Central Nervous System Metastases In Patients Research Articles

A Phase 2 Single-Arm Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis NSCLC: Results for the First-Line Cohort of the OCEAN Study (LOGIK 1603/WJOG 9116L)

IntroductionOsimertinib may be effective in treating central nervous system (CNS) metastasis, but its efficacy in treating radiation therapy (RT)-naive metastasis is unclear. The OCEAN study assessed the efficacy of osimertinib against RT-naive CNS metastasis in patients previously treated (T790M cohort) and untreated patients (first-line cohort) with EGFR mutation. Here, we report the results of the first-line cohort. MethodsPreviously untreated patients with RT-naive CNS metastasis and EGFR mutation-positive NSCLC were treated with osimertinib. The brain metastasis response rate (BMRR), progression-free survival (PFS), and overall survival in the first-line cohort were secondary end points. ResultsA total of 26 patients were enrolled in the study between September 2019 and July 2020. The median age was 72.0 years with 80.8% female. There were 20 patients who had multiple CNS metastases. BMRR assessed by PAREXEL criteria was 76.9% (90% confidence interval [CI]: 63.3%–90.5%), BMRR assessed by Response Evaluation Criteria in Solid Tumors was 76.9% (95% CI: 54.0%–99.8%), and median PFS of CNS metastasis was 22.0 months (95% CI: 9.7 mo–not reached). The overall response rate was 64.0% (95% CI: 45.2%–82.8%), median PFS was 11.5 months (95% CI: 6.9 mo–not reached), and median survival time was 23.7 months (95% CI: 16.5 mo–not reached). Paronychia and increased creatinine level were the most frequent nonhematological toxicities observed in 13 patients (50%). Grade three and higher adverse events were less than 10%, and there were no treatment-related deaths. Pneumonitis was observed in five patients (19.2%). ConclusionsThese results suggest that osimertinib is effective in untreated patients with RT-naive asymptomatic CNS metastasis in a clinical practice first-line setting. Trial registrationUMIN identifier: UMIN000024218. jRCT identifier: jRCTs071180017.

Economic burden of central nervous system metastases in human epidermal growth factor receptor 2-positive breast cancer.

Aim: Compare healthcare resource utilization and costs among patients with HER2+ metastatic breast cancer (MBC) with and without central nervous system (CNS) metastases. Methods: Retrospective matched cohort study using IQVIA's PharMetrics® Plus claims database. Results: Patients with CNS metastases (n=753) experienced more outpatient, emergency room and inpatient visits versus controls (n=753; all p<0.05). In the post-index year, median total all-cause healthcare costs were significantly higher among patients with CNS metastases versus controls ($112,402 vs $50,835; p<0.0001); outpatient costs primarily drove the cost differential. Conclusion: More effective therapies are needed that improve clinical outcomes and reduce economic burden associated with CNS metastases in patients with HER2+ MBC.

Routine Neuroimaging in Patients with Stage IV Non-Small Cell Lung Cancer: A Single Center Experience.

Background: There is a lack of consensus in current practice guidelines regarding routine neuroimaging in patients with stage IV non-small cell lung cancer (NSCLC) without neurologic symptoms, and there is a paucity of data on the impact of such imaging on overall survival (OS). Methods: This retrospective study included 257 patients with stage IV NSCLC without neurologic symptoms diagnosed between January 1, 2013 and December 31, 2016 at Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). The primary objective of this study was to compare the evolution of patients with stage IV NSCLC who had baseline brain imaging versus with who did not. Secondary objectives were to determine the proportion of patients who underwent brain imaging in their initial investigation and the proportion of patients who developed metachronous central nervous system (CNS) metastasis. Results: CNS imaging, mainly with computed tomography (CT), was performed at diagnosis in 56% of patients, and the prevalence of synchronous CNS metastasis among these patients was 32%. There was no difference in median OS between patients who underwent initial CNS imaging and those who did not, but we did show a tendency for a higher cumulative incidence of metachronous CNS metastasis in patients without baseline imaging. These metachronous metastases were symptomatic and were more often not treated when compared to synchronous metastases. Conclusions: In this small, unicentric retrospective study, there was no benefit with routine neuroimaging in terms of median OS in stage IV NSCLC patients without neurologic symptoms.

