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Small cell lung cancer (SCLC) remains one of the most aggressive and challenging malignancies to treat, with limited therapeutic options and poor outcomes. Recent advances in understanding SCLC biology have identified Delta-like ligand 3 (DLL3) as a promising target for novel therapies. This review explores the evolving landscape of DLL3-targeted therapies in SCLC, examining their mechanistic basis, preclinical promise, and clinical development. We discuss various therapeutic modalities, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), chimeric antigen receptor T-cell (CAR-T) therapies, and emerging approaches such as near-infrared photoimmunotherapy (NIR-PIT) and radiopharmaceutical therapy (RPT). The review highlights the challenges encountered in translating these promising approaches into clinical practice, including the setbacks faced by early DLL3-targeted therapies like Rovalpituzumab Tesirine (Rova-T). We also explore potential strategies to overcome these obstacles, emphasizing the need for a more nuanced understanding of DLL3 biology and its role in SCLC pathogenesis. The integration of cutting-edge technologies and interdisciplinary collaboration is proposed as a path forward to optimize DLL3-targeted therapies and improve outcomes for SCLC patients. This comprehensive overview provides insights into the current state and future directions of DLL3-targeted therapies, underscoring their potential to revolutionize SCLC treatment paradigms. [ABSTRACT FROM AUTHOR]

This study evaluates the efficacy of [131I]I-ERIC1 in targeting and inhibiting the growth of SCLC tumors in mice, focusing on tumor accumulation and regression and potential side effects. NCAM-positive NCI-H69 SCLC cells were implanted in CB 17 SCID mice, and [131I]I-ERIC1 biokinetics were measured in organs and tissues at four post-injection time points (24, 72, 96, and 120 h). The experimental series compared tumor growth, survival, and changes in blood counts among three treatment groups (1, 2, or 3 MBq) and a control group, with treatments initiated either two or five days post implantation. [131I]I-ERIC1 was synthesized with >95% radiochemical purity and a specific activity of 15 TBq/mmol. Tumor activity peaked at 31.5 ± 6.6% ID/g after four days, demonstrating significant antitumor efficacy, which resulted in sustained remission and extended survival. Hematological toxicity was observed, with the optimal dose identified as 2 MBq per animal administered two days post implantation. [131I]I-ERIC1 shows promise as a theranostic agent for personalized cancer treatment by effectively targeting SCLC tumors with manageable side effects. However, further studies are required to optimize dosing strategies and minimize toxicity. [ABSTRACT FROM AUTHOR]

Introduction: Various strategies, starting with surgery, systemic radiation therapy with cytotoxic chemotherapy, and immunotherapy, have been carried out to address mortality from lung cancer. None of these therapies has showed remarkably successful treatments for lung cancer. Developing technology leads to innovation of cancer-targeted therapy as an ideal strategy. Chimeric antigen receptor T cells (CAR-T cells) are one of the novel immunotherapy approaches in genetic engineering. CAR-T therapy has showed promising results as the cancer-targeted therapy. Methods: This review identifies relevant research by the Keywords: "Lung Cancer", "CAR-T for Lung Cancer", "CAR-T for solid tumor", "CAR-T for SCLC" or "CAR-T for NSCLC". The articles are extracted from Pubmed, Web of Science, Scopus, Science Direct, and Google Scholar. Data are shown based on discussions of the modification receptor, co-stimulator, and CAR-T cells. Results: CAR-T acts to overcome lung cancer by targeting several receptors, such as mesothelin and c-Met. Several generations have also evolved to more specific and effective therapy. CAR-T modifications like BBIR, SUPRA CAR, and UIR have also been developed to minimize side effects. Conclusion: CAR-T developments are not limited to CAR modification, but include its components and structure. [ABSTRACT FROM AUTHOR]

Background: Small Cell Lung Cancer (SCLC) presents a significant clinical challenge due to its aggressive nature and the need for effective biomarkers for treatment monitoring. This study aimed to compare ProGRP and CEA as serological markers in the monitoring of SCLC treatment. Methods: We retrospectively analyzed data from 80 SCLC patients and 80 matched controls. ProGRP and CEA levels were measured, and their associations with clinical parameters, including tumor stage and treatment response, were assessed using Spearman's rank correlation coefficient. Multivariate logistic regression models were employed to identify independent predictors of treatment response and disease progression. Results: ProGRP and CEA levels were considerably higher in cases than controls, with median ProGRP levels at 198.5 pg/mL versus 48.7 pg/mL and median CEA levels at 5.2 ng/mL versus 2.9 ng/mL (both p < 0.001). ProGRP levels correlated positively with tumor stage (ρ = 0.58, p < 0.001) and negatively with treatment response (ρ = − 0.45, p = 0.001). CEA levels also showed positive correlation with tumor stage (ρ = 0.48, p = 0.002) and negative correlation with treatment response (ρ = − 0.35, p = 0.005). Multivariate analysis revealed that ProGRP was an independent predictor for treatment response (OR 1.25 per 100 pg/mL increase, p = 0.001) and disease progression (OR 1.25 per 50 pg/mL increase, p = 0.012), while CEA was a marginal predictor for treatment response (OR 0.95 per 1 ng/mL increase, p = 0.045). Conclusion: Both ProGRP and CEA are significant serological markers in SCLC patients, with ProGRP showing a stronger correlation with tumor stage and treatment response. ProGRP may serve as a superior independent predictor of treatment response and disease progression compared to CEA. These findings support the incorporation of ProGRP in SCLC treatment monitoring protocols. [ABSTRACT FROM AUTHOR]

