Effect of Prophylactic Cranial Irradiation on Overall Survival in Metastatic Small-Cell Lung Cancer: A Propensity Score-Matched Analysis

doi:10.1016/j.cllc.2017.12.003

Clinical Lung Cancer

Volume 19, Issue 3, May 2018, Pages 260-269.e3

https://doi.org/10.1016/j.cllc.2017.12.003 Get rights and content

Abstract

Introduction

Patients with small-cell lung cancer (SCLC) have a high incidence of occult brain metastases and are often treated with prophylactic cranial irradiation (PCI). Despite a small survival advantage in some studies, the role of PCI in extensive stage SCLC remains controversial. We used the National Cancer Database to assess survival of patients with metastatic SCLC treated with PCI.

Patients and Methods

Metastatic SCLC patients without brain metastases were identified. To minimize treatment selection bias, patients with an overall survival (OS) < 6 months were excluded. Cox regression identified variables associated with OS. Patients were propensity score-matched on factors associated with receipt of PCI or OS. The effect of PCI on OS was examined using Kaplan–Meier estimates.

Results

In the overall cohort (n = 4257), treatment with PCI (n = 473) was associated with improved survival (hazard ratio, 0.66; 95% confidence interval, 0.60-0.74; P < .0001). Comparisons of propensity score-matched cohorts revealed a significant survival benefit for patients who received PCI in median OS (13.9 vs. 11.1 months; P < .0001), as well as 1- and 2-year OS (61.2% vs. 44.0% and 19.8% vs. 11.5%, respectively; P < .0001). This survival benefit persisted even after excluding patients who survived < 9 months (median: 15.3 vs. 12.9 months; P < .0001). In multivariable analysis, predictors of receipt of PCI were Caucasian race, younger age, and lower Charlson–Deyo score.

Conclusion

Using a modern population-based data set, we showed that metastatic SCLC patients treated with PCI have significantly improved OS. This large retrospective study helps address the conflicting prospective data.

Introduction

Small-cell lung cancer (SCLC) comprises approximately 13% of all new lung cancer diagnoses with approximately 31,000 cases annually in the United States.1, 2 SCLC is characterized by its aggressive nature, rapid doubling time, and high metastatic potential. Most patients (60%-70%) present with disseminated, extensive-stage (ES) disease at diagnosis, for which the primary treatment is chemotherapy.3, 4

Small-cell lung cancer has a notoriously high rate of brain metastases, with > 50% of patients developing intracranial involvement over the course of their disease.5, 6 As a result, for patients who respond well to initial chemotherapy, prophylactic cranial irradiation (PCI) is used to decrease the risk of brain metastases and the associated neurological morbidity of intracranial progression as shown in multiple meta-analyses.7, 8, 9 In patients with limited-stage disease, there is evidence that PCI decreases the risk of brain metastases and improves survival.8, 9 Therefore, the National Comprehensive Cancer Network (NCCN) guidelines provide a category 1 recommendation to offer PCI in patients with limited-stage SCLC who respond to initial therapy.³

In patients with ES disease, PCI also decreases the risk of developing symptomatic brain metastases,10, 11 but its effect on overall survival (OS) is controversial. PCI appeared to offer a survival benefit in one randomized trial of patients with ES disease who responded to chemotherapy.¹⁰ However, this trial has been criticized, because patients were not screened for brain metastases with brain imaging before PCI unless they had neurological symptoms. As a result, some patients likely had brain metastases at the time of PCI and might have achieved a survival benefit through the treatment of known intracranial disease. Per current NCCN guidelines, PCI is generally reserved for patients with an objective clinical or radiographic response to chemotherapy and negative post-chemotherapy brain imaging.³ Interestingly, the results of another recent phase III trial reported that ES-SCLC patients who responded to initial chemotherapy and had a negative brain magnetic resonance imaging (MRI) scan did not have a survival benefit when treated with PCI.¹¹

Because of the disparate results of prospective trials on the role of PCI in ES-SCLC and the low likelihood that additional randomized studies will be performed, we undertook this study to better understand the clinical effect of PCI on survival outcomes using a modern, population-based database at the national level. Although we recognize that prospective randomized controlled trials are the gold standard, we hope that this study adds clinically meaningful data to an area of controversy. We assessed clinical outcomes using the National Cancer Database (NCDB) and propensity score-matching to better elucidate the potential benefits of PCI in patients with ES-SCLC and to help direct the clinical management of these patients. We hypothesized that PCI would confer an OS benefit in patients with ES-SCLC without brain metastases who respond to standard chemotherapy.

