Rational and design of prophylactic cranial irradiation (PCI) and brain MRI surveillance versus brain MRI surveillance alone in patients with limited-stage small cell lung cancer achieving complete remission (CR) of tumor after chemoradiotherapy: a multicenter prospective randomized study.

BACKGROUND: Prophylactic cranial irradiation (PCI) is part of standard care in limited-stage small cell lung cancer (SCLC) at present. As evidence from retrospective studies increases, the benefits of PCI for limited-stage SCLC are being challenged. METHODS: A multicenter, prospective, randomized controlled study was designed. The key inclusion criteria were: histologically or cytologically confirmed small cell carcinoma, age ≥ 18 years, KPS ≥ 80, limited-stage is defined as tumor confined to one side of the chest including ipsilateral hilar, bilateral mediastinum and supraclavicular lymph nodes, patients have received definitive thoracic radiotherapy (regardless of the dose-fractionation of radiotherapy used) and chemotherapy, evaluated as complete remission (CR) of tumor 4-6 weeks after the completion of chemo-radiotherapy. Eligible patients will be randomly assigned to two arms: (1) PCI and brain MRI surveillance arm, receiving PCI (2.5 Gy qd to a total dose of 25 Gy in two weeks) followed by brain MRI surveillance once every three months for two years; (2) brain MRI surveillance alone arm, undergoing brain MRI surveillance once every three months for two years. The primary objective is to compare the 2-year brain metastasis-free survival (BMFS) rates between the two arms. Secondary objectives include 2-year overall survival (OS) rates, intra-cranial failure patterns, 2-year progression-free survival rates and neurotoxicity. In case of brain metastasis (BM) detect during follow-up, stereotactic radiosurgery (SRS) will be recommended if patients meet the eligibility criteria. DISCUSSION: Based on our post-hoc analysis of a prospective study, we hypothesize that in limited-stage SCLC patients with CR after definitive chemoradiotherapy, and ruling out of BM by MRI, it would be feasible to use brain MRI surveillance and omit PCI in these patients. If BM is detected during follow-up, treatment with SRS or whole brain radiotherapy does not appear to have a detrimental effect on OS. Additionally, this approach may reduce potential neurotoxicity associated with PCI.

Predicting overall survival and prophylactic cranial irradiation benefit in small-cell lung cancer with CT-based deep learning: A retrospective multicenter study.

BACKGROUND AND PURPOSE: To develop a computed tomography (CT)-based deep learning model to predict overall survival (OS) among small-cell lung cancer (SCLC) patients and identify patients who could benefit from prophylactic cranial irradiation (PCI) based on OS signature risk stratification. MATERIALS AND METHODS: This study retrospectively included 556 SCLC patients from three medical centers. The training, internal validation, and external validation cohorts comprised 309, 133, and 114 patients, respectively. The OS signature was built using a unified fully connected neural network. A deep learning model was developed based on the OS signature. Clinical and combined models were developed and compared with a deep learning model. Additionally, the benefits of PCI were evaluated after stratification using an OS signature. RESULTS: Within the internal and external validation cohorts, the deep learning model (concordance index [C-index] 0.745, 0.733) was far superior to the clinical model (C-index: 0.635, 0.630) in predicting OS, but slightly worse than the combined model (C-index: 0.771, 0.770). Additionally, the deep learning model had excellent calibration, clinical usefulness, and improved accuracy in classifying survival outcomes. Remarkably, patients at high risk had a survival benefit from PCI in both the limited and extensive stages (all P < 0.05), whereas no significant association was observed in patients at low risk. CONCLUSIONS: The CT-based deep learning model exhibited promising performance in predicting the OS of SCLC patients. The OS signature may aid in individualized treatment planning to select patients who may benefit from PCI.

Construction of brain metastasis prediction model in limited stage small cell lung cancer patients without prophylactic cranial irradiation.

INTRODUCTION: Small cell lung cancer (SCLC) is a highly aggressive lung cancer variant known for its elevated risk of brain metastases (BM). While earlier meta-analyses supported the use of prophylactic cranial irradiation (PCI) to reduce BM incidence and enhance overall survival, modern MRI capabilities raise questions about PCI's universal benefit for limited-stage SCLC (LS-SCLC) patients. As a response, we have created a predictive model for BM, aiming to identify low-risk individuals who may not require PCI. METHODS: A total of 194 LS-SCLC patients without PCI treated between 2009 and 2021 were included. We conducted both univariate and multivariate analyses to pinpoint the factors associated with the development of BM. A nomogram for predicting the 2- and 3-year probabilities of BM was then constructed. RESULTS: Univariate and multivariate analyses revealed several significant independent risk factors for the development of BM. These factors include TNM stage, the number of chemotherapy (ChT) cycles, Ki-67 expression level, pretreatment serum lactate dehydrogenase (LDH) levels, and haemoglobin (HGB) levels. These findings underscore their respective roles as independent predictors of BM. Based on the results of the final multivariable analysis, a nomogram model was created. In the training cohort, the nomogram yielded an area under the receiver operating characteristic curve (AUC) of 0.870 at 2 years and 0.828 at 3 years. In the validation cohort, the AUC values were 0.897 at 2 years and 0.789 at 3 years. The calibration curve demonstrated good agreement between the predicted and observed probabilities of BM. CONCLUSIONS: A novel nomogram has been developed to forecast the likelihood of BM in patients diagnosed with LS-SCLC. This tool holds the potential to assist healthcare professionals in formulating more informed and tailored treatment plans.