Trilaciclib, a novel cyclin-dependent kinase 4/6 inhibitor, has demonstrated the ability to protect bone marrow from chemotherapy toxicity, improving patients' quality of life (QoL). This review describes the mechanism of action, efficacy, and toxicity profile of trilaciclib. Trilaciclib halts retinoblastoma protein phosphorylation during the early G1 phase, preventing the transition from the G1/S phase and inducing the cell cycle arrest in the G1 phase, which protects the hematopoietic cell lineages. Trilaciclib is indicated by the United States Food and Drug Administration and National Comprehensive Cancer Network to decrease the incidence of chemotherapy-induced myelosuppression in adult patients before a platinum/etoposide or topotecan containing regimen for extensive stage small cell lung cancer. Its ease of administration as an intravenous infusion, given before starting chemotherapy, and the favorable side effect profile make it a better-tolerated drug, improving patient QoL. [ABSTRACT FROM AUTHOR]

Background: Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)‐SCLC, to assess whether conventional NE markers are predictive of ICIs. Methods: Patients with untreated ED‐SCLC who received first‐line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first‐line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI‐chemo group) and with chemotherapy alone (chemo group). Results: A total of 227 patients were included in the ICI‐chemo and chemo groups, respectively. The progression‐free survival (PFS) tended to be better in patients in the ICI‐chemo group than those treated with chemotherapy alone in patients with NE marker‐positive SCLC. In particular, it was statistically significant in patients with chromogranin A‐positive SCLC (p = 0.036). In patients with NE marker‐negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker. Conclusion: Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker‐negative SCLC. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the leading causes of death among all cancer deaths. This cancer is classified into two different histological subtypes: non-small cell lung cancer (NSCLC), which is the most common subtype, and small cell lung cancer (SCLC), which is the most aggressive subtype. Understanding the molecular characteristics of lung cancer has expanded our knowledge of the cellular origins and molecular pathways affected by each of these subtypes and has contributed to the development of new therapies. Traditional treatments for lung cancer include surgery, chemotherapy, and radiotherapy. Advances in understanding the nature and specificity of lung cancer have led to the development of immunotherapy, which is the newest and most specialized treatment in the treatment of lung cancer. Each of these treatments has advantages and disadvantages and causes side effects. Today, combination therapy for lung cancer reduces side effects and increases the speed of recovery. Despite the significant progress that has been made in the treatment of lung cancer in the last decade, further research into new drugs and combination therapies is needed to extend the clinical benefits and improve outcomes in lung cancer. In this review article, we discussed common lung cancer treatments and their combinations from the most advanced to the newest. [ABSTRACT FROM AUTHOR]

Trabectedin (TRB) and Lurbinectedin (LUR) are alkaloid compounds originally isolated from Ecteinascidia turbinata with proven antitumoral activity. Both molecules are structural analogues that differ on the tetrahydroisoquinoline moiety of the C subunit in TRB, which is replaced by a tetrahydro-β-carboline in LUR. TRB is indicated for patients with relapsed ovarian cancer in combination with pegylated liposomal doxorubicin, as well as for advanced soft tissue sarcoma in adults in monotherapy. LUR was approved by the FDA in 2020 to treat metastatic small cell lung cancer. Herein, we systematically summarise the origin and structure of TRB and LUR, as well as the molecular mechanisms that they trigger to induce cell death in tumoral cells and supporting stroma cells of the tumoral microenvironment, and how these compounds regulate immune cell function and fate. Finally, the novel therapeutic venues that are currently under exploration, in combination with a plethora of different immunotherapeutic strategies or specific molecular-targeted inhibitors, are reviewed, with particular emphasis on the usage of immune checkpoint inhibitors, or other bioactive molecules that have shown synergistic effects in terms of tumour regression and ablation. These approaches intend to tackle the complexity of managing cancer patients in the context of precision medicine and the application of tailor-made strategies aiming at the reduction of undesired side effects. [ABSTRACT FROM AUTHOR]

Lung cancer stands as one of the most prevalent malignancies worldwide, bearing the highest morbidity and mortality rates among all malignant tumors. The treatment of lung cancer primarily encompasses surgical procedures, radiotherapy, and chemotherapy, which are fraught with significant side effects, unfavorable prognoses, and a heightened risk of metastasis and relapse. Although targeted therapy and immunotherapy have gradually gained prominence in lung cancer treatment, diversifying the array of available methods, the overall recovery and survival rates for lung cancer patients remain suboptimal. Presently, with a holistic approach and a focus on syndrome differentiation and treatment, Traditional Chinese Medicine (TCM) has emerged as a pivotal player in the prognosis of cancer patients. TCM possesses characteristics such as targeting multiple aspects, addressing a wide range of concerns, and minimizing toxic side effects. Research demonstrates that Traditional Chinese Medicine can significantly contribute to the treatment or serve as an adjunct to chemotherapy for lung cancer and other lung-related diseases. This is achieved through mechanisms like inhibiting tumor cell proliferation, inducing tumor cell apoptosis, suppressing tumor angiogenesis, influencing the cellular microenvironment, regulating immune system function, impacting signal transduction pathways, and reversing multidrug resistance in tumor cells. In this article, we offer an overview of the advancements in research concerning Traditional Chinese Medicine extracts for the treatment or adjunctive chemotherapy of lung cancer and other lung-related conditions. Furthermore, we delve into the challenges that Traditional Chinese Medicine extracts face in lung cancer treatment, laying the foundation for the development of diagnostic, prognostic, and therapeutic targets. [ABSTRACT FROM AUTHOR]

This summary provides an update on combination therapy for lung cancer, a leading cause of death worldwide. It discusses advancements in immune-checkpoint inhibitors and targeted agents that have improved survival rates. The article explores challenges in treatment sequencing, the role of anti-angiogenic drugs, and the efficacy of chemo-immunotherapy. It also highlights the use of computational biology to identify new targets for cancer treatment. [Extracted from the article]

