Smallcell lung cancer (SCLC) represents roughly 15% of all lung cancers.1The tumor, node, metastasis (TNM) (American Joint Committee on Cancer, 8th edition) convention is used for official staging,2but for treatment purposes, the older Veterans Administration Lung Study Group (VALSG) staging model differentiates between limited-stage SCLC (LS-SCLC) and extensive-stage SCLC (ES-SCLC).3Compared with ES-SCLC, with a median survival of 9–12 months,4,5LS-SCLC 50%与-85%完成响应se rates to chemotherapy combined with thoracic radiotherapy and a median duration of survival of 12–20 months and 2-year progression-free survival (PFS) rates of 15%–40%.6,7
CNS metastases are a common complication of SCLC, occurring either at diagnosis or throughout the disease’s course.8While only 10% of patients have brain metastasis (BM) at diagnosis, the cumulative incidence at 2 years is more than 50%,9aligning with autopsy series rates.10Contrarily, more than 60% of patients are diagnosed with ES-SCLC at the time of diagnosis, with an 18% incidence of BM at initial staging,11which reaches approximately 58% within 2 years12and 65% at death,13according to autopsy series. Hence, cranial irradiation was proposed in the early 1970s as a potential prevention method for clinically evident BM.14
The predisposition to intracranial dissemination has prompted numerous investigations of prophylactic cranial irradiation (PCI) to treat subclinical disease.15,16A randomized trial from the European Organisation for Research and Treatment of Cancer showed that PCI could lower the risk of BMs and improve the overall survival (OS) of ES-SCLC patients with a response to initial chemotherapy.17However, preliminary data from a phase 3 randomized trial from Japan indicated that PCI had a detrimental effect on OS in ES-SCLC patients.18这些发现支持mpted the National Comprehensive Cancer Network to revise their clinical practice guideline concerning PCI recommendations for ES-SCLC patients with initial chemotherapy response, degrading the evidence level from 1 to 2A in 2016, and awaiting more prospective data to strengthen or deny such a recommendation.19In this study, we conducted a meta-analysis to elucidate the inconsistencies in the current findings on PCI’s effect in patients with SCLC.
开云体育世界杯赔率
Search Strategy
斯高帕斯数据库搜索PubMed包含,我们b of Science, and Cochrane Central Register of Controlled Trials. The literature search was conducted initially from the date of database inception until January 20, 2023. The search strategy used for PubMed is shown inSupplementary Table 1. The search was limited to clinical studies. Eligible published trials were also identified from reference lists from observational studies, randomized clinical trials, and systematic reviews.
Selection Criteria
Articles that met the following criteria were included: 1) participants: patients with cytologically or histologically confirmed SCLC; 2) intervention: PCI group; 3) comparison: non-PCI group; 4) reported outcome: OS, PFS, and BM-free survival (BMFS); and 5) language: English only. Reviews without original data, meta-analyses, animal studies, and studies with abstracts only or duplicated data were excluded.
Data Extraction and Quality Assessment
两个独立的研究人员回顾了冠军,abstracts, and full-text papers and collected data from the included full-text papers in a predesigned Excel sheet (Microsoft Corp.). The information extracted from studies included general information about the included studies, study design, and treatment outcome (in the form of OS, PFS, and BMFS). If the data of the same patient cohort were published in multiple reports, the most recently published data were collected. Discrepancies were resolved by a third researcher.
In order to minimize the lost data and hence publication bias, hazard ratios (HRs) were extracted according to the previously described method by Tierney et al. (mostly from Kaplan-Meier curves) to incorporate summary time-to-event data into the meta-analysis.20Furthermore, we recorded the method used for HR extraction for each study.
For risk of bias assessment in nonrandomized studies, the Risk of Bias in Non-Randomized Studies–of Interventions (ROBINS-I) tool was used.21Individual aspects important to validity were discussed among the researchers. In case of disagreement, the study was reviewed by an unbiased third researcher.
