 The concept of the currently used platinum-based combination chemotherapy was defined in the 1980s, when multiple studies demonstrated that the addition of combination platinum-based chemotherapy given concurrently with chest radiotherapy improved survival in patients with limited stage SCLC, and platinum-based combinations that included etoposide provided superior survival in those with extensive-stage disease (Figure 1).15-17 Thus, the etoposide/platinum (EP) combination was standard until 2019, when it was demonstrated that the incorporation of antiprogrammed death-ligand 1 (anti–PD-L1) immunotherapy into EP chemotherapy improved survival, with a small percentage of patients remaining alive at 3 years.18-20 Importantly, in addition to the lack of potentially targetable oncogenic drivers, therapeutic advancements were also hindered by the scarcity of surgically resected tissue specimens ideal for profiling studies.2 This shortage of adequate patient materials ultimately increased the importance of preclinical models and patient-derived xenografts for understanding the biology of SCLC and supporting translational research.2

Details are in the caption following the image

Major discoveries and therapeutic advancements in SCLC. ASCL1 indicates achaete-scute homolog 1; IHC, immunohistochemistry; NEUROD1, neurogenic differentiation factor 1; NFIB, nuclear factor IB; POU2F3, POU class 2 homeobox 3; RB1, retinoblastoma 1; SCLC, small cell lung cancer; SVV, Seneca Valley virus; YAP1, yes-associated protein 1.3, 6, 8, 9, 11, 15-17, 19, 20, 50, 51, 53, 66, 67, 74, 75, 77, 78, 88, 89, 95, 97, 103, 104, 110, 224, 312-316 Created with BioRender.com.

The emergence of multimodal approaches, the increased research funding, as well as the recent resurgence of profiling studies because of the development of representative disease models have enhanced SCLC research. In the context of these impressive advances, the objective of this in-depth review of the primary literature was to offer clinicians a comprehensive outlook on the most important challenges in tackling this highly recalcitrant disease. Specifically, here, we provide a synthesis of our understanding of SCLC, highlight the most recent translational discoveries, and summarize the current trends in epidemiology, diagnosis, screening, and treatment.

EPIDEMIOLOGY

Incidence and mortality

SCLC comprises an estimated 250,000 new cases globally each year and contributes to at least 200,000 deaths.2, 21 In the United States, approximately 30,000–35,000 new SCLC cases are diagnosed annually.7, 22 Because there is a strong epidemiologic link with heavy smoking, the worldwide incidence of SCLC tends to mirror smoking habits of certain time periods, with a lag time of approximately 30 years.4, 23 Accordingly, because of the adoption of clinical and public health interventions to discourage smoking initiation and encourage cessation programs as well as changes in cigarette composition and reduction of occupational hazards, the incidence rate of SCLC has declined steadily since the late 1980s.4, 24 SCLC incidence is slightly higher in males than in females; however, the incidence gap between sexes has narrowed down over the past 3 decades, again reflecting the changes in smoking habits.4, 24, 25 The incidence of SCLC also varies according to geographic and racial/ethnic differences.2 Reflecting trends in smoking prevalence, the incidence of SCLC is decreasing in high-income countries, but it is increasing in low-income and middle-income regions.26 SCLC incidence is lower and the survival rates are higher in African American individuals compared with White individuals despite the lower smoking prevalence in the latter racial group.24, 27-29 Importantly, although the relative incidence of SCLC has indeed decreased over the past decades, patients' overall survival (OS) has remained notoriously poor.30, 31

Risk factors

SCLC tumorigenesis is commonly linked to excessive tobacco exposure, and 94% and 93.9% of men and women with SCLC, respectively, are ever-smokers.32 Smoking is associated with intrinsic aggressive disease, which is reflected by odds ratios (ORs) of 12.9 (95% confidence interval [CI], 9.79–17.1) and 42.0 (CI 21.7–81.2) in ever-smokers or current-smokers diagnosed with SCLC, respectively.33 Compared with other types of lung cancer, patients who have SCLC display the highest smoking intensity (>30 cigarettes a day: OR, 18.3; 95% CI, 9.26–36.4) and the longest duration of smoking (≥40 years: OR, 38.6; 95% CI, 11.9–125).33 Notably, secondhand smoking also contributes to SCLC carcinogenesis because the association between secondary smoke exposure and the development of SCLC is two to three times greater than that in other histologic types.34 Interestingly, the fraction of never-smokers with SCLC appears to be somewhat higher in Asians, among whom >10% of patients are never-smokers.35, 36 Nevertheless, the risk of SCLC steadily decreases over the years after smoking cessation, underscoring the importance of quitting smoking as early as possible.23 Regarding pathogenic mechanisms, the assault on lung cells of genotoxic carcinogens in cigarette smoke (e.g., polycyclic aromatic hydrocarbons, N-nitrosamines, aromatic amines) has disastrous effects on DNA, leading to miscoding and mutations in critical growth-control genes.37, 38 In addition, co-carcinogens and tumor promoters, such as undecane, pyrene, and fluoranthene, enhance the carcinogenicity of cigarette smoke carcinogens through mechanisms that usually lead to the stimulation of cell proliferation.39 Finally, proinflammatory changes have been observed in smokers that are closely associated with tumor promotion and NF-κB signaling, a pathway that regulates multiple aspects of innate and adaptive immune functions.40-43 Although never-smokers lack mutational signatures related to tobacco exposure and their tumors have a lower tumor mutational burden (TMB), there are no differences in the survival of patients who have SCLC between never-smokers and smokers.44 Indoor radon exposure and air pollution are most likely the second most important risk factors for SCLC worldwide and the main risk factor for never-smokers.45, 46 Indeed, radon disintegration emits alpha radiation, which damages cells in the lung lining and produces mutations.46 Meanwhile, air pollutants, such as particulate matter with an aerodynamic diameter <10 μm and nitrogen dioxide, have direct carcinogenic effects, especially in the case of SCLC and squamous cell lung cancer.47, 48 This is mainly because the wretched effects of these air pollutants are more evident in the central sites of the bronchial tree (the place of origin of most SCLCs and squamous cell carcinomas) than in the peripheral bronchi.34 Among respiratory comorbidities, chronic obstructive pulmonary disease is an independent risk factor for SCLC development.23 Studies of familial aggregation suggest a higher risk of SCLC among first-degree relatives.38 Yet, this is mostly because of shared smoking patterns rather than the consequence of hereditary germinal mutations.49

PATHOLOGY AND GENOMICS

Cell of origin and pathogenesis of SCLC

In contrast to NSCLC, in which precancerous conditions offer valuable insights into the cellular origin of both lung adenocarcinoma and squamous cell carcinoma, the explosive tumor growth in SCLC precludes the detection of these lesions; therefore, oncogenesis remains poorly understood.7 However, it is thought that concomitant inactivation of the tumor suppressors p53 and RB (encoded by TP53 and RB1, respectively) is necessary for tumorigenesis in the vast majority of patients (Figure 2A).3, 50, 51 These dual inactivation events usually target achaete-scute homolog 1 (ASCL1)-expressing pulmonary neuroendocrine (NE) cells located predominantly in larger airways and initiate molecular events necessary for tumor development. Actually, a comprehensive preclinical study suggests that loss of Trp53 and RB1 transforms both NE cells and type 2 alveolar cells to SCLC, albeit the latter are transformed with much lower efficiency.52 Accordingly, SCLC arises with greatest efficiency from pulmonary NE cells but could also arise seldom from epithelial cells, such as type 2 alveolar cells, basal cells, or club cells (Figure 2A).7, 52 Recent studies suggest that certain SCLC tumors harbor tuft cell-like gene expression signatures.53 These tumors most likely originate from the chemosensory epithelial cells of the respiratory tract and have widely different morphologic features compared with the classical NE form of this disease (Figure 2A).53 Undifferentiated stem cells also have the potential to form SCLC-like tumors through NOTCH, TP53, and RB1 inactivation.54 Finally, although uncommon, epidermal growth factor receptor (EGFR)-driven, ALK-driven, or RET-driven lung adenocarcinomas can also transdifferentiate to an SCLC phenotype through lineage plasticity upon treatment with targeted therapies, as discussed below.55-57

Details are in the caption following the image

(A) Cellular origin and concepts on tumoral heterogeneity in SCLC concerning morphology, key characteristics, and genomic alterations (B) in 1985 and (C) today. ASCL1 indicates achaete-scute homolog 1; ATOH1, atonal bHLH transcription factor 1; NE, neuroendocrine; NEUROD1, neurogenic differentiation factor 1; PNEC, pulmonary neuroendocrine cells; POU2F3, POU class 2 homeobox 3; Rb1, retinoblastoma 1; SCLC, small cell lung cancer. Created with BioRender.com.

Lineage plasticity and transdifferentiation

Histologic transformation to SCLC may occur in up to 15% of EGFR-mutant lung adenocarcinomas and is mostly triggered by acquired resistance to tyrosine kinase inhibitors.58-60 The median elapsed time from the initiation of anti-EGFR therapy to the transformation to SCLC is approximately 16–19 months, and it mostly affects a subset of tumors characterized by concomitant biallelic loss of TP53 and RB1.55, 58, 61, 62 Genomic sequencing of tumor samples from repeated biopsies suggests that transformed SCLCs harbor the original activating EGFR mutation present in the adenocarcinoma counterpart, but EGFR protein expression is downregulated after transdifferentiation.56 The clinical behavior of transdifferentiated tumors mimics the characteristics of primary SCLCs, exhibiting rapid tumor growth and early metastatic spread.55 Likewise, survival outcomes concerning both progression-free survival (PFS) and OS are also comparable to those seen in classical extensive-stage SCLC.61 Importantly, SCLC transdifferentiation can also occur in patients who have ALK-translocated NSCLC treated with ALK inhibitors and even in those who have wild-type EGFR or ALK tumors treated with immunotherapy.63, 64 The potential mechanisms underlying this SCLC phenotype conversion are poorly understood, yet a possible explanation might lie in the shared ancestry of some SCLC and NSCLC tumors.59 Accordingly, as elaborated previously, type 2 alveolar cells (the cellular origin of some adenocarcinomas) also have the capacity to become SCLC (Figure 2A).59 Of note, a similar transdifferentiation can also occur in prostate cancer when prostate adenocarcinoma acquires the histologic features of small cell NE cancer after developing resistance to traditional systemic therapies. These castration-resistant NE cancers are clonally derived from prostate adenocarcinomas but possess a unique NE-differentiated phenotype and have recurrent TP53 and RB1 alterations.65

Genomic landscape, key genetic alterations, and pathways

In addition to the loss of TP53 and RB1, genome sequencing has revealed several other recurrent genetic alterations in SCLC particularly linked with NE differentiation and either therapeutic resistance or therapeutic sensitivity.3 A small but significant fraction of SCLC is characterized by recurrent amplification of BCL2 and the MYC family of proto-oncogenes as well as by the loss of the tumor suppressor PTEN.3, 66, 67 The amplification of MYC, MYCL, and MYCN and the inactivating mutations in MYC-regulatory factors MAX, MGA, and BRG1 result in tumors with distinct morphologies, expression profiles, and gene dependencies.7, 68 Specifically, amplification of MYC (i.e., c-Myc) promotes an NE-low phenotype associated with high expression of neurogenic differentiation factor 1 (NEUROD1) and thus with variant morphology (as discussed below).69 In line with this, c-Myc induces transition from ASCL1-defined to NEUROD1-defined SCLC.70 Meanwhile, increased MYCL expression is associated with high NE marker expression and elevated levels of the transcription factor ASCL1.4 Accordingly, by activating Notch signaling, MYC plays a prominent role in mediating NE plasticity.52 Suppression of apoptosis is a hallmark of SCLC. This is mainly achieved by elevated expression of the antiapoptotic gene BCL2, which acts as a promoter of carcinogenesis and cancer progression through cell death resistance.71 Importantly, BCL2 is a conserved transcriptional target of ASCL1.71 In addition to influencing NE fate, Notch signaling also acts as a tumor suppressor in SCLC.72 In the vast majority of tumors, Notch appears to be inactivated, especially in those expressing the full set of NE markers.3 Nevertheless, Notch-active SCLCs also exist. Consistent with the tumor suppressive role of Notch, these tumors grow slowly and are characterized by loss of NE differentiation.73 Other recurrent genetic alterations in SCLC include the activating mutation of PIK3A and the deletion of KMT2D, PTEN, and CREBBP.

