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Open AccessEditorial

Small Cell Lung Cancer: A New Era Is Beginning?

by Alessandro Morabito and Christian Rolfo

Cancers 2021, 13(11), 2646; https://doi.org/10.3390/cancers13112646 - 28 May 2021

Cited by 4 | Viewed by 2023

Abstract

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers and it is the most aggressive one [...] Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

Research

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17 pages, 3885 KiB

Open AccessArticle

Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

by Hsiao-Ling Chen, Yu-Kang Tu, Hsiu-Mei Chang, Tai-Huang Lee, Kuan-Li Wu, Yu-Chen Tsai, Mei-Hsuan Lee, Chih-Jen Yang, Jen-Yu Hung and Inn-Wen Chong

Cancers 2020, 12(12), 3629; https://doi.org/10.3390/cancers12123629 - 03 Dec 2020

Cited by 18 | Viewed by 2835

Abstract

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus [...] Read more.

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46–0.98 for nivolumab, HR = 0.70, 95% CI = 0.54–0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59–0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46–0.92 for nivolumab, HR = 0.77, 95% CI = 0.61–0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65–0.94 for durvalumab, HR = 0.75, 95% CI = 0.61–0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3–4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3–4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions. Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

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Review

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16 pages, 1059 KiB

Open AccessReview

Promising Role of Circulating Tumor Cells in the Management of SCLC

by Antonella De Luca, Marianna Gallo, Claudia Esposito, Alessandro Morabito and Nicola Normanno

Cancers 2021, 13(9), 2029; https://doi.org/10.3390/cancers13092029 - 22 Apr 2021

Cited by 9 | Viewed by 2291

Abstract

Small cell lung cancer is an aggressive disease for which few therapeutic options are currently available. Although patients initially respond to therapy, they rapidly relapse. Up to today, no biomarkers for guiding treatment of SCLC patients have been identified. SCLC patients rarely undergo [...] Read more.

Small cell lung cancer is an aggressive disease for which few therapeutic options are currently available. Although patients initially respond to therapy, they rapidly relapse. Up to today, no biomarkers for guiding treatment of SCLC patients have been identified. SCLC patients rarely undergo surgery and often the available tissue samples are inadequate for biomarker analysis. Circulating tumor cells (CTCs) are rare cells in the peripheral blood that might be used as surrogates of tissue samples. Different methodological approaches have been developed for studies of CTCs in SCLC. In addition to CTC count, which might provide prognostic and predictive information, genomic and transcriptomic analyses allow the characterization of molecular profiles of CTCs and permit the study of tumor heterogeneity. The employment of CTC-derived xenografts offers complementary information to genomic analyses and CTC enumeration about the mechanisms involved in the sensitivity/resistance to treatments. Using these approaches, CTC analysis is providing relevant information on SCLC biology that might aid in the development of personalized therapeutic strategies for SCLC patients. Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

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12 pages, 1003 KiB

Open AccessReview

Small Cell Lung Cancer: State of the Art of the Molecular and Genetic Landscape and Novel Perspective

by Valeria Denninghoff, Alessandro Russo, Diego de Miguel-Pérez, Umberto Malapelle, Amin Benyounes, Allison Gittens, Andres Felipe Cardona and Christian Rolfo

Cancers 2021, 13(7), 1723; https://doi.org/10.3390/cancers13071723 - 06 Apr 2021

Cited by 14 | Viewed by 7644

Abstract

Small cell lung cancer (SCLC) is a highly proliferative lung cancer that is not amenable to surgery in most cases due to the high metastatic potential. Precision medicine has not yet improved patients’ survival due to the lack of actionable mutations. Intra- and [...] Read more.

Small cell lung cancer (SCLC) is a highly proliferative lung cancer that is not amenable to surgery in most cases due to the high metastatic potential. Precision medicine has not yet improved patients’ survival due to the lack of actionable mutations. Intra- and intertumoral heterogeneity allow the neoplasms to adapt to various microenvironments and treatments. Further studying this heterogeneous cancer might yield the discovery of actionable mutations. First-line SCLC treatment has added immunotherapy to its armamentarium. There has been renewed interest in SCLC, and numerous clinical trials are underway with novel therapeutic approaches. Understanding the molecular and genetic landscape of this heterogeneous and lethal disease will pave the way for novel drug development. Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

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17 pages, 323 KiB

Open AccessReview

Novel Cytotoxic Chemotherapies in Small Cell Lung Carcinoma

by Diego Cortinovis, Paolo Bidoli, Stefania Canova, Francesca Colonese, Maria Gemelli, Maria Luisa Lavitrano, Giuseppe Luigi Banna, Stephen V. Liu and Alessandro Morabito

Cancers 2021, 13(5), 1152; https://doi.org/10.3390/cancers13051152 - 08 Mar 2021

Cited by 10 | Viewed by 2493

Abstract

Small cell lung cancer (SCLC) is one of the deadliest thoracic neoplasms, in part due to its fast doubling time and early metastatic spread. Historically, cytotoxic chemotherapy consisting of platinum–etoposide or anthracycline-based regimens has demonstrated a high response rate, but early chemoresistance leads [...] Read more.

