Radiosurgery and whole brain therapy in the treatment of brainstem metastases

Purpose  

The incidence of brainstem metastasis (BSM) accounts for 1–3% of brain metastases (BM). They are often associated with multiple BM and produce significant neurological symptoms. We retrospectively analyse the results of treatment with stereotactic radiosurgery (SRS).     

Carmustine and methotrexate in combination after whole brain radiation therapy in breast cancer patients presenting with brain metastases: a retrospective study

Background  

Since 1999, patients presenting with brain metastases (BM) from breast cancer (BC) are treated in our institution with a carmustine (BCNU) - methotrexate (MTX) combination. We report here our clinical experience regarding this combination.     

Breast cancer subtypes and survival in patients with brain metastases

Introduction

Brain metastases (BM) occur in up to one third of patients with metastatic breast cancer (MBC), whose incidences and prognoses by breast cancer subtypes in BM have not been well delineated.

Methods

Retrospective survival analyses were performed in 126 BM patients from 805 MBC patients treated at the National Cancer Center between August 2001 and April 2006, according to clinical characteristics, breast cancer subtypes, and receipt of trastuzumab. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor-2 (HER2) statuses were tested by immunohistochemical (IHC) staining, and HER2 FISH analysis conducted for IHC 2+.

Results

The proportion of HER2+/ER- (29% vs 16%) and triple-negative (37% vs 25%) tumors was higher in the 126 BM patients than those without BM. While median survival after recurrence was longer in patients with luminal A disease (median survival of luminal A vs luminal B vs HER2+/ER- vs triple-negative: p = 0.0246; 39.6 vs 27.4 vs 20.9 vs 15.5 months), survival was shorter from BM to death in luminal A and triple negatives (median survival: p = 0.0113; 4.0 vs 9.2 vs 5.0 vs 3.4 months). Receipt of trastuzumab after BM was a significant variable for survival in HER2+ patients. Multivariate analyses identified ER-negative, HER2-negative, or triple-negative, as well as older age, presence of leptomeningeal disease, and three or more extracranial disease sites, as poor prognostic factors for survival after BM.

Conclusion

MBC patients who developed BM had higher proportions of triple-negative and HER2+/ER- tumor status. Triple receptor status is a useful prognostic marker for predicting survival after BM in metastatic breast cancer patients.     

Recursive partitioning analysis classification and graded prognostic assessment for non-small cell lung cancer patients with brain metastasis: A retrospective cohort study

Objective:To assess prognostic factors and validate the effectiveness of recursive partitioning analysis (RPA) classes and graded prognostic assessment (GPA) in 290 non-small cell lung cancer (NSCLC) patients with brain metastasis (BM).Methods:From Jan 2008 to Dec 2009,the clinical data of 290 NSCLC cases with BM treated with multiple modalities including brain irradiation,systemic chemotherapy and tyrosine kinase inhibitors (TKIs) in two institutes were analyzed.Survival was estimated by Kaplan-Meier method.The differences of survival rates in subgroups were assayed using log-rank test.Multivariate Cox’s regression method was used to analyze the impact of prognostic factors on survival.Two prognostic indexes models (RPA and GPA) were validated respectively.Results:All patients were followed up for 1-44 months,the median survival time after brain irradiation and its corresponding 95% confidence interval (95% CI) was 14 (12.3-15.8) months.1-,2-and 3-year survival rates in the whole group were 56.0%,28.3%,and 12.0%,respectively.The survival curves of subgroups,stratified by both RPA and GPA,were significantly different (P<0.001).In the multivariate analysis as RPA and GPA entered Cox’s regression model,Karnofsky performance status (KPS) ≥ 70,adenocarcinoma subtype,longer administration of TKIs remained their prognostic significance,RPA classes and GPA also appeared in the prognostic model.Conclusion:KPS ≥70,adenocarcinoma subtype,longer treatment of molecular targeted drug,and RPA classes and GPA are the independent prognostic factors affecting the survival rates of NSCLC patients with BM.     