Neuroendocrine features of SCLC

Because of the presence of sparse, fairly small, dense-core granules in the majority of SCLC cells, which are all part of the ultrastructural hallmark of NE cells, SCLC was historically regarded as an NE malignancy.74 Indeed, this classic form of SCLC is associated with typical morphology, high expression of NE markers, and nonadherent growth patterns in cell cultures (Figure 2B).75 These SCLCs share histologic features with extrapulmonary small cell carcinomas arising from the gastrointestinal and genitourinary systems.76 Although they are relatively rare, extrapulmonary small cell carcinomas have an aggressive natural history and a dismal prognosis, similar to SCLCs. Importantly, in 1985 (Figure 1), Gazdar et al. also provided evidence for a distinct SCLC phenotype with variant morphology (Figure 2B). This subset of SCLC tumors is characterized by larger cells with prominent nucleoli, partial or complete loss of NE cell properties, and epithelial-mesenchymal transition (EMT).77

Drivers of metastatic spread

The transcription factor NFIB is frequently overexpressed and amplified in SCLC and has been shown to function as a major determinant driving tumor progression, invasion, and metastasis (Figure 1).78, 79 In addition to being associated with several gene expression programs related to metastasis, such as cell migration, cell adhesion, and neuronal differentiation, NFIB also promotes multiple steps of the metastatic cascade through a widespread increase in chromatin accessibility.78, 80 Accordingly, high NFIB expression is generally associated with late-stage disease and, consequently, worse patient survival.79 Recently, EMT has also been associated with metastasis. Because yes-associated protein 1 (YAP1) is frequently linked with EMT, its elevated expression might endow SCLC cells with the ability to metastasize.81 Other mechanisms underlying the ability of malignant cells to metastasize remain relatively poorly understood, but factors associated with migration and neuronal differentiation might as well be implicated in the metastatic spread of SCLC.4, 82

AN EMERGING MOLECULAR CLASSIFICATION AND ITS CLINICAL IMPACT

Neuroendocrine and molecular subtypes of SCLC

Except for minor attempts in classifying the disease by its dominant phenotype (classic vs. variant),75, 77 SCLC was considered a single, monolithic entity in both clinics and laboratories for decades. Consequently, clinical study protocols are still generally based on disease stage, with no consideration of predefining distinct molecular marker expressions that have predictive or prognostic significance.6, 30 However, the recent worldwide resurgence of profiling studies and the development of the preclinical models highlighted below led to the refinement of the SCLC classification scheme.7 Accordingly, based on the expression pattern of certain well established NE cell markers, SCLC tumors can be classified either as NE-high or NE-low subtypes.2, 6, 83, 84 In addition, a further subset of SCLC lacks any sign of NE differentiation; therefore, these termed non-NE tumors.6 These subtypes can also be characterized by NE-related scoring systems and EMT.83 Importantly, NE subtypes have major differences concerning their immunologic landscape because NE-high SCLCs are considered immune desert tumors characterized by low numbers of infiltrating immune cells, whereas NE-low tumors have an immune oasis phenotype with increased immunogenicity.85

Emerging knowledge suggests that SCLC subtypes are defined not necessarily by their mutational landscape but, instead, by the expression of certain transcription factors and features of inflammation that can provide a biologic framework for the distinct SCLC entities.86 SCLC tumors originating both from limited stage and extensive-stage disease have recently been stratified into different subtypes based on the elevated expression of transcription factors ASCL1, NEUROD1, and POU class 2 homeobox 3 (POU2F3) and on inflammatory characteristics (Figures 1 and 2C).6, 87-89 Of note, it has been demonstrated that ASCL1, NEUROD1, and POU2F3 expression levels define distinct SCLC subtypes in metastatic lymph nodes as well.90 These novel subtypes are of clinical importance because they correlate with therapeutic responsiveness and have major differences in morphology, growth properties, genetic alterations, and prognosis.87, 89 The most common is the ASCL1-defined SCLC-A subtype, comprising approximately 40%–50% of all SCLCs.6, 88, 89 Pathologically, these tumors are associated with elevated expression of NE markers and classic morphology.30 Importantly, recent studies on patients with surgically treated SCLC suggest that high ASLC1 expression is associated with impaired survival outcomes in surgically treated individuals.89, 91, 92 Indeed, high-grade NE features and elevated ASCL1 levels have been described as a potential sign of poor prognosis in other histologic subtypes of lung cancer, including lung adenocarcinoma.93 Further subdivision of ASCL1-driven tumors into two subclusters (namely, SCLC-A and SCLC-A2) is suggested based on expression differences concerning other factors, such as HES1.94 SCLC-N was originally described as a distinct, NEUROD1-defined subtype susceptible to the Seneca Valley virus.95 These tumors are associated with lower overall NE marker expression and thus with variant phenotype.6, 30 Importantly, combined SCLC-AN tumors also exist.88, 89 POU2F3 is a master transcriptional regulator of tuft cells, a rare cell type thought to have chemosensory and immunomodulatory functions.53 These cells can be found in a wide variety of epithelia and are alternatively referred to as brush cells in the lung airways.96 Accordingly, POU2F3-driven SCLCs (SCLC-P subtype) might represent a specific tuft-cell variant of SCLC and thus might have a distinct cellular origin compared with SCLC-A and SCLC-N.53 These tumors do not express classical NE markers. Therefore, from a clinical point of view, these tumors may represent diagnostic challenges and often require an extensive immunohistochemical (IHC) work-up to exclude other entities.96 Interestingly, in-depth analyses of basaloid squamous cell carcinomas revealed strong and diffuse POU2F3 immunoreactivity, suggesting a possibly closer biologic relationship between SCLC-P and this primitive phenotype of lung squamous cell carcinoma than expected.96 High POU2F3 expression was recently associated with improved survival outcomes in patients with surgically treated SCLC.89, 91 However, survival analyses in patients with extensive-stage disease yielded conflicting results.96, 97 Accordingly, our current understanding concerning its clinical relevance is still limited. Initially, a putative fourth molecular subtype driven by the transcription factor YAP1 was also proposed,6 yet multiple independent studies (including those from the investigators originally proposing YAP1 as a candidate subtype) failed to confirm the existence of a major, distinct SCLC-Y subtype.88, 89, 98 Instead, a recent study based on RNA sequencing data and subsequent IHC validation provided evidence for an SCLC-inflamed subtype (SCLC-I). In addition to the lack of prominent ASCL1, NEUROD1 and POU2F3 expression, SCLC-I is accompanied by an inflamed gene signature and mesenchymal characteristics (Figure 2C).97 Concerning the nomenclature, an alternative for SCLC-I might be the newly proposed quadruple-negative subtype (SCLC-QN) characterized by low expression of all four (ASCL1, NEUROD1, POU2F3, and YAP1) transcription regulators.89 Although neither of these is defined by YAP1 expression, currently it is still debatable whether SCLC-I and SCLC-QN are identical subtypes or they form two distinct subsets within the scale of non-NE SCLCs. Finally, it is worth mentioning that a rare subtype demonstrating elevated expression of the transcription factor ATOH1 might also exist; yet, to date, little is known about its specific genomic features.99

Phenotype switching and tumoral heterogeneity

Although a dominant molecular subtype can be distinguished in the majority of cases, recent studies described substantial heterogeneity.88, 89, 97 Pathologically, two manifestation forms of intratumoral heterogeneity were detected. In some cases, tumors have both subtype-specific marker-expressing and nonexpressing cells within the same areas, whereas, in other cases, clusters of these cells can be found in spatially distinct regions.89, 97 In addition to raising diagnostic issues, this also indicates a potential temporal evolution between subtypes. Indeed, several studies suggest a potential sequential hierarchy between subtypes, with SCLC-A being a necessary precursor for SCLC-N.69, 100 The dominant phenotype might as well be influenced by systemic therapy. High YAP1-expressing tumor cells are thought to be resistant to the majority of standard-of-care chemotherapeutics.89, 97 Accordingly, after chemotherapy, YAP1-high cells have the potential to replenish the tumor.97, 101 Subtype switching was also described during metastatic spread in mediastinal lymph nodes.84 In this form of intertumoral heterogeneity, some NE-low primary tumors gave rise to NE-high metastases, suggesting that tumor cells with NE differentiation tend to be more aggressive and thus more metastatic than NE-low cells.84

It is also important to mention that, apart from subtypes, dynamic heterogeneity can be observed in the expression of several SCLC candidate targets, such as DLL3, aurora kinase (AURK) A and B (AURKA)/(AURKB), and poly(ADP-ribose) 1 (PARP1).102 This may contribute to therapeutic resistance and the lower-than-expected response rates, despite biomarker-guided patient selection.

Subtype-specific therapeutic targets

The identification of subtype-specific molecular profiles and clinically meaningful biomarkers may contribute to novel targeted strategies. Indeed, recent genomic and proteomic data suggest that several putative targets in patients with SCLC representing subtype-specific vulnerabilities might exist (Figure 2C).30, 97, 103 Among others, DLL3, a target of multiple SCLC therapeutics now in clinical development, is reported to be highly expressed in SCLC-A tumors.6, 92 Likewise, BCL-2 is also preferentially expressed in this subtype.71, 104, 105 Histone demethylase LSD1 activity depends on the disruption of INSM1, which is linked to the NE subtypes SCLC-A and SCLC-N.106 MYC amplification is frequently associated with SCLC-N, thus serving as a potential therapeutic target for this subtype.69 Both arginine biosynthesis and increased AURKA activity are also specific features of this particular molecular subtype.30, 69, 107 Regarding SCLC-P, CRISPR screening identified IGF-1R as a unique dependency in SCLC cells with high POU2F3 expression.53 However, the most evident clinical implications have been linked with SCLC-I, given the elevated expression of genes associated with immune checkpoints and human leukocyte antigens in this subtype.97, 108, 109 In support of this, the retrospective analysis of the phase 3 IMpower133 trial (ClinicalTrials.gov identifier NCT02763579), which assessed the addition of atezolizumab to EP, revealed that the highest benefit of the addition of immunotherapy can be seen in patients with SCLC-I.19, 97 Specifically, the median OS was approximately 8 months higher in patients with SCLC-I who received EP plus atezolizumab compared with those who received EP alone.97

PRECLINICAL MODELS FOR THE STUDY OF SCLC

Cell cultures and organoids

The scarcity of representative, surgically removed SCLC tissue samples urged the development of adequate preclinical models. Beginning in the 1970s (Figure 1) and continuing throughout the decades, a focus was laid on the establishment of SCLC cell lines from biopsies or pleural effusions for further in vitro research (Figure 3).110, 111 Currently, the pathologic signature of SCLC is frequently investigated using a comparative approach between cancer cell lines and human bronchial epithelial cells, such as hTERT and Cdk4 immortalized human bronchial epithelial cells.112 However, as with any tumor entity, the study of cell lines comprises major limitations, such as the high chance of genetic transformations, frequent discrepancies between in vitro and in vivo drug efficacies, or the missing exposure to the microenvironment, especially the immune system.113 Nevertheless, despite these disadvantages, human SCLC cell lines still represent an important resource for preclinical research. In contrast to other tumor types, such as colon or breast cancer, three-dimensional models that include organoids are rarely used in SCLC because of its extensive heterogeneity and complexity.114, 115

Details are in the caption following the image

Frequently used in vitro and in vivo models of SCLC. 2D/3D indicates 2-dimensional/3-dimensional; CDX, cell line-derived xenograft; GEMMs, genetically engineered mouse models; HSCs, hematopoietic stem cells; PBMCs, peripheral blood mononuclear cells; PDX, patient-derived xenograft; SCLC, small cell lung cancer. Created with BioRender.com.