Statistical Analyses
All analyses were conducted in R (version 4.1.2, The R Foundation for Statistical Computing) using the "meta" package.22Regarding data on reported durations, the median and range were converted to mean and SD using the method proposed by Hozo et al.23The "metagen," "metacont," and "metabin" functions with the inverse variance method and DerSimonian-Laird estimator were used to pool the effect of interest (HR, odds ratio [OR], and mean difference [MD]). With consideration of the clinical diversities and methodological differences between studies, the random-effects model was used for calculations. Leave-one-out analysis was performed to assess the impact of each study on the reported effect. Publication bias was assessed using Egger’s regression analysis. Meta-regression was conducted to find factors influencing the observed effect. A p value < 0.05 was considered significant.
Results
Study Selection
The search strategy resulted in 4286 publications. After removing duplicates (n = 1942), we screened the title and abstract of 2344 articles, which resulted in the exclusion of 1854 unrelated records. The full texts of the remaining 490 records were screened for inclusion based on the predefined eligibility criteria, of which 194 were nonoriginal records or abstracts, 13 were non-English articles, 7 records were not found, and 206 were not related to the topic of interest or did not report any outcome. Four articles were added through reference checking. The study selection process is depicted inFig. 1.
Flowchart of review and selection process. Data added to the PRISMA template (from Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ. 2021;372:n71) under the terms of the Creative Commons Attribution (CC BY 4.0) License (https://creativecommons.org/licenses/by/4.0/).
Characteristics of the Studies
The 74 included studies were published between 1983 and 2022. Among the included studies, 11 publications were prospective and randomized, while the majority of the remaining papers were retrospective observational studies. These studies were conducted in 16 different countries, with most studies being from the United States (n = 23), followed by China (n = 18) and Japan (n = 8).
The included studies resulted in the inclusion of 31,551 SCLC patients, of whom 26.7% received PCI. LS-SCLC patients accounted for 78.3% of the total population. The most commonly used main treatment approach among these studies was chemoradiotherapy (n = 52, 70.3%), while surgery was used as the main treatment in 11 studies (14.9%). Regarding the response to chemoradiotherapy, the primary cancer in the majority of patients (84.4%) had a complete to near-complete response. Among studies reporting PCI plans, the most commonly used radiation dose was 25 Gy, ranging from 20 to 40 Gy; this dose was higher in earlier studies. The mean age of the patients in the included studies ranged from 55 to 75 years, and 57.2% of the included patients were male. The mean duration of follow-up ranged from 12 to 207.6 months. Detailed characteristics of the included studies are presented inSupplementary Table 2.
Risk of Bias Assessment
Risk of bias assessment using the ROBINS-I tool revealed an overall moderate to serious risk of bias in the included studies (Supplementary Fig. 1). The most commonly observed sources of bias were in the second and first domains, bias in selection of participants into the study and bias due to confounding, respectively.
Outcomes
Overall Survival
Seventy studies compared the OS of patients receiving PCI and those not receiving PCI. OS was better for patients receiving PCI in both LS-SCLC (HR 0.64, 95% CI 0.59–0.70; p < 0.01) and ES-SCLC (HR 0.69, 95% CI 0.59–0.82; p < 0.01) (Supplementary Fig. 2). The improved survival did not change when subgroup analyses were performed based on stage, PCI dose, imaging modalities, year of publication, data extraction method, main therapeutic approach for primary cancer, and equality of PCI and non-PCI groups in the study (Table 1). Meanwhile, the survival improvement pattern was not observed in all subgroups when stratifying based on stage and imaging modalities (Table 1). To further assess the association of the observed effect with other variables, meta-regression was performed. Only the size of the PCI group was associated with the observed effect (Table 2).