Re-examining prophylactic cranial irradiation in small cell lung cancer: a systematic review and meta-analysis.

Background: Patients with small cell lung cancer (SCLC) are at high risk for brain metastases. Prophylactic cranial irradiation (PCI) is recommended in this population to reduce the incidence of brain metastases and prolong survival. We aimed to assesses the efficacy of PCI in this population in the era of routine brain imaging. To our knowledge, this is the first systematic review and meta-analysis to examine the use among patients who were radiographically confirmed not to have brain metastases after completion of first-line therapy. Methods: In this systematic review and meta-analysis, cohort studies and controlled trials reporting on the use of PCI for patients SCLC were identified in EMBASE, MEDLINE, CENTRAL, and grey literature sources. The literature search was conducted on November 12, 2023. Summary data were extracted. Random-effects meta-analyses pooled hazard ratios (HR) for the primary outcome of overall survival between PCI and no intervention groups. This study is registered with the Open Science Framework, DOI:10.17605/OSF.IO/BC359, and PROSPERO, CRD42021249466. Findings: Of 4318 identified records, 223 were eligible for inclusion. 109 reported on overall survival in formats amenable to meta-analysis; PCI was associated with longer survival in all patients with SCLC (HR 0.59; 95% CI, 0.55-0.63; p < 0.001; n = 56,770 patients), patients with limited stage disease (HR 0.60; 95% CI, 0.55-0.65; p < 0.001; n = 78 studies; n = 27,137 patients), and patients with extensive stage disease (HR 0.59; 95% CI, 0.51-0.70; p < 0.001; n = 28 studies; n = 26,467 patients). Between-study heterogeneity was significant when pooled amongst all studies (I2 = 73.6%; 95% CI 68.4%-77.9%). Subgroup analysis did not reveal sources of heterogeneity. In a subgroup analysis on studies that used magnetic resonance imaging to exclude presence of brain metastases at restaging among all patients, overall survival did not differ significantly between patients who did or did not receive PCI (HR 0.74; 95% CI, 0.52-1.05; p = 0.08; n = 9 studies; n = 1384 patients). Interpretation: Our findings suggested that administration of PCI is associated with a survival benefit, but not when considering studies that radiographically confirmed absence of brain metastases, suggesting that the survival benefit conferred by PCI might be therapeutic rather than prophylactic. Funding: No funding.

Cranial radiation therapy with hippocampus avoidance in lung cancer treatment: systematic review and meta-analysis.

Background: The role of cranial radiation therapy with hippocampus avoidance (HA-CRT) in neurocognitive function (NCF), brain metastasis (BM), and overall survival (OS) in lung cancer remains unclear. Methods: A meta-analysis was conducted to evaluate the impact of HA-CRT in lung cancer. Data from studies on hippocampal-avoidance prophylactic cranial irradiation (HA-PCI) and whole brain radiotherapy (HA-WBRT) were pooled. Results: A total of 14 studies, including 5 randomized controlled trials, were included. The focus of NCF was mainly via the Hopkins Verbal Learning Test-Revised or the Free and Cued Selective Reminding Test. At 6 months post-radiotherapy, the pooled proportion of participants with decline in the performance of total recall, delayed recall, and discrimination in neurocognitive tests were 0.22 (95% CI 0.15, 0.29), 0.20 (95% CI 0.13, 0.27), and 0.14 (95% CI 0.05, 0.24) respectively. After 12 months, the proportion were 0.16 (95% CI 0.08, 0.23), 0.10 (95% CI 0.04, 0.16), and 0.04 (95% CI 0, 0.09) respectively. For HA zone relapse, the RR of HA-CRT versus CRT was 2.72 (95% CI 0.53, 13.87), and for 2-year BM, it was 1.20 (95% CI 0.82, 1.75). Regarding HA-PCI in SCLC, the 1-year BM rate was 0.12 (95% CI 0.07, 0.17), and the 2-year BM rate was 0.20 (95% CI 0.16, 0.25). For HA-WBRT in NSCLC with BM, the 2-year intracranial progression rate was 0.38 (95% CI 0.13, 0.62). There was no significant difference in OS between HA-CRT and CRT. Conclusions: HA-CRT appears to be safe in lung cancer, but it may not outperform conventional CRT. Larger RCTs comparing HA-CRT and CRT are warranted. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022360890, identifier CRD42022360890.