Despite recent progress in subtype classification for small cell lung carcinoma (SCLC), little is known about the biomarker for triple‐negative (ASCL1, NEUROD1, and POU2F3 negative) tumors. The long‐term survival, adjuvant chemotherapy (ACT) response, and immune milieu in different SCLC subtypes have also not been well established. Here, we retrospectively collected a large cohort of 192 primary SCLC tumors and reported that ASCL1‐, NEUROD1‐ and POU2F3‐dominant subtypes counted for 61.38%, 19.31%, and 6.21%, respectively. Subtype intra‐tumoral heterogeneity and co‐expression at the single‐cell level existed substantially. The expression of tumor‐derived Vimentin (VIM) was nearly restricted to triple‐negative SCLC tumors (15/19, 78.9%) while YAP1 expression was distributed widely in other subtypes. The SCLC subtyping model was independently prognostic of OS and RFS (p < 0.001 and p = 0.043). In particular, patients with ASCL1‐positive SCLC tumors can benefit more from ACT, and VIM‐positive tumors did the opposite. Compared with other subtypes, the VIM‐dominant SCLC subtype was associated with abundant but functionally impaired CD4+ and CD8+ T‐cells, which highly expressed inhibitory checkpoints and potentially benefit from PD‐L1 blockade therapy. Our study showed that tumor‐derived SCLC‐V subtype could independently predict ACT response. The distinct immune landscape between subtypes may help inform personalized immune therapeutic approaches. [ABSTRACT FROM AUTHOR]

Purpose: Although a long-term goal of cancer therapy always has been the development of agents that selectively destroy cancer cells, more recent trends have been to seek secondary agents that sensitize cancer cells to existing treatment regimens. In this regard, the present study explored the possibility of using small molecule inhibitors of p38MAPK/MK2 stress signaling pathways as potential agents to enhance the sensitivity of cancer cells with abrogated G1 checkpoint to the DNA damaging agent etoposide by specifically targeting the DNA damage-induced G2 cell cycle checkpoint. Methods: We have applied CCK8 and FACS-based viability assays and cell cycle analysis to investigate the effect of small molecules SB203580 and MK2.III on the sensitivity of small cell lung cancer cells (SCLC) that lack the G1 checkpoint to the DNA damaging agent Etoposide when used in combination. We have also assessed the effectiveness of combination chemotherapy on tumor xenograft suppression with etoposide and MK2.III in immunosuppressed mice. In addition, additional CCK8 cell viability analysis of the MDA-MB-231 breast cancer cell line, and SW620, and SW480 colorectal cancer cell lines was performed. Results: Results suggest that etoposide produces a profound effect on the cell cycle profile of cells in a manner that is consistent with the degree of cell viability that is seen using the viable cell assay. Results of the co-treatment experiments revealed that the p38/MK2 kinase inhibitors SB203580 and MK2.III both enhanced the DNA-damaging effects of etoposide on NCI-H69 cell viability in vitro. Results revealed that in vivo MK2.III was able to act as a chemosensitizer when used in combination with etoposide making NCI-H69 lung cancer cells sensitive to chemotherapeutic drug by 45% compared to single usage of the drug. We also report that MK2.III sensitizes metastatic cell lines SW-620 and MDA-MB-231 to etoposide but does not increase the sensitivity of non-metastasizing SW-480 colorectal cells to DNA damaging agent in vitro. Conclusion: Findings reported in this study provide evidence that specific inhibitors of MK2 may indeed improve overall cancer therapy; however, their effectiveness depends on cell types. [ABSTRACT FROM AUTHOR]

Through a unique genomics and drug screening platform with ~800 solid tumor cell lines, we have found a subset of SCLC cell lines are hypersensitive to venetoclax, an FDA-approved inhibitor of BCL-2. SCLC-A (ASCL1 positive) and SCLC-P (POU2F3 positive), which make up almost 80% of SCLC, frequently express high levels of BCL-2. We found that a subset of SCLC-A and SCLC-P showed high BCL-2 expression but were venetoclax-resistant. In addition, most of these SCLC cell lines have TP53 missense mutations, which make a single amino acid change. These mutants not only lose wild-type (WT) p53 tumor suppressor functions, but also acquire novel cancer-promoting activities (oncogenic, gain-of-function). A recent study with oncogenic mutant (Onc)-p53 knock-in mouse models of SCLC suggests gain-of-function activity can attenuate chemotherapeutic efficacy. Based on these observations, we hypothesize that Onc-p53 confers venetoclax resistance and that simultaneous inhibition of BCL-2 and Onc-p53 induces synergistic anticancer activity in a subset of SCLC-A and SCLC-P. We show here that (1) down-regulation of Onc-p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells; (2) targeting Onc-p53 by the HSP90 inhibitor, ganetespib, increases BIM expression and sensitizes to venetoclax in SCLC-P and SCLC-A cells. Although there are currently many combination studies for venetoclax proposed, the concept of simultaneous targeting of BCL-2 and Onc-p53 by the combination of venetoclax and HSP90 inhibitors would be a promising approach for SCLC treatment. [ABSTRACT FROM AUTHOR]

Objective: In this study, a retrospective trial was done to determine the rate of development of brain metastasis in small-cell lung cancer patients treated with concomitant chemoradiotherapy or after chemotherapy chest radiotherapy and then prophylactic cranial radiotherapy and to evaluate the overall survival of the patients and compare it with literature data. Methods: In this study, patients who were diagnosed with small-cell lung cancer between 2014 and 2022, who received concomitant chemoradiotherapy or thoracic radiotherapy after chemotherapy, whose disease was stable or in remission, without brain metastases, who did not receive cranial radiotherapy before, and who received 25 Gy (2.5 Gy/10) fraction undergoing prophylactic cranial radiotherapy were included. A total of 87 patients were included in this study. Results: Of the 87 patients, 9 (10%) patients were female and 78 (90%) were male, with a mean age of 62.17 ± 8.33 (range: 41-80) years. The median follow-up was 23 months (range: 5-82 months). Brain metastases developed in 21 (24%) of the patients. The time between thoracic radiotherapy and prophylactic cranial radiotherapy in these patients was 1.92 ± 1.89 (range: 0-7) months. The time between prophylactic cranial radiotherapy and brain metastasis was 8.64 ± 7.3 (range: 2-30) months. The mean overall survival time of all patients was 33.47 ± 5.06 months (confidence interval, 23.66-43.28), and the median overall survival was 18 ± 2.67 (95% confidence interval, 12.74-23.25) months. The 1-, 2-, 3-, and 5-year overall survival rates were 84.7%, 49.2%, 36.3%, and 12.5%, respectively. Conclusion: Prophylactic cranial radiotherapy is now used to treat both limited and extensive-stage small-cell lung cancer that responds to initial therapy. With combined therapy, the risk of thoracic recurrence is reduced, and as a result, brain metastases become one of the main types of recurrence. Our study demonstrates that prophylactic cranial radiotherapy is a low-risk, safe treatment option for small-cell lung cancer patients to avoid brain metastases. However, additional long-term, large-scale studies are needed to back up these findings and draw firm conclusions. [ABSTRACT FROM AUTHOR]

