Advanced-Stage Small-Cell Lung Cancer Research Articles

Thoracic Radiotherapy in Extensive Disease Small Cell Lung Cancer: Multicenter Prospective Observational TRENDS Study.

(1) Introduction: Small cell lung cancer (SCLC) is an aggressive tumor type, accounting for about 15% of all lung cancers. Radiotherapy (RT) plays a fundamental role in both early and advanced stages. Currently, in advanced disease, the use of consolidative chest RT should be recommended for patients with good response to platinum-based first-line chemotherapy, but its use has not yet been standardized. The present prospective study aims to evaluate the pattern of care of consolidative chest RT in patients with advanced stage SCLC, and its effectiveness in terms of disease control and tolerability. (2) Materials and methods: This study was a multicenter prospective observational trial, proposed and conducted within the AIRO lung study group to evaluate the pattern of care of consolidative chest RT after first-line chemotherapy in patients with advanced SCLC. The patient and tumor characteristics, doses, fractionation and volumes of thoracic RT and prophylactic cranial irradiation (PCI), as well as the thoracic and extrathoracic response to the treatment, toxicity and clinical outcomes, were collected and analyzed. (3) Results: From January 2017 to December 2019, sixty-four patients were enrolled. Median follow-up was 33 months. The median age was 68 years (range 42-81); 38 patients (59%) were male and 26 (41%) female. Carboplatin + etoposide for 6 cycles was the most commonly used first-line therapeutic scheme (42%). With regard to consolidative chest RT, 56% of patients (35) received 30 Gy in 10 factions and 16 patients (26%) received 45 Gy in 15 sessions. The modulated intensity technique was used in 84.5% of cases, and post-chemotherapy macroscopic residual disease was the target volume in 87.5% of patients. Forty-four patients (69%) also underwent PCI. At the last follow-up, over 60% of patients did not experience chest disease progression, while 67% showed extrathoracic progression. At the first radiological evaluation after RT, complete response and stable disease were recorded in 6% and 46% of the cases, respectively. Two patients had a long-term complete response to the combined treatment. The brain was the first site of extrathoracic progression in 28%. 1y and 2y OS and PFS were 67%, 19%, 28% and 6%, respectively. Consolidative chest RT was well-tolerated in the majority of patients; it was interrupted in three cases (due to G2 pulmonary toxicity, disease progression and clinical decay, respectively). Only 1 patient developed G3 asthenia. (4) Conclusions: Consolidative chest RT has been shown to be useful in reducing the risk of thoracic disease progression and is absolutely well-tolerated in patients with advanced stage SCLC with good response after first-line chemotherapy. Among the Italian centers that participated in this study, there is still variability in the choice of fractionation and target volumes, although the guidelines contain clear recommendations. The aim of future research should be to clarify the role and modalities of chest RT in the era of immunotherapy in advanced-stage SCLC.

Neuronal survival factor VGF promotes chemoresistance and predicts poor prognosis in lung cancers with neuroendocrine feature.

High-grade neuroendocrine tumors (NETs) of the lung consist of small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high-grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR-TKI selection enriched VGF expression in TKI-resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature.

Propensity score matched analysis for the role of surgery in stage Ⅲ small cell lung cancer based on the eighth edition of the TNM classification: a population study of the US SEER database and a Chinese hospital

ObjectivePatients with very early stage small cell lung cancer (SCLC) can benefit from surgery. However, the role of surgery in local advanced SCLC patients remains controversial. We designed this study to investigate the role of surgery on survival of this subset population. MethodsThe included patients were identified from the Surveillance, Epidemiology, and End Results SEER database from 1998 to 2016 and Shanghai Chest Hospital of China from 2009 to 2016. Propensity score matching(PSM) was used to balance clinical bias. The overall survival (OS) and lung cancer-specific survival (LCSS) were compared by the Kaplan–Meier analysis. Cox proportional hazards regression was used to identify factors associated with survival. ResultsAmong the 3005 stage Ⅲ patients, 570 (18.97%) patients underwent surgery. Compared with non-surgical group, patients undergoing surgery were more likely to be male, had smaller tumor size, mediastinal lymph node involvement and lower pathologic stage. The Kaplan-Meier analysis showed that surgical patients had a better OS and LCSS before and after PSM. 418 surgical patients were well matched with non-surgical patients. In matched surgical group, there were 224 (53.59%) patients who underwent lobectomy (LB), 147 (35.17%) patients who received sublobectomy (SLB), 31 (7.41%) patients who underwent pneumonectomy and 16 (3.83%) patients with unknown surgery type. The 5-year OS of the 4 subgroups were 28.80%, 12.50%, 8.70% and 13.50%, respectively (P = 0.002). In a multivariable Cox model, SLB (hazard ratio, 1.53; 95%CI, 1.20–1.96; P = 0.001) and pneumonectomy (hazard ratio, 1.72; 95%CI, 1.12–2.65; P = 0.013) were associated with worse OS compared with LB. ConclusionSurgical resection significantly improved OS and LCSS of stage Ⅲ SCLC patients in our study. Furthermore, LB had advantage over other surgery type but further exploration in larger prospective clinical trials is needed.