Details of subgroup analyses of OS based on different factors
| Subgroup | No. of Studies* | HR (95% CI) | p Value |
|---|---|---|---|
| Stage | 0.46 | ||
| LS-SCLC | 51 | 0.64 (0.59–0.70) | |
| ES-SCLC | 16 | 0.69 (0.59–0.82) | |
| Imaging | 0.14 | ||
| CT | 13 | 0.76 (0.65–0.89) | |
| MRI | 23 | 0.64 (0.55–0.74) | |
| Stage + imaging | 0.12 | ||
| LS-SCLC + CT | 7 | 0.56 (0.40–0.78) | |
| LS-SCLC + MRI | 15 | 0.58 (0.52–0.65) | |
| ES-SCLC + CT | 1 | 0.64 (0.31–1.32) | |
| ES-SCLC + MRI | 6 | 0.85 (0.63–1.14) | |
| Treatment | 0.91 | ||
| CRT | 52 | 0.67 (0.61–0.73) | |
| CRT + op | 12 | 0.70 (0.59–0.83) | |
| Op | 11 | 0.68 (0.58–0.80) | |
| Dose, Gy | 0.65 | ||
| <26 | 22 | 0.69 (0.61–0.79) | |
| ≥26 | 38 | 0.67 (0.60–0.74) | |
| Baseline characteristic equality | 0.04 | ||
| Equal | 23 | 0.74 (0.66–0.83) | |
| Not equal | 52 | 0.64 (0.58–0.70) | |
| Data | 0.36 | ||
| HR reported | 50 | 0.66 (0.61–0.72) | |
| HR not reported | 25 | 0.71 (0.62–0.82) | |
| Publication year | 0.41 | ||
| Before 2000 | 13 | 0.78 (0.66–0.93) | |
| 2000–2010 | 8 | 0.64 (0.49–0.82) | |
| 2011–2018 | 28 | 0.65 (0.58–0.73) | |
| 2019 & later | 26 | 0.69 (0.64–0.75) |
CRT = chemoradiotherapy.
Some studies reported several subgroups; hence, the number of studies in different subgroups is sometimes more than the total of the included studies.
Details of meta-regression assessing factors affecting the observed heterogeneity in OS analysis
| Factor | p Value | I2 | R2 |
|---|---|---|---|
| No. of pts w/ PCI | 0.0346 | 49.40% | 10.87% |
| No. of pts w/o PCI | 0.0258 | 47.73% | 15.00% |
| Dose | 0.1718 | 51.97% | 7.60% |
| Sex | 0.1250 | 61.31% | 14.07% |
| Age | 0.6825 | 69.58% | 0.00% |
| Publication year | 0.0659 | 64.59% | 10.70% |
| Complete remission rate | 0.4593 | 68.03% | 0.00% |
pts = patients.
While there was no significant publication bias in studies reporting OS for ES-SCLC (p = 0.31), there was a significant publication bias in favor of improved survival in studies reporting LS-SCLC (p < 0.01). This publication bias was not resolved in the analysis of any subgroups.
Data regarding OS were extracted from 13 studies. Patients receiving PCI survived significantly longer than patients in the non-PCI group (MD 6.47, 95% CI 2.49–10.46; p < 0.01; I2= 91.7%) (Supplementary Fig. 3).
Progression-Free Survival
PFS was reported in 22 studies. Similar to OS, PCI significantly improved PFS in both LS-SCLC (HR 0.69, 95% CI 0.58–0.83; p < 0.01) and ES-SCLC (HR 0.66, 95% CI 0.52–0.85; p < 0.01) (Supplementary Fig. 4). Improved PFS was not observed in subgroup analyses based on primary cancer treatment. Furthermore, a subgroup analysis based on publication year showed nonsignificant improvement in studies published before 2000. Similar to OS, stratification based on stage and imaging modality found subgroups without improved survival. Details on subgroup analyses and the results of meta-regression are shown inTables 3and4, respectively.
Details of subgroup analyses of PFS based on different factors
| Subgroup | No. of Studies | HR (95% CI) | p Value |
|---|---|---|---|
| Stage | 0.76 | ||
| LS-SCLC | 12 | 0.69 (0.58–0.83) | |
| ES-SCLC | 7 | 0.66 (0.51–0.85) | |
| Imaging | 0.42 | ||
| CT | 4 | 0.76 (0.58–0.98) | |
| MRI | 10 | 0.66 (0.53 - -0.82) | |
| Stage + imaging | 0.02 | ||
| LS-SCLC + CT | 1 | 0.91 (0.80–1.04) | |
| LS-SCLC + MRI | 5 | 0.59 (0.45–0.78) | |
| ES-SCLC + CT | 0 | NA | |
| ES-SCLC + MRI | 3 | 0.82 (0.56–1.20) | |
| Treatment | 0.70 | ||
| CRT | 18 | 0.72 (0.63–0.83) | |
| CRT + op | 2 | 0.54 (0.27–1.11) | |
| Op | 2 | 0.63 (0.33–1.23) | |
| Dose, Gy | 0.62 | ||
| <26 | 14 | 0.70 (0.59–0.83) | |
| ≥26 | 5 | 0.74 (0.59–0.93) | |
| Baseline characteristic equality | <0.01 | ||
| Equal | 8 | 0.82 (0.71–0.95) | |
| Not equal | 16 | 0.59 (0.51–0.69) | |
| Data | 0.78 | ||
| HR reported | 13 | 0.67 (0.59–0.78) | |
| HR not reported | 11 | 0.70 (0.56–0.88) | |
| Publication year | 0.56 | ||
| Before 2000 | 4 | 0.74 (0.49–1.10) | |
| 2000–2010 | 3 | 0.75 (0.66–0.87) | |
| 2011–2018 | 7 | 0.66 (0.46–0.92) | |
| 2019 & later | 10 | 0.65 (0.56–0.76) |
NA = not applicable.