(1) Background: Analysis of tumor DNA by next-generation sequencing (NGS) plays various roles in the classification and management of cancer. This study aimed to assess the performance of two similar and large, comprehensive gene panels with a focus on clinically relevant variant detection and tumor mutation burden (TMB) assessment; (2) Methods: DNA from 19 diagnostic small cell lung cancer biopsies and an AcroMetrix™ assessment sample with >500 mutations were sequenced using Oncomine™ Comprehensive Assay Plus (OCAP) on the Ion Torrent platform and TruSight Oncology 500 Assay (TSO500) on the Illumina platform; (3) Results: OCAP and TSO500 achieved comparable NGS quality, such as mean read coverage and mean coverage uniformity. A total of 100% of the variants in the diagnostic samples and 80% of the variants in the AcroMetrix™ assessment sample were detected by both panels, and the panels reported highly similar variant allele frequency. A proportion of 14/19 (74%) samples were classified in the same TMB category; (4) Conclusions: Comparable results were obtained using OCAP and TSO500, suggesting that both panels could be applied to screen patients for enrolment in personalized cancer treatment trials. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumour with metastatic propensity. Stereotactic body radiation therapy (SBRT) is an emerging therapeutic option for SCLC, despite limited supporting evidence. By evaluating the use of SBRT in very limited stage (VLS) SCLC at our institution, we aimed to contribute to the existing knowledge in this area while establishing a basis for further research. We performed a retrospective review of all cases of VLS-SCLC treated with SBRT between 2013 and 2020. Baseline demographics, diagnostic, and treatment information were collected. The primary outcome was overall survival (OS). We identified 46 patients with pathologically confirmed VLS-SCLC; 25 were treated with SBRT, and the remainder received either surgery, conventional radiation therapy, chemotherapy, or palliative-intent therapy. After a median follow-up of 23.7 months, 44% of the patients had died; the median OS was of 24.4 months for the SBRT cohort and 67.0 months for the curative intent non-SBRT cohort. The difference in disease recurrence and survival between cohorts was underpowered and not statistically significant. Higher baseline ECOG and comorbidity was noted in the SBRT cohort. [ABSTRACT FROM AUTHOR]

Introduction: Lung carcinoma is the leading cause of death in men and is closely related to smoking. The article focuses on the current statistics of this pathology in the world. Materials and methods: The literature review was carried out using PubMed database and included articles published from 2006 to 2021. The current schemes of chemotherapy and diagnostic options of small cell lung cancer were analyzed. The mechanisms of drug action on tumor cells were considered. An analysis of the publication activity in PubMed database related to pharmacotherapy of small cell lung cancer allows reporting a twofold increase in the number of publications over the period from 2007 to 2017. Results and discussion: A systematic review presenting staging of small cell lung cancer (SCLC) and its radiation diagnostics has been conducted. As demonstrated, there are no current methods with proven effectiveness to early detect this pathology. However, it has been found that annual low-dose CT screenings helped detect a significant number of lung cancer cases at the early stage, although, the proportion of small cell carcinoma is still very high. Analyses of clinical outcomes of small cell lung cancer have showed that cisplatin/etoposide (EP) or carboplatin/etoposide (EC) appear to be the key combinations with high treatment efficacy. The article also discusses chemotherapy for small cell lung cancer, namely and the principle of its effect on tumor cells. However, this chemotherapy remains very toxic and causes a number of life-threatening side effects. It is necessary to assess the effectiveness of chemotherapy immediately after the start of treatment in order to balance benefits and risks. Conclusion: The search is currently under way for less toxic but effective compounds, this fact being a crucial issue of healthcare in providing high-quality medical and pharmaceutical care for cancer patients. Chemotherapy of the pathology under study requires high costs; therefore, a pharmacoeconomical assessment of the prescription of chemotherapy for small cell lung cancer is necessary to compare the costs of treatment and its effectiveness. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is treated as a monolithic disease despite the evident intra- and intertumoral heterogeneity. Non-specific DNA-damaging agents have remained the first-line treatment for decades. Recently, emerging transcriptomic and genomic profiling of SCLC tumors identified distinct SCLC subtypes and vulnerabilities towards targeted therapeutics, including inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARPi). SCLC cell lines and tumors exhibited an elevated level of PARP1 protein and mRNA compared to healthy lung tissues and other subtypes of lung tumors. Notable responses to PARPi were also observed in preclinical SCLC models. Clinically, PARPi monotherapy exerted variable benefits for SCLC patients. To date, research is being vigorously conducted to examine predictive biomarkers of PARPi response and various PARPi combination strategies to maximize the clinical utility of PARPi. This narrative review summarizes existing preclinical evidence supporting PARPi monotherapy, combination therapy, and respective translation to the clinic. Specifically, we covered the combination of PARPi with DNA-damaging chemotherapy (cisplatin, etoposide, temozolomide), thoracic radiotherapy, immunotherapy (immune checkpoint inhibitors), and many other novel therapeutic agents that target DNA damage response, tumor microenvironment, epigenetic modulation, angiogenesis, the ubiquitin-proteasome system, or autophagy. Putative biomarkers, such as SLFN11 expression, MGMT methylation, E2F1 expression, and platinum sensitivity, which may be predictive of response to distinct therapeutic combinations, were also discussed. The future of SCLC treatment is undergoing rapid change with a focus on tailored and personalized treatment strategies. Further development of cancer therapy with PARPi will immensely benefit at least a subset of biomarker-defined SCLC patients. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) arises in peribronchial locations and infiltrates the bronchial submucosa, including about 15% of lung cancer cases. Despite decades of research, the prognosis for SCLC patients remains poor because this tumor is characterized by an exceptionally high proliferative rate, strong tendency for early widespread metastasis and acquired chemoresistance. Omics profiling revealed that SCLC harbor extensive chromosomal rearrangements and a very high mutation burden. This led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy, which however resulted in a prolonged benefit only for a small subset of patients. Thus, the present review discusses the rationale and limitations of immunotherapeutic approaches, presenting the current biological understanding of aberrant signaling pathways that might be exploited with new potential treatments. In particular, new agents targeting DNA damage repair, cell cycle checkpoint, and apoptosis pathways showed several promising results in different preclinical models. Epigenetic alterations, gene amplifications and mutations can act as biomarkers in this context. Future research and improved clinical outcome for SCLC patients will depend on the integration between these omics and pharmacological studies with clinical translational research, in order to identify specific predictive biomarkers that will be hopefully validated using clinical trials with biomarker-selected targeted treatments. [ABSTRACT FROM AUTHOR]