Central nervous system metastases of lung adenocarcinoma harboring EGFR-activating mutations: survival results from a multidisciplinary approach, including EGFR-TKIs

OBJECTIVES: Central nervous system (CNS) metastases are frequent in advanced lung adenocarcinomas harboring EGFR-activating mutations. However, the best treatment approach must be defined. We aimed to evaluate the effectiveness of a multidisciplinary approach for CNS metastases in patients previously untreated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). METHODS: We performed a retrospective analysis of EGFR-TKI naïve patients with CNS metastases from lung adenocarcinomas harboring EGFR-activating mutations treated in a Brazilian academic cancer center. Data were collected from electronic records. Overall survival (OS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method and compared by logrank test. Cox model was used to evaluate prognostic factors. RESULTS: 35 consecutive patients were included. Treatment included an EGFR-TKI (erlotinib or gefitinib) for all patients, whole brain radiation therapy for 26 patients, stereotactic radiosurgery for 2 patients, and surgery for 8 patients. Median PFS and OS were 8.2 and 11.9 months, respectively. In a multivariable analysis, poor Eastern Cooperative Oncology Group performance status (3-4 vs 0-2) was associated with inferior OS (HR 2.86; 95% CI 1.12-6.74; p=0.016), while radiation therapy to treat brain lesions (yes vs no) showed a trend towards improved OS (HR 0.40; 95% CI 0.15-1.06; p=0.066). No difference was seen between upfront and salvage radiation therapy to the brain. CONCLUSIONS: A multidisciplinary treatment approach, including an EGFR-TKI, allowed promising outcomes for patients with CNS metastases of lung adenocarcinoma harboring EGFR-activating mutations, but the small number of patients here studied precludes definitive conclusions. Although radiation therapy to treat brain metastases has an important role, the best treatment sequence remains unclear. Currently, the approach must be individualized, considering patient characteristics, tumor biology and healthcare resources availability.

Management of CNS metastases in patients with EGFR mutation-positive NSCLC.

Central nervous system (CNS) metastases are a frequent and severe complication associated with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) have shown considerable efficacy in EGFR-mutated NSCLC. However, their limited potential to cross the blood-brain barrier (BBB) renders them less effective in the management of CNS metastases in NSCLC. Osimertinib, a third-generation irreversible EGFR-TKI with good potential to cross the BBB, has shown significant clinical activity and acceptable safety profile in patients with EGFR-positive NSCLC brain and leptomeningeal metastases. The progression-free survival (PFS) of up to 15.2 months in CNS metastases patients in the FLAURA trial and the CNS objective response rates (ORRs) of 54% and 43% in the AURA/AURA2 and BLOOM trials, respectively, have established the role of osimertinib in patients with NSCLC with CNS metastases. The AURA3 trial also reported a PFS of 8.5 months and overall ORR of 71%. These data have supported osimertinib to be recognized as a "preferred" first-line treatment for EGFR-positive metastatic NSCLC by the National Comprehensive Cancer Network (NCCN). With limited treatment options available, upfront administration of osimertinib in patients with NSCLC irrespective of EGFR T790M and CNS metastases may improve the overall response rate and potentially reduce the adverse effects of radiotherapy. Our review focuses on the management of EGFR-mutated NSCLC CNS metastases in the context of recent NCCN guidelines.

Diagnosis of brain metastases in breast cancer patients resulting from neurological symptoms