Details of meta-regression assessing factors affecting the observed heterogeneity in PFS analysis
| Factor | p Value | I2 | R2 |
|---|---|---|---|
| No. of pts w/ PCI | 0.4024 | 54.36% | 0.00% |
| No. of pts w/o PCI | 0.8039 | 54.20% | 0.00% |
| Dose | 0.8113 | 52.00% | 0.00% |
| Sex | 0.8056 | 52.22% | 0.00% |
| Age | 0.3819 | 52.81% | 0.00% |
| Publication year | 0.3644 | 45.74% | 2.83% |
| Complete remission rate | 0.7121 | 59.74% | 0.00% |
Publication bias was observed when analyzing PFS in all the studies (p = 0.03). This publication bias was resolved when omitting studies on ES-SCLC (p = 0.10). Because of the limited number of studies on ES-SCLC, further assessment for the source of publication bias was not possible.
The mean PFS times could not be compared as only 2 studies reported data on PFS.
Brain Metastases
Data on BMFS were extracted from 38 studies. The pooled HR showed improved survival in patients receiving PCI (HR 0.46, 95% CI 0.40–0.53; p < 0.01). This observed effect was significant in both LS-SCLC and ES-SCLC patients (Supplementary Fig. 5). The observed effect did not change in different scenarios of subgroup analyses, except for publication years between 2001 and 2010, which could be attributed to the limited number of studies in this subgroup (n = 2). Details on subgroup analyses and the results of meta-regression are shown inTables 5and6, respectively.
Details of subgroup analyses of BMFS based on different factors
| Subgroup | No. of Studies | HR (95% CI) | p Value |
|---|---|---|---|
| Stage | 0.68 | ||
| LS-SCLC | 24 | 0.44 (0.36–0.54) | |
| ES-SCLC | 7 | 0.42 (0.34–0.52) | |
| Imaging | 0.06 | ||
| CT | 9 | 0.57 (0.43–0.74) | |
| MRI | 15 | 0.40 (0.31–0.52) | |
| Stage + imaging | 0.37 | ||
| LS-SCLC + CT | 3 | 0.28 (0.06–1.23) | |
| LS-SCLC + MRI | 10 | 0.37 (0.26–0.53) | |
| ES-SCLC + CT | 0 | NA | |
| ES-SCLC + MRI | 4 | 0.50 (0.38–0.67) | |
| Treatment | 0.51 | ||
| CRT | 29 | 0.44 (0.37–0.52) | |
| CRT + op | 6 | 0.53 (0.40–0.71) | |
| Op | 4 | 0.50 (0.34–0.72) | |
| Dose, Gy | 0.48 | ||
| <26 | 24 | 0.46 (0.40–0.53) | |
| ≥26 | 11 | 0.40 (0.27–0.59) | |
| Baseline characteristic equality | 0.65 | ||
| Equal | 11 | 0.44 (0.34–0.57) | |
| Not equal | 28 | 0.47 (0.40–0.56) | |
| Data | 0.09 | ||
| HR reported | 15 | 0.41 (0.31–0.53) | |
| HR not reported | 24 | 0.53 (0.46–0.60) | |
| Publication year | 0.89 | ||
| Before 2000 | 10 | 0.49 (0.36–0.66) | |
| 2000–2010 | 2 | 0.44 (0.18–1.05) | |
| 2011–2018 | 12 | 0.48 (0.37–0.61) | |
| 2019 & later | 15 | 0.71 (0.35–0.53) |
Details of meta-regression assessing factors affecting the observed heterogeneity in BMFS analysis
| Factor | p Value | I2 | R2 |
|---|---|---|---|
| No. of pts w/ PCI | 0.0905 | 47.13% | 14.68% |
| No. of pts w/o PCI | 0.0522 | 48.45% | 9.58% |
| Dose | 0.2433 | 55.07% | 0.00% |
| Sex | 0.4801 | 53.51% | 0.00% |
| Age | 0.5969 | 55.80% | 1.11% |
| Publication year | 0.2392 | 50.54% | 2.95% |
| Complete remission rate | 0.8069 | 57.61% | 0.00% |
Similar to previous outcomes, significant publication bias was observed for studies reporting BMFS (p < 0.01). This bias could not be resolved when omitting studies in which data were extracted from the Kaplan-Meier curve or studies on ES-SCLC. Only when analyzing matched studies was the publication bias resolved (p = 0.34).