Non‐small cell lung cancer brain metastasis screening in the era of positron emission tomography‐CT staging: Current practice and outcomes

Introduction

Several clinical guidelines indicate that brain metastasis screening (BMS) should be guided by disease stage in non‐small cell lung cancer (NSCLC). We estimate that screening is performed more broadly in practice, and patients undergo brain imaging at considerable cost with questionable benefit. Our aim was to quantify the use and detection rate of BMS in a contemporary cohort staged with ¹⁸F‐fluorodeoxyglucose positron emission tomography/computed tomography (PET‐CT).

Methods

We conducted a retrospective review of prospectively collected data from three major lung cancer referral centres in Brisbane between January 2011 and December 2015. Patients included had a new diagnosis of NSCLC and had undergone a PET‐CT to stage extra‐cranial disease. BMS was defined as dedicated brain imaging with contrast‐enhanced computed tomography (CE‐CT) or magnetic resonance (MR), in the absence of clinically apparent neurological deficits.

Results

A total of 1751 eligible cases were identified and of these 718 (41%) underwent BMS. The majority had CE‐CT imaging (n = 703). Asymptomatic brain metastases (BM) were detected in 18 patients (2.5%). Of these patients, 12 had concurrent non‐brain metastases. Only six patients (0.8%) had BM alone. The rate of detection increased with N‐stage (P = 0.02) and overall stage (P < 0.001). It was 0.5%, 1%, 1.6% and 7.3% for stage I, II, III and IV respectively. The overall screening rate increased with T‐stage (P = 0.001), N‐Stage (P < 0.001) and overall stage (P < 0.001).

Conclusions

Non‐small cell lung cancer BMS practices remain at odds with published guidelines. The low number of occult BMs detected supports the existing international recommendations. Rationalising BMS would minimise the burden on patients and the health care system.     

Concomitant treatment of brain metastasis with Whole Brain Radiotherapy [WBRT] and Temozolomide [TMZ] is active and improves Quality of Life

Background  

Brain metastases (BM) represent one of the most frequent complications related to cancer, and their treatment continues to evolve. We have evaluated the activity, toxicity and the impact on Quality of Life (QoL) of a concomitant treatment with whole brain radiotherapy (WBRT) and Temozolomide (TMZ) in patients with brain metastases from solid tumors in a prospective Simon two stage study.     

Incidence of brain metastasis at initial presentation of lung cancer

Background

No reliable estimates are available on the incidence of brain metastasis (BM) in cancer patients. This information is valuable for planning patient care and developing measures that may prevent or decrease the likelihood of metastatic brain disease.

Methods

We report the first population-based analysis on BM incidence at cancer diagnosis using the Kentucky Cancer Registry (KCR) and Alberta Cancer Registry (ACR). All cancer cases with BM were identified from KCR and ACR, with subsequent focus on metastases from lung primaries; the annual number of BMs at initial presentation was derived. Comparisons were made between Kentucky and Alberta for the stage and site of organ involvement of lung cancer.

Results

Low incidence of BM was observed in the United States until mandatory reporting began in 2010. Both the KCR and ACR recorded the highest incidence of BM from lung cancer, with total BM cases at initial presentation occurring at 88% and 77%, respectively. For lung cancer, stage IV was the most common stage at presentation for both registries and ranged from 45.9% to 57.2%. When BM from lung was identified, the most common synchronous organ site of metastasis was osseous, occurring at 28.4%.

Conclusion

Our analysis from the Kentucky and Alberta cancer registries similarly demonstrated the aggressive nature of lung cancer and its propensity for BM at initial presentation. Besides widespread organ involvement, no synchronous organ site predicted BM in lung cancer. BM is a common and important clinical outcome, and use of registry data is becoming more available.     

Assessment of prognostic scores in brain metastases from breast cancer

Background

Breast cancer (BC) is the second most common cause of brain metastases (BM). Optimal management of BM from BC is still debated. In an attempt to provide appropriate treatment and to assist with optimal patient selection, several specific prognostic classifications for BM from BC have been established. We evaluated the prognostic value and validity of the 6 proposed scoring systems in an independent population of BC patients with BM.

Methods

We retrospectively reviewed all consecutive BC patients referred to our institution for newly diagnosed BM between October 1995 and July 2011 (n = 149). Each of the 6 scores proposed for BM from BC (Sperduto, Niwinska, Park, Nieder, Le Scodan, and Claude) was applied to this population. The discriminative ability of each score was assessed using the Brier score and the C-index. Individual prognostic values of clinical and histological factors were analyzed using uni- and multivariate analyses.