Radiotherapy for extensive-stage small-cell lung cancer in the immunotherapy era.

Currently, chemoimmunotherapy is the first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC). However, only 0.8%-2.5% of the patients presented complete response after chemoimmunotherapy. Considering that ES-SCLC is highly sensitive to radiotherapy, the addition of radiotherapy after first-line treatment for ES-SCLC could further improve local control, which may be beneficial for patients' survival. Prior studies have shown that consolidative thoracic radiotherapy (cTRT) can decrease disease progression and improve overall survival in patients with ES-SCLC who respond well to chemotherapy. However, the efficacy and safety of cTRT in the immunotherapy era remain unclear owing to a lack of prospective studies. Prophylactic cranial irradiation (PCI) has been shown to decrease brain metastasis (BM) and prolong survival in patients with limited-stage SCLC in previous reports. However, according to current guidelines, PCI is not commonly recommended for ES-SCLC. Immunotherapy has the potential to reduce the incidence of BM. Whether PCI can be replaced with regular magnetic resonance imaging surveillance for ES-SCLC in the era of immunotherapy remains controversial. Whole brain radiation therapy (WBRT) is the standard treatment for BM in SCLC patients. Stereotactic radiosurgery (SRS) has shown promise in the treatment of limited BM. Considering the potential of immunotherapy to decrease BM, it is controversial whether SRS can replace WBRT for limited BM in the immunotherapy era. Additionally, with the addition of immunotherapy, the role of palliative radiotherapy may be weakened in patients with asymptomatic metastatic lesions. However, it is still indispensable and urgent for patients with obvious symptoms of metastatic disease, such as spinal cord compression, superior vena cava syndrome, lobar obstruction, and weight-bearing metastases, which may critically damage the quality of life and prognosis. To improve the outcome of ES-SCLC, we discuss the feasibility of radiotherapy, including cTRT, PCI, WBRT/SRS, and palliative radiotherapy with immunotherapy based on existing evidence, which may offer specific prospects for further randomized trials and clinical applications.

Prophylactic cranial irradiation effect on survival in patients with small cell lung cancer: a comprehensive systematic review and meta-analysis.

OBJECTIVE: Prophylactic cranial irradiation (PCI) is a companion treatment option for small cell lung cancer (SCLC) patients. However, its efficacy and associated risk factors have not been clearly defined. In this study, the authors aimed to systematically assess the effectiveness and role of PCI in the treatment plan of SCLC. METHODS: The PubMed, Scopus, Web of Science, and Cochrane databases were searched using the following key terms and their equivalents: "brain," "radiotherapy," "metastases," "prophylactic," and "small cell lung cancer." Studies comparing overall survival (OS), progression-free survival (PFS), brain metastasis-free survival (BMFS), and incidence of brain metastases between patients receiving PCI and those not receiving it were considered eligible. Risk of bias was assessed using the Risk of Bias in Non-Randomized Studies-of Interventions (ROBINS-I) tool. Meta-analysis was conducted on the mentioned outcomes with subgrouping based on different factors. RESULTS: The authors identified 74 studies published between 1983 and 2022 with 31,551 SCLC patients, of whom 26.7% received PCI. The studies were a mix of prospective randomized and retrospective observational studies. Patients with limited-stage disease receiving PCI had better OS, PFS, and BMFS than those not receiving PCI. Patients receiving PCI also had significantly longer OS times and developed brain metastases significantly later. However, findings regarding extensive-stage SCLC were not as promising. CONCLUSIONS: PCI is an effective option for limited-stage SCLC patients. It improves OS and PFS, delays brain metastases, and reduces the incidence of brain metastases. However, it might not benefit patients with extensive-stage SCLC under adequate follow-up with MRI surveillance. Finally, the heterogeneity of the included studies and publication bias were the main limitations of this study.

The incorporation of cognitive-sparing techniques into prophylactic cranial irradiation in the management of small cell lung cancer.

The use of prophylactic cranial irradiation (PCI) remains an important component in the management of small cell lung cancer (SCLC). This is due to the high rates of subclinical brain metastases at the time of diagnosis. Following a response to initial treatment, PCI historically has been associated with improvements in overall survival and decreased development of brain metastases in patients with limited stage (LS-SCLC) and extensive stage (ES-SCLC) SCLC. However, PCI is commonly withheld in these settings in favor of observation, largely due to its association with cognitive sequelae following treatment. While randomized data has demonstrated that in patients with ES-SCLC, PCI may be withheld in favor of close MRI surveillance without a detriment in overall survival or cognitive functioning, these patients did not undergo formal neuropsychological assessments. In recent years, cognitive sparing techniques incorporated into whole brain radiation therapy and PCI, such as the addition of memantine and hippocampal avoidance, have demonstrated significant improvements in cognitive outcomes. As the overall survival in patients with SCLC continues to improve due to the incorporation of novel systemic therapies (e.g., immune checkpoint inhibitors), the role of PCI and maximizing quality of life remains a highly relevant topic. This article reviews the role of PCI and cognitive-sparing techniques in the management of SCLC.