Section snippets

Data Source

After obtaining approval from our institutional review board, we conducted a propensity score-matched cohort study using the NCDB. The NCDB is a large national oncology registry sponsored by the American College of Surgeons and the American Cancer Society encompassing > 1500 Commission on Cancer (CoC) institutions. Approximately 70% of new nationwide cancer diagnoses are recorded in this database.¹²

Patient Selection

Patients with metastatic SCLC without brain metastases treated with chemotherapy between 2010 and

Characteristics of the Overall, Unmatched Study Population

In the overall cohort of patients with metastatic SCLC without brain metastases who survived at least 6 months (n = 4257), 473 patients (11.1%) received PCI, whereas 3784 patients (88.9%) received only chemotherapy without PCI. Among the patients who received PCI, the most common dose fractionation was 25 Gy in 10 fractions (n = 391; 83%). Baseline characteristics of the cohorts are shown in Table 1. Before propensity score-matching, the PCI cohort differed significantly from the no PCI group

Discussion

In this study, we analyzed the survival outcomes of patients with metastatic SCLC treated with or without PCI using the NCDB. To our knowledge, this represents the largest retrospective study to date on the efficacy of PCI in this patient population. We identified 4257 patients with metastatic SCLC without brain metastases and a minimum survival of at least 6 months treated from 2010 to 2012. After propensity score-matching with a median follow-up of 30.4 months, we found that PCI was

Conclusion

This retrospective cohort study further supports the benefits of PCI in patients with ES-SCLC who respond to initial chemotherapy. On the basis of the results of this large, modern, population-based study, PCI might offer a significant OS benefit in the appropriately selected ES-SCLC patient. Further prospective, randomized trials are needed to reconcile divergent reports of the clinical effect of PCI on survival and further guide the management of these patients.

Disclosure

The authors have stated that they have no conflicts of interest.

Acknowledgments

Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001879. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The data used in this study were derived from a deidentified NCDB file. The American College of Surgeons and the CoC have not verified and are not responsible for the

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Cited by (22)