The odds of BMs were also lower when using PCI (OR 0.42, 95% CI 0.34–0.52; I2= 68%) 44研究报告发病率of BMs. This observed effect did not change when stratifying into LS-SCLC (OR 0.43, 95% CI 0.32–0.57) or ES-SCLC (OR 0.35, 95% CI 0.23–0.52), surgery (OR 0.50, 95% CI 0.32–0.78) or chemoradiotherapy (OR 0.37, 95% CI 0.30–0.46), and being equal (OR 0.41, 95% CI 0.27–0.62) or unequal (OR 0.42, 95% CI 0.32–0.55) in baseline characteristics.
Data regarding time to BM were extracted from 8 studies. Patients receiving PCI developed BMs significantly later than patients in the non-PCI group (MD 11.04, 95% CI 6.01–16.07; p < 0.01; I2= 95.3%) (Supplementary Fig. 6).
Discussion
PCI is a therapeutic strategy that involves the delivery of radiotherapy to the brain to prevent or reduce the incidence of BMs. In SCLC, PCI has been shown to be an effective prophylactic therapy to decrease the incidence of BMs and improve OS. Several meta-analyses have demonstrated that PCI reduces the incidence of BMs and improves OS in both LS-SCLC and ES-SCLC.24–28However, a substantial number of studies were not included in previous systematic reviews, possibly because of insufficient reporting of data and the sole use of curves such as the Kaplan-Meier survival curve for reporting OS and BMFS. Our present review pooled a wide range of studies, including 61 retrospective studies and 13 prospective studies. The current meta-analysis shows that PCI significantly improved OS, PFS, and BMFS (p < 0.01) in patients with SCLC, and the results remained significant when analyzed in subgroups of limited or extensive disease, equal baseline or nonequal studies, and previous resection or chemoradiotherapy. Moreover, PCI was associated with a significantly longer OS and time to BM, with MDs of 6.47 and 11.04, respectively.
In our subgroup analysis of LS-SCLC, PCI significantly improved survival outcomes. However, there was considerable publication bias regarding the improvements in OS, where studies with nonsignificant results were not published or did not report their results. Interestingly, after excluding the studies that used Kaplan-Meier curves, the publication bias was more significant (Fig. 2). A possible reason could be that the researchers did not anticipate that the results of PCI would deviate from the meta-analysis carried out by Aupérin et al.29
Funnel plots showing the publication bias (asymmetry of the plots) observed regarding OS when all studies were used (A) and when only studies reporting HR were used (B).
Currently, because of the application of MRI in detecting BM, the standard recommendation of PCI for LS-SCLC in contemporary practice is under debate. Gadolinium-enhanced MRI is more sensitive than CT in detecting BMs in patients with SCLC (24% vs 10%).30Also, a single-center study in 2008 showed that in a sample of 40 patients with LS-SCLC and complete remission after chemoradiotherapy, BMs were detected in 13 patients by pre-PCI MRI.31This suggests that there could be occult BMs that exaggerate the effects of PCI. Two recent matched retrospective studies using brain MRI before PCI confirmed this by showing that although PCI reduced the incidence of BM, its effect on OS was not significant.32,33In our analysis, we found that in LS-SCLC and ES-SCLC patients with negative pre-PCI brain MRI, the application of PCI resulted in increased BMFS. Furthermore, in studies that used pre-PCI brain MRI in LS-SCLC patients, PCI improved both OS and PFS. These results are in line with some previous studies34–36suggesting that more accurate identification of patients who attained complete response and exclusion of patients with occult BMs leads to the selection of patients who are more responsive to PCI. Prospective clinical trials (including NCT04829708, NCT04790253, NCT05651802, and NCT04155034;ClinicalTrials.gov) could further elaborate on these findings.