In vivo models

Genetically engineered mouse models (GEMMs) bearing SCLC tumors were first designed using a double-gene (TP53 and RB1) knockout (KO) approach.116, 117 In line with the aggressive potential of SCLC, corresponding GEMMs were frequently associated with vascular or lymphatic invasion as well as metastatic spread to the mediastinum or extrathoracic organs.117 In addition to the SCLC double-KO mouse model, triple-KO mice harboring additional loss of P130 or PTEN also exist.118, 119 Of note, triple-KO mice lacking P130 are representative of the SCLC-A subtype.118, 120 In turn, PTEN triple-KO mice display variant features of SCLC but also characteristics from large cell NE carcinoma and NSCLC.119 Importantly, GEMMs provide a faithful immunocompetent model for testing treatment efficacy and investigating the mechanism of action of immunotherapeutic agents.121

Mouse xenograft models (Figure 3) are defined by the engraftment of SCLC cell lines (cell line-derived xenografts), circulating tumor cells (CTCs), or tissue specimens (patient-derived xenografts) into immunodeficient mice and are common tools to investigate the efficacy of cytotoxic agents.122 Although this experimental approach may provide information about the in vivo efficacy of cancer therapeutics, the results might be biased because of the lacking influence of the tumor microenvironment.123 In addition, this preclinical model is usually not applicable to immunologic studies. These limitations are counterbalanced by the high feasibility of CTC-derived patient-derived xenografts because SCLC is one of the very few cancers in which engraftment of CTCs is actually possible and effective.124

One way of generating so-called humanized mice harboring major components of the human immune system is the engraftment of nude mice with human hematopoietic stem cells or peripheral blood mononuclear cells.125 However, humanized mouse models are hampered by immunoglobulin switching, deficiency in T-cell development, and predominant affinity to the murine rather than the human major histocompatibility complex because of their education in the murine thymus.125 Nevertheless, humanized animal models are powerful tools to investigate drug safety and efficacy, especially for immunotherapies in the presence of immunologic processes.

DIAGNOSIS, SCREENING, AND PREVENTION

Presentation and symptoms

SCLC occurs predominantly in the central airways and is typically associated with strong metastatic potential.24 Given its explosive growth rate and aggressive nature, most patients with extensive-stage disease have some clinical manifestations. These signs and symptoms usually begin <12 weeks before presentation and depend on the localization and bulk of the primary tumor.24 Local tumor growth explains the cough, dyspnea, and, eventually, the hemoptysis. In addition, intrathoracic tumor growth can also cause superior vena cava syndrome and upper body edema. Esophageal compression causes dysphagia, whereas compression of the recurrent laryngeal nerve leads to vocal cord paresis or hoarseness. Weight loss, fatigue, and neurologic disabilities are the results of extrapulmonary distant spread. The most common sites of metastasis include the brain, bones, liver, and adrenal glands.126

SCLC is the lung cancer subtype most often associated with paraneoplastic syndromes (PNSs). Indeed, approximately 10% of all patients with SCLC develop some kind of PNS throughout the course of their disease (Figure 4).127, 128 Endocrine PNSs (Figure 4) are caused by the ectopic production of biologically active hormones or peptides by the cancer cells themselves and include the syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) and ectopic Cushing syndrome.127 The syndrome of inappropriate antidiuretic hormone secretion is the most common PNS in patients with SCLC and manifests as euvolemic, hypo-osmolar hyponatremia characterized by low serum osmolality and high urine osmolality, which is secondary to ectopic antidiuretic hormone production.129 Clinically, this may present as headache, nausea, fatigue, and muscle cramps.129 Meanwhile, the manifestation of ectopic Cushing syndrome results from the unregulated production of adrenocorticotropic hormone and includes hypokalemia, muscle weakness, acne, and peripheral edema.130

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SCLC-associated PNSs and their clinical presentations. Orange indicates endocrine PNSs; cyan, neurologic PNSs. ACTH indicates adrenocorticotropic hormone; PNSs, paraneoplastic syndromes; SCLC, small cell lung cancer. Created with BioRender.com.

Neurologic PNSs (Figure 4) are immune-mediated consequences of SCLC tumors and are characterized by an autoantibody response against tumoral antigens.129, 131 The most commonly diagnosed neurologic PNS in SCLC is the Lambert–Eaton myasthenic syndrome, which features progressively worsening proximal muscle weakness and fatigue. It is caused by onconeural antibodies directed against voltage-gated calcium channels.127, 132 If the autonomic nervous system and cranial nerves are involved, symptoms such as dry mouth, constipation, ptosis, and respiratory weakness can also appear in Lambert–Eaton myasthenic syndrome.127 Anti-Hu antibodies are directed against RNA-associated neuronal proteins.133 PNSs associated with the presence of anti-Hu antibodies occur in SCLC at a frequency of 1% and are characterized by inflammation and neuronal loss.134 Among others, these include paraneoplastic encephalomyelitis, limbic encephalitis, and subacute sensory neuropathy, and their clinical manifestations vary according to the affected part of the nervous system (Figure 4).127 For instance, limbic encephalitis is primarily characterized by mood and behavior changes with occasional seizures, whereas the specific symptoms in subacute sensory neuropathy include paresthesia and pain involving all limbs.127, 129 Importantly, in addition to anti-Hu antibodies, several other neural autoantibodies also contribute to the development of neurologic PNSs (Figure 4).129, 135

Diagnostic work-up and diagnosis

Posteroanterior and lateral chest radiographs are usually the first imaging tests performed in patients with SCLC (Figure 5A).136 However, chest radiographs are unremarkable in approximately 4% of patients with SCLC; and, in the absence of evident signs of invasiveness, chest radiography is frequently nonspecific.137 Generally, tumors appear as hilar masses on chest radiographs, frequently accompanied by mediastinal widening caused by lymph node enlargement.136 Whenever clinical and radiologic suspicion for lung cancer is raised by chest radiographs, a contrast-enhanced computed tomography (CT) scan of the chest (Figure 5A) and upper abdomen should also be performed for further evaluation. On CT scans, SCLC tumors are usually characterized as mass lesions with margins that are smooth, lobulated, or irregular and spiculated.138 Necrosis and hemorrhage are both fairly common, as well as the bulky mediastinal nodes that conglomerate to form large masses.138 Rarely, SCLC tumors can also appear as solitary pulmonary nodules.138 Nevertheless, because of its frequent central localization, the primary tumor often cannot be visualized as a distinct entity because it merges with the nodal disease.139 As the cornerstone of lung cancer imaging, CT scans play a pivotal role in determining the tumor's local invasiveness and its anatomic relationship to neighboring structures, such as vessels, the heart, pleura, chest wall, and esophagus.140 This is of clinical importance because the evaluation of mediastinal involvement is crucial for correct staging. SCLC typically demonstrates intense uptake on fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-CT scans, reflecting its high metabolic activity (Figure 5A).86, 141 Importantly, in addition to its diagnostic value concerning the primary tumor and distant metastases, 18F-FDG PET-CT imaging might also help in estimating the prognosis. Indeed, higher maximum standardized uptake values can be observed more often in extensive-stage disease than in limited stage SCLC, and high metabolic tumor burden as well as high total lesion glycolysis are associated with a poor prognosis.141-143 Because some SCLC tumors have high expression of somatostatin receptors, PET-CT imaging with gallium-68 dotatate, a positron emitter-labeled somatostatin analog, might also improve staging.144

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Diagnosis of SCLC and its distant metastases. (A) Imaging techniques for the primary tumor (indicated by arrows). (B) Schematic representations of the different techniques used to obtain tumor specimens. (C) Imaging techniques for the diagnosis of distant metastases. CT indicates computed tomography; EBUS, endobronchial ultrasound; MRI, magnetic resonance imaging; PET, positron emission tomography; SCLC, small cell lung cancer. Created with BioRender.com.

Before treatment can commence, a firm tissue diagnosis of SCLC is required, even in patients with impaired lung function. Sampling methods (Figure 5B) are chosen by oncologists, surgeons, or interventional radiologists primarily based on the tumor's anatomic localization. The decision must also take into account the likely stage of the disease and the overall performance status (PS) of the patient.145 Generally, it is advised that the diagnosis of lung lesions be made by the most convenient and least invasive method available.146 It is usually advisable to biopsy distant metastases because this allows simultaneous diagnosis of the tumor and confirmation of advanced tumor stage. Because many patients with SCLC have supraclavicular lymph node metastases, percutaneous ultrasound-guided biopsy can be the easiest way to get a sufficient amount of tissue.147 Flexible bronchoscopy is usually recommended in patients with centrally located tumors.148, 149 Importantly, in addition to obtaining diagnostic tissue specimens using biopsy forceps, bronchoscopy with brushing or bronchoalveolar lavage can also contribute to the diagnosis with remarkable specificity.150 Among the newer bronchoscopy-based technologies,151 endobronchial ultrasound-guided transbronchial needle aspiration is preferably used for tumors with peribronchial localization and for enlarged mediastinal or hilar lymph nodes.146, 152 Another approach for mediastinal staging is mediastinoscopy (Figure 5B), which is performed under general anesthesia. However, endobronchial ultrasound-guided is a less invasive method with fewer complications and has higher diagnostic sensitivity than mediastinoscopy.153 Therefore, whenever the lymph node station is reachable, endobronchial ultrasound-guided transbronchial needle aspiration should be considered as the procedure of choice for mediastinal staging.154 When results of the bronchoscopy-based investigation are nondiagnostic, transthoracic needle biopsy (Figure 5B) can be applied, especially in peripheral lesions.155 Transthoracic needle biopsy is usually performed using real-time CT visualization for improved yield and has a sensitivity exceeding 90%.156, 157 In rare cases when none of the previously elaborated methods are successful or feasible, thoracoscopy and surgical biopsy should be considered as the ultimate diagnostic approach.158 Meanwhile, in patients with an accessible pleural effusion, thoracentesis is recommended to facilitate diagnosis.155 Finally, given the high amount of circulating tumor DNA and CTCs in the bloodstream of patients who have SCLC, liquid biopsy also holds a potential diagnostic role, especially concerning monitoring disease progression.159, 160

Radiologic diagnosis of distant metastases varies according to their anatomic localization (Figure 5C). However, except for brain metastases, PET-CT remains the imaging approach of choice in identifying extrathoracic metastases, especially bone and adrenal lesions.161 Indeed, recent studies suggest that 18F-FDG PET-CT is more sensitive than multidetector row CT scans, and even bone scintigraphy, for detecting osseous metastases in SCLC.162 This is most likely because PET-CT scans also detect lytic lesions.163 The traditional imaging method for the evaluation of brain metastases is contrast-enhanced magnetic resonance imaging (MRI).164 Depending on accessibility, distal metastatic sites can also be used for diagnostic tissue sampling.