The Impact of Prophylactic Cranial Irradiation and Consolidative Thoracic Radiation Therapy for Extensive Stage Small-Cell Lung Cancer in the Transition to the Chemo-Immunotherapy Era: A Single Institution Series
2023, Clinical Lung Cancer
Extensive-stage small-cell lung cancer (ES-SCLC) continues to have poor survival due to its aggressive behavior, despite improvements with incorporation of immunotherapy with standard chemotherapy. Controversy exists regarding the role of consolidative thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) in ES-SCLC due to high recurrence rates. We report our institutional result of the benefit of PCI and TRT in ES-SCLC.
Patients with ES-SCLC without intracranial metastasis at diagnosis (N = 163) were included. All patients completed systemic therapy with or without immunotherapy based on time of standard of care. Cohorts were divided by systemic therapy use and further subdivided by treatment with PCI and TRT. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method with log-rank test for comparison. The effects of TRT and PCI were estimated by multivariable (MVA) Cox regression.
Seventy-four patients (45.4%) received TRT, and 33.1% (n = 54) received PCI. The median follow-up was 11 months (3-85 months). PCI improved median OS to 15 months from 10 months, P = .02) and median PFS to 8.5 months from 5 months (P = .02) which remained significant on MVA, P = .02 and P = .02, respectively. TRT improved OS on UVA (P = 0.002) but was not significant on MVA. TRT did not improve PFS.
This study including chemotherapy and chemo-immunotherapy suggests improved outcomes with addition of PCI in patients with ES-SCLC while TRT did not show benefit to either OS or PFS. A future trial is needed to evaluate the role of TRT and PCI in the era of chemo-immunotherapy.
Utility of Prophylactic Cranial Irradiation for Extensive-Stage Small-Cell Lung Cancer in the MRI Screening Era
2021, Clinical Lung Cancer
Citation Excerpt :
A common criticism of the EORTC trial that had demonstrated improved OS with PCI was lack of mandatory brain imaging prior to enrollment, and a subsequent trial from Takahashi et al.10 demonstrated no OS benefit with strict requirement of magnetic resonance imaging (MRI) screening prior to PCI.4,10 Since the publication of these trials, multiple retrospective studies have demonstrated an OS benefit with PCI in patients with ES-SCLC.11-14 Following the results of the trial from Takahashi et al.10 in which PCI was only associated with reduced incidence of brain metastases, only 44% of surveyed radiation oncologists continue to routinely offer PCI to patients with ES-SCLC.15
Conflicting data exists regarding the benefit of prophylactic cranial irradiation (PCI) in patients with extensive-stage small-cell lung cancer (ES-SCLC). We sought to retrospectively review outcomes of patients within our network with ES-SCLC treated with and without PCI between 2009 and 2020.
Endpoints assessed using the Kaplan-Meier estimator were overall survival (OS), freedom from death with uncontrolled intracranial disease (UI-DFS), brain metastasis-free survival (BMFS), and symptomatic BMFS (SBMFS). Log-rank test was performed for univariate comparison of outcomes, with Cox regression performed for univariate and multivariable analysis of OS and UI-DFS.
Some 250 patients were determined to be eligible for PCI based on any response to upfront chemotherapy, with 46 patients excluded owing to lack of negative staging brain magnetic resonance imaging (MRI). Brain MRI was performed both at diagnosis and near completion of chemotherapy in 108 patients, with brain metastases identified near completion of chemotherapy in 17 patients (15.7%), excluding them from further analysis. Median OS in remaining eligible 187 patients was 9.0 months, with 2-year Kaplan-Meier estimate of OS of 21.9%. PCI was associated with improved UI-DFS, BMFS, and SBMFS. However, PCI was not associated with improved OS in the entire cohort or the propensity matched cohort.
Our study suggests screening with MRI following chemotherapy is important because of the identification of unsuspected brain metastases in nearly 16% of patients with response to chemotherapy. PCI is associated with reduction in brain metastases, without a demonstrable impact on OS in the era of MRI screening.
Prophylactic cranial irradiation in patients with small cell lung cancer in The Netherlands: A population-based study
2021, Clinical and Translational Radiation Oncology
Citation Excerpt :
Identified factors independently determining PCI prescription in both ES-SCLC and LS-SCLC in the 2010–2018 cohorts were younger age, better WHO performance status and use of thoracic radiotherapy. These results are in line with a recently reported prediction model in ES-SCLC patients from the United States that reported age (≥65 versus < 65 years, OR = 0.65, p = 0.003) and Charlson Comorbidity Score (≥1 vs. 0, OR 0.76, p = 0.006) as determinants for PCI [23]. In further support, the European Society for Medical Oncology (ESMO) clinical practice guidelines and Dutch guidelines recommend to take PCI in consideration in patients with a good WHO performance status and after any response to chemotherapy [9,10].