Small cell lung cancer (SCLC) is one of the deadliest thoracic neoplasms, in part due to its fast doubling time and early metastatic spread. Historically, cytotoxic chemotherapy consisting of platinum–etoposide or anthracycline-based regimens has demonstrated a high response rate, but early chemoresistance leads to a poor prognosis in advanced SCLC. Only a fraction of patients with limited-disease can be cured by chemo-radiotherapy. Given the disappointing survival rates in advanced SCLC, new cytotoxic agents are eagerly awaited. Unfortunately, few novel chemotherapy drugs have been developed in the latest decades. This review describes the results and potential application in the clinical practice of novel chemotherapy agents for SCLC. Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

14 pages, 733 KiB

Open AccessReview

History of Extensive Disease Small Cell Lung Cancer Treatment: Time to Raise the Bar? A Review of the Literature

by Chiara Lazzari, Aurora Mirabile, Alessandra Bulotta, Maria Grazia Viganó, Francesca Rita Ogliari, Stefania Ippati, Italo DellOca, Mariacarmela Santarpia, Vincenza Lorusso, Martin Reck and Vanesa Gregorc

Cancers 2021, 13(5), 998; https://doi.org/10.3390/cancers13050998 - 27 Feb 2021

Cited by 7 | Viewed by 2559

Abstract

Several trials have tried for decades to improve the outcome of extensive disease small cell lung cancer (ED-SCLC) through attempts to modify the standard treatments. Nevertheless, platinum/etoposide combination and topotecan have remained respectively the first and the second line standard treatments for the [...] Read more.

Several trials have tried for decades to improve the outcome of extensive disease small cell lung cancer (ED-SCLC) through attempts to modify the standard treatments. Nevertheless, platinum/etoposide combination and topotecan have remained respectively the first and the second line standard treatments for the last 40 years. With the advent of immunotherapy, this scenario has finally changed. Our review aims to provide an overview of the primary studies on the actual therapeutic strategies available for ED-SCLC patients, and to highlight emerging evidence supporting the use of immunotherapy in SCLC patients. Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

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11 pages, 3101 KiB

Open AccessReview

Pathology and Classification of SCLC

by Maria Gabriela Raso, Neus Bota-Rabassedas and Ignacio I. Wistuba

Cancers 2021, 13(4), 820; https://doi.org/10.3390/cancers13040820 - 16 Feb 2021

Cited by 62 | Viewed by 11071

Abstract

Lung cancer is consistently the leading cause of cancer-related death worldwide, and it ranks as the second most frequent type of new cancer cases diagnosed in the United States, both in males and females. One subtype of lung cancer, small cell lung carcinoma [...] Read more.

Lung cancer is consistently the leading cause of cancer-related death worldwide, and it ranks as the second most frequent type of new cancer cases diagnosed in the United States, both in males and females. One subtype of lung cancer, small cell lung carcinoma (SCLC), is an aggressive, poorly differentiated, and high-grade neuroendocrine carcinoma that accounts for 13% of all lung carcinomas. SCLC is the most frequent neuroendocrine lung tumor, and it is commonly presented as an advanced stage disease in heavy smokers. Due to its clinical presentation, it is typically diagnosed in small biopsies or cytology specimens, with routine immunostaining only. However, immunohistochemistry markers are extremely valuable in demonstrating neuroendocrine features of SCLC and supporting its differential diagnosis. The 2015 WHO classification grouped all pulmonary neuroendocrine carcinomas in one category and maintained the SCLC combined variant that was previously recognized. In this review, we explore multiple aspects of the pathologic features of this entity, as well as clinically relevant immunohistochemistry markers expression and its molecular characteristics. In addition, we will focus on characteristics of the tumor microenvironment, and the latest pathogenesis findings to better understand the new therapeutic options in the current era of personalized therapy. Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

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16 pages, 1326 KiB

Open AccessEditor’s ChoiceReview

PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses

by Erik H. Knelson, Shetal A. Patel and Jacob M. Sands

Cancers 2021, 13(4), 727; https://doi.org/10.3390/cancers13040727 - 10 Feb 2021

Cited by 31 | Viewed by 4435

Abstract

Despite recent advances in first-line treatment for small-cell lung cancer (SCLC), durable responses remain rare. The DNA repair enzyme poly-(ADP)-ribose polymerase (PARP) was identified as a therapeutic target in SCLC using unbiased preclinical screens and confirmed in human and mouse models. Early trials [...] Read more.