Self-Reported Cognitive Function and Quality of Life in Patients With SCLC in the Hippocampal Avoidance Prophylactic Cranial Irradiation Versus Prophylactic Cranial Irradiation Randomized Phase 3 Trial (NCT01780675).

Introduction: In the randomized controlled trial in patients with SCLC comparing standard prophylactic cranial irradiation (PCI) with hippocampal avoidance PCI (HA-PCI), we did not observe beneficial effects of HA-PCI on tested cognition. Here, we report findings on self-reported cognitive functioning (SRCF) and quality of life (QoL). Methods: Patients with SCLC were randomized to receive PCI with or without HA (NCT01780675) and assessed at baseline (82 HA-PCI and 79 PCI patients) and at 4, 8, 12, 18, and 24 months of follow-up, using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and EORTC QLQ-brain cancer module (BN20). SRCF was assessed with the cognitive functioning scale of the EORTC QLQ-C30 and the Medical Outcomes Study questionnaire. A change of 10 points was used for minimal clinically important differences. Percentages of patients classified with having improved, stable, or deteriorated SRCF were compared between groups using chi-square tests. Changes in mean scores were analyzed using linear mixed models. Results: There was no significant difference in the percentage of patients with deteriorated, stable, or improved SRCF between the treatment arms. Depending on the evaluated time point, 31% to 46% and 29% to 43% of patients in the HA-PCI and PCI arm, respectively, reported a deteriorated SRCF on the basis of the EORTC QLQ-C30 and Medical Outcomes Study. QoL outcomes were not significantly different between the study arms, except for physical functioning at 12 months (p = 0.019) and motor dysfunction at 24 months (p = 0.020). Conclusions: Our trial did not find beneficial effects of HA-PCI over PCI on SRCF and QoL. The cognitive benefit of sparing the hippocampus in the context of PCI is still a subject of debate.

Prophylactic cranial irradiation for extensive stage small cell lung cancer: a meta-analysis of randomized controlled trials.

Background: Previous studies have demonstrated that prophylactic cranial irradiation (PCI) could reduce the risk of brain metastases and prolong the overall survival (OS) of patients with small cell lung cancer (SCLC). However, it remains controversial whether the efficacy and safety of PCI would be subjected to the different characteristics of patients with extensive stage of SCLC. This meta-analysis aims to evaluate the efficacy and safety of PCI in patients with extensive stage SCLC. Methods: PubMed, Embase, and the Cochrane Library were searched for relevant studies from inception to May, 2021. Hazard ratios (HRs) were used to measure the OS and progression-free survival (PFS), and relative risks (RRs) were employed to calculate the incidence of brain metastases, survival rate, and adverse events. Summary results were pooled using random-effect models. Results: There were 1215 articles identified, and 15 trials were included, with a total of 1,623 participants. Patients who received PCI did not result in significantly improved OS [HR=0.87, 95%CI (0.70, 1.08) p=0.417] and PFS [HR=0.81, 95%CI (0.69, 0.95) p=0.001], compared with those who did not receive PCI, while patients who received PCI had a significantly decreased incidence of brain metastases [RR=0.57, 95%CI (0.45, 0.74), p<0.001]. PCI group showed no improvements in 2-year (RR=1.03, p=0.154), 3-year (RR=0.97, p=0.072), 4-year (RR=0.71, p=0.101) and 5-year survival rates (RR=0.32, p=0.307), compared with non-PCI group, whereas the overall RR indicated that PCI was associated with a higher 1-year survival rate [RR=1.46, 95%CI (1.08, 1.97), p=0.013]. In addition, PCI treatment was shown to be associated with increased incidence of adverse events, including fatigue, dermatitis, anorexia, nausea, vomiting, malaise, and cognitive impairment. Conclusion: This meta-analysis suggests that PCI can reduce the incidence of brain metastases in extensive stage SCLC. Although PCI has no significant effect on the OS, it improves 1-year survival in patients with extensive stage SCLC. However, PCI does not significantly affect 2,3,4,5-year survival and may result in a significantly increased risk of adverse events.

Lung Large Cell Neuroendocrine Carcinoma: A Population-Based Retrospective Cohort Study.

