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Patients with small-cell lung cancer (SCLC) are at high risk for intracranial metastatic disease (IMD). Although stereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as first-line treatment for IMD in most solid cancers, WBRT remains first-line treatment for IMD in patients with SCLC. We aimed to evaluate the efficacy of SRS in comparison with WBRT and assess treatment outcomes following SRS. In this systematic review and meta-analysis, we searched MEDLINE, Embase, CENTRAL, and grey literature sources for controlled trials and cohort studies published in English reporting on SRS for IMD treatment in patients with SCLC from inception to March 23, 2022. Studies were excluded that did not report on SRS for IMD secondary to SCLC. Summary data were extracted. The primary outcome was overall survival, presented as pooled hazard ratios (HR) through random-effects meta-analysis for studies comparing SRS with WBRT with or without SRS boost, and as medians for single-arm SRS studies. This study is registered with the Open Science Framework, DOI 10.17605/OSF.IO/8M4HC, and PROSPERO, CRD42021258197. Of 3823 identified records, 31 were eligible for inclusion; seven were included in the meta-analysis. Overall survival following SRS was longer than following WBRT with or without SRS boost (HR 0·85; 95% CI 0·75–0·97; n=7 studies; n=18 130 patients), or WBRT alone (0·77; 0·72–0·83; n=7 studies; n=16 961 patients), but not WBRT plus SRS boost (1·17, 0·78–1·75; n=4 studies; n=1167 patients). Using single-arm studies, pooled median overall survival from SRS was 8·99 months (95% CI 7·86–10·16; n=14 studies; n=1682 patients). Between-study heterogeneity was considerable when pooled among all comparative studies (I2=71·9%). These results suggest survival outcomes are equitable following treatment with SRS compared with WBRT in patients with SCLC and IMD. Future prospective studies should focus on tumour burden and differences in local and distant intracranial progression between WBRT-treated and SRS-treated patients with SCLC. None.

Immunotherapy (IO) is an effective treatment for various cancers; however, the benefits are modest for small cell lung cancer (SCLC). The poor response of SCLC to anti-PD-1/PD-L1 IO is due in part to the lack of cytotoxic T cells because of limited chemokine expression from SCLC tumors. Immunogenic radiosensitizers that enhance chemokine expression may be a promising strategy forward. Here, we show that the PARP inhibitors (PARPi), including olaparib, talazoparib and veliparib, in combination with radiotherapy (RT) enhance the immune activation and anti-tumor efficacy in SCLC cell lines, patient-derived xenograft (PDX) and syngeneic mouse models. The effect is further enhanced by continued delivery of adjuvant PARPi. The combination treatment (PARPi with RT) activates the cGAS-STING pathway and increases the mRNA levels of the T cell chemo-attractants CCL5 and CXCL10. In addition to upregulation of transcription, the combination treatment increases chemokine CXCL10 protein levels via stabilization of CXCL10 mRNA in an EIF4E2-dependent manner. The incorporation of anti-PD-L1 IO into the PARPi with RT combination therapy further improves the anti-tumor efficacy by increasing T cell infiltration and function. This study thus provides a proof of principle for the combination of PARP inhibitors, RT and anti-PD-L1 IO as a treatment strategy for SCLC. ‘Small cell lung cancers do not respond well to immune checkpoint blockade therapy, due to the poor recruitment of CD8 + T cells to the tumours. Here authors show that via combining radiotherapy, PARP inhibitors and anti-PD-L1 treatments, T cell infiltration and function could be improved via mechanisms that increase the chemo-attractants CCL5 and CXCL10.

Insufficient chemotherapy response and rapid disease progression remain concerns for small-cell lung cancer (SCLC). Oncologists rely on serial CT scanning to guide treatment decisions, but this cannot assess in vivo target engagement of therapeutic agents. Biomarker assessments in biopsy material do not assess contemporaneous target expression, intratumoral drug exposure, or drug-target engagement. Here, we report the use of PARP1/2-targeted imaging to measure target engagement of PARP inhibitors in vivo. Using a panel of clinical PARP inhibitors, we show that PARP imaging can quantify target engagement of chemically diverse small molecule inhibitors in vitro and in vivo. We measure PARP1/2 inhibition over time to calculate effective doses for individual drugs. Using patient-derived xenografts, we demonstrate that different therapeutics achieve similar integrated inhibition efficiencies under different dosing regimens. This imaging approach to non-invasive, quantitative assessment of dynamic intratumoral target inhibition may improve patient care through real-time monitoring of drug delivery. Treatment of small-cell lung cancer remains a challenge due to multiple mechanisms of resistance to current therapies; measuring patient response is crucial in adapting and choosing adequate treatment. Here the authors develop a strategy to visualise in vivo dynamics of a class of widely used PARP inhibitors.