Background: An influx of systematic reviews (SRs) of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) checkpoint inhibitors in cancer treatment with or without meta-analysis and with different methodological quality and inconsistent results have been published, confusing clinical decision making. The aim of this study was to comprehensively evaluate and summarize the current evidence of PD-(L)1 inhibitors in the treatment of cancer. Methods: A comprehensive search of SRs, which included meta-analyses of PD-(L)1 inhibitors on cancer, was performed on eight databases with a cutoff date of 1 January 2022. Two authors independently identified SRs, extracted data, assessed the report quality according to the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, evaluated the methodological quality by the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2), and appraised the quality of evidence by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Results: A total of 172 SRs with meta-analysis met the inclusion criteria. The report quality of included SRs was quite good, with 128 (74.42%) SRs of high quality and 44 (25.58%) of moderate quality. The methodological quality was alarming, as only one (0.58%) SR had high quality, five (2.91%) SRs had low quality, and the other 166 (96.51%) SRs had critically low quality. For GRADE, 38 (3.77%) outcomes had high-quality evidence, 288 (28.57%) moderate, 545 (54.07%) low, and 137 (13.59%) critically low-quality evidence. Current evidence indicated that treatment with PD-(L)1 inhibitors were significantly effective in non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, malignant melanoma, renal cell carcinoma, and urothelial carcinoma, breast cancer, and head and neck squamous cell carcinoma with PD-L1 expression level=1%, whereas the evidence in gastroesophageal and colorectal tumors is still controversial. Monotherapy with PD-(L)1 inhibitors was associated with a lower frequency of any grade and high-grade adverse events (AEs). The incidence of any grade and high-grade AEs caused by PD-(L)1 inhibitors in combination with other therapies was no lower than the controls. However, PD-(L)1 inhibitors were associated with a higher frequency of any grade and high-grade immune-related AEs. Conclusions: PD-(L)1 inhibitors appeared to be effective and safe for cancer treatment, except for gastrointestinal tumors; however, the quality of the evidence is not convincing. Future studies should improve methodological quality and focus on the sequential trial analysis of subgroups and safety. [ABSTRACT FROM AUTHOR]

Oral cyclin-dependent kinase (CDK) 4/6 inhibitors are routinely used to treat metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer in combination with endocrine therapy; however, they have not been widely used for other tumour types. Trilaciclib is an intravenous CDK 4/6 inhibitor that causes reversible cell cycle arrest in the G1 phase and transient haematopoietic stem and progenitor cell arrest. Ultimately, this protects the bone marrow and immune system from the cytotoxic impact of chemotherapy. Trilaciclib has been evaluated in extensive-stage small cell lung cancer in combination with chemotherapy as a myeloprotective agent and was approved by the US Food and Drug Administration for this use in February 2021. In metastatic triple-negative breast cancer, trilaciclib plus chemotherapy had a survival benefit over chemotherapy alone. This is being further investigated in a phase III trial. This review outlines the mechanism of this novel agent and describes preclinical and clinical data, characterizing its use in extensive-stage small cell lung cancer and advanced triple-negative breast cancer. [ABSTRACT FROM AUTHOR]

