Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing.

Small cell lung carcinoma (SCLC) is a highly lethal, smoking-associated cancer with few known targetable genetic alterations. Using genome sequencing, we characterized the somatic evolution of a genetically engineered mouse model (GEMM) of SCLC initiated by loss of Trp53 and Rb1. We identified alterations in DNA copy number and complex genomic rearrangements and demonstrated a low somatic point mutation frequency in the absence of tobacco mutagens. Alterations targeting the tumor suppressor Pten occurred in the majority of murine SCLC studied, and engineered Pten deletion accelerated murine SCLC and abrogated loss of Chr19 in Trp53; Rb1; Pten compound mutant tumors. Finally, we found evidence for polyclonal and sequential metastatic spread of murine SCLC by comparative sequencing of families of related primary tumors and metastases. We propose a temporal model of SCLC tumorigenesis with implications for human SCLC therapeutics and the nature of cancer-genome evolution in GEMMs.

A new nomogram and risk classification system for predicting survival in small cell lung cancer patients diagnosed with brain metastasis: a large population-based study.

BACKGROUND: The prognosis of patients with small cell lung cancer (SCLC) is poor, most of them are in the extensive stage at the time of diagnosis, and are prone to brain metastasis. In this study, we established a nomogram combined with some clinical parameters to predict the survival of SCLC patients with brain metastasis. METHODS: The 3522 eligible patients selected from the SEER database between 2010 and 2015 were randomly divided into training cohort and validation cohort. Univariate and multivariate Cox regression analysis were used to evaluate the ability of each parameter to predict OS. The regression coefficients obtained in multivariate analysis were visualized in the form of nomogram, thus a new nomogram and risk classification system were established. The calibration curves were used to verify the model. And ROC curves were used to evaluate the discrimination ability of the newly constructed nomogram. Survival curves were made by Kaplan-Meier method and compared by Log rank test. RESULTS: Univariate and multivariate analysis showed that age, race, sex, T stage, N stage and marital status were independent prognostic factors and were included in the predictive model. The calibration curves showed that the predicted value of the 1- and 3-year survival rate by the nomogram was in good agreement with the actual observed value of the 1- and 3-year survival rate. And, the ROC curves implied the good discrimination ability of the predictive model. In addition, the results showed that in the total cohort, training cohort, and validation cohort, the prognosis of the low-risk group was better than that of the high-risk group. CONCLUSIONS: We established a nomogram and a corresponding risk classification system to predict OS in SCLC patients with brain metastasis. This model could help clinicians make clinical decisions and stratify treatment for patients.

Role of radiation in extensive stage small cell lung cancer: a National Cancer Database registry analysis.

The role of prophylactic cranial irradiation (PCI) and thoracic radiation therapy (TRT) in extensive-stage small cell lung cancer remains controversial. The authors examined the National Cancer Database and identified patients with extensive-stage small cell lung cancer with no brain metastasis. Patients were excluded if they died 30 days from diagnosis, did not receive polychemotherapy, had other palliative radiation or had missing information. A propensity score-matched analysis was also performed. A total of 21,019 patients were identified. The majority of patients did not receive radiation (69%), whereas 10% received PCI and 21% received TRT. The addition of PCI and TRT improved median survival and survival at 1 and 2 years (p ≤ 0.05). The propensity score-matched analysis confirmed the same overall survival benefit with both PCI and TRT. This registry-based analysis of >1500 accredited cancer programs shows that PCI and TRT are not commonly utilized for extensive-stage small cell lung cancer patients who are treated with multiagent chemotherapy. The addition of PCI and TRT significantly improves overall survival in this otherwise poor prognostic group. Further research is needed to confirm the role of PCI and TRT, especially in the era of improved systemic therapy.

Lay abstract The role of radiation therapy in patients with metastatic small cell lung cancer remains controversial. The authors examined the National Cancer Database and identified patients with metastatic small cell lung cancer without brain metastasis. Patients were excluded if they died 30 days from diagnosis, did not receive multiagent chemotherapy, had other palliative radiation or had missing information regarding treatment. A total of 21,019 patients were identified. The majority of patients did not receive radiation (69%), whereas 10% received radiation to the brain and 21% received radiation to their lungs. The addition of brain and lung radiation therapy improved median survival and survival at 1 and 2 years. The addition of prophylactic cranial irradiation and thoracic radiation therapy improves survival in extensive-stage small cell lung cancer. Future research is needed to evaluate the role of radiation in the era of chemoimmunotherapy.