BACKGROUNDS: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rarely high-grade neuroendocrine carcinoma of the lung with features of both small cell and non-small cell lung cancer. In this study, we aim to construct a prognostic nomogram that integrates the clinical features and treatment options to predict disease-specific survival (DSS). METHODS: A total of 713 patients diagnosed with LCNEC were from the US National Cancer Institute's Surveillance Epidemiology and End Results (SEER) registry between 2010-2016. Cox proportional hazards analysis was conducted to choose the significant predictors of DSS. External validation was performed using 77 patients with LCNEC in the West China Hospital Sichuan University between 2010-2018. The predictive accuracy and discriminative capability were estimated by the concordance index (C-index), calibration curve, and receiver operating characteristic (ROC) curve. The clinical applicability of the nomogram was verified through the decision curve analysis (DCA). Additionally, we conducted a subgroup analysis of data available in the external cohort that may impact prognosis but was not recorded in the SEER database. RESULTS: Six independent risk factors for DSS were identified and integrated into the nomogram. The nomogram achieved good C- indexes of 0.803 and 0.767 in the training and validation group, respectively. Moreover, the calibration curves for the probability of survival showed good agreement between prediction by nomogram and actual observation in 1-, 3- and 5-year DSS. The ROC curves demonstrated the prediction accuracy of the established nomogram (all Area Under Curve (AUC) > 0.8). DCA exhibited the favorable clinical applicability of the nomogram in the prediction of LCNEC survival. A risk classification system was built which could perfectly classify LCNEC patients into high-, medium- and low-risk groups (p < 0.001). The survival analysis conducted on the West China Hospital cohort indicated that whole brain radiation therapy (WBRT), prophylactic cranial irradiation (PCI), surgical procedures, tumor grade, Ki-67, and PD-L1 expression were not significantly associated with DSS. CONCLUSION: This study has effectively developed a prognostic nomogram and a corresponding risk stratification system, which demonstrate promising potential for predicting the DSS of patients with LCNEC.

Prophylactic cranial irradiation-related lymphopenia affects survival in patients with limited-stage small cell lung cancer.

Background: The study aimed to identify the relations of the absolute lymphocyte count (ALC) nadir during prophylactic cranial irradiation (PCI) and patient outcomes in limited-stage small cell lung cancer (LS-SCLC). Methods: We analyzed 268 L S-SCLC patients who underwent PCI from 2012 to 2019. ALC values were collected prior, during, and 3 months post PCI. Kaplan-Meier and Cox regression analyses were performed to assess the relation of ALC to patient prognosis. Two nomograms were developed on the basis of clinical variables for survival prediction. Results: Compared with the ALC before PCI (1.13 × 109 cells/L), the ALC nadir during PCI was significantly reduced by 0.68 × 109 cells/L (P < 0.001) and raised to 1.02 × 109 cells/L 3 months post PCI. Patients with a low ALC nadir during PCI (<0.68 × 109 cells/L) had inferior progression free survival (PFS) (median PFS: 17.2 m vs. 43.7 m, P = 0.019) and overall survival (OS) (median OS: 29.0 m vs 39.1 m, P = 0.012). Multivariate Cox analysis revealed that age, smoking history, clinical stage, and ALC nadir were independent OS (P = 0.006, P = 0.005, P < 0.001 and P = 0.027, respectively), as well as independent PFS predictors (P = 0.032, P = 0.012, P = 0.012 and P = 0.018, respectively). After internal cross-validation, the corrected concordance indices of the predictive nomograms for PFS and OS were 0.637 and 0.663, respectively. Conclusion: LS-SCLC patients with a low ALC nadir during PCI likely have worse survival outcomes. Dynamic evaluation of the ALC during PCI is recommended for LS-SCLC patients.

Survival benefit of prophylactic cranial irradiation in limited-stage small-cell lung cancer in modern magnetic resonance imaging staging: a systematic review and meta-analysis.

BACKGROUND: The use of prophylactic cranial irradiation (PCI) in patients suffering from limited-stage small-cell lung cancer (LS-SCLC) remains controversial in modern brain magnetic resonance imaging (MRI) staging. To this end, a systematic review with meta-analysis was hereby performed to investigate the overall survival (OS) in these patients. METHODS: Relevant studies from the PubMed and EMBASE databases were reviewed, and pooled hazard risks were obtained using fixed-effects models. The PRISMA 2020 checklist was used. RESULTS: Fifteen retrospective studies were identified, with a total of 2,797 patients with LS-SCLC included in the analysis, 1,391 of which had received PCI. For all included patients, PCI was associated with improved OS [hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.58-0.70]. The combination of subgroup analysis and sensitivity analysis suggested that the effect of PCI on OS was independent of primary tumor treatment, proportion of complete response (CR), median age, PCI dose, publication years, etc. Additionally, the OS curve of 1,588 patients having undergone thoracic radiotherapy (TRT) as the primary tumor treatment from 8 studies were reconstructed, and the pooled 2-, 3- and 5-year OS rates of limited stage patients were 59% vs. 42%, 42% vs. 29% and 26% vs. 19% (HR: 0.69, 95% CI: 0.61-0.77) in the PCI group and the no PCI group, respectively. Another reconstructed OS curve of 339 patients having undergone radical surgery as the primary tumor treatment from 2 studies presented better results, and the pooled 2-, 3- and 5-year OS rates of in the PCI group and the no PCI group were 85% vs. 71%, 70% vs. 56% and 52% vs. 39% (HR: 0.59, 95% CI: 0.40-0.87), respectively. CONCLUSIONS: This meta-analysis demonstrates a significant beneficial effect of PCI on the OS in patients with LS-SCLC in modern pretreatment MRI staging. However, considering the absence of a strict follow-up of brain MRI recommended by the guideline for the control group from most of the included studies, the superiority of PCI to the treatment strategy of no PCI plus brain MRI surveillance remains unclear.

