Small Cell Lung Cancer: Advances in Diagnosis and Management

AbstractSmall cell lung cancer (SCLC) is an aggressive subtype of lung cancer characterized by rapid growth and early spread. It is a highly lethal disease that typically is diagnosed at a late stage. Surgery plays a very small role in this cancer, and management typically involves chemotherapy, delivered with thoracic radiation in early-stage disease. Platinum-based chemotherapy is initially very effective, inducing rapid and often deep responses. These responses, though, are transient, and upon relapse, SCLC is highly refractory to therapy. Immunotherapy has shown promise in delivering meaningful, durable responses and the addition of immunotherapy to first-line chemotherapy has led to the first improvements in survival in decades. Still, the disease remains difficult to manage. Incorporating radiation therapy at specific points in patient management may improve disease control. The development of predictive biomarkers and novel targeted therapies will hopefully improve options for patients in the near future. This review focuses on the current standards of care and future directions.

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Chemo-immunotherapy as first-line treatment for small-cell lung cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920980365 ◽

2020 ◽

Vol 12 ◽

pp. 175883592098036

Author(s):

Saira Farid ◽

Stephen V. Liu

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Predictive Biomarkers ◽

High Response Rate ◽

Small Cell ◽

Standards Of Care ◽

Small Cell Lung ◽

First Line ◽

Line Chemotherapy

Small-cell lung cancer (SCLC) is a highly lethal subtype of lung cancer. Despite concerted efforts over the past several decades, there have been limited therapeutic advances. Traditional chemotherapy offers a high response rate and rapid symptomatic improvement, but its benefit is fleeting, and relapse is quick and unforgiving. Immunotherapy has delivered improved outcomes for patients with many cancers and there was compelling rationale for development in SCLC. While initial efforts with cytotoxic T-lymphocyte protein-4 inhibitors failed to improve upon chemotherapy alone, the addition of programmed death ligand-1 (PD-L1) inhibitors to first-line chemotherapy finally provided long-awaited gains in survival. Atezolizumab, when added to carboplatin and etoposide, improved both progression-free survival and overall survival. Durvalumab, when added to platinum plus etoposide, similarly improved OS. Biomarker development has stalled as PD-L1 expression and tumor mutational burden have not been useful predictive biomarkers. However, based on the significant survival improvements, both atezolizumab and durvalumab were approved by the US Food and Drug Administration to be given with first-line chemotherapy, and these regimens represent the new standards of care for SCLC.

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Small Cell Lung Cancer in Elderly Patients: A Review

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2008.0028 ◽

2008 ◽

Vol 6 (3) ◽

pp. 333-344 ◽

Cited By ~ 8

Author(s):

Taofeek K. Owonikoko ◽

Suresh Ramalingam

Keyword(s):

Lung Cancer ◽

Elderly Patients ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Therapeutic Interventions ◽

Small Cell Lung ◽

Platinum Based Chemotherapy ◽

Thoracic Radiation ◽

Modality Approach

Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer cases. Approximately 40% of those cases are diagnosed in patients older than 70 years, and this proportion continues to rise in contrast to the continued decline in incidence of SCLC among the general population. The optimal strategy to manage limited-stage SCLC involves a combined modality approach with platinum-based chemotherapy and external-beam thoracic radiation therapy. For extensive-stage disease, platinum-based combination chemotherapy is a mainstay of therapy. Elderly patients present unique challenges in terms of drug metabolism and organ reserve, which impact the outcome of therapeutic interventions. However, limited data are available to guide management decisions for SCLC in elderly patients, and therefore this article discusses recommendations for treatment.

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Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.615967 ◽

2021 ◽

Vol 11 ◽

Author(s):

Sarah-Louise Ryan ◽

Keyur A. Dave ◽

Sam Beard ◽

Martina Gyimesi ◽

Matthew McTaggart ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cellular Response ◽

Predictive Biomarkers ◽

Small Cell ◽

Learning Approaches ◽

Small Cell Lung ◽

Platinum Based Chemotherapy ◽

Novel Biomarkers

Platinum-based chemotherapy remains the cornerstone of treatment for most people with non-small cell lung cancer (NSCLC), either as adjuvant therapy in combination with a second cytotoxic agent or in combination with immunotherapy. Resistance to therapy, either in the form of primary refractory disease or evolutionary resistance, remains a significant issue in the treatment of NSCLC. Hence, predictive biomarkers and novel combinational strategies are required to improve the effectiveness and durability of treatment response 6for people with NSCLC. The aim of this study was to identify novel biomarkers and/or druggable proteins from deregulated protein networks within non-oncogene driven disease that are involved in the cellular response to cisplatin. Following exposure of NSCLC cells to cisplatin, in vitro quantitative mass spectrometry was applied to identify altered protein response networks. A total of 65 proteins were significantly deregulated following cisplatin exposure. These proteins were assessed to determine if they are druggable targets using novel machine learning approaches and to identify whether these proteins might serve as prognosticators of platinum therapy. Our data demonstrate novel candidates and drug-like molecules warranting further investigation to improve response to platinum agents in NSCLC.