ObjectivesBreast cancer (BC) is the leading cause of morbidity and mortality. Neurological symptoms are highly feared because they are associated with central nervous system metastases (CNSm). So, we aimed to analyze the association of neurological symptoms with CNSm. Patients & MethodsPatients with BC referred for a neuro-oncological evaluation at a cancer referral center from June 2012 to December 2017 were included. Demographic, oncological history, comorbidities, clinical symptoms and signs, and their correlation with CNSm were prospectively acquired during consultation in a computerized database. Analyses included descriptive observations, bivariate, and logistic linear regression tests that compared associations. ResultsA total of 857 patients with BC were referred for assessment. The most frequently occurring symptoms included headache, focal motor weakness, focal-sensitive complaints, and visual complaints. Of the 1029 neuro-oncology diagnoses made, the most common were CNSm, primary headache, and chemotherapy-induced neuropathy. The risk factors associated with CNSm in patients with neurological symptoms were HER2+, younger age at cancer diagnosis, presence of extracranial metastases, and >1 neurological symptom (mainly headache: hazard ratio (HR), 2.1 [95% confidence interval (CI), 1.5–2.7]; visual complaints: HR, 2.3 (95%CI, 1.2–4.2); and ataxia: HR, 2.1 (95%CI,1.04–4.3). ConclusionsClinical symptoms and cancer characteristics were correlated with the development of CNSm. Specific risk and protective factors were identified.Among BC patients with neurological symptoms, CNSm should always be considered, especially in patients with certain oncological and clinical features.

Analysis of central nervous system efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer

ObjectivesWe determined the central nervous system (CNS) efficacy of alectinib by calculating time to CNS progression and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and death in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) enrolled in the J-ALEX phase III study. Materials and methodsJapanese patients aged ≥20 years with ALK-positive NSCLC who were ALK inhibitor-naïve and chemotherapy-naïve, or who had received one previous chemotherapy regimen, were enrolled. Patients with treated or untreated asymptomatic CNS metastases were eligible. Treatment comprised oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death or withdrawal. Imaging scans (computed tomography/magnetic resonance imaging) were taken at baseline and at regular intervals throughout the study. The CIRs for CNS progression, non-CNS progression and death were calculated for patients with and without baseline CNS metastases using a competing risks method. ResultsThe hazard ratio for time to CNS progression in patients with and without baseline CNS metastases was 0.51 (95% confidence interval [CI]: 0.16–1.64; P = 0.2502) and 0.19 (95% CI: 0.07–0.53; P = 0.0004), respectively. The CIRs of CNS progression and non-CNS progression were lower in the alectinib group than in the crizotinib group at all time points. The 1-year CIRs of CNS progression were 16.8% and 5.9% with crizotinib and alectinib, respectively, and the 1-year CIRs of non-CNS progression were 38.4% and 17.5%, respectively. Comparable findings were obtained in patients with or without baseline CNS metastases. ConclusionAlectinib appears to avert the progression of CNS metastases in patients with ALK-positive NSCLC and baseline CNS metastases, and to prevent the development of new CNS lesions in patients without baseline CNS disease.

Gastric cancer with brain metastasis and the role of human epidermal growth factor 2 status.

Central nervous system (CNS) metastases from cancers of the gastrointestinal tract (GIT) are rare, and occur in 0.16-0.69% of patients with gastric or gastro-esophageal (GE) junction cancer. Overexpression of the human epidermal growth factor 2 (HER-2) is associated with poor prognosis in the absence of HER-2-targeted therapy, and with an increased incidence of CNS metastases in patients with breast cancer. The role of HER-2 overexpression in CNS metastases is not well known in gastric adenocarcinoma. The purpose of the present retrospective study was to assess the incidence of CNS metastases and to evaluate the associations between the CNS and HER-2 status in a series of consecutive patients with gastric or GE junction cancer. Between 2007 and 2013, 300 patients with gastric cancer (GC) or gastroesophageal junction, were admitted to Piacenza General Hospital, Italy. These cases were retrospectively analyzed to evaluate CNS metastases. The metastases were diagnosed with imaging techniques performed on symptomatic patients. Gastric histological samples of patients with CNS metastases were reviewed and tested for HER-2. A total of 7 of the 300 patients (2.33%) with GC were observed to have CNS metastases and 6 (85.71%) had HER-2 positive disease. These patients exhibited a poor prognosis with a median overall survival rate of 4.1 months (range, 2.1-6.6 months). These results suggested there may be CNS recurrence susceptibility in patients with HER-2 positive GC. To the best of our knowledge, this is the first report that associates CNS metastases and HER-2 status in gastric or GE junction cancer.