A study of the prognosis of patients with limited-stage small cell lung cancer who did or did not receive prophylactic cranial irradiation after effective chemoradiotherapy.

Objective: To investigate the prognosis of patients with LS-SCLC who responded to chest chemoradiotherapy but did not receive PCI. Methods: A retrospective analysis was conducted on LS-SCLC patients who had achieved complete remission (CR) or partial remission (PR) after definitive chemoradiotherapy but did not receive PCI. The survival rates were calculated using Kaplan-Meier method. The prognosis was analyzed using Cox proportional hazard regression model. The main endpoint was OS. Results: Of the 500 patients with LS-SCLC admitted between June 2002 and January 2018, 327 achieved CR or PR after definitive chest chemoradiotherapy, 103 did not receive PCI, and 63 of them developed brain metastases (BM). The 1-year and 3-year OS rates in PCI group were 87.5% and 42.3% respectively, versus 70.4% and 20.9% for non-PCI group(P=0.002). The median survival time after BM was 8.7 months (range: 0.3-48.7), and 3-year OS rate was 15.0%, the median survival time of patients without BM was 20.1 months (range: 2.9-79.4), and 3-year OS was 33.4% (P=0.014). Patients with BM were subsequently treated with palliative therapy. Multivariate analysis showed that compared with no treatment, brain radiotherapy alone (HR: 0.131, 95%CI: 0.035-0.491, P=0.003) and radiotherapy combined with chemotherapy (HR: 0.039, 95%CI: 0.008-0.194, P<0.001) significantly reduced the risk of death. Multiple BM (HR: 2.391, 95%CI: 1.082-5.285, P=0.031) was an independent adverse prognostic factor for OS. Conclusion: LS-SCLC patients who achieved good response after chest chemoradiotherapy without receiving PCI were prone to develop BM and have a poor prognosis. Multiple BM was an independent adverse prognostic factor. PCI remains the standard of care for LS-SCLC patients.

Development and validation of a nomogram for the prediction of brain metastases in small cell lung cancer.

INTRODUCTION: The aim was to develop and validate a nomogram for the prediction of brain metastases (BM) in small cell lung cancer (SCLC), to explore the risk factors and assist clinical decision-making. METHODS: We reviewed the clinical data of SCLC patients between 2015 and 2021. Patients between 2015 and 2019 were included to develop, whereas patients between 2020 and 2021 were used for external validation. Clinical indices were analysed by using the least absolute shrinkage and selection operator (LASSO) logistic regression analyses. The final nomogram was constructed and validated by bootstrap resampling. RESULTS: A total of 631 SCLC patients between 2015 and 2019 were included to construct model. Gender, T stage, N stage, Eastern Cooperative Oncology Group (ECOG), haemoglobin (HGB), the absolute value of lymphocyte (LYMPH #), platelet (PLT), retinol-binding protein (RBP), carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) were identified as risk factors and included into the model. The C-indices were 0.830 and 0.788 in the internal validation by 1000 bootstrap resamples. The calibration plot revealed excellent agreement between the predicted and the actual probability. Decision curve analysis (DCA) showed better net benefits with a wider range of threshold probability (net clinical benefit was 1%-58%). The model was further externally validated in patients between 2020 and 2021 with a C-index of 0.818. CONCLUSIONS: We developed and validated a nomogram to predict the risk of BM in SCLC patients, which could help clinicians to rationally schedule follow-ups and promptly implement interventions.

Efficacy of Prophylactic Cranial Irradiation According to the Risk of Extracranial Recurrence in Limited-Stage Small Cell Lung Cancer.