Regarding patients with ES-SCLC, our findings suggest that PCI significantly improved OS, BMFS, and PFS. This is in line with a previous meta-analysis of 8 studies with 982 patients who received PCI and 4509 patients who did not, which reported that PCI significantly improved the 1-year OS rate and reduced the incidence of BM.27However, in a phase 3 randomized clinical trial consisting of 113 patients with ES-SCLC receiving PCI and 111 under observation, Takahashi et al. reported that there was no significant difference between the PCI and observation cohorts in terms of OS (11.6 months in PCI and 13.7 months in observation, p = 0.094).15The variations in findings could be due to different patient selection methods, availability of baseline brain imaging, and timing of brain radiotherapy.37,38We observed that in the pooled analysis of studies using pre-PCI MRI for the detection of BMs in ES-SCLC patients, PCI was not associated with improved OS and PFS, suggesting death and progression due to other causes before the occurrence of BMs. The improved survival of ES-SCLC patients following PCI, observed in previous studies and our subgroup analysis solely based on staging, could be due to the presence of occult and asymptomatic BMs in studies using brain CT, leading to the therapeutic effects of whole-brain radiotherapy on metastatic lesions instead of prophylactic effects. Overall, our findings imply that PCI is not necessary for patients with ES-SCLC with adequate MRI follow-up visits and should be used cautiously because of the possibility of negative side effects. Future clinical trials with robust inclusion criteria are required to clarify the efficacy of PCI in ES-SCLC.
Although PCI is a standard of care for patients with LS-SCLC and a therapeutic option for those with ES-SCLC,17,29there are concerns regarding the adverse events of PCI. Several factors, including age, the toxicity of anticancer drugs, and vascular comorbidities, influence the risk of neurotoxicity and cognitive decline and need to be considered in the clinical decision to use PCI.39Although a meta-analysis is available on the adverse events of PCI in stage II or III non-SCLC that shows a higher rate of fatigue in PCI patients and a comparable cognitive disturbance between groups, no review is available on SCLC patients.40In the current review, 9 studies assessed the adverse events of PCI in SCLC patients, but because of the heterogeneity in reporting outcomes, quantitative analyses were not possible. Accordingly, the North Central Cancer Treatment Group study on the use of PCI in SCLC patients showed significantly higher rates of lethargy and alopecia.41,42Consistently, Slotman et al. found hair loss, fatigue, appetite loss, constipation, nausea and vomiting, reduced social functioning, future uncertainty, headaches, and motor dysfunction to be more common in PCI patients, without any impairments in role functioning, cognitive functioning, or emotional functioning.17,43In another trial, Takahashi et al. reported the association of acute side effects with PCI, including alopecia, headache, fatigue, and nausea and vomiting, along with severe memory loss, intellectual impairment, dementia, and ataxia.15Furthermore, Nakahara et al. found significantly higher rates of gait disturbances and dementia in the PCI group.44In contrast, Gondi et al. reported more moderate results, showing no association between PCI and a decline in global health status or any other functional or symptom scales previously assessed by Slotman et al., while demonstrating a decline of performance in the Hopkins Verbal Learning Test.45Similarly, Gregor et al. found no significant differences in many tests, including the Paced Auditory Serial Addition Task, Rey Osterrieth Complex Figure test, Rotterdam Symptom Checklist, Hospital Anxiety and Depression Scale, and Auditory Verbal Learning Test.46Two more previous studies further demonstrated similar results by showing no significant differences in higher cognitive, motor, and sensory functions between PCI and surveillance, suggesting the appropriateness of PCI when indicated.9,47Considering the observed heterogeneity and controversies regarding cognition and quality of life of PCI patients, more studies are required on these matters. Moreover, modifying the amount and timing of PCI treatment can significantly reduce the risk of side effects.42,48Our analysis, in line with previous findings,49,50showed that the dose of PCI had no significant impact on the efficacy of PCI, suggesting that patients could benefit from lower doses while experiencing fewer side effects.
