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.

In patients requiring prophylactic cranial irradiation (PCI) or whole-brain radiotherapy (WBRT) for brain metastases (BMs), hippocampal avoidance (HA) has been shown to preserve neurocognitive function and quality of life. Here, we aim to estimate the incidence of hippocampal and perihippocampal BMs and the subsequent risk of local undertreatment in patients undergoing hippocampal sparing radiotherapy.
MEDLINE, Embase, and Scopus were searched with the terms \"Hippocampus\", \"Brain Neoplasms\", and related terms. Trials reporting on the incidence of hippocampal and/or perihippocampal BMs or hippocampal failure rate after PCI or WBRT were included.
Forty records were included, encompassing a total of 5,374 patients with over 32,570 BMs. Most trials employed a 5 mm margin to define the HA zone. In trials reporting on BM incidence, 4.4 % (range 0 - 27 %) and 9.2 % (3 - 41 %) of patients had hippocampal and perihippocampal BMs, respectively. The most common risk factor for hippocampal BMs was the total number of BMs. The reported failure rate within the HA zone after HA-PCI or HA-WBRT was 4.5 % (0 - 13 %), salvageable with radiosurgery in most cases. SCLC histology was not associated with a higher risk of hippocampal failure (OR = 2.49; p = 0.23). In trials comparing with a conventional (non-HA) PCI or WBRT group, HA did not increase the hippocampal failure rate (OR = 1.90; p = 0.17).
The overall incidence of hippocampal and perihippocampal BMs is considerably low, with a subsequent low risk of local undertreatment following HA-PCI or HA-WBRT. In patients without involvement, the hippocampus should be spared to preserve neurocognitive function and quality of life.

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.

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.

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.
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.
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.
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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

BACKGROUND: Prophylactic cranial irradiation (PCI) reduces brain metastasis incidence in lung cancer, however with risk of neurocognitive decline. Nevertheless, risk factors for neurocognitive decline after PCI remain unclear.
METHODS: We systematically reviewed the PubMed database according to the PRISMA guideline. Inclusion criteria were: randomized clinical trials (RCTs) and observational/single arm trials evaluating PCI, including ≥20 patients, reporting neurocognitive test results for lung cancer. Primary aim: evaluate risk factors associated with neurocognitive decline after PCI.
RESULTS: Twenty records were eligible (8 different RCTs, 8 observational studies), including 3553 patients in total (858 NSCLC, 2695 SCLC) of which 73.6% received PCI. Incidence of mild/moderate cognitive decline after PCI varied from 8 to 89% (grading not always provided); for those without PCI, this was 3.4-42%. Interestingly, 23-95% had baseline cognitive impairment. Risk factors were often not reported. In one trial, both age (>60 years) and higher PCI dose (36 Gy) including twice-daily PCI were associated with a higher risk of cognitive decline. In one trial, white matter abnormalities were more frequent in the concurrent or sandwiched PCI arm, but without significant neuropsychological differences. One trial identified hippocampal sparing PCI to limit the neurocognitive toxicities of PCI and another reported an association between hippocampal dose volume effects and memory decline. As neurocognition was a secondary endpoint in most RCTs, and was assessed by various instruments with often poor/moderate compliance, high-quality data is lacking.
CONCLUSIONS: Age, PCI dose, regimen and timing might be associated with cognitive impairment after PCI in lung cancer patients, but high-quality data is lacking. Future PCI trials should collect and evaluate possible risk factors systematically.