Despite recent advances in first-line treatment for small-cell lung cancer (SCLC), durable responses remain rare. The DNA repair enzyme poly-(ADP)-ribose polymerase (PARP) was identified as a therapeutic target in SCLC using unbiased preclinical screens and confirmed in human and mouse models. Early trials of PARP inhibitors, either alone or in combination with chemotherapy, showed promising but limited responses, suggesting that selecting patient subsets and treatment combinations will prove critical to further clinical development. Expression of SLFN11 and other components of the DNA damage response (DDR) pathway appears to select for improved responses. Combining PARP inhibitors with agents that damage DNA and inhibit DDR appears particularly effective in preclinical and early trial data, as well as strategies that enhance antitumor immunity downstream of DNA damage. A robust understanding of the mechanisms of DDR in SCLC, which exhibits intrinsic replication stress, will improve selection of agents and predictive biomarkers. The most effective combinations will target multiple nodes in the DNA damage/DDR/immune activation cascade to minimize toxicity from synthetic lethality. Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

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15 pages, 295 KiB

Open AccessReview

Front Line Applications and Future Directions of Immunotherapy in Small-Cell Lung Cancer

by Selina K. Wong and Wade T. Iams

Cancers 2021, 13(3), 506; https://doi.org/10.3390/cancers13030506 - 29 Jan 2021

Cited by 11 | Viewed by 2515

Abstract

After being stagnant for decades, there has finally been a paradigm shift in the treatment of small-cell lung cancer (SCLC) with the emergence and application of immune checkpoint inhibitors (ICIs). Multiple trials of first-line ICI-chemotherapy combinations have demonstrated survival benefit compared to chemotherapy [...] Read more.

After being stagnant for decades, there has finally been a paradigm shift in the treatment of small-cell lung cancer (SCLC) with the emergence and application of immune checkpoint inhibitors (ICIs). Multiple trials of first-line ICI-chemotherapy combinations have demonstrated survival benefit compared to chemotherapy alone in patients with extensive-stage SCLC, establishing this as the new standard of care. ICIs are now being applied in the potentially curative limited-stage setting, actively being investigated as concurrent treatment with chemoradiation and as adjuvant treatment following completion of chemoradiation. This review highlights the evidence behind the practice-changing addition of ICIs in the first-line setting of extensive-stage SCLC, the potentially practice-changing immunotherapy trials that are currently underway in the limited-stage setting, and alternate immunotherapeutic strategies being studied in the treatment of SCLC. Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

14 pages, 277 KiB

Open AccessReview

Surgery in Small-Cell Lung Cancer

by Nicola Martucci, Alessandro Morabito, Antonello La Rocca, Giuseppe De Luca, Rossella De Cecio, Gerardo Botti, Giuseppe Totaro, Paolo Muto, Carmine Picone, Giovanna Esposito, Nicola Normanno and Carmine La Manna

Cancers 2021, 13(3), 390; https://doi.org/10.3390/cancers13030390 - 21 Jan 2021

Cited by 17 | Viewed by 2455

Abstract

Small-cell lung cancer (SCLC) is one of the most aggressive tumors, with a rapid growth and early metastases. Approximately 5% of SCLC patients present with early-stage disease (T1,2 N0M0): these patients have a better prognosis, with a 5-year survival up to 50%. Two [...] Read more.

Small-cell lung cancer (SCLC) is one of the most aggressive tumors, with a rapid growth and early metastases. Approximately 5% of SCLC patients present with early-stage disease (T1,2 N0M0): these patients have a better prognosis, with a 5-year survival up to 50%. Two randomized phase III studies conducted in the 1960s and the 1980s reported negative results with surgery in SCLC patients with early-stage disease and, thereafter, surgery has been largely discouraged. Instead, several subsequent prospective studies have demonstrated the feasibility of a multimodality approach including surgery before or after chemotherapy and followed in most studies by thoracic radiotherapy, with a 5-year survival probability of 36–63% for patients with completely resected stage I SCLC. These results were substantially confirmed by retrospective studies and by large, population-based studies, conducted in the last 40 years, showing the benefit of surgery, particularly lobectomy, in selected patients with early-stage SCLC. On these bases, the International Guidelines recommend a surgical approach in selected stage I SCLC patients, after adequate staging: in these cases, lobectomy with mediastinal lymphadenectomy is considered the standard approach. In all cases, surgery can be offered only as part of a multimodal treatment, which includes chemotherapy with or without radiotherapy and after a proper multidisciplinary evaluation. Full article

(This article belongs to the Special Issue Small Cell Lung Cancer: A New Era Is Beginning?)

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