Risk of cerebral metastases and neurological death after pathological complete response to neoadjuvant therapy for locally advanced nonsmall‐cell lung cancer

Chen, Allen M.; Jahan, Thierry; Jablons, David M.; Garcia, Joaquin; Larson, David A.

doi:10.1002/cncr.22565

Cited by 127 publications

(107 citation statements)

References 34 publications

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“…As known, EGFR mutations, being deemed to be a biological marker of NSCLC in recent decades, account for 10%‐25% of NSCLC 53. As a result of its constitutive activation of EGFR signaling and oncogenic transformation, EGFR was confirmed to be an independent risk factor and served as a crucial role 54.…”

Section: The Mechanism Of Brain Metastasismentioning

confidence: 99%

Emerging findings into molecular mechanism of brain metastasis

Chen

2018

Cancer Medicine

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Brain metastasis is an important cause of morbidity and mortality in cancer patients. Hence, the need to develop improved therapies to prevent and treat metastasis to the brain is becoming urgent. Recent studies in this area are bringing about some advanced progress on brain metastasis. It was concluded that the occurrence and poor prognosis of brain metastasis have been mostly attributed to the exclusion of anticancer drugs from the brain by the blood‐brain barrier. And several highly potent new generation targeted drugs with enhanced CNS distribution have been developed constantly. However, the noted “seed and soil” hypothesis also suggests that the outcome of metastasis depends on the relationship between unique tumor cells and the specific organ microenvironment. Moreover, increasing studies in multiple tumor types demonstrated that brain metastasis has great molecular differences between primary tumors and extracranial metastasis to a large extent. Here, the authors summarized the most common malignancies that could lead to brain metastasis—lung cancer, breast cancer and melanoma and their related mutated factors. Only by comprehending a deeper understanding of the molecular mechanisms, more effective brain‐specific therapies will be developed for brain metastasis.

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Section: The Mechanism Of Brain Metastasismentioning

confidence: 99%

Emerging findings into molecular mechanism of brain metastasis

Chen

2018

Cancer Medicine

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“…Although several clinical and pathologic factors have been associated with the development of brain metastases in locally advanced disease, [31][32][33][34][35] few studies have evaluated risk factors in early stage disease (Table 3). On multivariate analysis, we identified 4 factors that were independently associated with a higher risk of developing brain metastases.…”

Section: Clinical and Pathologic Risk Factorsmentioning

confidence: 99%

“…Whereas several other series found a similar finding, 7,31,36 age in other series was not prognostic. 33,34,37 Tumor size is an important prognostic factor in NSCLC and a primary basis for the TNM staging system. 15 Bajard et al showed that clinical T classification was significant for development of brain metastases in a cohort of 305 NSCLC patients (168 with stage I-II disease).…”

Section: Clinical and Pathologic Risk Factorsmentioning

confidence: 99%

“…38 In contrast, other studies have shown that for resected stage IIIA patients, pathologic T classification was not significantly associated with incidence of brain metasteses. 33,34 …”

Section: Clinical and Pathologic Risk Factorsmentioning

confidence: 99%

“…45 Histology was not a statistically significant factor in our series (P ¼ .14). Nonsquamous histology, adenocarcinoma in particular, has been associated with an increased risk of developing brain metastases in some, 33,34,38,39,46 but not all, [35][36][37] studies.…”

Section: Original Article 5042mentioning

confidence: 99%

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Factors associated with the development of brain metastases

