Small cell lung cancer (SCLC) is the most malignant pathological type of lung cancer with the highest mortality, and the incidence of brain metastasis (BM) is in high frequency. So far, prophylactic cranial irradiation (PCI) has been suggested as an effective treatment for preventing brain metastasis of SCLC. PCI has long been applied to limited-stage SCLC (LS-SCLC) patients who have achieved complete remission after radiotherapy and chemotherapy as a standard treatment. However, the neurocognitive decline is a major concern surrounding PCI. New therapeutic approaches targeting PCI-induced neurotoxicity, including hippocampal protection or memantine, have been increasingly incorporated into the therapeutic interventions of PCI. Helical tomotherapy, RapidArc, and Volumetric-modulated arc therapy (VMAT) with a head-tilting baseplate are recommended for hippocampal protection. Besides, in the MRI and immunotherapy era, the significance of PCI in SCLC patients is controversial. SCLC patients with PCI should be recruited in clinical trials since this is the only way to improve the existing standard of care. This review summarizes the current therapeutic strategy and dilemma over PCI for SCLC, providing a theoretical basis for clinical decision-making and suggestions for PCI practice in clinical.

OBJECTIVE: In the context of the widespread availability of magnetic resonance imaging (MRI) and aggressive salvage irradiation techniques, there has been controversy surrounding the use of prophylactic cranial irradiation (PCI) for small-cell lung cancer (SCLC) patients. This study aimed to explore whether regular brain MRI plus salvage brain irradiation (SBI) is not inferior to PCI in patients with limited-stage SCLC (LS-SCLC).
METHODS: This real-world multicenter study, which was conducted between January 2014 and September 2020 at three general hospitals, involved patients with LS-SCLC who had a good response to initial chemoradiotherapy and no brain metastasis confirmed by MRI. Overall survival (OS) was compared between patients who did not receive PCI for various reasons but chose regular MRI surveillance and followed salvage brain irradiation (SBI) when brain metastasis was detected and patients who received PCI.
RESULTS: 120 patients met the inclusion criteria. 55 patients received regular brain MRI plus SBI (SBI group) and 65 patients received PCI (PCI group). There was no statistically significant difference in median OS between the two groups (27.14 versus 33.00 months; P = 0.18). In the SBI group, 32 patients underwent whole brain radiotherapy and 23 patients underwent whole brain radiotherapy + simultaneous integrated boost. On multivariate analysis, only extracranial metastasis was independently associated with poor OS in the SBI group.
CONCLUSIONS: The results of this real-world study showed that MRI surveillance plus SBI is not inferior to PCI in OS for LS-SCLC patients who had a good response to initial chemoradiotherapy.

This review discusses the topic of prevention of brain metastases from the most frequent solid tumor types, i.e., lung cancer, breast cancer and melanoma. Within each tumor type, the risk of brain metastasis is related to disease status and molecular subtype (i.e., EGFR-mutant non-small cell lung cancer, HER2-positive and triple-negative breast cancer, BRAF and NRAF-mutant melanoma). Prophylactic cranial irradiation is the standard of care in patients in small cell lung cancer responsive to chemotherapy but at the price of late neurocognitive decline. More recently, several molecular agents with the capability to target molecular alterations driving tumor growth have proven as effective in the prevention of secondary relapse into the brain in clinical trials. This is the case for EGFR-mutant or ALK-rearranged non-small cell lung cancer inhibitors, tucatinib and trastuzumab-deruxtecan for HER2-positive breast cancer and BRAF inhibitors for melanoma. The need for screening with an MRI in asymptomatic patients at risk of brain metastases is emphasized.

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.
CONCLUSIONS: 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.

BACKGROUND: 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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: No funding.

Prophylactic cranial irradiation (PCI) is considered an important technological advance made in oncology in an effort to reduce the incidence of brain metastases (BM) and improve overall survival (OS) of patients with small cell lung cancer (SCLC). Although it is often reported that PCI improves the therapeutic potential in limited-stage (LS) SCLC, no randomised trial has ever conclusively confirmed this. Nevertheless, PCI has been considered the standard of care for LS-SCLC since the late 1990s. The data supporting the use of PCI in LS-SCLC are based on an analysis of work performed prior to the current approach to staging [brain magnetic resonance imaging (MRI), positron emission tomography (PET)/computed tomography (CT)]. The evidence for the rationale and feasibility of this approach in the modern diagnostic era should be demonstrated. The situation with extensive stage (ES) SCLC is seemingly easier because, unlike LS-SCLC, we have data from two randomised trials. Unfortunately, their results are in direct conflict with each other. Although it is generally assumed that good control of brain disease leads to better quality of life, this has never been prospectively demonstrated. In fact, PCI is associated not only with increased treatment costs and some patient discomfort, but also with non-negligible potential toxicity. For this reason, efforts have been made to preserve cognitive function by sparing the hippocampus. This concept is called hippocampal avoidance. The optimal fractionation regimen is currently less controversial than the optimal integration of PCI into the treatment algorithm. A dose of 25 Gy administered in 10 fractions should remain the standard for the eventual use of PCI in patients with SCLC. In summary, PCI is not a conditio sine qua non in any indication. Neither in patients with LS-SCLC nor in patients with ES-SCLC has a clear improvement in OS been demonstrated at follow-up using current imaging modalities.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022360890, identifier CRD42022360890.

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.

BACKGROUND: 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.
CONCLUSIONS: 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.