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Objective: To explore the molecular biological mechanism of the "salvia chinensis and radix ranunculi ternati" drug pair in the treatment of lung cancer based on network pharmacology. Methods: Searching the TCMSP database and previous literatures to screen the active compounds which resist lung cancer activity in salvia chinensis and radix ranunculi ternati. The candidate compounds were unified in the DrugBank to find the corresponding drug targets which were corrected to the standard gene names by the UniProt database. The SwissTargetPrediction platform was used to predict other targets. Searching GeneCards, OMIM and DrugBank to obtain genes related to lung cancer. After taking the intersection, the candidate gene target of drug pair in the treatment of lung cancer could be obtained. The "herbs-compounds-targets-disease" network was bulit with Cytoscape, and the PPI network was bulit on the STRING platform while the core network nodes were screened. GO and KEGG analysis on candidate genes was implemented through Metacape platform, and a "pathways-targets" network was bulit to further screen key genes. Results: A total of 16 active compounds in salvia chinensis, 18 active compounds in radix ranunculi ternati, 164 candidate targets, 2443 GO functions and 170 KEGG pathways was obtained. Conclusion: The effective compounds of " salvia chinensis and radix ranunculi ternati " drug pair in the treatment of lung cancer are quercetin, ursolic acid, β-sitosterol and caffeic acid. The key targets are MAPK1, AKT1, PIK3R1, RAF1 and EGFR. GO functions mainly include cytokines, oxidative stress, plasma membrane transmission, protein kinase binding and activity, apoptosis. KEGG could directly regulate pathways in cancer, non-small cells lung cancer pathway and small cell lung cancer pathway. KEGG also involves EGFR tyrosine kinase inhibitor resistance, IL-17, TNF, PI3K-AKT signaling pathway and apoptosis. This study reveals the molecular biological mechanism of "salvia chinensis and radix ranunculi ternati" drug pair in the treatment of lung cancer. It is reasoned that its potential targets affect multiple signaling pathways and ultimately resist the proliferation, differentiation, invasion, metastasis and promote apoptosis of lung cancer cells. Evidence for further experimental study is provided by this study. [ABSTRACT FROM AUTHOR]

• SCLC is associated with a high risk of brain metastases. • The role of PCI remains controversial in certain patient subgroups. • Key PCI trials and current guidelines in both LS and ES SCLC summarised. • Role of hippocampal avoidance radiotherapy, neuroprotective drugs and SRS discussed. • Highlights areas of interest under evaluation and current gaps in knowledge. Small cell lung cancer (SCLC) is an aggressive form of lung cancer associated with an increased risk of develping brain metastases (BM), which are a significant cause of morbidity and mortality. Prophylactic cranial irradiation (PCI) was first introduced in the 1970s with the aim of reducing BM incidence and improving survival and quality of life (QoL). Prospective clinical trials and meta -analyses have demonstrated its effectiveness in reducing BM incidence and improving survival, across all stages of the disease following response to induction chemotherapy. Despite its long history, "unknowns" surrounding PCI use still exist and there are particular subgroups of patients for which its use remains controversial. PCI is known to cause neurocognitive toxicity which can have a significant impact on a patient's QoL. Strategies to minimise this, including the use of hippocampal avoidance radiotherapy techniques, neuroprotective drugs and stereotactic radiosurgery in place of whole brain radiotherapy for the treatment of BM, are under evaluation. This review offers a summary of the key PCI trials published to date and the current treatment recommendations based on available evidence. It also discusses the key questions being addressed in ongoing clinical trials and highlights others where there is currently a knowledge gap and therefore where further data are urgently required. [ABSTRACT FROM AUTHOR]

Lung cancer treatment is constantly evolving due to technological advances in the delivery of radiation therapy. Adaptive radiation therapy (ART) allows for modification of a treatment plan with the goal of improving the dose distribution to the patient due to anatomic or physiologic deviations from the initial simulation. The implementation of ART for lung cancer is widely varied with limited consensus on who to adapt, when to adapt, how to adapt, and what the actual benefits of adaptation are. ART for lung cancer presents significant challenges due to the nature of the moving target, tumor shrinkage, and complex dose accumulation because of plan adaptation. This article presents an overview of the current state of the field in ART for lung cancer, specifically, probing topics of: patient selection for the greatest benefit from adaptation, models which predict who and when to adapt plans, best timing for plan adaptation, optimized workflows for implementing ART including alternatives to re-simulation, the best radiation techniques for ART including magnetic resonance guided treatment, algorithms and quality assurance, and challenges and techniques for dose reconstruction. To date, the clinical workflow burden of ART is one of the major reasons limiting its widespread acceptance. However, the growing body of evidence demonstrates overwhelming support for reduced toxicity while improving tumor dose coverage by adapting plans mid-treatment, but this is offset by the limited knowledge about tumor control. Progress made in predictive modeling of on-treatment tumor shrinkage and toxicity, optimizing the timing of adaptation of the plan during the course of treatment, creating optimal workflows to minimize staffing burden, and utilizing deformable image registration represent ways the field is moving toward a more uniform implementation of ART. [ABSTRACT FROM AUTHOR]

This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR , ALK , or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC. • Nivolumab with carboplatin, paclitaxel, and bevacizumab was evaluated as first-line therapy for nonsquamous NSCLC. • The nivolumab combination therapy provided superior PFS across all patients with any PD-L1 expression levels. • The median PFS of 12.1 months is the longest among all phase III studies for nonsquamous NSCLC without driver mutations. • No new safety signals were observed. [ABSTRACT FROM AUTHOR]

Objective: To assess the clinical application of lurbinectedin and its role in the therapy of small-cell lung cancer (SCLC). Data Sources: PubMed database and ClincialTrials.gov were utilized to perform a comprehensive literature search from August 2011 to mid-November 2020 with the terms lurbinectedin and PM01183. Study Selection and Data Extraction: English-language clinical trials of lurbinectedin were evaluated. Data Synthesis: Lurbinectedin, as second-line therapy in SCLC, demonstrated an overall response (OR) rate of 35.2% and median overall survival of 9.3 months. Phase II studies in multiple cancers revealed myelosuppression (>95%), increased liver enzymes (>70%), nausea (up to 80%), vomiting (54%), and fatigue (>50%) as the most common adverse events associated with lurbinectedin. CYP3A4 drug interactions affect lurbinectedin exposure (severe pancytopenia occurred after coadministration with aprepitant), and protein binding can affect its clearance. Patients with cardiac comorbidities were not included in published lurbinectedin trials because of cardiotoxicity associated with trabectedin. Relevance to Patient Care and Clinical Practice: Lurbinectedin is an option in SCLC after failure of a platinum-based regimen. Dose adjustments, drug interactions, antiemetic regimen choice, and patient comorbidities are important clinical considerations with lurbinectedin use. Likewise, its place in therapy in the era of immune checkpoint inhibitors requires further exploration. Conclusions: With a promising OR compared with other second-line options, lurbinectedin should be considered in patients who have failed first-line therapy. Studies are ongoing with lurbinectedin in combination with other agents in SCLC, and a phase III trial is assessing use in combination with doxorubicin compared with other second-line regimens. [ABSTRACT FROM AUTHOR]