PURPOSE: We aimed to evaluate the effectiveness of prophylactic cranial irradiation (PCI) for "early brain metastasis", which occurs before extracranial recurrence (ECR), and "late brain metastasis", which occurs after ECR, in limited-stage small cell lung cancer (LS-SCLC). Materials and Methods: We retrospectively analyzed 271 LS-SCLC patients who underwent definitive chemoradiation. All patients were initially staged with brain magnetic resonance imaging and positron emission tomography. Intracranial recurrence (ICR), ECR, progression-free rate (PFR), and overall survival (OS) were analyzed as clinical endpoints. The competing risk of the first recurrence with ICR (ICRfirst) was evaluated. Significantly associated variables in multivariate analysis of ECR were considered as ECR risk factors. Patients were stratified according to the number of ECR risk factors. RESULTS: The application of PCI was associated with higher PFR (p=0.008) and OS (p=0.045). However, PCI was not associated with any of the clinical endpoints in multivariate analysis. The competing risk of ICRfirst was significantly decreased with the application of PCI (hazard ratio, 0.476; 95% confidence interval, 0.243 to 0.931; p=0.030). Stage III disease, sequential, and stable disease after thoracic radiation were selected as ECR risk factors. For patients without these risk factors, the application of PCI was significantly associated with increased OS (p=0.048) and a decreased risk of ICRfirst (p=0.026). CONCLUSION: PCI may play a role in preventing early brain metastasis rather than late brain metastasis after ECR, suggesting that only patients with a low risk of ECR may currently benefit from PCI.

Volumetric modulated arc therapy for hippocampal-sparing prophylactic cranial irradiation: Planning comparison of Halcyon and C-arm accelerators.

Background: The purpose of the study was to evaluate the dosimetry of the Halcyon in prophylactic cranial irradiation (PCI) with volumetric modulated arc therapy (VMAT) and hippocampal-sparing for small cell lung cancer (SCLC). Methods: Five VMAT plans were designed on CT images of 15 patients diagnosed with SCLC and received PCI. Three plans with two full arcs were generated on the Trilogy and the TrueBeam accelerators, and flattening filter (FF) and flattening filter free (FFF) modes were used on TrueBeam. Two Halcyon plans with two and three full arcs were generated, referred to as H-2A and H-3A, respectively. The prescription dose was 25 Gy in 2.5-Gy fractions. The dose limit for hippocampus were D100 ≤ 9Gy and Dmax ≤ 16Gy. The Wilcoxon matched-paired signed-rank test was used to evaluate the significance of the observed differences between the five plans. Results: H-2A plans significantly increased the D2 of PTV, and H-3A plans showed comparable or even better target dosimetry (better conformity) compared to the three plans on C-arm accelerators. Compared to T and TB plans, the two Halcyon plans significantly reduced the D100 and mean doses of bilateral hippocampus, the mean doses of eyeballs, and the maximum doses of lenses. D100 of hippocampus was reduced in TrueBeam plans comparing to Trilogy plans. The FFF plans on TrueBeam also represented advantages in Dmean and D100 of hippocampas, Dmean and Dmax of eyeballs, and the Dmax of lenses compared to FF plans. Halcyon plans and TrueBeam plans with FFF mode increased the MUs compared to FF plans. Comparing to H-2A, the H-3A plans exhibited additional dosimetric advantages, including D2, CI and HI of PTV, as well as the maximum and mean doses of hippocampus and eyeballs, and the maximum doses of optic nerves and brainstem. The two Halcyon plans significantly reduced the delivery time and showed the higher gamma passing rate than the three plans of C-arm accelerators. Conclusions: Compared with the C-arm accelerators, the dose of hippocampus and the delivery times on Halcyon are relatively significantly reduced for hippocampal-sparing PCI. Three arcs are recommended for VMAT plans with the Halcyon in hippocampal-sparing PCI.

Use of radiation therapy among patients with Extensive-stage Small-cell lung cancer receiving Immunotherapy: Canadian consensus recommendations.

OBJECTIVES: Thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) are commonly used in the management of extensive-stage small-cell lung cancer (ES-SCLC); however, Phase III trials of first-line immunotherapy often excluded these options. Guidance is needed regarding appropriate use of TRT, PCI, and magnetic resonance imaging (MRI) surveillance while new data are awaited. MATERIALS AND METHODS: In two web-based meetings, a pan-Canadian expert working group of five radiation oncologists and four medical oncologists addressed eight clinical questions regarding use of radiation therapy (RT) and MRI surveillance among patients with ES-SCLC receiving immunotherapy. A targeted literature review was conducted using PubMed and conference proceedings to identify recent (January 2019-April 2022) publications in this setting. Fifteen recommendations were developed; online voting was conducted to gauge agreement with each recommendation. RESULTS: After considering recently available evidence across lung cancer populations and clinical experience, the experts recommended that all patients with a response to chemo-immunotherapy, good performance status (PS), and limited metastases be considered for consolidation TRT (e.g., 30 Gy in 10 fractions). When considered appropriate after multidisciplinary team discussion, TRT can be initiated during maintenance immunotherapy. All patients who respond to concurrent chemo-immunotherapy should undergo restaging with brain MRI to guide decision-making regarding PCI versus MRI surveillance alone. MRI surveillance should be conducted for two years after response to initial therapy. PCI (e.g., 25 Gy in 10 fractions or 20 Gy in 5 fractions) can be considered for patients without central nervous system involvement who have a response to chemo-immunotherapy and good PS. Concurrent treatment with PCI and immunotherapy or with TRT, PCI, and immunotherapy is appropriate after completion of initial therapy. All recommendations were agreed upon unanimously. CONCLUSIONS: These consensus recommendations provide practical guidance regarding appropriate use of RT and immunotherapy in ES-SCLC while awaiting new clinical trial data.