Potential prognostic value of delta-like protein 3 in small cell lung cancer: a meta-analysis

BackgroundCurrent researches have revealed that delta-like protein 3 (DLL3) may be related with prognosis in patients with small cell lung cancer (SCLC). However, this finding remains controversial in small cell lung cancer. This meta-analysis was systematically performed to evaluate the prognostic value of DLL3 in SCLC.MethodsThe PubMed, EMBASE and Web of Science databases were retrieved to collect the eligible references. Through Stata 15.0 software, we pooled hazard ratios (HR) with 95% confidence intervals (CI) by using random or fixed-effects models to evaluate the association between DLL3 and SCLC survival results.ResultsA total of 6 inter-related studies including 645 patients were qualified. After we removed 1 study, the remaining 5 studies including 601 patients were pooled to testify that high expression of DLL3 was an inferior prognostic for patients with SCLC in Asian populations (HR = 1.37, 95% CI = 1.05, 1.69; I2 = 0.0%, p = 0.000). The pooled results showed that DLL3 might be higher expression in advanced metastasis SCLC in Asian populations (RR = 0.84, 95% CI = 0.71, 0.99; I2 = 44.7%, p = 0.039). But the expression of DLL3 was not correlated with sex (RR = 1.33, 95% CI = 0.98, 1.80; I2 = 0.0%, p = 0.064), smoking history (RR = 1.01, 95% CI = 0.58, 1.75; I2 = 72.1%, p = 0.967) and tumour stage (RR = 0.68, 95% CI = 0.44, 1.05; I2 = 66.6%, p = 0.081).ConclusionsOur meta-analysis confirms that in Asian populations, high expression of DLL3 was a potential poor prognostic biomarker for SCLC and DLL3 highly expressed in advanced stage SCLC in Asian populations.

Surgery for small cell lung cancer: A Surveillance, Epidemiology, and End Results (SEER) Survey from 2010 to 2015.

The role of surgery in small cell lung cancer (SCLC) is controversial. This study explored whether surgery offered a survival benefits for patients with SCLC.Patients diagnosed with SCLC between 2010 and 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. The tumor, node, and metastasis (TNM) stage of SCLC in these patients was reclassified according to the 8th edition of the TNM classification for lung cancer. Overall survival (OS) was separately compared according to TNM stage between patients who underwent surgery and those who did not using Kaplan–Meier method. A Cox regression model was used to identify relevant variables affecting survival. Additional Kaplan–Meier curves were created to compare different types of surgery. Cox regression models and Forest plots were used to identify the predictors of survival in the surgery cohort.A total of 26,659 patients with SCLC were included, among which 627 (2.4%) patients underwent surgery. Surgery was associated with longer survival in patients with stage IA (45.0 vs 20.0 months, P < .001), stage IB (47.0 vs 19.0 months, P = .001), stage IIA (16.0 m vs NR, P = .007), stage III (18.0 vs 12.0 months, P < .001), and stage IV (9.0 vs 5.0 months, P < .001) disease, although the difference was not statistically significant for patients with stage IIB disease. Multivariate analysis identified surgery as an independent predictor of improved survival for all cohorts divided by stages except for stage IIB. Lobectomy was the most commonly performed procedure. Multivariate analysis in patients who underwent surgery identified lobectomy (hazard ratio [HR], 0.544; 95% confidence interval [CI], 0.341–0.869; P = .011) and chemotherapy (HR, 0.634; 95% CI, 0.487–0.827; P < .001) as independent predictors of improved survival in the surgery cohort.In a national analysis, surgery was performed in some patients for both early and advanced-stage SCLC. Surgery for SCLC was associated with improved survival except for patients with stage IIB disease. These results support an increased role of surgery in multimodal therapy for SCLC.