Differentiation of brain metastases from small and non-small lung cancers using apparent diffusion coefficient (ADC) maps.

BACKGROUND: Brain metastases are particularly common in patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC showing a less  aggressive clinical course and lower chemo- and radio sensitivity compared to SCLC. Early adequate therapy is highly desirable and depends on a reliable classification of tumor type. The apparent diffusion coefficient is a noninvasive neuroimaging marker with the potential to differentiate between major histological subtypes. Here we determine the sensitivity and specificity of the apparent diffusion coefficient to distinguish between NSCLC and SCLC. METHODS: We enrolled all NSCLC and SCLC patients diagnosed between 2008 and 2019 at the University Medical Center Göttingen. Cranial MR scans were visually inspected for brain metastases and the ratio of the apparent diffusion coefficient (ADC) was calculated by dividing the ADC measured within the solid part of a metastasis by a reference ADC extracted from an equivalent region in unaffected tissue on the contralateral hemisphere. RESULTS: Out of 411 enrolled patients, we detected 129 patients (83 NSCLC, 46 SCLC) with sufficiently large brain metastases with histologically classified lung cancer and no hemorrhage. We analyzed 185 brain metastases, 84 of SCLC and 101 of NSCLC. SCLC brain metastases showed an ADC ratio of 0.68 ± 0.12 SD, and NSCLC brain metastases showed an ADC ratio of 1.47 ± 0.31 SD. Receiver operating curve statistics differentiated brain metastases of NSCLC from SCLC with an area under the curve of 0.99 and a 95% CI of 0.98 to 1, p < 0.001. Youden's J cut-point is 0.97 at a sensitivity of 0.989 and a specificity of 0.988. CONCLUSIONS: In patients with lung cancer and brain metastases with solid tumor parts, ADC ratio enables an ad hoc differentiation of SCLC and NSCLC, easily achieved during routine neuroradiological examination. Non-invasive MR imaging enables an early-individualized management of brain metastases from lung cancer. TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register (DRKS00023016).

Study protocol: watchful observation of patients with limited small cell lung cancer instead of the PCI-prospective, multi-center one-arm study.

BACKGROUND: Prophylactic cranial irradiation (PCI) is a current standard of care after confirmed response to radical chemoradiotherapy for limited disease small cell lung cancer (LD-SCLC). This standard is mostly based on results of old randomized studies when brain imaging with magnetic resonance (MRI) was not available. Survival benefit of PCI in extended disease SCLC was recently challenged by the results of randomized phase III study from Japan. METHODS: Eighty patients with LD-SCLC after response to chest chemoradiotherapy will be enrolled. Patients will be followed up by brain MRI every 3 to 6 months up to 3 years. Neurocognitive function tests will be performed at baseline and after 12 and 24 months. Patients who develop brain metastases will be irradiated with stereotactic (SRT) or whole brain RT (WBRT). The primary endpoint is overall survival. The secondary endpoints are: response rate to radiotherapy of early detected brain metastases, analysis of efficacy of SRT and WBRT; assessment and analysis of neurocognitive functions and QoL in the studied cohorts: QLQ-C30 questionnaire and the California Verbal Learning Test, Color connection test, Benton visual retention test, and verbal fluency test will be carried out. DISCUSSION: The results of this trial may contribute to changing of LD-SCLC clinical management by deescalating the treatment. There is a lack of prospective, recent studies in LD-SCLC patients with omission of PCI and modern radiation therapy technologies for developed brain metastases. The comprehensive neurocognitive function testing will help to assess the impact of modern radiotherapy (SRT) compared with WBRT and no-PCI in SCLC patients. A subgroup of long-term survivors, who will not develop brain metastases, will not be exposed to unnecessary brain irradiation with its deleterious consequences. The limitation of our study is a lack of parallel randomized control arm. This is a potential source of bias; however, randomized study will be difficult to complete for two major reasons: (1) limited population of LD-SCLC eligible for the study and (2) opinions of our patients, who after information and discussion about benefits and potential harms of PCI, often choose to omit PCI in our practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04168281, 19 Nov. 2019.

Integration of Bronchoscopic Transesophageal Ultrasound Examination of the Left Adrenal Gland into Routine Lung Cancer Staging Workup: A Prospective Trial.