Hubbs

Boyd

Hollis

et al. 2010

Cancer

120

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BACKGROUND The risk of developing brain metastases after definitive treatment of locally advanced nonsmall cell lung cancer (NSCLC) is approximately 30%-50%. The risk for patients with early stage disease is less defined. The authors sought to investigate this further and to study potential risk factors. METHODS The records of all patients who underwent surgery for T1-T2 N0-N1 NSCLC at Duke University between the years 1995 and 2005 were reviewed. The cumulative incidence of brain metastases and distant metastases was estimated by using the Kaplan-Meier method. A multivariate analysis assessed factors associated with the development of brain metastases. RESULTS Of 975 consecutive patients, 85% were stage I, and 15% were stage II. Adjuvant chemotherapy was given to 7%. The 5-year actuarial risk of developing brain metastases and distant metastases was 10%(95% confidence interval [CI], 8-13) and 34%(95% CI, 30-39), respectively. Of patients developing brain metastases, the brain was the sole site of failure in 43%. On multivariate analysis, younger age (hazard ratio [HR], 1.03 per year), larger tumor size (HR, 1.26 per cm), lymphovascular space invasion (HR, 1.87), and hilar lymph node involvement (HR, 1.18) were associated with an increased risk of developing brain metastases. CONCLUSIONS In this large series of patients treated surgically for early stage NSCLC, the 5-year actuarial risk of developing brain metastases was 10%. A better understanding of predictive factors and biological susceptibility is needed to identify the subset of patients with early stage NSCLC who are at particularly high risk. Cancer 2010;116:5038-46.

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Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non–Small Cell Lung Cancer

Sun

Wong

et al. 2019

JAMA Oncol

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IMPORTANCE Brain metastasis (BM) rates are high in locally advanced non-small cell lung cancer (LA-NSCLC), approaching rates seen in small cell lung cancer, where prophylactic cranial irradiation (PCI) is standard of care. Although PCI decreases the incidence of BM in LA-NSCLC, a survival advantage has not yet been shown. OBJECTIVE To determine if PCI improves survival in LA-NSCLC. DESIGN, SETTING, AND PARTICIPANTS Radiation Therapy Oncology Group (RTOG) 0214 was a randomized phase 3 clinical trial in stage III NSCLC stratified by stage (IIIA vs IIIB), histologic characteristics (nonsquamous vs squamous) and therapy (no surgery vs surgery). The study took place at 291 institutions in the United States, Canada, and internationally. Of 356 patients with stage III NSCLC entered onto this study, 16 were ineligible; therefore, 340 patients were randomized. INTERVENTION FOR CLINICAL TRIALS Observation vs PCI. MAIN OUTCOMES AND MEASURESThe primary outcome was overall survival (OS). The secondary end points were disease-free survival (DFS) and incidence of BM. RESULTSOf the 340 total participants, mean (SD) age was 61 years; 213 of the participants were men and 127 were women. The median follow-up time was 2.1 years for all patients, and 9.2 years for living patients. The OS for PCI was not significantly better than observation (hazard ratio [HR], 0.82; 95% CI, 0.63-1.06; P = .12; 5-and 10-year rates, 24.7% and 17.6% vs 26.0% and 13.3%, respectively), while the DFS (HR, 0.76; 95% CI, 0.59-0.97; P = .03; 5-and 10-year rates, 19.0% and 12.6% vs 16.1% and 7.5% for PCI vs observation) and BM (HR, 0.43; 95% CI, 0.24-0.77; P = .003; 5-and 10-year rates, 16.7% vs 28.3% for PCI vs observation) were significantly different. Patients in the PCI arm were 57% less likely to develop BM than those in the observation arm. Younger patients (<60 years) and patients with nonsquamous disease developed more BM. On multivariable analysis, PCI was associated with decreased BM and improved DFS, but not improved OS. Multivariable analysis within the nonsurgical arm suggests that PCI effectively prolongs OS, DFS, and BM. CONCLUSIONS AND RELEVANCEIn patients with stage III LA-NSCLC without progression of disease after therapy, PCI decreased the 5-and 10-year rate of BM and improved 5-and 10-year DFS, but did not improve OS. Although this study did not meet its primary end point, the long-term results reveal many important findings that will benefit future trials. Identifying the appropriate patient population and a safe intervention is critical.TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00048997

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Risk of cerebral metastases and neurological death after pathological complete response to neoadjuvant therapy for locally advanced nonsmall‐cell lung cancer

Cited by 127 publications

References 34 publications

Emerging findings into molecular mechanism of brain metastasis

Emerging findings into molecular mechanism of brain metastasis

Factors associated with the development of brain metastases

Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non–Small Cell Lung Cancer

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