The definitive diagnosis of SCLC is established by histopathologic and/or cytopathologic examination. Notably, cytology is an especially reliable method in SCLC diagnosis because bronchial biopsies may contain crush artifacts and necrosis, hampering the definitive diagnosis.165 Cytologic smears and cell blocks often show small blue cells (approximately 1.5 times the size of lymphocytes) with scant cytoplasm, loosely arranged or in a syncytial pattern.165, 166 Their oval or elongated nuclei are hyperchromatic, and nuclear molding is well developed.165 Tumor cells usually have high mitotic activity. In addition, well preserved cells show a finely dispersed or salt and pepper chromatin pattern.165, 166 On hematoxylin and eosin-stained histopathologic slides, the small to medium-sized, round or fusiform tumor cells have scant cytoplasm, finely granular nuclear chromatin, and inconspicuous or absent nucleoli.165 Necrosis and apoptosis of individual cells as well as the presence of crush artefacts are common.4 Characteristic NE traits, including nested and trabecular growth patterns, rosettes, and peripheral palisading, are more obvious in surgical samples than in small biopsies.167 In current practice, IHC assays are frequently performed when the hematoxylin and eosin–based diagnosis needs to be confirmed or when a differential diagnosis must be addressed.165 SCLC tumors are usually positive for common NE markers, such as synaptophysin, chromogranin, CD56, or INSM1. Importantly, NE-differentiated SCLCs without extensive necrotic areas uniquely resemble pulmonary carcinoid tumors concerning both their NE marker expression and morphologic features.168 In this context, the Ki67 labeling index is of diagnostic importance because it is considerably higher in SCLCs than in carcinoids.165 Although it has not yet been implemented in the clinics, POU2F3 also may constitute a potential additional diagnostic marker for tumors that lack or exhibit minimal levels of standard NE markers and thus are negative for the aforementioned classical IHC markers.96

Differential diagnoses

SCLC has well defined diagnostic criteria, yet some other tumors tend to mimic its clinical, radiologic, and histologic features. The symptoms caused by local tumor growth and intrathoracic metastatic spread are the general clinical features of the majority of lung cancers, including NSCLC. PNSs are not exclusively specific either because they can also be associated with other NE tumors, although at a much lower percentage.169 With regard to imaging, because of its central localization and mediastinal involvement, SCLC might appear similar to lymphomas or other mediastinal tumors.138 From a pathologic point of view, SCLC should be distinguished from large cell NE carcinoma and carcinoid tumors, NSCLC, basaloid squamous cell carcinoma, and non-Hodgkin lymphoma.4, 165

Screening

The US National Lung Screening Trial demonstrated that screening with low-dose CT reduced lung cancer mortality and resulted in a shift to earlier stage disease detection at diagnosis. However, these benefits were limited to NSCLC.170 In the National Lung Screening Trial, a significant proportion of SCLC cases were interval cancers (diagnosed within 1 year after a negative screening), and only one third of all patients with SCLC were screen-detected.171 In addition, the vast majority of these rare screen-detected individuals presented with advanced-stage disease.171 Therefore, annual low-dose CT screening does not improve the survival or therapeutic outcome of SCLC.172 However, because low-dose CT screening still identifies a considerable number of early stage NSCLC tumors (and a very small number of early stage SCLC tumors), screening should be applied in all individuals at risk according to evidence-based guidelines,173 although its efficacy in SCLC lags far behind that observed in NSCLC.171

Notably, the fast progression and the high circulating tumor DNA burden in SCLC provide a rationale for conducting studies of liquid biopsy screening tests. Although multiple large-scale studies are evaluating the feasibility of blood-based screening tests for lung cancer (some with promising preliminary data),174-176 these assays have not yet been translated into routine clinical practice.

Prevention

Considering the strong causal link between smoking and SCLC, avoidance of tobacco use is the most important way of preventing the disease.177 Indeed, the risk of SCLC development decreases gradually after quitting smoking. In addition, quitters also tend to have improved survival in already developed, limited stage SCLC compared with continuing smokers.177 The US Environmental Protection Agency recommends testing all homes below the third floor for radon and mitigation for homes with levels of 4 picocuries per liter or higher.178 The European multidisciplinary RadoNorm Project aims to assure effective radiation protection through radon risk management and exposure normalization.179 Carcinogenic air pollutants should also be avoided; although this risk factor is harder to elude on an individual level, clinicians should support relevant regulations that help prevent lung cancer.

STAGING OF SCLC

Principally, the therapeutic management of patients with SCLC (Figure 6) substantially differs according to the extent of tumoral spread and the patient's clinical condition (i.e., PS). In SCLC, tumor spread can be classified based on two staging approaches: (1) the tumor, node, metastasis (TNM) staging system, implemented by the American Joint Committee on Cancer (AJCC)180 and updated by the International Association for the Study of Lung Cancer (IASLC),181, 182 and (2) the staging system of the Veterans Administration Lung Study Group (VALG).183 The AJCC-IASLC TNM staging system has been developed over the past decades, allowing for a precise definition of tumor spread by containing detailed information about the size of the primary tumor as well as the extent of lymph node involvement and distant metastatic spread.180-182 Although it has been continuously adapted at regular intervals, it should be noted that the AJCC-IASLC TNM staging system was primarily developed and validated with data originating from patients who had NSCLC. Meanwhile, the VALG staging system was specially adopted for patients who have SCLC to provide a simple staging approach for routine clinical practice by only distinguishing between limited stage and extensive-stage disease.183 In this context, limited stage refers to localized disease affecting only one hemithorax that can be treated with a single radiation field.183 Ipsilateral or supraclavicular lymph nodes—that can be included in the same radiation portal as the primary tumor—might also be affected.183 Meanwhile, patients with both lungs affected or those with extrathoracic metastases are considered to have extensive-stage SCLC.183 In an attempt to synchronize the two staging systems, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for SCLC generally refer to patients who have limited stage disease as those with stage I–III SCLC according to the AJCC-IASLC TNM staging system.184 TNM stage IV is considered extensive-stage disease.184 Currently, the VALG staging system is still the most frequently used approach in SCLC, although its prognostic capacity was shown to be significantly inferior compared with the AJCC-IASLC TNM staging system.183, 185 The overall condition of patients with SCLC both in clinical trials and in everyday clinical routine is standardly represented by calculating the Eastern Cooperative Oncology Group PS, which was published in 1982.186

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Therapeutic approaches in SCLC according to disease stage. CAV indicates cyclophosphamide, doxorubicin, and vincristine; M, maintenance; SCLC, small cell lung cancer. Created with BioRender.com.

THERAPEUTIC APPROACHES

Surgery

Surgical resection has been widely excluded from the therapeutic armamentarium of SCLC for decades mainly because of the somewhat disappointing outcomes of surgery-based randomized clinical trials from the 1970 and 1990s.187, 188 Still, in patients with very limited disease stage (T1–T2N0M0), lobectomy with mediastinal lymph node dissection followed by adjuvant chemotherapy has resulted in 3-year survival rates >50%.189, 190 Moreover, recent propensity-score-matched trials reported encouraging long-term survival rates for surgically managed patients who had even more advanced disease stage.191, 192 However, it has been widely demonstrated that durable long-term results after surgical resection can only be achieved if multicyclic, adjuvant, systemic chemotherapy is applied (Figure 6).190, 193 Specifically, in a study conducted on a large population-based cohort, treatment with adjuvant chemotherapy with or without radiotherapy, compared with no adjuvant therapy, resulted in a significant increase of >12% in the 5-year survival rate.193 This is even greater than the absolute benefit reported from postoperative chemotherapy in NSCLC, in which cisplatin-based chemotherapy increased the 5-year survival rate by 5.4%.194 Accordingly, current practice guidelines recommend adjuvant chemotherapy for all patients who undergo lung resection because of T1–T2N0M0 SCLC.184 Further strong predictors of durable long-term outcomes are anatomic lung resection (preferably lobectomy), sex (with a significant survival benefit for females), and pathologically confirmed complete tumor resection (R0 resection).195-197 Here, the exact definition of R0 resection could be substantially complemented with negative results of assays for postoperative detection of circulating tumor cells or DNA in the near future.198 Importantly, in case of nodal upstaging (N1 or N2) or incomplete surgical resection (i.e., R1), adjuvant chemotherapy should be complemented with thoracic radiotherapy.199, 200 In this setting, postoperative thoracic radiotherapy significantly decreases the 1-year, 2-year, and 3-year local recurrence rates in patients with nodal involvement (i.e., N1 and N2).199 Postoperative prophylactic cranial irradiation (PCI) has been shown to significantly reduce the risk of brain metastasis and prolong OS in patients who undergo surgery for SCLC.201, 202 However, the overall risk for developing brain metastases in surgically resected patients who have early stage disease (especially stage I) is generally very low; therefore, active MRI surveillance might be equally effective.203, 204

Altogether, the role of surgery in SCLC is still debatable.200, 205 Yet, after adequate staging, some patients with localized, very limited stage disease might indeed benefit from surgical removal of the primary tumor.205, 206 Accordingly, based on the contemporary NCCN guidelines, surgery should be applied to all individuals with clinical stage I–IIA (T1–T2N0M0) SCLC, and lobectomy supplemented with lymphadenectomy should always be followed by postoperative systemic therapy (Figure 6).184

Chemotherapy and radiotherapy

Systemic chemotherapy represents the backbone of therapeutic management across all stages of SCLC, and numerous cytostatic regimens have demonstrated activity in both upfront and subsequent lines of systemic therapy (Figure 6). Indeed, combinatory treatments of platinum-based, DNA-crosslinking agents (such as cisplatin or carboplatin) and topoisomerase inhibitors (such as etoposide or irinotecan) are currently the chemotherapeutic regimens of choice in patients with SCLC.184, 207, 208 This combination is efficacious, and its application has been widely tested and is safe alone or in combination either with other systemic agents (e.g., immunotherapy) or treatment modalities (e.g., radiotherapy or surgery). However, given the heterogenous toxicity profile of these cytostatic agents, treatment should be personalized according to the general condition, comorbidity profile, and personal preferences of each patient. Cisplatin is more nephrotoxic and emetogenic but less myelotoxic than carboplatin.209-211 Carboplatin-containing regimens are preferred in patients who are unfit for cisplatin-based chemotherapy (e.g., in elderly patients.209

The number of cycles differs according to disease stage. Generally, four cycles of cisplatin/carboplatin and etoposide are recommended for patients with limited stage SCLC, including those who underwent lung resection surgery (Figure 6).184 Meanwhile, individuals with extensive-stage disease may receive up to six cycles of chemotherapy based on response and tolerability after four cycles (Figure 6).184

In addition to systemic chemotherapy, conformal radiotherapy also plays a pivotal role in the therapeutic management (Figure 6) of patients with SCLC as part of either definitive or palliative therapy.184, 212 Specifically, concurrent or sequential radiochemotherapy is part of the standard of care for patients with limited stage disease (up to N3, M0), whereas radiotherapy in those with extensive-stage SCLC mainly consists of consolidative thoracic radiation therapy or PCI after first-line treatment.184 In addition, surgically treated patients with regional nodal involvement are also advised to undergo radiotherapy, either sequentially or concurrently with chemotherapy, as stated previously.184