Background: The purpose of this study was to reevaluate the efficacy of prophylactic cranial irradiation (PCI) in non-small cell lung cancer (NSCLC) with the most recent published data and to identify subgroups who may be more likely to gain benefit from PCI. Methods: We searched PubMed, Embase, and Cochrane databases for randomized trials comparing PCI with non-PCI in NSCLC patients. We pooled the data of randomized controlled trials and compared brain metastasis (BM) and overall survival (OS) between PCI group and non-PCI group. Results: Seven studies including 1,462 patients were eligible for the current meta-analysis. Compared to non-PCI group, PCI group achieved decreased BM (RR = 0.37, 95% CI: 0.26-0.52) but similar OS (HR = 1.01, 95% CI: 0.87-1.22). In subgroup analyses of BM, PCI decreased BM for subgroups by pathology (squamous cell carcinoma or non-squamous cell carcinoma) and local treatment modality (surgery or no surgery). However, PCI failed to reduce BM for patients with poor performance status (WHO 2-3). The incidence of PCI related toxicities was low and PCI was well-tolerated by the majority of NSCLC. Low grade neurocognitive function (NCF) decline was reported in NAVLT study and greater deterioration in immediate and delayed recall was reported in RTOG 0214. No significant difference in quality of life (QOL) after PCI was reported. Conclusion: PCI reduces the incidence of BM except for patients with poor performance status. However, PCI fails to prolong OS significantly for NSCLC. An individual patient data meta-analysis may identify patients that could achieve OS prolongation with PCI.

Prophylactic cranial irradiation (PCI) improves survival and prevents intracranial recurrence (IR) in limited stage (LS) and extensive stage (ES) small cell lung cancer (SCLC). However, despite PCI, IR affects 12%-45%, and limited data exist regarding salvage brain reirradiation (ReRT). We performed a population-based review of IR in SCLC.
Demographic, treatment, and outcome data of consecutive patients (N = 371) with SCLC assessed at a tertiary cancer centre (01/2013-12/2015) were abstracted, and summary statistics calculated. Kaplan-Meier estimates and univariate and multivariate analysis (MVA) via the Cox proportional hazard model were performed.
Median age was 66.1 years, and 59.8% were Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Median survival was 24 months (95% CI 18.3-29.7 months) for LS (N = 103) and 7 months (95% CI 6.1-7.9 months) for ES (N = 268). 72 of 103 patients with LS and 97 of 214 of those with ES received PCI. 54 of 268 ES presented with brain metastases (BM) of whom 46 of 54 received whole brain RT (WBRT). 18.9% (32/169) recurred post-PCI (13 LS; 19 ES) and 30.4% (14/46) recurred after WBRT. Of those who recurred/progressed after cranial RT, 56.5% (26/46) had <5 BM, 39.1% had no extracranial disease, and 50% were ECOG 0-2. In retrospect, 17 of 46 would have been candidates for salvage stereotactic radiosurgery: 13 post-PCI and 4 post-WBRT.
This cohort challenges commonly held beliefs that IR is always diffuse, associated with clinical deterioration, and synchronous with systemic failure. Approximately 1 in 3 SCLC patients with IR after PCI or WBRT appear clinically appropriate for salvage stereotactic radiosurgery.

BACKGROUND: The efficacy of prophylactic cranial irradiation (PCI) in treating patients with small cell lung cancer (SCLC) has not been clear, and recent randomized studies have demonstrated conflicting results from previously published findings. The purpose of this study was to reevaluate the efficacy of PCI in patients with SCLC and to assess factors associated with its efficacy.
METHODS: We conducted a quantitative meta-analysis to explore the efficacy of PCI in patients with SCLC. A literature search was performed using EMBASE, MEDLINE, Cochrane and ClinicalTrials.gov databases. We pooled the data and compared overall survival (OS) and brain metastasis (BM) between patients treated with PCI (PCI group) and patients without PCI treatment (observation group).
RESULTS: Of the 1074 studies identified in our analysis, we selected seven studies including 2114 patients for the current meta-analysis. Our results showed that the PCI group showed decreased BM (HR = 0.45, 95% CI: 0.38-0.55, P < 0.001) and prolonged OS (HR = 0.81, 95% CI: 0.67-0.99, P < 0.001). However, in terms of OS, the pooled analysis showed a high heterogeneity (I2 = 74.1%, P = 0.001). In subgroup analyses of OS, we found that the heterogeneity mainly came from patients with brain imaging after initial chemoradiotherapy (HR = 0.94, 95% CI: 0.74-1.18, P = 0.59).
CONCLUSIONS: The results of this study showed that PCI has a significant effect on decreasing BM but little benefit in prolonging OS when brain imaging was introduced to confirm lack of BM after initial chemoradiotherapy and before irradiation.