Patient derived xenografts (PDXs) are widely used in preclinical research. However, lymphoproliferative ‘outgrowths’ at the site of tumour xenoplantation are a common source of failure in the creation of the disease model. In this work, we assessed the performance of 10-second molecular profiling of xenoplanted tissue with picosecond infrared laser mass spectrometry (PIRL-MS) as a new method for rapid identification of lymphoproliferative ‘outgrowths’ in serial passages to streamline the quality control workflow. PIRL-MS can identify ‘imposter’ lymphoproliferative tumours with sensitivity and specificity values of > 99%. This observation is established over n  = 258 independent PDX specimens and n  = 3,393 ten-second mass spectral data points used for building and validating (blind assessment) a classifier multivariate model to enable discrimination. We first established a classifier model based on principal component analysis coupled with linear discriminant analysis (PCA-LDA) to discriminate between true solid tumour PDXs (of 5 common epithelioid cancer types originating from lung, pancreas, ovarian, colon and head & neck as well as imposter tumours of lymphoproliferative origin. Implementation of the classifier only requires 10 seconds of mass spectral data collection (using a hand-held probe) and less than an additional second for data processing and evaluation against the model towards a classification. In addition, PIRL-MS analysis does not require any tissue preparation before analysis, and from previous research can also be deployed in situ/in vivo to save time. These attributes, coupled with its reported high sensitivity and specificity for identification of imposter lymphoproliferative tumours, position PIRL-MS as a rapid quality control method for fidelity assessment of xenoplanted tissues. These observations motivate follow-on work to reduce the cost and the footprint of the PIRL-MS platform towards lowering the adoption barrier for routine use.

Purpose Small cell lung cancer (SCLC) is a highly fatal disease associated with significant morbidity, with a need for real-world symptom and health utility score (HUS) data. HUS can be measured using an EQ-5D-5L questionnaire, however most captured data is available in non-SCLC (NSCLC) only. As new treatment regimens become available in SCLC it becomes important to understand factors which influence health-related quality of life and health utility. Methods A prospective observational cohort study (2012–2017) of ambulatory histologically confirmed SCLC evaluated patient-reported EQ-5D-5L-derived HUS, toxicity and symptoms. A set of NSCLC patients was used to compare differential factors affecting HUS. Clinical and demographic factors were evaluated for differential interactions between lung cancer types. Comorbidity scores were documented for each patient. Results In 75 SCLC and 150 NSCLC patients, those with SCLC had lower mean HUS ((SCLC vs NSCLC: mean 0.69 vs 0.79); ( p  < 0.001)) when clinically stable and with progressive disease: ((SCLC mean HUS = 0.60 vs NSCLC mean HUS = 0.77), ( p  = 0.04)). SCLC patients also had higher comorbidity scores ((1.11 vs 0.73); ( p  < 0.015)). In multivariable analyses, increased symptom severity and comorbidity scores decreased HUS in both SCLC and NSCLC ( p  < 0.001); however, only comorbidity scores differentially affected HUS ( p  < 0.0001), with a greater reduction of HUS adjusted per unit of comorbidity in SCLC. Conclusion Patients with advanced SCLC had significantly lower HUS than NSCLC. Both patient cohorts are impacted by symptoms and comorbidity, however, comorbidity had a greater negative effect in SCLC patients.

Background Emerging randomized data, mostly from phase II trials, have suggested that patients with oligometastatic cancers may benefit from ablative treatments such as stereotactic ablative radiotherapy (SABR). However, phase III data testing this paradigm are lacking, and many studies have examined SABR in the setting of metachronous oligometastatic disease. The goal of the SABR-SYNC trial is to assess the effect of SABR in patients with oligometastatic cancers and a synchronous primary tumor. Methods One hundred and eighty patients will be randomized in a 1:2 ratio between standard of care (SOC) palliative-intent treatments vs. SOC + ablative therapy (SABR preferred) to all sites of known disease. Randomization will be stratified based on histology and number of metastases at enrollment. SABR may be delivered in 1-, 3- and 5-fraction regimens, with recommended doses of 20 Gy, 30 Gy, and 35 Gy, respectively. Non-SABR local modalities (e.g. surgery, thermal ablation, conventional radiation) may be used for treatment of the primary or metastases at the discretion of the treating physicians, if those modalities are clinically preferred. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, time to initiation of next systemic therapy, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor DNA and immunological predictors of outcomes. Discussion SABR-SYNC will provide phase III data to assess the impact of SABR on overall survival in a population of patients with synchronous oligometastases. The translational component will attempt to identify novel prognostic and predictive biomarkers to aid in clinical decision making. Trial registration Clinicaltrials.gov NCT05717166 (registration date: Feb. 8, 2023).