Machine learning-based automated planning for hippocampal avoidance prophylactic cranial irradiation

Purpose Design and evaluate a knowledge-based model using commercially available artificial intelligence tools for automated treatment planning to efficiently generate clinically acceptable hippocampal avoidance prophylactic cranial irradiation (HA-PCI) plans in patients with small-cell lung cancer. Materials and methods Data from 44 patients with different grades of head flexion (range 45°) were used as the training datasets. A Rapid Plan knowledge-based planning (KB) routine was applied for a prescription of 25 Gy in 10 fractions using two volumetric modulated arc therapy (VMAT) arcs. The 9 plans used to validate the initial model were added to generate a second version of the RP model (Hippo-MARv2). Automated plans (AP) were compared with manual plans (MP) according to the dose-volume objectives of the PREMER trial. Optimization time and model quality were assessed using 10 patients who were not included in the first 44 datasets. Results A 55% reduction in average optimization time was observed for AP compared to MP. (15 vs 33 min; p = 0.001).Statistically significant differences in favor of AP were found for D98% (22.6 vs 20.9 Gy), Homogeneity Index (17.6 vs 23.0) and Hippocampus D mean (11.0 vs 11.7 Gy). The AP met the proposed objectives without significant deviations, while in the case of the MP, significant deviations from the proposed target values were found in 2 cases. Conclusion The KB model allows automated planning for HA-PCI. Automation of radiotherapy planning improves efficiency, safety, and quality and could facilitate access to new techniques (AU)

A "Seed-and-Soil" Radiomics Model Predicts Brain Metastasis Development in Lung Cancer: Implications for Risk-Stratified Prophylactic Cranial Irradiation.

Introduction: Brain is a major site of metastasis for lung cancer, and effective therapy for developed brain metastasis (BM) is limited. Prophylactic cranial irradiation (PCI) has been shown to reduce BM rate and improve survival in small cell lung cancer, but this result was not replicated in unselected non-small cell lung cancer (NSCLC) and had the risk of inducing neurocognitive dysfunctions. We aimed to develop a radiomics BM prediction model for BM risk stratification in NSCLC patients. Methods: 256 NSCLC patients with no BM at baseline brain magnetic resonance imaging (MRI) were selected; 128 patients developed BM within three years after diagnosis and 128 remained BM-free. For radiomics analysis, both the BM and non-BM groups were randomly distributed into training and testing datasets at an 70%:30% ratio. Both brain MRI (representing the soil) and chest computed tomography (CT, representing the seed) radiomic features were extracted to develop the BM prediction models. We first developed the radiomic models using the training dataset (89 non-BM and 90 BM cases) and subsequently validated the models in the testing dataset (39 non-BM and 38 BM cases). A radiomics BM score (RadBM score) was generated, and BM-free survival were compared between RadBM score-high and RadBM score-low groups. Results: The radiomics model developed from baseline brain MRI features alone can predict BM development in NSCLC patients. A fusion model integrating brain MRI features with primary tumor CT features (seed-and-soil model) provided synergetic effect and was more efficient in predicting BM (areas under the receiver operating characteristic curve 0.84 (95% confidence interval: 0.80−0.89) and 0.80 (95% confidence interval: 0.71−0.88) in the training and testing datasets, respectively). BM-free survival was significantly shorter in the RadBM score-high group versus the RadBM score-low group (Log-rank, p < 0.001). Hazard ratios for BM were 1.056 (95% confidence interval: 1.044−1.068) per 0.01 increment in RadBM score. Cumulative BM rates at three years were 75.8% and 24.2% for the RadBM score-high and RadBM score-low groups, respectively. Only 1.2% (7/565) of the BM lesions were located within the hippocampal avoidance region. Conclusion: The results demonstrated that intrinsic features of a non-metastatic brain exert a significant impact on BM development, which is first-in-class in metastasis prediction studies. A radiomics BM prediction model utilizing both primary tumor and pre-metastatic brain features might provide a useful tool for individualized PCI administration in NSCLC patients more prone to develop BM.