Controversy has arisen regarding the benefit of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC), particularly since the 2017 Takahashi trial publication that supports MRI surveillance in extensive-stage (ES-)SCLC. The primary aim of this study was to assess trends and determinants in PCI use over the years 2010–2018. A secondary aim was to determine contemporary practice considerations among radiation oncologists (ROs).
A nationwide population-based cohort study was conducted using the Netherlands Cancer Registry data on all newly diagnosed SCLC patients (2010–2018). The change in PCI frequency over the years and determinants for PCI were analyzed using logistic regression models. Second, an online survey was performed among Dutch lung cancer ROs in 2020.
Among 10,264 eligible patients, 4,894 (47%) received PCI. Compared to 2010–2014, PCI use significantly decreased in 2017–2018 in ES-SCLC (OR 0.68, 95%CI 0.60–0.77) and LS-SCLC (OR 0.56, 95%CI 0.47–0.67). Incidence year, age, performance status, and thoracic radiotherapy were independent determinants for PCI. Among 41 survey participants, PCI was recommended always/sometimes/never by 22%/71%/7% in ES-SCLC and 54%/44%/2% in LS-SCLC. For ES-SCLC and LS-SCLC, 63% and 25% of ROs, respectively, confirmed influence of the Takahashi trial on PCI recommendations. Denial of such influence was associated with insufficient institutional MRI capacity.
A significant declining trend of PCI use in both ES-SCLC and LS-SCLC was observed in The Netherlands since 2017. The Takahashi trial seems an explanation for this trend even in LS-SCLC, with differential influence of the trial depending on institutional MRI capacity. An alarming increase in practice variation regarding PCI was found which stresses the importance of ongoing trials.
Racial and Other Healthcare Disparities in Patients With Extensive-Stage SCLC
2021, JTO Clinical and Research Reports
Systemic treatment with chemotherapy is warranted for patients with extensive-stage SCLC (ES-SCLC). The objective of this study was to determine whether racial and other healthcare disparities exist in receipt of chemotherapy for ES-SCLC.
Utilizing the National Cancer Database, 148,961 patients diagnosed to have stage IV SCLC from 2004 to 2016 were identified. Adjusted ORs with 95% confidence intervals (95% CIs) were computed for receipt of chemotherapy using multivariate logistic regression modeling. Cox regression modeling was used to perform overall survival analysis, and adjusted hazard ratios were calculated.
A total of 82,592 patients were included, among which chemotherapy was not administered to 6557 (7.9%). Higher education, recent year of diagnosis, and treatment at more than one facility were associated with increased odds of receiving chemotherapy. Factors associated with a decreased likelihood of receiving chemotherapy were increasing age, race, nonprivate insurance, and comorbidities. On multivariate analysis, black patients had lower odds of receiving chemotherapy compared with white patients (adjusted OR, 0.85; 95% CI: 0.77–0.93, p = 0.0004). Furthermore, black patients had better survival compared with white patients (adjusted hazard ratio, 0.91; 95% CI: 0.89–0.94, p = 0.91). The 1-year survival (median survival) for black and white patients was 31.7% (8.3 mo) and 28.6% (8 mo), respectively.
Black patients with ES-SCLC were less likely to receive chemotherapy, as were elderly, uninsured, and those with nonprivate insurance. Further studies are required to address underlying reasons for lack of chemotherapy receipt in black patients with ES-SCLC and guide appropriate interventions to mitigate disparities.
Meta-analysis of prophylactic cranial irradiation or not in treatment of extensive-stage small-cell lung cancer: The dilemma remains
2020, Cancer/Radiotherapie
Citation Excerpt :
The 1-year overall survival rate in the PCI group was significantly higher than that in the control group (50.8% vs. 42%; HR = 1.50; 95% CI: 1.23–1.82; I2 = 67%; P < 0.0001) (Fig. 2). Two-year OS: A total of 8 studies [5,9–11,19–22] were included in the meta-analysis random-effect model. There was no significant difference in the 2-year overall survival rates in the PCI and non-PCI groups (HR = 1.48; 95% CI: 0.97–2.26; I2 = 91%; P = 0.07) (Fig. 3).
The role of prophylactic cranial irradiation (PCI) in treatment of extensive-stage small-cell lung cancer (SCLC) is controversial. The aim of this study was to systematically evaluate the efficacy and safety of using PCI in the treatment of extensive-stage SCLC. In the present study, we examined whether PCI was essential for the optimal treatment of extensive-disease small-cell lung cancer.
We searched the PubMed, Embase, Medline, and China National Knowledge Infrastructure databases to identify articles that assessed the efficacy of PCI in treating extensive-stage small-cell lung cancer patients.