Key Points Small-cell lung cancer (SCLC) is a high-grade neuroendocrine tumour associated with a poor overall survival, and limited progress has been made in the treatment of this disease over the past three decades Over the past 5 years, advances in our understanding of multiple aspects of the biology of SCLC have led to the development of new therapies that are currently under clinical investigation Poly [ADP-ribose] polymerase (PARP) is abundantly expressed in SCLC and is involved in DNA-damage repair; clinical trials of the PARP inhibitors veliparib, olaparib, and talazoparib are ongoing in patients with SCLC Enhancer of zeste homologue 2 (EZH2) is a regulator of chromatin remodelling that can drive acquired chemoresistance; therapeutic targeting of EZH2 might augment and extend the durability of chemotherapy responses Delta-like protein 3 (DLL3) is an inhibitory Notch ligand that is overexpressed in many SCLCs; rovalpituzumab tesirine (Rova-T), an anti-DLL3-antibody–drug conjugate, has shown promising activity in preclinical and early phase clinical studies SCLC has a high mutational burden, raising hopes regarding immunotherapy, and immune-checkpoint blockade has shown encouraging clinical activity in patients with this disease, despite typically low tumoural expression of immune-checkpoint proteins For three decades, the treatment of small-cell lung cancer (SCLC) has remained essentially unchanged, and patient outcomes remain dismal. In the past 5 years, however, advances in our understanding of the disease, at the molecular level, have resulted in the development of new therapeutic strategies, encompassing immunotherapies and novel molecularly targeted agents. Herein, authors review the breakthroughs that hold the promise to improve SCLC outcomes. Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints.Preclinical data indicate that targeting of histone-lysine N -methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaete-scute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody–drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.

Limited-stage (LS) small-cell lung cancer (SCLC) is defined as disease confined to a tolerable radiation portal without extrathoracic metastases. Despite clinical research over two decades, the prognosis of LS-SCLC patients remains poor. The current standard of care for LS-SCLC patients is concurrent platinum-based chemotherapy with thoracic radiotherapy (RT). Widespread heterogeneity on the optimal radiation dose and fractionation regimen among physicians highlights the logistical challenges of administering BID regimens. Prophylactic cranial irradiation (PCI) is recommended to patients following a good initial response to chemoradiation due to improved overall survival from historical trials and the propensity for LS-SCLC to recur with brain metastases. However, PCI utilization is being debated due to the greater availability of magnetic resonance imaging (MRI) and data in extensive-stage SCLC regarding close MRI surveillance in lieu of PCI while spurring novel RT techniques, such as hippocampal-avoidance PCI. Additionally, novel treatment combinations incorporating targeted small molecule therapies and immunotherapies with or following radiation for LS-SCLC have seen recent interest and some concepts are being investigated in clinical trials. Here, we review the landscape of progress, limitations, and challenges for LS-SCLC including current standard of care, novel radiation techniques, and the integration of novel therapeutic strategies for LS-SCLC.

Background: Small cell lung cancer (SCLC) is a lethal form of lung cancer with few treatment options and a high rate of relapse. While SCLC is initially sensitive to first-line DNA-damaging chemo- and radiotherapy, relapse disease is almost universally therapy-resistant. As a result, there has been interest in understanding the mechanisms of therapeutic resistance in this disease. Conclusions: Progress has been made in elucidating these mechanisms, particularly as they relate to the DNA damage response and SCLC differentiation and transformation, leading to many clinical trials investigating new therapies and combinations. Yet there remain many gaps in our understanding, such as the effect of epigenetics or the tumor microenvironment on treatment response, and no single mechanism has been found to be ubiquitous, suggesting a significant heterogeneity in the mechanisms of acquired resistance. Nevertheless, the advancement of techniques in the laboratory and the clinic will improve our ability to study this disease, especially in patient populations, and identify methods to surmount therapeutic resistance.