Indeed, several studies suggest that chemotherapy supplemented with radiotherapy prolongs both OS and disease-free survival of patients with SCLC.213, 214 The manner of radiotherapy administration (i.e., sequential or concurrent, twice daily, or once daily) in limited stage disease should be individually adapted to clinicopathologic factors or practical reasons.215-217 When feasible, patients with limited stage SCLC should be treated with concurrent chemoradiotherapy, and sequential treatment should be limited to patients with large tumor volumes or poor PS.218 With regard to scheduling, neither the toxicity profiles nor the survival outcomes differ significantly between twice-daily and once-daily radiotherapy.217 Therefore, given the shorter treatment time, twice-daily radiotherapy concurrently with chemotherapy might represent a more appealing approach.217, 219 However, the thumb rule is that radiation should be initiated as early as possible, and patients should be endorsed to quit smoking to further improve the prognosis and therapeutic efficacy.220, 221 Also, platinum-containing agents and etoposide in combination with radiotherapy should be preferred over other regimens because of clear superiority in efficacy and toxicity.207, 222, 223 Regarding the role of PCI in patients who have limited stage disease treated only with systemic therapy, previous studies suggest that PCI reduces the risk of developing brain metastases in those who have good responses to initial therapy.184, 224, 225 Notably, however, those past studies did not use active brain MRI follow-up in the control group. Consequently, the beneficial effects of PCI compared with active MRI surveillance alone warrants further investigation in this patient population.226 Furthermore, if applied, the risk of treatment-related side effects and chronic neurologic sequelae, such as memory decline, should be minimized. Of note, modern PCI with hippocampal avoidance is similarly efficacious but can significantly reduce radiation-related cognitive or neurologic side effects.227 Likewise, subsequent administration of neuroprotective drugs, such as memantine or donepezil, might be beneficial. The use of these neuroprotectants was associated with fewer declines and modest improvements in cognitive functions in two randomized phase 3 trials, although the results were not statistically significant.228, 229

In addition to its use in limited stage SCLC, radiotherapy can also be administered as part of consolidation therapy for residual tumor eradication in extensive-stage disease (Figure 6).230 It should be noted, however, that radiotherapy in this patient population primarily offers delayed survival benefits: a large, phase 3, randomized controlled trial demonstrated that thoracic radiotherapy after chemotherapy did not significantly improve the survival outcomes at 1 year in patients with extensive-stage disease.231 However, in that study, the 2-year OS was significantly improved, and PFS was also significantly greater in the thoracic radiotherapy group. In addition, the authors of that study reported an almost 50% reduction in intrathoracic recurrences.231 Moreover, based on subsequent exploratory analyses, they concluded that the beneficial effects of consolidative radiotherapy are more evident in those with residual intrathoracic lesions after systemic therapy.232 In light of this and other studies,233, 234 consolidative radiotherapy might be beneficial for selected patients with good clinical responses to systemic chemotherapy or chemoimmunotherapy, especially in those with low-bulk extrathoracic metastases and residual thoracic disease.212, 235

Patients with extensive-stage SCLC who respond to initial chemotherapy and have a PS of 0–1 are often offered PCI.224, 236-238 Of note, the evidence supporting PCI is not as clear in elderly patients with a PS >2 and in those with preexisting neurologic conditions.239 In addition, PCI warrants further validation in patients who have extensive-stage SCLC in the era of modern imaging. In this regard, a recent Japanese randomized trial showed that PCI is not associated with a clear survival benefit compared with strict MRI follow-up in patients who have extensive-stage SCLC.240

In light of the controversies on the role of surgery in SCLC, some studies suggest that concomitant thoracic radiochemotherapy is superior to surgical resection in patients who have limited stage, nonmetastatic (N0, M0) disease.241 Therefore, stereotactic ablative radiotherapy is an appealing treatment approach for patients with limited stage disease in whom a decision was made not to pursue surgery and for those with a medically inoperable tumor. To date, the first reports concerning local tumor control and OS after stereotactic ablative radiotherapy in SCLC are promising.242

Immunotherapy

After decades without meaningful changes in the standard of care, 2019 produced a new landmark in the treatment of SCLC through US Food and Drug Administration (FDA) approval of the PD-L1 inhibitor atezolizumab in combination with first-line platinum doublet chemotherapy for patients with extensive-stage disease.19, 87, 184 This approval was foreshadowed by the results of the IMpower133 randomized, phase 3 trial, in which the addition of atezolizumab (Figure 7) to first-line treatment resulted in a significant improvement of 0.9 and 2 months concerning the median PFS and OS, respectively.19 In addition, both 1-year and 1.5-year survival rates were higher in patients who received atezolizumab compared with the placebo group.243 The phase 3 CASPIAN study (ClinicalTrials.gov identifier NCT03043872) yielded results comparable to those observed in IMpower133, using a different PD-L1 inhibitor.20 Here, in the planned interim analysis, durvalumab (Figure 7) in combination with chemotherapy significantly improved the median OS by 2.7 months compared with the chemotherapy-alone group.20, 244 The FDA approved the use of durvalumab for extensive-stage SCLC in the first-line setting shortly thereafter.245 Of note, the approximately 2-month extension of median survival seen in these studies may seem modest, yet median values do not tell the full story. Taking a glance at the tail of the survival curves, it becomes evident that the addition of immune checkpoint inhibitors to the platinum-based backbone leads to an approximate tripling of 3-year survival.4, 246 Currently, the NCCN SCLC panel recommends platinum-based chemotherapy plus etoposide plus atezolizumab or durvalumab as the preferred first-line systemic therapy option, followed by maintenance atezolizumab or durvalumab for patients with extensive-stage SCLC (Figure 6) based on the aforementioned clinical trials and FDA approval.184 In contrast to chemotherapy alone, administration of PD-L1 inhibitors within the framework of chemoimmunotherapy is not terminated after four to six cycles, and maintenance immunotherapy is continued until progression.184 This raises questions about the applicability of radiotherapy in this setting because the effects of both consolidative thoracic radiotherapy and PCI were primarily interpreted in chemotherapy-treated patients after termination of systemic therapy.230 Current practice guidelines support the idea that consolidative thoracic radiotherapy can be applied both before and during maintenance immunotherapy.184 There are no solid, evidence-based data on optimal sequencing or safety to date.184 Recent studies, however, suggest that the combination of thoracic radiotherapy and immunotherapy exhibits a synergistic effect by upregulating major histocompatibility complex class I expression and promoting CD8-positive T-cell infiltration.247 Further data on the benefit of thoracic radiotherapy in the context of chemoimmunotherapy will be delivered by the RAPTOR/NRG LU007 trial (ClinicalTrials.gov identifier NCT04402788).248 To date, the benefit of PCI in patients with active tumor control achieved by immunotherapy maintenance is unclear.230 For patients with limited stage disease, consolidative pembrolizumab had favorable tolerability and activity in a recent phase 1/2 trial.249 Nevertheless, in the randomized phase 2 STIMULI trial (ClinicalTrials.gov identifier NCT02046733), consolidation combination immunotherapy did not improve PFS.250 Given these mixed data, to date, immune checkpoint inhibitors are not part of the standard of care for limited stage SCLC. Ongoing clinical trials, such as the phase 3 ADRIATIC study (ClinicalTrials.gov identifierNCT03703297), will help to define the role of immunotherapy in this patient population.

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Areas of current therapeutic interest in SCLC. Schematic depiction of important molecular targets on a tumor cell (cyan), target sites for immunotherapy (orange), and the respective drugs. APC indicates antigen-presenting cell; RTK, receptor tyrosine kinase; SCLC, small cell lung cancer; TCE, T-cell engager. Created with BioRender.com.

Mechanisms of drug resistance and relapsed SCLC

In contrast to NSCLC, which has an intrinsic tendency for chemotherapy resistance, approximately 75%–80% of all untreated SCLCs are initially highly sensitive to DNA-damaging agents, with clinical response rates nearly double those observed in NSCLC.7 However, the development of resistance is essentially inevitable, and response rates to second-line therapy are markedly reduced.251 The EMT as well as the downregulation of Schlafen11 (SLFN11) expression by methylation has been historically implicated in the resistance to treatment for SCLC.2, 252, 253 In addition, the occurrence of drug resistance might also be linked to DNA-related processes, such as promoting cellular DNA damage repair and preventing antitumor drugs from interacting with DNA.254 One other mechanism might be that the various molecular and cellular fates adopted by SCLC provide reservoirs of cells with intrinsic resistance to treatment.4 Regarding transcription factors, although YAP1 is not expressed to a sufficient extent in treatment-naive patients to define a distinct subtype, its elevated level is linked with platinum resistance. Accordingly, an intratumoral shift toward increased YAP1 expression may underlie platinum resistance.81, 89, 97, 255 Finally, suppression of apoptosis by BCL2 expression and TP53 mutations may also result in chemoresistance.2

Subsequent systemic therapy in SCLC (Figure 6) depends on the administered therapeutic agent in the first-line setting as well as the disease-free interval since termination of the initial therapy.184 According to the contemporary NCCN guidelines, rechallenging with the original regimen or a similar platinum-based regimen is recommended if more than 6 months have elapsed (sensitive disease) from initial therapy to relapse and may be considered if there has been a disease-free interval of at least 3–6 months (refractory or resistant disease).184 It should be noted that the European Society for Medical Oncology guidelines use cutoffs of ≥3 and <3 months to define sensitive and resistant SCLC, respectively.256 If rechallenging is not feasible, the topoisomerase 1 inhibitor topotecan represents a therapeutic agent of choice as second-line therapy.184 Topotecan can be administered orally or intravenously because its antitumor activity and tolerability are similar with either route.257 Nevertheless, because oral topotecan offers a useful and compassionate treatment alternative for patients, many practicing oncologists prefer this option. Oral topotecan at 2.3 mg/m2 or intravenous topotecan at 1.5 mg/m2 (as a 30-minute infusion) should be administered on a daily basis for 5 days every 3 weeks.257 Notably, in addition to yielding survival benefits similar to those obtained with the combination regimen of cyclophosphamide, doxorubicin, and vincristine, intravenous topotecan causes less grade 4 neutropenia and improves the symptoms of dyspnea, fatigue, hoarseness, and anorexia.258 In certain circumstances (e.g., bone marrow deficiency), irinotecan can also be used as an alternative to topotecan in relapsed disease because of its less frequent dosing (i.e., weekly) and lower occurrence rates of myelosuppressive adverse events.259, 260 Recently, lurbinectedin, a synthetic derivative of the marine drug trabectedin (Figure 7) (a DNA-binding, alkylating agent that selectively inhibits RNA polymerase II transcription), also demonstrated activity against SCLC both as a single agent and in combination with doxorubicin.261 This led to its accelerated FDA approval as second-line therapy after progression on platinum-based chemotherapy. Of note, in the subsequent phase 3 randomized ATLANTIS study (ClinicalTrials.gov identifier NCT02566993), lurbinectedin plus doxorubicin did not improve OS in patients who had relapsed SCLC compared with those in the control group.262 Immune checkpoint inhibitors have also been evaluated in patients with relapsed SCLC. At first, the anti-PD1 monoclonal antibodies nivolumab and pembrolizumab were granted accelerated FDA approval for patients whose disease has progressed after platinum-based chemotherapy and at least one other prior line of systemic therapy. This was based on the encouraging response rates and durations of response seen in the CheckMate 032 (ClinicalTrials.gov identifier NCT01928394), KEYNOTE-158 (cohort G; ClinicalTrials.gov identifier NCT01928394), and KEYNOTE-028 (cohort C1; ClinicalTrials.gov identifier NCT02054806) trials.263, 264 However, subsequent confirmatory trials (CheckMate 451 [ClinicalTrials.gov identifier NCT02538666], CheckMate 331 [ClinicalTrials.gov identifier NCT02481830], and KEYNOTE-604 [ClinicalTrials.gov identifier NCT03066778]) in different treatment settings did not meet their primary end point.265-267 Despite having manageable toxicity profiles and prolonging PFS, nivolumab and pembrolizumab failed to demonstrate a clear OS benefit. Because of the frail results from these later studies, the FDA and the manufacturers withdrew their indication of nivolumab and pembrolizumab for treating patients with SCLC.268, 269 Accordingly, to date, contemporary practice guidelines recommend neither of these immune checkpoint inhibitors in relapsed SCLC. Nevertheless, in some cases, their off-label and experimental use within the confines of a clinical trial can still be considered based on individualized considerations when no immunotherapeutics have been administered in previous lines. Radiotherapy, clinical trial enrollment, and other chemotherapeutic regimens (Figure 6) might also represent possible therapeutic approaches for refractory SCLC.