Abstract #133 Ectopic Cushing’s Syndrome Due to Advanced-Stage Small Cell Lung Cancer, with an Emphasis on Palliation

Abstract #133 Ectopic Cushing’s Syndrome Due to Advanced-Stage Small Cell Lung Cancer, with an Emphasis on Palliation

Beneficial effect of additional treatment with widely available anticancer agents in advanced small lung cell carcinoma: A case report.

Small-cell lung carcinoma is a type of lung cancer characterized by very poor prognosis, as the majority of the patients have already developed metastases at initial diagnosis. Small-cell lung cancer accounts for ~15% of all lung cancer cases. The present study reports the case of a female patient with advanced-stage small-cell lung cancer. The patient received the standard treatments (6 cycles of platinum and etoposide chemotherapy followed by Gamma Knife treatment of suspicious mediastinal lymphnodes); in addition, naturally derived agents (curcumin, parthenolide, betuline, sulforaphane, withanolides, lactoferrin, pomegranate fruit extract, flaxseed and dioscorea) were alternately administered at increased doses, while previously prescribed medications for other comorbidities (metformin and atorvastatin) were continued. Complete regression of the tumour was observed, and the patient remains in full remission and cancer-free for >7 years. Moreover, no treatment-related side effects and no drug interactions were observed.

Broca's aphasia due to cerebral venous sinus thrombosis following chemotherapy for small cell lung cancer: A case report and review of literature.

Cancer is associated with an increased risk of cerebrovascular incidents and treatment with chemotherapy enhances that risk further. Brocha’s aphasia is a stroke-related syndrome, the presentation of which has been rarely reported during cisplatin-based chemotherapy. The current study presents the case of a 27-year-old male with advanced-stage small cell lung cancer. The patient developed Broca’s aphasia following cisplatin-based chemotherapy.

Mir-24-3p downregulation contributes to VP16-DDP resistance in small-cell lung cancer by targeting ATG4A.

Although the combination of etoposide (VP16) and cisplatin (DDP) is widely used as a first-line treatment for advanced-stage small-cell lung cancer (SCLC), chemoresistance limits its clinical use. Abnormalities of autophagy are associated with tumor chemoresistance. The present study found that miR-24-3p, a recently discovered microRNA, is significantly downregulated in VP16-DDP-resistant SCLC cells (H446/EP) compared with VP16-DDP-sensitive parent cells (H446). Forced expression of miR-24-3p sensitized H446/EP cells to VP16-DDP treatment because of a blockade of autophagic activity. We further found that downregulated miR-24-3p enhanced autophagy activation as it directly targets and inhibits autophagy-associated gene 4A (ATG4A). Overexpression of miR-24-3p into H446/EP cells led to reduction of the ATG4A protein level, allowing SCLC cells to resensitize to VP16-DDP. We conclude that miR-24-3p regulates autophagy by targeting ATG4A. Inhibition of autophagy by increasing miR-24-3p could be the basis of a strategy to prevent and treat SCLC with combination chemotherapy, particularly in chemoresistant disease.

Phase I trial of belinostat in combination with cisplatin (Cis) and etoposide (Etop).