CMET-40. THE DEVELOPMENT OF BRAIN METASTASIS IN THE PATIENTS WITH METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) AND MELANOMA TREATED WITH IMMUNE CHECKPOINT INHIBITORS: A RETROSPECTIVE ANALYSIS

AbstractBACKGROUNDSurvival benefit with immune checkpoints inhibitors in patients with metastatic NSCLC and Melanoma has been demonstrated. However, the published results do not describe the incidence of brain metastasis as a site of recurrence in these patients. We sought to determine the incidence of central nervous system (CNS) relapse/progression relative to systemic response in patients with NSCLC or Melanoma treated with a PD-1 inhibitor.METHODSWe retrospectively identified 217 patients (145 with metastatic NSCLC, 72 with metastatic Melanoma) treated with Pembrolizumab or Nivolumab, between 2009 and 2016. Demographic and clinical variable were assessed to determine CNS and systemic response using descriptive statistics.RESULTSThe median age of the cohort was 65 years (22–93), with a median of 1 (0–6) treatment prior to PD-1 inhibitor therapy and median follow-up of 344 days. Of the 217 patients, 213 received monotherapy with either Nivolumab (99) or Pembrolizumab (114). Four patients received Nivolumab combined with Bevacizumab. The median time on therapy was 113 days for Nivolumab (14–1598) and 149 for Pembrolizumab (21–1099). Forty patients had brain metastases at the time of initiation of treatment, and 28 of these patients received treatment for at least one brain metastasis prior to immunotherapy. Thirty-two patients (15%) had CNS disease progression during immunotherapy treatment: 15 patients (7%) developed new CNS disease and 17 (8%) had progression of pre-existing CNS metastasis (7/17 received prior CNS directed treatment). In these 32 patients, concomitant systemic disease progression was observed in 27, and 5 patients progressed only in the CNS.CONCLUSIONThis retrospective analysis showed that development/progression of CNS metastasis in patients on treatment with a PD-1 inhibitor has good concordance with systemic disease status. The incidence of CNS disease in patients on this therapy is comparable to historic cohorts treated with conventional chemotherapy.

Identification of single nucleotide polymorphism of PI3k-AKT-TOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer.

2007 Background: Although new therapeutic options are available, an early diagnosis of central nervous system (CNS) metastasis may be needed to improve the prognosis. The PI3k-Akt-mTor pathway has been shown to be relevant in the development of CNS metastasis. Our aim was to identify risk-associated single nucleotide polymorphisms (SNP) of the PI3K Akt-mTOR pathway in the development of CNS metastasis in patients with metastatic breast cancer. Methods: We performed a secondary analysis in a subpopulation of patients from the GENEOM study (NCT00959556). In this previous study, blood samples were collected from 914 breast cancer patients treated by chemotherapy in the neoadjuvant, adjuvant or metastatic setting for genomic analysis. We identified CNS metastatic patients (both leptomeningeal and parenchymal) and non-CNS metastatic patients (no neurological symptoms or normal brain MRI before death or during 5-years metastatic period). Based on the literature, 88 SNPs of the PI3K-Akt-mTOR pathway were analyzed, including AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). Results: Of the 342 patients with metastases in the GENEOM cohort, 100 patients with CNS metastasis (parenchymal lesions only, n = 51; leptomeningeal lesions only, n = 18; both, n = 31) and 107 patients without CNS metastasis were included. Negative hormonal status (p = 0.002) and presence of vascular emboli on breast cancer samples (p = 0.006) were associated with CNS metastasis. In univariate analysis, genotypes CC of AKT1 rs3803304, AA of AKT2 rs3730050, CC of AKT2 rs8100018, TT of PDK1 rs1168690, GG of PDK1 rs11904366 and GG of PI3KR1 rs251408 were associated with CNS metastasis at the p &lt; 0.05 threshold. Only genotype TT of PI3KR1-rs706716 was statistically associated with CNS metastasis after Bonferroni correction (p = 0.0003, &lt; 0.00085). Conclusions: PI3KR1-rs706716 is associated with CNS metastasis in metastatic breast cancer patients, in addition to negative hormonal status and presence of vascular emboli and could be combined in a composite score to predict the risk of and to detect early CNS metastasis in this population.