BACKGROUND: Endobronchial ultrasound (EBUS) with transbronchial needle aspiration increases the diagnostic yield of lung cancer staging. The left adrenal gland (LAG) is a common site for lung cancer metastasis. The modality of transesophageal examination with an EBUS bronchoscope (EUS-B) routinely for LAG has not been assessed. OBJECTIVE: The aim of this study was to prospectively assess if evaluation and tissue sampling of the LAG could routinely be implemented in an EBUS procedure. METHODS: Patients referred for EBUS between March and August 2017 had assessment of the LAG via EUS-B. Fine-needle aspiration (FNA) was performed in cases with a suspicious LAG. The detection rate, procedure time, and learning curve of four experienced EBUS-bronchoscopists was assessed, plus the diagnostic accuracy and complication rate of FNA. RESULTS: In total, 313 consecutive patients were included. The overall LAG detection rate was 87.5%. After the initial learning curve, the detection rate for all four bronchoscopists was >93%. The detection rate did not correlate with any patient characteristics. EUS-B-FNA revealed nine LAG metastases, with a sensitivity, specificity, and accuracy of 75%, 100%, and 99%, respectively. The mean EUS-B operation time was 194.4 s, with 594.8 s for FNA. There were no FNA-associated complications. CONCLUSIONS: Evaluation of the LAG with EUS-B could routinely be included in an EBUS procedure if necessary. A high detection rate can be achieved after an initial learning period. FNA of the LAG was feasible and safe. EUS-B of the LAG could be integrated into the usual EBUS/EUS-B procedure in lung cancer staging workup.

Chemotherapy and Tyrosine Kinase Inhibitors in the last month of life in patients with metastatic lung cancer: A patient file study in the Netherlands.

OBJECTIVE: Chemotherapy in the last month of life for patients with metastatic lung cancer is often considered as aggressive end-of-life care. Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) is a relatively new treatment of which not much is known yet about use in the last month of life. We examined what percentage of patients received chemotherapy or TKIs in the last month of life in the Netherlands. METHODS: Patient files were drawn from 10 hospitals across the Netherlands. Patients had to meet the following eligibility criteria: metastatic lung cancer; died between June 1, 2013 and July 31, 2015. RESULTS: From the included 1,322 patients, 39% received no treatment for metastatic lung cancer, 52% received chemotherapy and 9% received TKIs. A total of 232 patients (18%) received treatment in the last month of life (11% chemotherapy, 7% TKIs). From the patients who received chemotherapy, 145 (21%) received this in the last month of life and 79 (11%) started this treatment in the last month of life. TKIs were given and started more often in the last month of life: from the patients who received TKIs, 87 (72%) received this treatment in the last month of life and 15 (12%) started this treatment in the last month of life. CONCLUSION: A substantial percentage of patient received and even started chemotherapy or TKIs in the last month of life. For chemotherapy, this might be seen as aggressive care. TKIs are said to have less side effects, do not lead to many hospital visits and due to the rapid response, are considered good palliation. However, it is not known, yet possible that, when patients still receiving treatment until shortly before death, this might influence preparing for death in a negative way.

Apatinib in patients with extensive-stage small-cell lung cancer after second-line or third-line chemotherapy: a phase II, single-arm, multicentre, prospective study.

BACKGROUND: Small-cell lung cancer (SCLC) remains an aggressive cancer with short-term survival due to limited therapeutic options. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies. METHODS: Eligible patients were histologically confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients received apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate. RESULTS: Forty patients were enrolled. At the data cut-off time (November 15, 2018), the median follow-up was 7.4 months; no patients remained on treatment, and five were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the intention-to-treat population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3.0 months and 5·8 months, respectively. The most commonly observed grade 3 or greater treatment-related adverse events were hypertension, hand-foot syndrome, increased L-gamma-glutamyltransferase. CONCLUSIONS: Apatinib exhibited efficacy and an acceptable safety profile in previously heavily-treated ES-SCLC patients. Further exploration of apatinib in phase III trials is warranted. TRIAL REGISTRATION: NCT02945852.

Circulating tumor cell and cell-free RNA capture and expression analysis identify platelet-associated genes in metastatic lung cancer.