Predictive biomarkers and immune landscape

Cell line screening for biomarker candidates revealed that SLFN11 expression is strongly associated with sensitivity to a broad spectrum of DNA-damaging agents and inhibitors and thus might represent a promising predictor of sensitivity to chemotherapy.7 Although this association has since been confirmed in various preclinical models, and high SLFN11 IHC expression was indeed associated with increased survival outcomes in patients treated with temozolomide plus veliparib (PARP-inhibitor) even in a phase 1 clinical trial, its use as a predictive biomarker is still not validated in the clinics.270-272

Both high TMB and microsatellite instability have shown promise as biomarkers of response to immune checkpoint blockage across cancer types.273 In SCLC, however, because tumors are almost always associated with the chemical mutagenic effects of tobacco exposure and thus generally have a high clonal mutational load, establishing a clear predictive cutoff might be difficult.87 Reflecting on this, the role of TMB as a predictive biomarker of SCLC response to immunotherapy is controversial. In the CheckMate 032 study, tumors in the highest tertile of TMB were more sensitive to nivolumab or to the combination of ipilimumab and nivolumab, as defined by the survival outcomes.274 Yet subsequent analyses of the IMpower133 trial showed no evident association between blood-based TMB and responsiveness to atezolizumab.243 Another potential biomarker of responsiveness to immune checkpoint blockage might be PD-L1 IHC expression, which is an approved biomarker in other solid tumors. Nevertheless, PD-L1 is scarcely expressed in SCLC, and its predictive value is rather contentious.275 Neither the subsequent results of the CheckMate 032 study nor the outcomes of the exploratory analyses of the IMpower133 trial demonstrated a PD-L1–dependent treatment benefit in patients treated with nivolumab or atezolizumab, respectively.243, 263 In contrast, the combined PD-L1 expression on tumor and immune stromal cells might constitute a positive predictive biomarker in patients with SCLC who receive pembrolizumab.87 Recently, the different SCLC molecular subtypes were also linked with distinct sensitivity profiles to immunotherapy. As discussed above, NE-low SCLCs, and specifically SCLC-I tumors, have a higher abundance of cytotoxic T cells, natural killer cells, and macrophages and higher expression of checkpoint molecules compared with NE-high SCLCs.85, 97 Indeed, the results of the IMpower133 trial support the idea that the addition of atezolizumab to standard-of-care chemotherapy is more beneficial in SCLC-I than in SCLC-A and SCLC-N.19, 97

Insights into potential targeted therapy

Several targeted agents are being tested for the treatment of SCLC (Figure 7). Compared with other lung cancer subtypes and normal lung epithelial cells, SCLC cells show a high PARP expression profile and thus are sensitive to PARP inhibitors.30, 276 Moreover, PARP inhibitors have the potential to enhance the cytotoxic response to chemotherapy, immunotherapy, and ionizing radiation in SCLC.276, 277 The phase 2 Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group 2511 trial (ClinicalTrials.gov identifier NCT01642251) partly confirmed these preclinical suspicions by demonstrating a 1.4-month OS benefit in patients who received veliparib in combination with a cisplatin and etoposide doublet.278 Nevertheless, because the results did not reach statistical significance, predictive biomarkers are required to maximize the clinical efficacy of PARP inhibitors. Here, an appealing biomarker might be the already mentioned SLFN11, which is strongly associated with veliparib efficacy.272 Another valid concern regarding PARP inhibitors is their more-than-additive toxicity profile when administered together with cytotoxic chemotherapy. Indeed, early phase clinical trials revealed a higher frequency of hematologic toxicities in veliparib-treated patients.278, 279 Importantly, however, these adverse events were all clinically manageable and did not affect the delivery of standard chemotherapy.

DLL3, an inhibitory Notch pathway ligand, might also represent a potential therapeutic target in SCLC because it is frequently expressed on the surface of SCLC tumor cells.280 After encouraging results from the first human phase 1 study,281 the targeted agent rovalpituzumab tesirine (Rova-T) only produced modest antitumor activity in the subsequent phase 2 TRINITY study (ClinicalTrials.gov identifier NCT02674568).282 Specifically, the objective response rates were 14.3% and 13.2% in DLL3-high and DLL3-positive patients, respectively.282 Unfortunately, patients who received treatment with Rova-T exhibited inferior OS and higher rates of toxicities in a recent phase 3 clinical trial compared with those who received the current standard second-line chemotherapy.283 Because of this lack of survival benefit, the phase 3 TAHOE trial (ClincalTrials.gov identifier NCT03061812) was halted after the Independent Data Monitoring Committee recommended stopping enrollment.280

Given the elevated expression of BCL-2 in certain SCLC tumors, BCL-2 antagonists may constitute an attractive therapeutic option for treating these patients. Certainly, the recent addition of these prosurvival BCL-2 family inhibitors to the repertoire of targeted therapies revealed remarkable preclinical activity in SCLC tumors.284 However, BCL-2 targeting by navitoclax showed only limited single-agent activity against advanced and recurrent SCLC in a phase 2 trial, because a partial response and stable disease were achieved in only one patient (2.6%) and eight patients (23%), respectively.285 Importantly, there was dose-limiting thrombocytopenia in the study, which reached grade 3–4 in 41% of patients.285 This may be caused in part by the nonselective nature of navitoclax because it targets both BCL-2 and BCL-xL, which leads to considerable toxicities. Venetoclax (an FDA-approved drug for hematologic malignancies), conversely, is a selective BCL-2 inhibitor that is well tolerated even in elderly patients with severe hematologic disease.284 Moreover, the observation that venetoclax induces tumor regressions in mice bearing high BCL-2-expressing SCLC tumors also provides a strong rationale for assessing its clinical efficacy in a biomarker-selected SCLC population.286

Targeted drug screening revealed that SCLC with high MYC expression is vulnerable to AURK inhibition, which, combined with chemotherapy, strongly suppresses proliferation and tumor growth in vitro and in vivo.287 A recently reported clinical trial demonstrated that the AURKA inhibitor alisertib plus paclitaxel produced improved PFS and OS compared with paclitaxel alone in patients with relapsed or refractory SCLC.288 Although these survival benefits were not statistically significant, c-Myc expression proved to be a reliable predictor of responsiveness to alisertib.288 Accordingly, patients with c-Myc-expressing tumors had significantly improved PFS in the alisertib/paclitaxel arm.288 Finally, several preclinical studies have demonstrated that inhibitors against c-Kit receptor, EGFR, insulin-like growth factor receptor, and c-MET receptor tyrosine kinases might also be efficacious in SCLC. However, subsequent clinical trials to date have failed to demonstrate the superiority of these agents against the current standard of care.

SURVEILLANCE AND FOLLOW-UP

Given the high relapse rates in SCLC, regular CT scans (chest scans with or without abdominal/pelvic scans) are recommended to identify recurrence as early as possible and to offer salvage treatment if appropriate. The frequency of surveillance depends on the disease stage and elapsed time since the completion of initial or subsequent therapy.184 Generally, follow-up visits are required every 2 to 3 months in the first 2 years and less frequently thereafter. Patients with extensive metastatic disease can be checked even more regularly. To allow the early treatment of potentially debilitating neurologic symptoms caused by brain metastases, it is important to scan for cranial lesions. Currently, brain MRI is the diagnostic approach of choice for the detection of cerebral metastases and should be performed regardless of the PCI status.184 In certain cases, brain MRI can be substituted with a contrast-enhanced brain CT. The contemporary NCCN guidelines do not recommend PET-CT for routine follow-up.184

Another particularity of SCLC is that patients who survive >2 years after initial diagnosis have a significantly increased risk of developing a second primary tumor, including lung cancer.289-291 Specifically, the relative risk of a second primary lung cancer in patients who have SCLC is 16.0 (95% CI, 8.4-27.0) compared with that in the general population.291 This further emphasizes the role of smoking cessation (see the contemporary smoking cessation guideline in the report by Shields et al.292) because quitting smoking after successful therapy significantly decreases the risk of secondary malignancies.289, 291 Nevertheless, if a new pulmonary nodule develops after a longer period of stable disease, it should prompt evaluation for new primary lung cancer. However, most screening guidelines state that asymptomatic cancer survivors with a high risk of developing a second malignancy should be screened at the same intervals as the general population unless they have another independent risk factor.290, 293

Finally, the management of long-term, treatment-related adverse effects, such as pulmonary fibrosis, cardiac complications, or polyneuropathy, also requires regular consulting.

ONGOING CLINICAL TRIALS

In addition to the extensive clinical studies of PD-(L)1 inhibition, other therapeutic approaches, such as targeting the T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory domains (TIGIT) are currently under investigation in patients with SCLC (Table 1). TIGIT is frequently co-expressed with PD-L1 on T cells or natural killer cells, likewise acting as a crucial modulator in T-cell–mediated immunity.294 The corresponding randomized phase 3 clinical trial SKYSCRAPER-02 (ClinicalTrials.gov identifier NCT04256421) compared standard-of-care carboplatin/etoposide plus atezolizumab in addition to placebo or tiragolumab (anti-TIGIT inhibitor) in patients who had treatment-naive SCLC. Unfortunately, the preliminary data on tiragolumab in combination with chemoimmunotherapy, recently reported at the 2022 American Society of Clinical Oncology Annual Meeting, did not reveal clinical benefit.295 Nevertheless, the combination was well tolerated, and no new safety signals were identified.295

TABLE 1. Completed and ongoing clinical trials evaluating the safety and efficacy of immune checkpoint inhibitors in patients with small cell lung cancer.
Study name Study phase Mechanism of action Agent Outcomes
IMpower133 (NCT02763579) 1/3 PD-L1 inhibitor Atezolizumab Safety, well tolerated
ORR, 60.2% vs. 64.4%
PFS, 5.2 vs. 4.3 months (p = .02)
OS, 12.3 vs. 10.3 months (p = .007)
CASPIAN (NCT03043872) 3 PD-L1 inhibitor Durvalumab Safety, well tolerated
ORR, 79% vs. 70%
PFS, 5.1 vs. 5.4 months (p = NS)
OS, 13.0 vs. 10.3 months (p = .004)
KEYNOTE-604 (NCT03066778) 3 PD-1 inhibitor Pembrolizumab Safety, well tolerated
ORR, 70.6% vs. 61.8%
12-month PFS, 13.6% vs. 3.1% (p = .0023)
24-month OS, 22.5% vs. 11.2% (p = .0164)
NCT01450761 3 CTLA-4 inhibitor Ipilimumab Safety, well tolerated
ORR, 62% vs. 62%
PFS, 4.6 vs. 4.4 months (p = .016)
OS, 11.0 vs. 10.9 months (p = .377)
CheckMate 331 (NCT02481830) 3 PD-1 inhibitor Nivolumab Safety, well tolerated
ORR, 14% vs. 16%
PFS, 1.4 vs. 3.8 months
OS, 7.5 vs. 8.4 months
CheckMate 451 (NCT02538666) 3 PD-1 and CTLA-4 inhibitors Nivolumab plus ipilimumab Primary end points not met
SKYSCRAPER-02 (NCT04256421) 3 TIGIT Tiragolumab Primary end points not met
ADRIATIC (NCT03703297) 3 PD-L1 and CTLA-4 inhibitors Durvalumab plus tremelimumab Ongoing
REACTION 2 PD-1 inhibitor Pembrolizumab Safety, well tolerated
ORR, 61%
PFS, 4.7 vs. 5.4 months
OS, 12.3 vs. 10.4 months
NCT02359019 2 PD-1 inhibitor Pembrolizumab Safety, well tolerated
ORR, 11.1%
PFS, 1.4 months
OS, 9.6 months
KEYNOTE-158 (NCT02628067) 2 PD-1 inhibitor Pembrolizumab Safety, well tolerated
ORR, 18.7%
PFS, 2.0 months
OS, 9.1 months
BIOLUMA (NCT03083691)a 2 PD-1 and CTLA-4 inhibitors Nivolumab plus ipilimumab Safety, high toxicity rates
ORR, 38.8%
CheckMate 032 (NCT01928394) 1/2 PD-1 and CTLA-4 inhibitors Nivolumab plus ipilimumab/nivolumab Safety, manageable safety profile
ORR, 21.9% vs. 11.6%
PFS, 1.5 vs. 1.4 months
OS, 4.7 vs. 5.7 months
NCT02261220 1/2 PD-L1 and CTLA-4 inhibitors Durvalumab plus tremelimumab Safety, well tolerated
ORR, 13.3%
PFS, 1.8 months
OS, 7.9 months
KEYNOTE-028 (NCT02054806) 1b PD-1 inhibitor Pembrolizumab Safety, well tolerated
ORR, 33.3%
PFS, 1.9 months
OS, 9.7 months
  • Abbreviations: CTLA-4, cytotoxic T-lymphocyte–associated protein 4; NCT, ClinicalTrials.gov identifier; NS, not significant; ORR, objective response rate; OS, overall survival; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TIGIT, T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory domains.
  • a Only patients with high tumor mutation burden were included.