Background: Irinotecan (CPT11) is an important drug for small cell lung cancer (SCLC) chemotherapy (CTx). UDP‐glucuronosyltransferase 1A1 (UGT1A1) polymorphisms can influence CPT11‐related toxicity. This study aimed to assess prevalence of UGT1A1 polymorphisms and their association with clinical outcomes in patients with SCLC on CPT11‐CTx. Methods: An observational cohort of treatment‐naïve patients with SCLC was given CPT11‐platinum doublet at a referral center in North India over 3 years. Clinical outcomes assessed were hematological and gastrointestinal toxicity (Common Terminology Criteria for Adverse Events, version 3.0), response rates (RECIST), and overall survival (OS). Peripheral blood was drawn from all enrolled patients just prior to CPT11‐CTx initiation, and genomic DNA was isolated. Genotyping was done by polymerase chain reaction (PCR)–restriction fragment length polymorphism for UGT1A1*7, UGT1A1*6, and UGT1A1*27 and by PCR‐DNA sequencing for UGT1A1*28. Patients were classified as homozygous wild‐type (WT/WT), heterozygous mutant (WT/M), or homozygous mutant (M/M) for each polymorphism assessed. Results: Of 140 patients enrolled, no mutant alleles were found for UGT1A1*27 or UGT1A1*7. Frequency of UGT1A1*6 polymorphisms (n = 111) was 89.2% for WT/WT, 8.1% for WT/M, and 2.7% for M/M. For UGT1A1*28 (n = 102), this was 41.2% for WT/WT, 43.1% for WT/M, and 15.7% for M/M. UGT1A1*6 WT/WT patients tolerated >95% predicted CPT11 dose more frequently (59.6% vs. 25.0% in WT/M‐M/M combined group; p =.026). The UGT1A1*6 WT/M‐M/M group also experienced severe (grade ≥3) diarrhea (41.7% vs. 17.2% in WT/WT; p =.044) and mucositis (41.7% vs. 8.1% in WT/WT; p =.005) more frequently. On multivariate logistic regression analysis, UGT1A1*6 WT/M‐M/M status was the only variable associated with occurrence of both mucositis (odds ratio [OR], 10.4) and severe diarrhea (OR, 4.8). UGT1A1*28 WT/M‐M/M patients had better OS (320 days [95% confidence interval, 203–437] vs. 216 days [95% confidence interval, 140–292] in WT/WT group; p =.047). On multivariate Cox proportional hazards analysis, UGT1A1*28 WT/M‐M/M status was independently associated with better OS (hazard ratio, 0.35), whereas lack of objective radiological response, moderate/heavy smoking, and increasing age were associated with worse OS. Conclusion: UGT1A1*6 and UGT1A1*28 polymorphisms were associated with increased gastrointestinal toxicity and improved OS, respectively, in North Indian patients with SCLC receiving CPT11‐CTx. Implications for Practice: UGT1A1 gene polymorphisms are known to influence irinotecan‐related toxicity. In this prospective cohort study of patients with small cell lung cancer receiving first‐line irinotecan‐platinum chemotherapy, the prevalence of UGT1A1*6 polymorphisms was found to be 10.8% UGT1A1*6 and 58.8% UGT1A1*28 homo/heterozygous mutant, respectively. UGT1A1*6 homo/heterozygous mutant status was associated with severe diarrhea and mucositis. UGT1A1*28 homo/heterozygous mutant status was independently associated with improved overall survival. This article describes the prevalence of UGT1A1 polymorphisms in a cohort of 140 patients with treatment‐naïve small cell lung cancer (SCLC) and assesses the association of UGT1A1 polymorphisms with clinical outcomes in patients treated with irinotecan‐based chemotherapy for SCLC. [ABSTRACT FROM AUTHOR]

Background: Extensive‐stage small cell lung cancer (ES‐SCLC) is deemed as a fatal malignancy with a poor prognosis. Although immunotherapy has gradually played an important role in the treatment of ES‐SCLC since 2018, ES‐SCLC treatment data and patient outcome before 2018, when chemotherapy served as a fundamental therapeutic strategy, is still meaningful as a summary of the situation regarding previous medical treatment and is a baseline for comparative data. In addition, the prognostic factors of ES‐SCLC have failed to reach a consensus until now. Therefore, this study aimed to evaluate survival and identify the prognostic factors in an ES‐SCLC population. Methods: We retrospectively collected the detailed medical records of 358 patients with ES‐SCLC from January 1, 2011 to December 31, 2018 in a Chinese top‐level cancer hospital. The prognostic factors were evaluated by Cox univariate and multivariate analysis. Results: The median overall survival (OS) of ES‐SCLC patients (N = 358) was 14.0 months, the one‐ and two‐year OS rates were 56.2% and 21.7%, respectively. Moreover, we identified two demographic characters (age ≥ 70, smoking index ≥ 400), one tumor burden factor (bone multimetastasis), two tumor biomarkers (cyfra211, CA125) and two laboratory indexes (decreased Na, PLR < 76) as independent prognostic factors for OS in this patient population. Progression‐free survival (PFS) data of 238 patients was obtained for further analysis, and the median PFS was 6.2 months, and six‐month and one‐year PFS rates were 51.7% and 14.3%, respectively. Elevated cyfra211, decreased Hb and Na were identified as independent prognostic factors for PFS. Conclusions: This study provides real‐world evidence of the survival and prognosis of ES‐SCLC patients which will enable better evaluation and clinical decision‐making in the future. [ABSTRACT FROM AUTHOR]