BACKGROUND: Circulating tumor cells (CTC) and plasma cell-free RNA (cfRNA) can serve as biomarkers for prognosis and treatment response in lung cancer. One barrier to the selected or routine use of CTCs and plasma cfRNA in precision oncology is the limited quantity of both, and CTCs are only seen in metastatic disease. As capture of CTCs and plasma cfRNA presents an opportunity to monitor and assess malignancies without invasive procedures, we compared two methods for CTC capture and identification, and profiled mRNA from CTCs and plasma cfRNA to identify potential tumor-associated biomarkers. METHODS: Peripheral blood was collected from ten patients with small cell lung cancer (SCLC), ten patients with non-small cell lung cancer (NSCLC) and four healthy volunteers. Two methods were used for CTC capture: the standard epithelial cell adhesion molecule (EpCam) CellSearch kit (unicapture) and EpCAM plus HER2, EGFR and MUC-1 specific combined ferrofluid capture (quadcapture). For the quadcapture, anti-cytokeratin 7 (CK7) was additionally used to assist in CTC identification. NanoString analysis was performed on plasma cfRNA and on mRNA from combined ferrofluid isolated CTCs. Expression data was analyzed using STRING and Reactome. RESULTS: Unicapture detected CTCs in 40% of NSCLC and 60% of SCLC; whereas, quadcapture/CK7 identified CTCs in 20% of NSCLC and 80% of SCLC. Bioinformatic analysis of NanoString data identified high expression of a platelet factor 4 (PF4)-related group of transcripts. CONCLUSIONS: Quadcapture ferrofluid reagent did not significantly improve CTC capture efficacy. NanoString analysis based on CTC and plasma cfRNA data highlighted an intriguing PF-4-centric network in patients with metastatic lung cancer.

Survival following Multimodality Treatment Including Surgery for Stage IA-IIIB Small-Cell Lung Cancer.

BACKGROUND: Prognosis in limited disease small-cell lung cancer (SCLC) after concurrent chemoradiotherapy is poor. While some studies show better survival after multimodality treatment including surgery, other trials failed to prove a surgery-related survival benefit. Therefore, this study investigated survival in stage IA-IIIB SCLC following surgery combined with chemotherapy and/or thoracic radiotherapy. METHODS: We retrospectively reviewed all stage IA-IIIB SCLC patients without supraclavicular lymph node involvement at a single institution between January 1999 and August 2016 after multimodality treatment with curative intent. This comprised surgery consisting of primary tumor resection and systematic lymph node dissection combined with chemotherapy, chemoradiotherapy, or thoracic radiotherapy. Survival was determined using the Kaplan-Meier method, and differences were compared using log-rank tests. The risk of locoregional relapse was calculated. RESULTS: A total of 47 patients (29 men, 18 women; mean age: 62 years) were included. Thirty-day mortality was 0%. Overall median survival was 56 months, and 2-, 3-, 5-, and 10-year survival rates were 69, 54, 46, and 30%, respectively. The only significant prognostic factor (p = 0.006) was R0 resection (n = 40) increasing median survival to 64 versus 17 months in case of technical inoperability (n = 5). The risk of locoregional relapse was 2.5% (n = 1) after R0 resection. CONCLUSIONS: Multimodality treatment including surgery was safe and led to considerable survival. R0 resection was the only factor extending survival. It could be achieved in most patients and was associated with a low risk of locoregional relapse. Prospective randomized controlled studies are needed to define best practice in stage IA-IIIB SCLC.

Will liquid biopsies improve outcomes for patients with small-cell lung cancer?

Small-cell lung cancer (SCLC) is an aggressive tumour that seeds metastases early with dismal outcomes. As expected from a disease that is closely associated with smoking, mutation burden in SCLC is high. Intratumoral and intertumoral heterogeneity is a substantial obstacle to successful treatment and the SCLC genomic landscape reveals few targets that are readily druggable. Chemotherapy elicits responses in most patients with SCLC, but their effects are short lived. Multiple clinical trials have been unsuccessful in showing positive survival outcomes and biomarkers to select patients and monitor responses to novel targeted treatments have been lacking, not least because acquisition of tumour biopsies, especially during relapse after chemotherapy, is a substantial challenge. Liquid biopsies via blood sampling in SCLC, notably circulating tumour cells and circulating free tumour DNA can be readily and repeatedly accessed, and are beginning to yield promising data to inform SCLC biology and patient treatment. Primary cell cultures and preclinical mouse models can also be derived from the relatively plentiful SCLC circulating tumour cells providing a tractable platform for SCLC translational research and drug development.