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Immunotherapy and Radiation Therapy for Non-Small Cell Lung Cancer—A Stimulating Partnership

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0039-3399578 ◽

2020 ◽

Vol 41 (03) ◽

pp. 360-368

Author(s):

Ritchell van Dams ◽

Ye Yuan ◽

Clifford G. Robinson ◽

Percy Lee

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Metastatic Disease ◽

Cell Lung Cancer ◽

Early Stage ◽

Locally Advanced ◽

Small Cell ◽

Standards Of Care ◽

Small Cell Lung ◽

Early Stage Disease

AbstractNon-small cell lung cancer (NSCLC) is the most common subtype of lung cancer and the leading cause of cancer-related death. Although durable local control rates are high after surgical resection or definitive radiotherapy for early-stage disease, a substantial proportion of these patients eventually experience regional and/or distant failure and succumb to their metastatic disease. The discovery of immunotherapeutics and targeted biologics has revolutionized the treatment of locally advanced and metastatic disease, improving progression-free and overall survival when incorporated with the current standards of care. Notably, post-hoc analyses and early clinical trials provide a growing body of evidence to support a synergistic effect between radiation and immunotherapy for the treatment of NSCLC from early-stage to metastatic disease. Radiotherapy appears to be capable of not only potentiating the effect of immunotherapy in targeted lesions, but also eliciting an antitumor response in distant lesions without any direct exposure to radiation. This review explores the biologic basis of immunotherapy, targeted biologics, and radiotherapy as well as the preclinical and clinical data that support the combined use of radioimmunotherapy for early-stage, locally advanced, and metastatic NSCLC.

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Systematic Review Evaluating the Timing of Thoracic Radiation Therapy in Combined Modality Therapy for Limited-Stage Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2004.01.178 ◽

2004 ◽

Vol 22 (23) ◽

pp. 4837-4845 ◽

Cited By ~ 253

Author(s):

Daniel B. Fried ◽

David E. Morris ◽

Charles Poole ◽

Julian G. Rosenman ◽

Jan S. Halle ◽

...

Keyword(s):

Lung Cancer ◽

Radiation Therapy ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Limited Stage ◽

Platinum Based Chemotherapy ◽

Thoracic Radiation ◽

The Impact

Purpose We employed meta-analytic techniques to evaluate early (E) versus late (L) timing of thoracic radiation therapy (RT) in limited-stage small-cell lung cancer (LS-SCLC). In addition, we assessed the impact of radiation fractionation and chemotherapeutic regimen on timing. Methods Randomized trials published after 1985 addressing timing of RT relative to chemotherapy in LS-SCLC were included. Trials were analyzed by risk ratio (RR), risk difference, and number-needed-to-treat methods. Results Overall survival (OS) RRs for all studies were 1.17 at 2 years (95% CI, 1.02 to 1.35; P = .03) and 1.13 at 3 years (95% CI, 0.92 to 1.39; P = .2), indicating a significantly increased 2-year survival for ERT versus LRT patients and suggestive of a similar trend at 3 years. Subset analysis of studies using hyperfractionated RT revealed OS RR for ERT versus LRT of 1.44 (95% CI, 1.17 to 1.77; P = .001) and 1.39 (95% CI, 1.02 to 1.90; P = .04) at 2 and 3 years, respectively, indicating a survival benefit of ERT versus LRT. Studies using once-daily fractionation showed no difference in 2- and 3-year OS RRs for ERT compared with LRT. Studies using platinum-based chemotherapy had OS RRs of 1.30 (95% CI, 1.10 to 1.53; P = .002) and 1.35 (95% CI, 1.07 to 1.70; P = .01) at 2 and 3 years, respectively, favoring ERT. Studies using nonplatinum-based chemotherapy regimens had nonsignificant differences in OS. Conclusion A small but significant improvement in 2-year OS for ERT versus LRT in LS-SCLC was observed, similar to the benefit of adding RT to chemotherapy or prophylactic cranial irradiation. A greater difference was evident for hyperfractionated RT and platinum-based chemotherapy.

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Surgery for Early-Stage Small Cell Lung Cancer

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2011.0094 ◽

2011 ◽

Vol 9 (10) ◽

pp. 1132-1139 ◽

Cited By ~ 12

Author(s):

Bryan J. Schneider ◽

Ashish Saxena ◽

Robert J. Downey

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Early Stage ◽

Small Cell ◽

Response To Therapy ◽

Small Cell Lung ◽

Early Stage Disease ◽

Limited Stage ◽

Thoracic Radiation

Limited-stage small cell lung cancer remains one of the more frustrating malignancies to treat. Current standard of care typically includes platinum-based chemotherapy with thoracic radiation, and although response to therapy is high, most patients will ultimately experience relapse and die of recurrent disease. No high-level data exist supporting surgical resection of early-stage disease; however, several retrospective reviews and small single-arm studies suggest surgery may benefit patients with very limited extent of disease. This article reviews the available literature, and proposes guidelines for including potentially curative resection in the management of patients with limited-stage small cell lung cancer.

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Molecular profiles of predictive biomarkers for platinum-based chemotherapy in Non-Small Cell Lung Cancer (NSCLC)

Meta Gene ◽

10.1016/j.mgene.2021.100993 ◽

2021 ◽

pp. 100993

Author(s):

NiloofarTaleghani Seyedabadi ◽

Sara YousefZadeh Shoushtari ◽

Asma Soofi ◽

Javad Arabpour ◽

Zinat Shams ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Predictive Biomarkers ◽

Small Cell ◽

Small Cell Lung ◽

Platinum Based Chemotherapy ◽

Molecular Profiles

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Neoadjuvant immunotherapy for non-small cell lung cancer: right drugs, right patient, right time?

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002248 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002248

Author(s):

Elizabeth Ahern ◽

Ben J Solomon ◽

Rina Hui ◽

Nick Pavlakis ◽

Ken O'Byrne ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Predictive Biomarkers ◽

Small Cell ◽

Phase Iii ◽

Direct Selection ◽

Small Cell Lung ◽

Platinum Based Chemotherapy ◽

The Right

Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative (neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC; the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach.

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