Another concern about the widespread use of PCI in patients with lung cancer is its cost-effectiveness, with only 1 applicable study found in our systematic review. The only study assessing the cost-effectiveness of PCI was conducted in 2002 by Tai et al. and showed no significant difference between the marginal cost of PCI and that of surveillance, $18,834 versus $17,885, respectively, while increasing the quality-of-life–adjusted survival.51Meanwhile, Kim et al., in their cost-effectiveness modeling, reported that in ES-SCLC the incremental cost-effectiveness of PCI was $168,456 per quality-adjusted life-year compared with MRI surveillance alone, suggesting that PCI is only cost-effective when the HR is lower than 0.77.52As the latter study’s assumptions are not in line with our findings, putting its findings at risk of amendable errors, we pinpoint the need for newer cost-effectiveness analyses of current clinical trials.
Recent studies have focused on both comparing PCI with other therapeutic options and modifying PCI to further improve its effectiveness and safety. Emerging methods including hippocampal avoidance PCI and using neuroprotective medications have been suggested as they reduce adverse events and improve the cost-effectiveness of conventional PCI.52–54Furthermore, the use of chemoimmunotherapy has been increasing in patients with SCLC; however, the evidence is limited regarding its combination with PCI. An ongoing trial (NCT04947774;ClinicalTrials.gov) is investigating the effects of PCI in ES-SCLC patients previously treated with chemoimmunotherapy and could further shed light on this topic. Finally, recent studies have suggested stereotactic radiosurgery (SRS) as a highly effective therapeutic option for BM in SCLC patients.55–57Considering SRS for treatment of BM in ES-SCLC patients may be more efficacious, as we found no role for PCI in ES-SCLC patients under MRI surveillance. Future studies comparing the efficacy and safety of PCI prior to BM with that of SRS after BM in both LS-SCLC and ES-SCLC patients are required to further establish more robust recommendations regarding the decision to use PCI or MRI surveillance.
Limitations
We acknowledge several limitations of our study. First, there was a significant publication bias in studies on LS-SCLC in favor of PCI. Also, in several studies the HRs were not reported because of nonsignificant results. We tried to mitigate this effect by extensive data extraction and analyzing the subgroup of studies based on whether they reported HR. Second, the majority of studies included in this review were retrospective, which subjects them to potential biases and inconsistencies in data quality and accuracy. To address this, we compared the studies based on their design and found no significant differences in outcomes except for PFS. Third, the studies were heterogeneous regarding their inclusion criteria, methods of BM detection, PCI fractions, and chemotherapy regimen, which was addressed in subgroup analyses if possible.
Conclusions
目前的荟萃分析证实了效率ss of PCI in reducing the incidence of BMs and improving OS in patients with SCLC. Our review included a wide range of studies, including retrospective studies, prospective studies, and randomized controlled trials, making the results more comprehensive and reliable. The findings demonstrate that PCI is associated with significant improvements in OS, PFS, and BMFS in patients with SCLC, regardless of disease stage or previous treatments. These results further support the use of PCI as a valuable prophylactic therapy for SCLC patients, highlighting the importance of early intervention to improve patient outcomes.
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: Maroufi, Sheehan. Acquisition of data: Maroufi, Fallahi, Kankam. Analysis and interpretation of data: Maroufi. Drafting the article: all authors. Critically revising the article: Maroufi, Fallahi, Sheehan. Reviewed submitted version of manuscript: Maroufi, Fallahi, Kankam. Approved the final version of the manuscript on behalf of all authors: Maroufi. Statistical analysis: Maroufi. Study supervision: Maroufi, Sheehan.
Supplemental Information
Online-Only Content
Supplemental material is available online.
Supplementary Tables and Figures.//www.prize-show.com/doi/suppl/10.3171/2023.5.FOCUS23225.
Data Availability
Data are available upon request from the corresponding author.
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