Risk factors for brain metastasis in patients with small cell lung cancer without prophylactic cranial irradiation.

BACKGROUND: This study aimed to determine the risk factors for brain metastasis (BM) and the prognostic factors for overall survival (OS) in patients with small cell lung cancer without prophylactic cranial irradiation (PCI). PATIENTS AND METHODS: Limited stage small cell lung cancer (LS-SCLC) patients achieving a complete response (CR) or partial response (PR) were enrolled into this study between January 2010 and December 2016. We retrospectively evaluated the influencing factors for time to BM and overall survival (OS). RESULTS: A total of 153 patients were enrolled into this study. Sixty-eight developed BM during the follow-up period. For the whole cohort, the 1­ and 2­year BM rates were 29.4 and 41.2%, respectively. Multivariate analysis showed that T stage (hazard ratio [HR] = 2.27, P = 0.024), neutrophil-to-lymphocyte ratio (NLR; HR = 2.07, P = 0.029), time to thoracic radiotherapy (HR = 0.34, P = 0.002) and chemotherapy cycles (HR = 0.49, P = 0.036) were the independent influencing factors of time to BM. Only NLR (HR = 2.11, P = 0.005) and time to thoracic radiotherapy (HR = 1.95, P = 0.011) were independent prognostic factors of OS. Of the 68 patients developing BM, those with BM occurring as the first relapse (42/68) had better OS than the others (39.5 months vs 23.0 months, P = 0.016). CONCLUSION: LS-SCLC patients without PCI had a high risk of BM. High T stage, high NLR, early thoracic radiotherapy and fewer chemotherapy cycles were the risk factors of BM. Further research is needed to confirm the results.

Efficacy of Platinum-Based Chemotherapy for Relapsed Small-Cell Lung Cancer after Amrubicin Monotherapy in Elderly Patients and Patients with Poor Performance Status.

BACKGROUND: Previous studies have shown amrubicin to be an effective first- or second-line treatment option for small-cell lung cancer (SCLC). However, there have been few studies reporting the efficacy of platinum-based chemotherapy after amrubicin therapy. We aimed to evaluate the efficacy of platinum-based chemotherapy as second-line treatment for elderly patients and those with SCLC with poor performance status (PS) previously treated with amrubicin monotherapy. METHODS: The records of SCLC patients who received platinum-based chemotherapy as a second-line chemotherapy after first-line treatment with amrubicin monotherapy were retrospectively reviewed and the treatment outcomes were evaluated. RESULTS: A total of 48 patients were enrolled in this study. Forty-one patients (85%) received carboplatin plus etoposide. The overall response rate was 39.6%. The median progression-free survival and overall survival were 3.7 and 7.6 months, respectively. The efficacy of the platinum-based regimen did not differ with the type of relapse after amrubicin monotherapy. The most common adverse events were hematological toxicities, including grade 3 or 4 neutropenia (38%), leukopenia (33%), and thrombocytopenia (10%). CONCLUSIONS: Platinum-based chemotherapy is potentially a valid treatment option for elderly patients or those with extensive-stage SCLC with poor PS as second-line chemotherapy, who progressed after first-line treatment with amrubicin monotherapy.

NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018.

The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on "Signs and Symptoms of SCLC" and "Principles of Pathologic Review."

The prognostic analysis of different metastatic patterns in extensive-stage small-cell lung cancer patients: a large population-based study.

AIM: To analyze the metastasis patterns and prognosis differences for extensive-stage small-cell lung cancer patients. METHODS: Log-rank tests were used to calculate and compare survival estimates. Cox regression analyses were used to evaluate the prognosis factors. RESULTS: The liver was the most common metastatic site, and lung was the least common. In two metastatic sites, liver and bone metastases were the most common combination of sites. An isolated liver metastasis had the worst overall survival (OS) and cancer-specific survival (CSS) among metastatic sites (both p < 0.001). Liver and lung metastases were associated with worse CSS (p < 0.039) and OS (p < 0.015). However, for patients with three metastatic sites showed no statistical differences in their CSS and OS (all, p > 0.05). CONCLUSION: Extensive-stage small-cell lung cancer patients with metastasis to the liver alone or in combination with other organs appear to have worse outcomes.