Abstract P4-12-27: Efficacy and safety of trastuzumab emtansine (T-DM1) vs lapatinib plus capecitabine (XL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and central nervous system (CNS) metastases: Results from a retrospective exploratory analysis of EMILIA

Abstract Introduction T-DM1 is an antibody–drug conjugate that was recently approved by the FDA for patients with HER2-positive MBC who have received prior treatment with trastuzumab and a taxane. In the phase 3 EMILIA trial, T-DM1 significantly prolonged progression-free survival (PFS) and overall survival (OS) compared with XL in patients with previously treated HER2-positive MBC (Verma 2012). Because the CNS is a common site of progression in HER2-positive MBC, it is of interest to characterize the incidence of CNS metastases in patients treated with TDM1 vs XL and the efficacy of T-DM1 in patients with pre-existing CNS metastases. Methods EMILIA is a multicenter, randomized, open-label trial in which patients with HER2-positive, unresectable, locally advanced or MBC previously treated with trastuzumab and a taxane were randomized (1:1) to T-DM1 (3.6 mg/kg every 21 days) or XL (X: 1000 mg/m2 bid on days 1–14 of each 21-day cycle; L: 1250 mg/day on days 1–21). Treatment continued until disease progression or unacceptable toxicity. All patients underwent brain magnetic resonance imaging or computed tomography at screening, and follow-up scans were performed as clinically indicated. Those with untreated or symptomatic brain metastases and those who required therapy for symptom control ≤2 months before randomization were excluded from the trial. Patients with CNS metastases at baseline or who developed CNS metastases on study were retrospectively identified using independent review committee data, and exploratory analyses were performed on data from these patients. Results Of the 896 patients without CNS metastases at baseline (T-DM1 = 450; XL = 446), 9 (1.8%) and 3 (0.6%), respectively, developed CNS progression on study. Of the 95 patients with CNS metastases at baseline (T-DM1 = 45; XL = 50), 10 (2.0%) and 8 (1.6%), respectively, developed CNS progression on study. Median PFS in patients with CNS metastases at baseline was 5.9 months in the T-DM1 arm and 5.7 months in the XL arm (HR = 1.000; 95% CI: 0.542–1.844; P = 0.9998). Median OS was 26.8 months and 12.9 months in the T-DM1 and XL arms, respectively (HR = 0.382; CI: 0.184–0.795; P = 0.0081). Multivariate analysis adjusting for baseline risk factors produced similar results. Safety profiles of T-DM1 and XL in patients with CNS metastases at baseline (T-DM1 = 43; XL = 49) were consistent with those for the overall study population. Grade ≥3 adverse events (AEs) were reported in 17 (39.5%) patients in the T-DM1 arm and 29 (59.2%) patients in the XL arm. Serious AEs were reported in 5 (11.6%) and 11 (22.4%) patients in the T-DM1 and XL arms, respectively. No new safety signals were identified. Conclusions In this retrospective exploratory analysis of data from EMILIA, the rate of CNS progression in patients with or without baseline CNS metastases was low in both treatment arms. In the subset of patients with brain metastases at baseline, similar to the intent-to-treat population, T-DM1 was associated with significantly improved OS compared with XL. Prospective phase 3 trials are necessary to confirm these results. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-27.

Predictive Factors for the Development of Brain Metastasis in Advanced Unresectable Metastatic Melanoma