2527 Background: Histone deacetylase inhibitors (HDIs) are epigenetic therapies in development. To exploit the unique activity in impairing DNA repair, HDIs have been combined with chemotherapy. Belinostat is a potent HDI combined with Cis and Etop based on enhanced DNA damage and apoptosis in small cell lung cancer (SCLC) cells. Methods: Patients with relapsed/refractory cancer or previously untreated advanced stage SCLC were eligible. Belinostat was administered by continuous infusion (CIV) over 48h, from 400 mg/m2/24h, in cohorts of 3. Cis was administered on day 1 and Etop daily X3. Belinostat pharmacokinetics (PK) and several pharmacodynamic (PD) measures were assessed, including lysine acetylation in peripheral blood mononuclear cells (PBMCs) and γH2Ax staining in PBMCs and in hair follicles. Results: Five dose levels were explored in 20 patients with solid tumors, including 5 patients with SCLC, two who had no prior therapy. At the first dose level, dose-limiting toxicities (DLT) of gr 4 ANC in 1, and gr 3 HTN in 1 were observed. Cis and Etop were reduced to 60 mg/m2 and 80 mg/m2, respectively, and the dose level repeated without DLT. At the next dose level, 800 mg/m2/24h belinostat, grade 3 HTN and grade 4 pneumonitis were observed. At the MTD of 600 mg/m2/24h belinostat, DLT was seen in 1 of 6 pts; however, all 6 pts required later dose reductions. We thus considered 500 mg/m2/24h in combination with Cis and Etop to be the recommended Phase II dose; confirmation ongoing. PKs show belinostat levels at 1 uM over the 48h infusion, decreasing rapidly to the 60h timepoint. In total 11 pts, 3 with SCLC, completed 6 cycles. PR was seen in 6 pts (3 with SCLC). PD studies confirmed γH2AX staining in PBMCs and hair follicles, peaking at 36h and 60h, respectively. Tubulin and lysine acetylation (Ac-K) in PBMCs peaked at 36h; Ac-K recovered more rapidly than tubulin, mirroring γH2AX. Conclusions: The MTD of belinostat over 48h by CIV was 600 mg/m2/24h, in combination with Cis 60 mg/m2 on day 1 and Etop 80 mg/m2 on days 1 - 3. PD endpoints indicate that belinostat is active in promoting both acetylation and DNA damage. The HDI combined with chemotherapy requires dose reduction and likely represents an on-target increase in DNA damage. Clinical trial information: NCT00926640.

Implications for preserving neural stem cells in whole brain radiotherapy and prophylactic cranial irradiation: a review of 2270 metastases in 488 patients

This study delineated the incidence of metastatic involvement of neural stem cell (NSC) regions and further aimed to explore the feasibility of selectively sparing the NSC compartments during whole brain radiotherapy (WBRT) and prophylactic cranial irradiation (PCI). A total of 2270 intracranial metastases in 488 patients were identified. Lesions were classified according to locations, including lesions in the NSC compartments (subventricular zone, SVZ, or hippocampus) and those in the rest of the brain/brainstem. The incidence of involvement of NSC regions was compared between oligometastatic patients (those with 1–4 lesions) and non-oligometastatic patients (those with 5 or more lesions) using a chi-square test. The volume of the NSC regions accounted for 2.23% of the whole brain, and the overall rate of metastatic lesions in NSC regions was 1.1% in 2270 metastases (25/2270), and 4.7% in 488 patients (23/488). Of the NSC region metastases, 7 (0.3%) involved the hippocampus and 18 (0.8%) occurred in the SVZ. Among the 7 hippocampal metastases identified in this study, 1/7 (14.3%) were found in oligometastatic patients, while 6/7 (85.7%) metastases were in non-oligometastatic patients. For metastases in the SVZ, all lesions occurred in non-oligometastatic patients with none in oligometastatic patients. Metastatic involvement of the NSC compartments was significantly lower in oligometastatic patients (0.15%, 1/670) than in non-oligometastatic patients (1.5%, 24/1600) (P < 0.001). Our retrospective review of 2270 metastases in 488 patients is that the volume of the compartments of NSC regions was 2.23% relative to the whole brain, but the incidence of involvement of the NSC compartments was 1.1%, and the vast majority of NSC lesions were found in non-oligometastatic patients. We believe our data supports selective reduction of doses for these aforementioned structures, when treating oligometastatic patients with WBRT and locally advanced-stage small-cell lung cancer patients with PCI.

Phase I dose escalation study of vinorelbine and topotecan combination chemotherapy in patients with recurrent lung cancer