A Long-Term Control of Intramedullary Thoracic Spinal Cord Metastasis from Small Cell Lung Cancer.

Radiotherapy with systemic corticosteroid therapy has been used to treat intramedullary spinal cord metastasis (ISCM), but recovery of function and long-term survival of these patients has been rarely observed. We report herein a small cell lung cancer (SCLC) patient with recurrent thoracic ISCM, who was successfully treated with radiotherapy and systemic corticosteroid therapy. A 70-year-old man, who was diagnosed as having SCLC seven months previously, developed thoracic ISCM. Soon after the detection of the lesion, the patient received radiotherapy with systemic corticosteroid therapy. Sensory disturbance in both extremities and neurogenic bladder and bowel dysfunction was recovered. The patient could walk after irradiation again. The patient received additional chemotherapy and survived 20 months after the diagnosis of ISCM recurrence. Prompt diagnosis and appropriate treatment for ISCM and effective chemotherapy for recurrent SCLC might be the favorable factors for such patients. Further studies will be required to define a favorable subset of patients most likely to benefit from a conventional approach.

Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer. However, because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses, concerns have been raised about these findings. We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer. METHODS: We did this randomised, open-label, phase 3 study at 47 institutions in Japan. Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were randomly assigned (1:1) to receive prophylactic cranial irradiation (25 Gy in ten daily fractions of 2·5 Gy) or observation. All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment. Randomisation was done by computer-generated allocation sequence, with age as a stratification factor and minimisation by institution, Eastern Cooperative Oncology Group performance status, and response to initial chemotherapy. The primary endpoint was overall survival, analysed in the intention-to-treat population. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000001755, and is closed to new participants. FINDINGS: Between April 3, 2009, and July 17, 2013, 224 patients were enrolled and randomly assigned (113 to prophylactic cranial irradiation and 111 to observation). In the planned interim analysis on June 18, 2013, of the first 163 enrolled patients, Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011%, resulting in early termination of the study because of futility. In the final analysis, median overall survival was 11·6 months (95% CI 9·5-13·3) in the prophylactic cranial irradiation group and 13·7 months (10·2-16·4) in the observation group (hazard ratio 1·27, 95% CI 0·96-1·68; p=0·094). The most frequent grade 3 or worse adverse events at 3 months were anorexia (six [6%] of 106 in the prophylactic cranial irradiation group vs two [2%] of 111 in the observation group), malaise (three [3%] vs one [<1%]), and muscle weakness in a lower limb (one [<1%] vs six [5%]). No treatment-related deaths occurred in either group. INTERPRETATION: In this Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer. Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up. FUNDING: The Ministry of Health, Labour and Welfare of Japan.

Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval.

BACKGROUND: In the USA annual lung cancer screening is recommended. However, the optimal screening strategy (eg, screening interval, screening rounds) is unknown. This study provides results of the fourth screening round after a 2.5-year interval in the Dutch-Belgian Lung Cancer Screening trial (NELSON). METHODS: Europe's largest, sufficiently powered randomised lung cancer screening trial was designed to determine whether low-dose CT screening reduces lung cancer mortality by ≥25% compared with no screening after 10 years of follow-up. The screening arm (n=7915) received screening at baseline, after 1 year, 2 years and 2.5 years. Performance of the NELSON screening strategy in the final fourth round was evaluated. Comparisons were made between lung cancers detected in the first three rounds, in the final round and during the 2.5-year interval. RESULTS: In round 4, 46 cancers were screen-detected and there were 28 interval cancers between the third and fourth screenings. Compared with the second round screening (1-year interval), in round 4 a higher proportion of stage IIIb/IV cancers (17.3% vs 6.8%, p=0.02) and higher proportions of squamous-cell, bronchoalveolar and small-cell carcinomas (p=0.001) were detected. Compared with a 2-year interval, the 2.5-year interval showed a higher non-significant stage distribution (stage IIIb/IV 17.3% vs 5.2%, p=0.10). Additionally, more interval cancers manifested in the 2.5-year interval than in the intervals of previous rounds (28 vs 5 and 28 vs 19). CONCLUSIONS: A 2.5-year interval reduced the effect of screening: the interval cancer rate was higher compared with the 1-year and 2-year intervals, and proportion of advanced disease stage in the final round was higher compared with the previous rounds. TRIAL REGISTRATION NUMBER: ISRCTN63545820.