We identified 8 studies that involved a total of 982 patients who received PCI (PCI group) and a total of 4509 patients who did not receive PCI (control group). The results showed that PCI significantly improved the 1-year overall survival rate (HR = 1.50; 95% CI: 1.23–1.82; I² = 67%; P < 0.0001) and reduced the incidence of brain metastasis (HR = 0.46; 95% CI: 0.37–0.58; I² = 6%; P < 0.00001).
PCI improves the 1-year overall survival rate and reduces the risk of brain metastasis in patients with extensive-stage SCLC.
Le rôle de l’irradiation intracrânienne prophylactique dans le traitement du cancer du poumon à petites cellules évolué est controversé. L’objectif de cette étude était d’évaluer systématiquement l’efficacité et la sécurité de l’utilisation de l’irradiation intracrânienne prophylactique dans le traitement du cancer du poumon à petites cellules évolué. Dans la présente étude, nous avons examiné si l’irradiation intracrânienne prophylactique était essentielle pour le traitement optimal du cancer du poumon à petites cellules évolué.
Nous avons consulté les bases de données PubMed, Embase, Medline et China National Knowledge Infrastructure pour identifier des articles évaluant l’efficacité de l’irradiation intracrânienne prophylactique dans le traitement du cancer du poumon à petites cellules évolué.
Nous avons identifié huit études impliquant un total de 982 patients ayant reçu une irradiation intracrânienne prophylactique et un total de 4509 patients n’ayant pas reçu une irradiation intracrânienne prophylactique. Les résultats ont montré que l’irradiation intracrânienne prophylactique améliorait significativement le taux de survie globale à 1 an (HR [Hazard Radio] = 1,50; IC 95% [intervalle de confiance à 95%]: 1,23–1,82; I² = 67%; p < 0,0001) et réduisait l’incidence de métastases cérébrales (HR = 0,46; 95% IC: 0,37–0,58; I² = 6%; p < 0,00001).
L’irradiation intracrânienne prophylactique améliore le taux de survie global à un an et réduit le risque de métastases cérébrales chez les patients atteints d’un cancer du poumon à petites cellules évolué.
Prophylactic cranial irradiation in extensive disease small cell lung cancer: An endless debate
2019, Critical Reviews in Oncology/Hematology
Citation Excerpt :
Median follow up across studies was 23 months (range, 9–36). Within the retrospective studies, the largest one (Sharma et al., 2018) used the American National Cancer Database and evaluated a total of 4257 SCLC metastatic patients (3784 not receiving PCI and 473 receiving PCI). In this large cohort, patients treated between 2010 and 2012 with chemotherapy for ED-SCLC and without BM have been analyzed.
Extensive disease Small cell lung cancer (ED-SCLC) represents a very aggressive malignancy in which brain metastases (BM) are quite common. Clinical trials on prophylactic cranial irradiation (PCI) have showed a clear decrease in the risk of developing BM but conflicting results concerning a possible survival advantage. A landmark European Organisation for Research and Treatment of Cancer (EORTC) prospective trial, as well as multitude of retrospective series confirm survival benefit after PCI. Recently, a Japan Clinical Oncology Group (JCOG) study did not find such survival benefit, provided that non-irradiated patients are closely followed by MRI. Henceforth, the role of PCI in this population has been questioned, on the ground of the possible absence of survival benefit, leading to a gradual shift in oncology practice. We performed a review of the literature on the subject of PCI in ED-SCLC patients. We conclude that PCI could still play a crucial role in these patients, considering not only a possible survival benefit, but also alternative endpoints, such as improved local control, delay in the onset of symptomatic BM and lower toxicity of a prophylactic- rather than an eventual active-intent treatment. Individualized attitude should be discussed with patients, while addressing all arguments in favour and against PCI.

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Original StudyEffect of Prophylactic Cranial Irradiation on Overall Survival in Metastatic Small-Cell Lung Cancer: A Propensity Score-Matched Analysis

Abstract

Introduction

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Data Source

Patient Selection

Characteristics of the Overall, Unmatched Study Population

Discussion

Conclusion

Disclosure

Acknowledgments

Ann Oncol

Lancet Oncol

Lancet Oncol

Ann Oncol

J Thorac Oncol

Eur J Cancer

J Thorac Oncol

Lancet

Cancer statistics, 2016

CA Cancer J Clin

Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database

J Clin Oncol

CNS metastases in small-cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival

Cancer

Asymptomatic brain metastases (BM) in small-cell lung cancer (SCLC): MR-imaging is useful at initial diagnosis

J Neurooncol

Original Study
Effect of Prophylactic Cranial Irradiation on Overall Survival in Metastatic Small-Cell Lung Cancer: A Propensity Score-Matched Analysis