Within the past years, research groups have focused on the efficacy of various targeted agents interfering with cell cycle, apoptosis, DNA-damage repair, epigenetic modifications, or angiogenesis. Currently, several phase 1/2 clinical trials elucidate the safety profile of PARP inhibitors other than veliparib, such as olaparib, rucaparib, or talazoparib (Table 2).296 Interim analysis concerning the efficacy of rucaparib plus nivolumab in a frontline setting showed clinical benefit in 56% of patients and a median PFS of 7.4 months from the time of diagnosis. Notably, the patient with the longest active treatment was approaching 16 months of therapy at the time of reporting.297

TABLE 2. Completed and ongoing clinical trials evaluating the safety and efficacy of targeted therapies in patients with small cell lung cancer.
Study name Study phase Mechanism of action Agent Outcomes
DNA damage repair
NCT02454972 2 RNA-polymerase II inhibitor Lurbinectedin ORR, 35.2%
PFS, 3.5 months
OS, 9.3 months
NCT01638546 2 PARP inhibitor Veliparib ORR, 39% vs. 14% (p = .016)
PFS, 3.8 vs. 2.0 months (p = .39)
OS, 8.2 vs. 7.0 months (p = .50)
ECOG-ACRIN 2511 (NCT01642251) 2 PARP inhibitor Veliparib ORR, 71.9% vs. 65.6% (p = .57)
PFS, 6.1 vs. 5.5 months (p = .06)
OS, 10.3 vs. 8.9 months (p = .17)
NCT02289690 1/2 PARP inhibitor Veliparib Safety, well tolerated
NCT01286987 1 PARP inhibitor Talazoparib Safety, well tolerated
NCT04334941 2 PARP inhibitor Talazoparib Ongoing
NCT03672773 2 PARP inhibitor Talazoparib Ongoing
NCT03958045 2 PARP inhibitor Rucaparib Recruiting
NCT04728230 1/2 PARP inhibitor Olaparib Recruiting
NCT03923270 1 PARP inhibitor Olaparib Recruiting
Neuroendocrine differentiation
TAHOE (NCT03061812) 3 DLL3-targeted antibody-drug conjugate Rova-T Primary end points not met
TRINITY (NCT02674568) 2 DLL3-targeted antibody-drug conjugate Rova-T Primary end points not met
NCT04471727 1/2 DLL3/CD3 trispecific T-cell engager HPN328 Well tolerated
Clinically active
NCT03319940 1 DLL3/CD3 bispecific T-cell engager Tarlatamab (AMG 757) Manageable safety profile
ORR, 24.0%
Median duration of response, 12.3 monthsa
NCT04429087 I DLL3/CD3 bispecific T-cell engager BI 764532 Ongoing
NCT03392064 I DLL3/chimeric antigen receptor T-cell (CAR-T) therapy AMG 119 Well tolerated
Promising antitumor activity
Angiogenesis
ALTER1202 (NCT03059797) 2 Tyrosine kinase inhibitor Anlotinib PFS, 4.1 vs. 0.7 months (p < .0001)
OS, 7.3 vs. 4.9 months (p = .029)
NCT00154388 2 Tyrosine kinase inhibitor Imatinib Primary end points not met
SALUTE (NCT00403403) 2 VEGF inhibitor Bevacizumab ORR, 58% vs. 48%
PFS, 5.5 vs. 4.4 months
OS, 9.4 vs. 10.9 months
CeLEBrATE (NCT04730999) 2 VEGF inhibitor Bevacizumab Ongoing
NCT01533181 2 IGF-R1 inhibitor Linsitinib Primary end points not met
NCT00869752 1 IGF-R1 inhibitor Dalotuzumab Safety, well tolerated
Cell cycle checkpoints
NCT02038647 2 AURKA inhibitor Alisertib ORR, 22% vs. 18% (p = .406)
PFS, 3.32 vs. 2.17 months (p = .113)
OS, 6.86 vs. 5.58 months (p = .714)
TAZMAN (NCT04745689) 2 AURKB inhibitor AZD2811 Ongoing
NCT04902885 3 CDK4/CDK6 Trilaciclib Recruiting
Apoptosis
NCT03366103 1/2 BCL-2/mTOR inhibitor Navitoclax/vistusertib Terminated
NCT00521144 1/2 BCL-2, BCL-XL, and MCL1 inhibitor Obatoclax mesylate Primary end points not met
NCT00042978 2 BCL-2 antisense oligonucleotide Oblimersen sodium Primary end points not met
  • Abbreviations: AURKA, aurora kinase A; DLL3, delta-like protein 3; ECOG-ACRIN, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group; IGF-R1, insulin-like growth factor 1 receptor; NCT, ClinicalTrials.gov identifier; ORR, objective response rate; OS, overall survival; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; Rova-T, rovalpituzumab tersirine; VEGF, vascular endothelial growth factor.
  • a Among responders.

As mentioned above, Rova-T produced a survival benefit neither in the phase 2 TRINITY trial nor in the phase 3 TAHOE trial. Nevertheless, DLL3 remains an intriguing target for multiple alternative therapeutic strategies, including bispecific and trispecific T-cell engagers (TCEs), and chimeric antigen receptor (CAR) T-cell therapy. Bi-specific TCEs bind to DLL3 and cells of the immune system (such as CD3-positive T cells) simultaneously, thus leading to T-cell–mediated tumor lysis.298 Meanwhile, trispecific agents are designed to also bind to albumin for half-life extension.299 In this context, two independent phase 1 studies and a phase 1/2 clinical trial are currently investigating the safety, tolerability, and preliminary efficacy of DLL3 targeting in SCLC (Table 2).298-300 Encouragingly, preliminary data on the bispecific, DLL3-targeted TCE tarlatamab (AMG 757) revealed a manageable safety profile and a median duration of response of 12.3 months among confirmed responders in heavily pretreated patients with SCLC.298 Likewise, HPN328, a trispecific DLL3-targeting TCE, also proved to be well tolerated and clinically active in patients with SCLC and other NE cancers.299 With regard to CAR T-cell therapy, AMG 119 is an adoptive cellular therapy targeting DLL3 and redirecting cytotoxic T-cell specificity to DLL3-positive cells. In addition to inhibiting tumor growth in SCLC xenograft models, AMG 119 was recently associated with a manageable safety profile and promising antitumor activity in a phase 1 study (Table 2).301

Another approach is cell cycle checkpoint inhibition, including AURK or CDK4/DCK6 targeting. Currently, two ongoing phase 2 and 3 clinical trials focus on the efficacy and safety profiles of AZD2811 (AURKB inhibitor) or trilaciclib (CDK4/6 inhibitor) in patients with advanced SCLC (Table 2). To date, the first-in-class agent trilaciclib is solely administered to reduce chemotherapy-induced bone marrow suppression in patients with SCLC because it maintains hematopoietic stem cells and progenitor cells in G1 arrest and protects them from the damaging effects of chemotherapy.302 Indeed, the addition of trilaciclib to standard-of-care chemotherapy resulted in increased tolerability of cytotoxic agents in a recent phase 2 trial, as demonstrated by myelopreservation across multiple hematopoietic lineages.302 In early 2021, this was shortly followed by the FDA approval of rilaciclib as a myeoloprotective agent in patients who had SCLC treated with EP-containing or topotecan-containing regimens.

It is to be highlighted that SCLC has been historically associated with increased vascularization, which furthermore correlates with prognosis. Although the first phase 2 trial (SALUTE; ClinicalTrials.gov identifier NCT00403403) investigating the efficacy of bevacizumab in previously untreated patients with extensive-stage SCLC did not result in an improvement in OS,303 it is hypothesized that the addition of bevacizumab to the chemoimmunotherapy backbone might improve the efficacy of immune checkpoint inhibitors. The ongoing CeLEBrATE trial (ClinicalTrials.gov identifier NCT04730999) is an open-label, multicenter, phase 2 study designed to assess the efficacy and safety of the combination of carboplatin/etoposide/atezolizumab plus bevacizumab in patients with treatment-naive SCLC.304 Similarly, antiangiogenic agents, such as anlotinib, apatinib, or cediranib, are also under investigation as potential frontline or maintenance treatment options for patients with advanced SCLC.305

Actively recruiting clinical trials sponsored by the National Institutes of Health are summarized in Table 3.