Melanoma that metastasizes to distant sites is associated with a grave prognosis. The objectives of the study were (1) to identify predictive factors for the development of brain metastases from the time of diagnosis of stage III/IV disease, (2) to identify predictive factors for the development of central nervous system (CNS) metastases from the time of diagnosis of primary melanoma, and (3) to assess whether the incidence of brain metastasis is more frequent in patients who had no tumor response to systemic therapy for stage III/IV disease compared with those who had partial or complete response. We collected and retrospectively analyzed information of 740 patients with advanced metastatic melanoma treated at MD Anderson Cancer Center over 15 years. Three hundred and twenty-nine patients had CNS metastases. The characteristics of these patients in terms of median age, sex, primary site, Breslow thickness, stage at first visit, baseline serum parameters, and response to systemic therapy were compared with those of patients who did not develop CNS metastasis. Cox proportional hazards models were used to analyze the cause-specific hazard function for CNS metastasis and deaths without CNS metastasis. We identified that M-stage [stage M1b vs. stage III or M1a, hazard ratio (HR)=2.64; stage M1c vs. stage III or M1a, HR=2.13, P<0.0001] and lactic acid dehydrogenase (LDH) (elevated vs. normal LDH, HR=1.51, P<0.001) at diagnosis of unresectable stage III/IV disease can independently predict the risk of developing CNS metastasis from the time of diagnosis of stage III/IV disease. Older age (HR=1.01, P=0.076), chemoresistance (stable disease+progressive disease vs. complete response+partial response HR=2.91, P<0.0001), low level of albumin (vs. normal HR=2.87, P<0.0001), elevated LDH (vs. normal HR=1.55, P=0.0004), and M-stage (M1c disease vs. stage III or M1a HR=1.89, P<0.0001) can independently predict shorter time to death without CNS metastasis from the diagnosis of stage III/IV disease. The location (head and neck vs. limbs HR=1.56, P=0.028; trunk and abdomen vs. limbs HR=1.45, P=0.029; unknown site vs. limbs HR=8.43, P=0.036) and pathology [Clark level (CL)=3 and/or BR2 to 4 mm vs. CL≤2 and/or BR<2 mm HR=1.60, P=0.037; CL>3 and/or BR> 4 mm vs. CL≤2 and/or BR<2 mm HR=2.03, P=0.001) of the primary melanoma can independently predict CNS metastasis-free interval from the time of diagnosis of primaries. Age (HR=1.012, P=0.034) and pathology of the primary melanoma (CL>3 and/or BR>4 mm vs. CL≤2 and/or BR<2 mm HR=1.54, P=0.024) can independently predict time to death without CNS metastasis from primaries. We identified the predictive factors associated with the development of CNS metastasis in patients with unresectable metastatic melanoma.

Clinical Utility of Continuing Trastuzumab Beyond Brain Progression in HER-2–Positive Metastatic Breast Cancer

In a previous issue of The Oncologist, Gori et al. [1] described well the patterns of progression and survival of human epidermal growth factor receptor (HER)-2–positive metastatic breast cancer (MBC) patients who develop central nervous system (CNS) metastases following treatment with trastuzumab-based therapies. Their results are consistent with previous findings reporting a higher-than-usual incidence of CNS metastases in patients treated with trastuzumab-including regimens [2, 3]. As highlighted by those authors, this phenomenon reflects the poor penetration of trastuzumab through the blood–brain barrier [4] rather than a loss of sensitivity to the treatment. In fact, most of the patients who develop CNS metastases on trastuzumab do so at a time when their extracranial disease is being controlled by trastuzumab itself [1–3]. For this reason, the longer survival observed in HER-2–positive MBC patients with CNS metastases has been attributed to the better control of extracranial disease obtained by trastuzumab [1, 5]. In this context, another issue that remains to be addressed is whether continuation of trastuzumab beyond brain progression would be beneficial for patients who develop CNS metastases while on treatment with trastuzumab, as compared with those individuals who crossover to second-line chemotherapy without trastuzumab. To address this question, we recently reviewed the medical records of the Division of Medical Oncology A at the Regina Elena National Cancer Institute in Rome in order to identify the HER-2–positive MBC patients who developed CNS metastases during treatment with trastuzumab either alone or in combination with chemotherapy and/or hormonal therapy. Figure 1 shows the flowchart of brain events and patterns of treatment of the 69 patients analyzed. Among the 20 patients who received further systemic treatment upon brain progression, 10 received further trastuzumab-based therapy and 10 received second-line chemotherapy without trastuzumab. Table 1 lists patient

Risk factors for central nervous system metastasis in patients with metastatic breast cancer