BackgroundA platinum doublet is the current standard treatment for good performance status patients with advanced non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC) with good performance status. However, platinum-based treatment may be associated with significant toxicities, therefore alternative platinum-free combinations should be investigated. Topotecan is a topoisomerase I inhibitor that exerts its cytotoxic effect through stabilization of the topoisomerase I-DNA complex. Preclinical data suggests synergy between topoisomerase I inhibitors and mitotic spindle poisons. Considerable hematologic toxicities have been reported with topotecan dosed for 5 consecutive days in combination with vinorelbine. Therefore, the aim of this study was to evaluate the optimal dosage and the maximal tolerated dose (MTD) of topotecan and vinorelbine in patients with relapsed or refractory non-small cell or small cell lung cancer administered on an alternate dosing schedule.MethodsFrom February, 2004 to March, 2007 eighteen patients with advanced or recurrent NSCLC or SCLC previously treated with chemotherapy were enrolled. Patients were heavily pretreated with 22% having received at least 3 prior lines of chemotherapy. Vinorelbine was administered at a fixed dose (20 mg/m2) and topotecan at escalating doses (2, 2.5, 3, 3.5, and 4 mg/m2) on days 1 and 8 every 21 days.ResultsThe MTD was not reached in any of the 5 cohorts, with only one dose limiting toxicity (DLT) occurring in cohort 4. Non-hematological toxicities were manageable. One patient had a partial response with four patients (27%) achieving stable disease. The median progression-free and overall survival for all patients, were 2.7 months (95% CI: 1.6, 9.1) and 10.5 months (95% CI: 4.2, 22.7), respectively.ConclusionVinorelbine and topotecan administered on days 1 and 8 every 21 days is well tolerated without any DLT seen with previously investigated topotecan schedules. This doublet provides a potentially active non-platinum containing doublet for the treatment of patients with advanced SCLC and NSCLC. Vinorelbine and topotecan should therefore be investigated in subsequent phase II studies at a dose of 20 mg/m2 and 4 mg/m2, respectively.Trial Registration NumberNCT00287963.

Phase I study of etoposide, cisplatin and irinotecan triplet in patients with advanced-stage small-cell lung cancer

The irinotecan-cisplatin combination has emerged as a new standard for the treatment of advanced-stage small-cell lung cancer (AS-SCLC). To move forward we developed a 3-day regimen of cisplatin, etoposide and irinotecan. Successive cohorts of AS-SCLC patients were treated with irinotecan administered as a single 1-h infusion in combination with fixed doses of cisplatin (20 mg/m(2)) and etoposide (75 mg/m(2)), both given for three consecutive days (ECI regimen). Irinotecan dose was escalated from 60 mg/m(2) by 40-mg/m(2) increments. At mid-step between the maximum tolerated dose (MTD) and the previous dose level, patients were randomized for the day of administration of irinotecan (day 1 vs day 3). A total of 36 AS-SCLC patients received 166 courses of treatment at four dose levels. The MTD of irinotecan was 140 mg/m(2) (three dose-limiting toxicities, DLTs), and the recommended optimal dose (ROD) 120 mg/m(2) (two DLTs). DLTs were febrile neutropenia and grade 3 diarrhea. Other toxicities were mild. No difference in toxicity was seen between the two time schedules. A 77% (95% CI 63.25-90.75%) response rate was recorded among 31 evaluable patients and the median survival was 12 months. The ECI regimen was well tolerated and showed considerable activity in patients with AS-SCLC. Phase II/III evaluation is ongoing.

Chemotherapy versus best supportive care for extensive small cell lung cancer.

Combination chemotherapy has been the mainstay of treatment for extensive stage small cell lung cancer (SCLC) over the last 25 years even though it only gives a short prolongation in median survival time. The main goal for these patients, if their survival prognosis is limited, should be adequate palliation with the aim of improving their quality of life. To evaluate the effectiveness of chemotherapy in extensive SCLC compared with best supportive care (BSC) or placebo treatment. Medline (1966-Jan 2003), Embase (1974-Jan 2003), Cancerlit (1993-Jan 2003) and the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2002) were searched. In addition experts in the field were contacted to identify further studies not found by electronic searches. Randomised controlled trials in which any chemotherapy treatment was compared with a placebo group or best supportive care in patients with extensive stage SCLC. Data extraction and quality assessment were undertaken independently by two reviewers and disagreements were resolved by a third author. Additional information on the included studies was obtained from the author of the original studies. Only two studies (the first published in 1977 and the second in 1982) met the inclusion criteria of the review. A total of 65 patients with extensive disease (33 in the first study and 32 in the second) were randomised to received either placebo treatment or ifosfamide. In the second study a third arm of comparison included ifosfamide plus CCNU. Ifosfamide gave an extra 78.5 days survival (mean survival time) compared with the placebo group. Partial tumour response was greater with the active treatment. Toxicity was only seen in the chemotherapy group. Pooled analysis was not possible because only mean survival time was reported in both studies for patients with extensive disease. Chemotherapeutic treatment prolongs survival in comparison with placebo in patients with advanced SCLC. Nevertheless the impact of chemotherapy on quality of life and in patients with poor prognosis is unknown. Well-designed, controlled trials are needed to further evaluate the risks and benefits of different chemotherapeutic schedules in patients with advanced small cell lung cancer.