TABLE 3. Actively recruiting clinical trials sponsored by the National Institutes of Health.
Study name Study phase Mechanism of action Therapeutic agent Disease stage Start of enrollment
NCT05353439 Phase 1 EZH2 inhibition Tazemetostat plus topotecan and pembrolizumab Recurrent SCLC May 12, 2022
NCT03811002 Phase 2/3 PD-L1 inhibition Atezolizumab plus chemoradiation LS SCLC May 28, 2019
NCT03554473 Phase 1/2 Bifunctional anti-PD-L1/TGFβ trap M7824 plus topotecan or temozolomide Relapsed SCLC September 11, 2018
NCT04155034 Phase 3 Radiation therapy MRI /prophylactic cranial irradiation LS/ES SCLC January 10, 2020
NCT04402788 (RAPTOR trial) Phase 2/3 Radiation therapy Atezolizumab alone or plus radiation ES SCLC August 17, 2020
NCT04560972 Phase 1 PP2A inhibition LB-100 plus carboplatin, etoposide, and atezolizumab Treatment-naive ES SCLC May 28, 2021
NCT04826341 Phase 1/2 Anti–Trop-2 antibody-drug conjugate Sacituzumab govitecan plus berzosertib SCLC September 20, 2021
NCT04728230 (PRIO trial) Phase 1/2 PARP inhibition Olaparib and durvalumab with carboplatin, etoposide, and/or radiation therapy ES SCLC January 5, 2021
NCT05450965 Phase 2 PLK1 inhibitor Onvansertib Relapsed SCLC July 19, 2022
NCT04538378 Phase 2 PARP inhibition Olaparib plus durvalumab Transformed SCLC July 7, 2021
NCT04516070 Phase 2 Stereotactic radiosurgery Stereotactic radiosurgery SCLC plus brain metastasis August 28, 2020
NCT02769962 Phase 1/2 Cyclodextrin linked to camptothecin EP0057 plus olaparib Relapsed/refractory SCLC May 9, 2016
NCT04514497 Phase 1 ATR inhibition BAY 1895344 plus chemotherapy SCLC February 11, 2021
NCT05191797 Phase 1/2 LSD1 inhibition Bomedemstat plus maintenance immunotherapy ES SCLC April 11, 2022
NCT05244239 Phase 1 Radiation therapy Palliative radiotherapy plus lurbinectedin ES SCLC July 27, 2022
NCT01737502 Phase 1/2 mTOR inhibition/inhibition of redox enzymes Sirolimus and auranofin ES/recurrent SCLC November 29, 2012
NCT04804644 Phase 3 Radiation therapy High-dose radiation ES/recurrent SCLC March 24, 2021
NCT04514484 Phase 1 Multiple tyrosine kinase receptor inhibition Cabozantinib and nivolumab Advanced/recurrent/metastatic SCLC November 4, 2020
NCT04140526 Phase 1/2 Anti–CTLA-4 monoclonal antibody ONC-392 alone or plus pembrolizumab SCLC September 16, 2020
NCT04491942 Phase 1 ATR inhibition BAY 1895344 plus chemotherapy SCLC February 1, 2021
NCT03735095 Phase 1/2 Photodynamic therapy Porfimer sodium SCLC February 12, 2020
  • Abbreviations: ATR, ataxia telangiectasia and Rad3; CTLA-4, cytotoxic T-lymphocyte–associated protein 4; ES, extensive-stage; EZH2, enhancer of zeste 2 polycomb-repressive complex 2 subunit; LS, limited stage; LSD1, lysine-specific demethylase 1; mTOR, mammalian target of rapamycin; NCT, ClinicalTrials.gov identifier; PARP, poly(ADP-ribose) polymerase; PD-L1, programmed death-ligand 1; PLK1, polo-like kinase 1; PP2A, protein phosphatase 2A; SCLC, small cell lung cancer; TGFβ, transforming growth factor beta.

FUTURE DIRECTIONS: SUBTYPE-SPECIFIC DIAGNOSTIC AND THERAPEUTIC APPROACHES

The implementation of targeted therapies to date has failed in SCLC, and the success of immunotherapy in NSCLC has not yet been entirely reflected in this malignancy. This lack of a breakthrough in the therapeutic armamentarium of SCLC is mainly because of its high tumoral plasticity and the nonselected patient groups upon clinical trial enrollment. Accordingly, stratifying patients by their dominant molecular subtypes and specific protein-level alterations may contribute to the development of novel targeted strategies in this hard-to-treat disease.

Because surgery is seldom performed in SCLC and small biopsies often fail to mirror the expression profile of the entire tumor, the diagnosis of molecular states might be a challenging notion, especially in clinical settings. The analysis of blood-based tumor components, such as circulating tumor cells, cell-free tumor DNA, and tumor-derived extracellular vesicles, could provide alternative opportunities to monitor the molecular phenotypes throughout the disease and to assess biomarkers of treatment response and prognosis.87 Recently, two independent, cell-free tumor DNA-based classifiers were reported to be able to distinguish between SCLC subtypes based on methylation profiling.306, 307 Importantly, despite the different teaching and training approaches, both were able to correctly identify SCLC subtypes with an accuracy of >90%. Because certain tumor-associated proteins are of diagnostic importance, in-depth proteomic profiling might also offer new insights into subtype-specific biomarkers. In total, 367 subtype-specific proteins were identified recently by mass spectrometry-based proteomics that were differentially expressed in a given subtype compared with all other subtypes.103 Considering that the cell pellet and culture media were analyzed separately, the results can also be interpreted as potential tissue-based and blood-based biomarkers. However, that study103 was conducted on SCLC cell lines; therefore, the clinical utility and applicability of these proteins warrant further validation using human tissue and blood samples.

The unique vulnerability profiles of each SCLC subtype may provide a future framework for choosing the most effective therapy. This is especially relevant because, in contrast to NSCLC, SCLC usually shows loss of tumor suppressors as a main genetic feature, resulting in much more limited possibilities to target oncogenic drivers. Given the direct transcriptional interaction of ASCL1 with DLL3 in Notch-inactive tumor cells, the SCLC-A subtype is expected to be sensitive to DLL3 inhibition.92, 308 In addition, as mentioned above, SCLC-A is highly dependent on both BCL-2 and INSM1 levels.6, 97 Therefore, BCL-2 inhibitors might represent potential subtype-specific therapeutic agents for this subset of SCLC, just like the LSD1 inhibitors, which disrupt the interaction between LSD1 and the transcriptional repressor INSM1 and thus inhibit the expression of NE-associated genes, such as ASCL1.106 CREBBP is an acetyltransferase that mediates chromatin accessibility and acts as a potent tumor suppressor in SCLC.309 Because SCLC-A is frequently associated with CREBBP inactivation, and Crebbp-deleted tumors are widely sensitive to histone deacetylase inhibition, histone deacetylase inhibitors like pracinostat or tinostamustine might open new avenues of treatment in ASCL1-defined tumors.309 Finally, inhibition of the SOX2 oncogene by hedgehog signal cascade inhibitors (sonidegib or vismodegib) might also represent an appealing targeted therapeutic approach in SCLC-A given the high expression of SOX2 in this subtype.67

With regard to SCLC-N, this subtype is often associated with MYC amplification, which serves as a potential target for specific MYC inhibitors (e.g., MYCi361) that engage MYC inside the cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression.310 In addition, because of the increased arginine biosynthesis and AURKA activity, NEUROD1-driven tumors are suspected to be sensitive to arginine depletion caused by pegylated arginine deaminase (ADI-PEG 20) and AURKA inhibition (e.g., alisertib).69, 107 SCLC-N exhibits selective tropism for the oncolytic Seneca Valley virus. Therefore, with appropriate biomarker-guided patient selection, the Seneca Valley virus may have selective efficacy either as single-agent therapy or in combination with immunotherapy. In this context, the NEUROD1-to-ASCL1 ratio may function as a predictive biomarker.95

Recent CRISPR screens revealed that POU2F3-driven tumors possess vulnerability to IGF-1R deficiency provoked by IGF-1R inhibitors like dalotuzumab.53 Moreover, PARP inhibitors like veliparib as well as nucleoside analogs are also anticipated to be most effective in SCLC-P. However, SLFN11 expression, known as a predictive biomarker for PARP-inhibition efficacy, does not seem to correlate with the expression of subtype-defining markers.30, 97

The SCLC-I subtype is preferentially linked to immune blockade targeting the PD-1/PD-L1 axis because these tumors are associated with an inflamed, immune oasis phenotype and high expression of immune-checkpoint markers.97, 101, 311 Notably, retrospective data analysis of the IMpower133 trial has already confirmed that the beneficial effects of incorporating immunotherapy into the EP backbone were more pronounced in patients with SCLC-I.97 This provides a rationale for the use of immunotherapeutic agents in this particular subtype. SCLC cell lines with high YAP1 expression show high sensitivity to mTOR, PLK, and CDK4/CDK6 inhibitors.30

CONCLUSION

SCLC remains a rare but highly aggressive and nearly universally fatal malignancy that is typified by genomic instability and early metastatic spread. Although the clinical armamentarium for patients with SCLC has changed minimally over several decades, we have witnessed an accelerating pace of biologic insights into the disease in recent years. Presented here is a comprehensive review of multimodal clinical approaches in SCLC, with a special focus on illuminating how the underlying pathobiology that drives this disease and the recent advancements in the field of SCLC research can be exploited in the clinic. In very early stage disease, surgical resection within the framework of multimodal treatment improves survival outcomes. Nevertheless, patients are typically diagnosed with a more advanced disease stage, when platinum-based chemotherapy supplemented with immunotherapy represents the therapeutic approach of choice. The role of radiotherapy with concomitant systemic therapy is also well established in the management of patients with SCLC. Although these therapeutic approaches are indeed efficacious at the beginning, most patients demonstrate rapid acquired resistance, highlighting the clear need to improve the effectiveness and expand the scope of current therapeutic strategies. The impressive preclinical advances during the past decade and the worldwide resurgence of profiling studies have converged on a new model of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes and the related genomic alterations have the potential to lead to the implementation of subtype-specific therapeutic approaches, with the goal of improving patient care for this once-enigmatic cancer.

ACKNOWLEDGMENTS

Balazs Dome and Zsolt Megyesfalvi were supported by funding from the Hungarian National Research, Development, and Innovation Office (KH130356 to Balazs Dome; 2020-1.1.6-JÖVŐ, TKP2021-EGA-33, and FK-143751 to Balazs Dome and Zsolt Megyesfalvi). Balazs Dome was also supported by the Austrian Science Fund (FWF I3522, FWF I3977, and I4677). Zsolt Megyesfalvi was supported by the New National Excellence Program of the Ministry for Innovation and Technology of Hungary (UNKP-20-3 and UNKP-21-3) and by the Hungarian Respiratory Society (MPA #2020). Zsolt Megyesfalvi is also the recipient of an International Association for the Study of Lung Cancer/International Lung Cancer Foundation Young Investigator Grant (2022). Karin Schelch was supported by the Austrian Science Fund (FWF No. T 1062-B33) and the City of Vienna Fund for Innovative Interdisciplinary Cancer Research. Karin Schelch is also the recipient of an International Association for the Study of Lung Cancer Early Career Education Award (2021). Carl M. Gay is the recipient of an American Society of Clinical Oncology Young Investigator Award, a Cancer Research Prevention Institute of Texas Early Clinical Investigator Award, and a LUNGevity Foundation Career Development Award.

    CONFLICT OF INTEREST STATEMENT

    Fred R. Hirsch reports participation on scientific advisory boards for Bristol-Myers Squibb (BMS), AstraZeneca, Sanofi, Novartis, Merck & Company Inc., Regeneron Pharmaceuticals, Blueprint, G1 Therapeutics, Merus, Genentech, Amgen, Novocure, NextCure, Nectin Therapeutics, OncoCyte, and Daiichi Sankyo Company, outside the submitted work. Carl M. Gay reports personal fees from AstraZeneca, BeiGene USA Inc., BMS, G1 Therapeutics, Jazz Pharmaceuticals, and Monte Rosa Therapeutics outside the submitted work. Paul A. Bunn Jr is a member of a Data Monitoring Committee at Merck & Company Inc. and BMS; a member of the Board of Directors of Verastem Inc.; and reports personal fees from BeiGene Ltd., CStone, Ascentage, Viecure, Imidex, Eli Lilly & Company, and Genentech outside the submitted work. Simon Heeke reports consulting fees from AstraZeneca, Boehringer Ingelheim, Nucleix, and Qiagen outside the submitted work. Helmut Prosch reports speakers' honoraria from AstraZeneca, BMS, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, Novartis, Roche/Intermune, Sanofi, Siemens Healthcare, and Takeda; and research support from AstraZeneca, Boehringer, Siemens, and EU4Health outside the submitted work. Konrad Hoetzenecker reports personal fees from Medtronic outside the submitted work. Robert Pirker reports speakers' fees and honoraria for advisory board service from AstraZeneca, Eli Lilly & Company, and Merck Serono outside the submitted work. Lauren A. Byers reports grants and personal fees from AstraZeneca, AbbVie, and GenMab; and personal fees from Alethia Biotherapeutics Inc., Amgen, Arrowhead Pharmaceuticals, BeiGene Ltd., BMS, Chugai Pharmaceutical Company Ltd., Daiichi Sankyo Company, Genentech Inc., Jazz Pharmaceuticals, Merck Sharp & Dohme, PharmaMar, and Puma Biotechnology outside the submitted work. The remaining authors declared no conflicts of interest.