Patients with metastatic breast cancer (MBC) and central nervous system (CNS) involvement have an impaired survival and quality of life. In this study, we investigated the risk factors for CNS metastasis among patients with MBC. The risk factors for development of CNS metastasis were analyzed in 154 patients with MBC. Expression of c-erbB-2, Ki-67, p53, and hormone receptors was examined by immunohistochemistry (IHC) in breast cancer tissue samples from the 154 patients. Kaplan-Meier and log-rank tests were used for the analysis of overall survival (OS). Chi-square test was used for univariate analysis. Median OS was significantly poorer for patients with CNS metastasis as compared with patients with no CNS metastasis (OS, 23 mo vs 30 mo, respectively;p = 0.03). Ki-67 and p53 overexpressions by IHC, and lung metastasis as the first site of relapse, were associated with a higher risk of developing CNS metastasis in the univariate analysis (p <or= 0.05). The presence of lung metastasis (odds ratio [OR]= 2.82, 95% confidence interval [CI]: 1.13-7.00,p = 0.02) and p53 overexpression (OR = 2.44, 95% CI: 0.99-6.00,p = 0.05) were the two predictive factors associated with occurrence of CNS metastasis in the multivariate analysis. In this study, the presences of lung metastasis as the first site of relapse and p53 overexpression were predictive for the occurrence of CNS metastasis in patients with MBC. Life expectancy of patients with CNS metastasis is significantly shorter than those without CNS metastasis. These results may have clinical significance in counseling MBC patients with regard to their prognosis.

Prophylactic Cranial Irradiation With Combined Modality Therapy for Patients With Locally Advanced Non-Small Cell Lung Cancer

Central nervous system (CNS) metastasis is a significant problem for many patients with non-small cell lung cancer (NSCLC). The earlier data reported a high incidence of CNS metastasis in patients with locally advanced NSCLC who were treated with radiotherapy alone. However, poor control of both thoracic and extracranial systemic disease dominated the results of the early trials. The risk for CNS metastasis as the first site of failure remains a significant concern for patients who have completed modern combined modality therapy. With improvements in the treatment of thoracic and systemic disease, there is renewed interest in prophylactic cranial irradiation (PCI). The results from the Radiation Therapy Oncology Group (RTOG) trial of PCI to prevent CNS relapse in patients with locally advanced NSCLC are anticipated.

The role of prophylactic cranial irradiation in the management of small cell lung cancer

Those patients who benefit most in terms of increased survival from the current treatment of small cell lung cancer (SCLC) are also those who run the greatest risk of developing brain metastases. In a compilation of 11 studies with 1688 patients, Pedersen (1) calculated that about 10% had central nervous system (CNS) metastases at diagnosis of SCLC, while a further 20% (range 7-30%) developed CNS metastases during therapy. At autopsy the frequency was found to be about 50% (1, 2). An increase in frequency of brain metastases in SCLC with increased survival was predicted as early as 1973 (3), and the prediction was confirmed in 1979 by Nugent et al. (4), who demonstrated an actuarial probability of developing brain metastases of 80% 2 years after diagnosis. Similar tendencies were subsequently demonstrated by others (5), and in a series from the Finsen Institute in Copenhagen the cumulative risk of brain metastases reached 50% at 2 years survival (1). An early and widely disseminated hypothesis explaining the increase in CNS metastases in patients with prolonged survival describe the brain as a pharmacologic sanctuary, where metastases can grow shielded from cytostatic agents by the blood-brain-barrier (BBB). This hypothesis has to some degree been corroborated by the clinical experience with childhood leukemia, where prophylactic cranial irradiation (PCI) is an integrated part of most treatment programmes. When CNS metastases are diagnosed by intravenous iodine contrast-enhanced CT-scan, the BBB is not intact in the tumor areas, and such areas therefore should be accessible to drugs according to the same principles that govern extracranial metastases. During the last decade, several reports about the effect of systemic chemotherapy on brain metastases from SCLC have been published, see (6, 7) for a review. Thus, the concept of the brain as a pharmacologic sanctuary site for metastases is inconsistent with newer clinical observations. In spite of the fact that clinical brain metastasis is an ominous prognostic indicator, it is disputable what influence the presence of brain metastases per se, if actively