Background: Small cell lung cancer (SCLC) is characterized by aggressive spread and poor prognosis, but has limited treatment options. Results of prognostic factors from randomized trials on treatment arrangement are conflicting and large‐scale real‐world analysis is lacking. Methods: Patients diagnosed SCLC between 2008 and 2018 in Peking University Cancer Hospital were included in this study. Kaplan–Meier methods were adopted, and univariate analysis and multivariate Cox regression models were constructed to analyze prognostic factors. Results: Among 1045 patients who presented to our center, 988 eligible patients were identified. Median overall survival (OS) was 16.0 months for the whole group, 24.0 months and 11.0 months for limited stage small cell lung cancer (LS‐SCLC) and extensive stage small cell lung cancer (ES‐SCLC), separately. Limited‐stage, good performance status (PS) (ECOG 0–1), response to primary systemic treatment, and patients who received initiative irradiation and three or more lines of chemotherapy were predicted to have better OS in the whole group. Only response to first‐line systemic therapy and prophylactic cranial irradiation (PCI) were independent prognostic factors of survival in LS‐SCLC; while good PS (ECOG 0–1), without liver, bone, or subcutaneous metastases, response to first‐line therapy, initial local irradiation, and three or more lines of systemic therapy predicted a favorable prognosis in ES‐SCLC. Conclusions: The present study retrieved from large real–world data suggested that response to primary systemic therapy and aggressive radiotherapy are independent prognostic factors for SCLC. PCI and initiative irradiation for original or metastatic sites improved the OS in LS‐SCLC and ES‐SCLC, respectively. [ABSTRACT FROM AUTHOR]

Clinical trials play a crucial role in advancing cancer care and improving patient outcomes. However, the proportion of cancer patients enrolled in clinical trials is low, even in advanced countries. Global studies tend to enroll patients from countries with robust clinical trial infrastructure, potentially leaving out patients from other regions. There are significant differences in the tolerability and efficacy of anticancer drugs between different populations, highlighting the need for research in countries where specific cancers are more prevalent. Lower- and middle-income countries bear a significant burden of cancer cases and deaths, but the benefits of research in developed countries are not reaching them. Conducting local research in these countries is essential to ensure that patients receive treatments relevant to their specific populations. However, there are challenges such as limited research training and time constraints for clinicians in these settings. Governments should facilitate clinical trials by establishing research infrastructure, providing training programs, and reducing barriers to research. This can lead to regional collaborations and improve the quality of cancer care worldwide, reducing disparities and alleviating the global cancer burden. [Extracted from the article]

Small cell lung cancer (SCLC) is an aggressive malignant tumour which accounts for approximately 13–15% of all newly diagnosed lung cancer cases. To date, platinum-based chemotherapy are still the first-line treatments for SCLC. However, chemotherapy resistance and systemic toxicity limit the long-term clinical outcome of first-line treatment in SCLC. Recent years, targeted therapy and immunotherapy have made great breakthrough in cancer therapy, and researchers aim to exploit both as a single agent or in combination with chemotherapy to improve the survival of SCLC patients, but limited effectiveness and the adverse events remain the major obstacles in the treatment of SCLC. To overcome these challenges for SCLC therapies, prevention and early diagnosis for this refractory disease is very important. At the same time, we should reveal more information about the pathogenesis of SCLC and the mechanism of drug resistance. Finally, new treatment strategies should also be taken into considerations, such as repurposing drug, optimising of targets, combination therapy strategies or prognostic biomarkers to enhance therapeutic effects and decrease the adverse events rates in SCLC patients. This article will review the molecular biology characteristics of SCLC and discuss the opportunities and obstacles of the current therapy for SCLC patients. [ABSTRACT FROM AUTHOR]

Background: Cancer survivors have a 14% increased risk of developing a malignancy compared with the general population. Second radiation-induced malignancies with different histologies have been described in different organs. Based on individual observations, we hypothesized that neuroendocrine carcinoma (NEC) could arise in irradiated organs. Methods: In a retrospective analysis of Gustave Roussy database of NEC patients (small cell lung cancer excluded) diagnosed as a second cancer, we looked for the frequency of grade 3 NEC that arose in patients who had received previous radiation therapy for a first cancer. Radiation therapy for the first cancer, dose, location of radiation therapy, pathological characteristics, overall survival, and response to treatment of secondary NEC were analyzed. Results: From January 1995 to December 2017, 847 cases of NEC were seen at Gustave Roussy. Among them, 95 (11.2%) patients had a history of previous malignancy of which 36 (4%) had been treated with radiation therapy. Out of these 36 patients, 12 (1.4% of all NEC patients) developed a NEC within the previous irradiated organ (median dose of 50 Gy, range 36–67.5). Most frequent first cancers were breast cancer (n = 4) and Hodgkin lymphoma (n = 3). NEC arose within a median time of 21.7 years (range 5.1–36.4) from radiation in the thorax (n = 5), digestive tract (n = 3), and other sites. Five large cell NEC, 3 small cell NEC, 1 mixed neuroendocrine neoplasm and 3 not otherwise specified NEC were diagnosed. Ten patients had stage IV disease at diagnosis; median overall survival was 37.8 months (95% CI [17.6 to NA]). Three patients (25%) achieved complete response with multimodal treatment. Conclusions: NEC can arise from previously irradiated organs and may have a better outcome in this setting. Other risk factors should be investigated to explain the high rate of previous cancer in this population of neuroendocrine neoplasm. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related death among all types of cancers. In lung cancer patients, hospitalization rates in intensive care units (ICUs) are gradually increasing due to both illness- and treatment-related complications. A 61-year-old male patient who had undergone radiotherapy for small cell lung cancer (SCLC) was admitted to the ICU on the 3rd day of his treatment because of hypercapnic respiratory failure. High-flow oxygen therapy was started. The mass lesion showed rapid progression. Chemotherapy was performed for SCLC which is a chemosensitive tumor. [ABSTRACT FROM AUTHOR]