Results

Median overall survival was 15.1 months (95% CI,11.5–18.7). Sperduto-GPA (P < .001), Nieder (P < .001), Park (P < .001), Claude (P < .001), Niwinska (P < .001), and Le Scodan (P = .034) scores all showed significant prognostic value. The Nieder score showed the best discriminative ability (C-index, 0.672; Brier score error reduction, 16.1%).

Conclusion

The majority of prognostic scores were relevant for patients with BM from BC in our independent population, and the Nieder score seems to present the best predictive value but showed a relatively low positive predictive value. Thus, these results remain insufficient and challenge the routine use of these scoring systems.     

Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy

Introduction

To explore the ability of gefitinib to penetrate blood brain barrier (BBB) during whole brain radiation therapy (WBRT).

Patients and Methods

Enrolled in this study were eligible patients who were diagnosed with BM from NSCLC. Gefitinib was given at 250 mg/day for 30 days, then concurrently with WBRT (40 Gy/20 F/4 w), followed by maintenance. Serial CSF and blood samples were collected on 30 day after gefitinib administration, and at the time of 10, 20, 30 and 40 Gy following WBRT. CSF and plasma samples of 13 patients without BM who were treated with gefitinib were collected as control. CSF and plasma gefitinib levels were measured by LC-MS/MS.

Results

Fifteen BM patients completed gefitinib plus WBRT. The CSF-to-plasma ratio of gefitinib in patients with BM was higher than that in patients without BM (1.34% vs. 0.36%, P < 0.001). The CSF-to-plasma ratio of gefitinib increased with the increased dose of WBRT and reached the peak (1.87 ± 0.72%) at 30 Gy, which was significantly higher than that 1.34 ± 0.49% at 0 Gy (P = 0.01). The median time to progression of brain lesions and the median overall survival were 7.07 and 15.4 months, respectively.

Conclusion

The BBB permeability of gefitinib increased in accordance with escalated dose of WBRT.     

Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases

Background:

Trastuzumab-based therapy after diagnosis of brain metastases (BM) may improve survival due to prolonged systemic disease control. We investigated whether lapatinib may yield additional survival benefit.

Methods:

Eighty patients with BM from HER2-positive breast cancer were identified. Karnofsky Performance Score (KPS) of at least 70 was required. We included a control group of 37 patients treated before 2003, when continuation of trastuzumab after diagnosis of BM was not yet recommended. Remainders received either trastuzumab or lapatinib and trastuzumab (either concomitantly or sequentially) with or without chemotherapy.

Results:

Median overall survival (OS) in patients receiving trastuzumab after diagnosis of BM was 13 months; corresponding numbers were 9 months in patients treated with chemotherapy, and 3 months with radiotherapy alone. Median OS was not reached in the lapatinib group. Addition of lapatinib prolonged OS over trastuzumab alone (P=0.002). After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival (HR 0.279; P=0.012).

Interpretation:

This retrospective single-centre study suggests that the introduction of lapatinib improved survival in patients with BM from HER2-positive breast cancer. Patients with KPS ⩾70 may benefit when treated with lapatinib in addition to trastuzumab after completion of local therapy.     

Survival in patients with brain metastases from breast cancer: the importance of HER-2 status

BACKGROUND

Brain metastases (BM) are the most common intracranial tumors in adults. To the authors' knowledge, established prognostic factors for survival after the diagnosis of BM in breast cancer patients do not take into account HER–2 status, which may have increasing relevance in the trastuzumab therapy era.

METHODS

The authors identified 83 patients with breast cancer and new parenchymal BM diagnosed between January 1, 2001 and December 31, 2005 who were treated at Massachusetts General Hospital. Survival was estimated using the Kaplan‐Meier method and curves were compared using the log‐rank test. A Cox proportional hazards model was used to determine independent predictors of survival.

RESULTS

The median overall survival from the time of BM was 8.3 months. On univariate analysis, HER‐2‐positive patients were found to have prolonged survival after BM compared with HER‐2‐negative patients (17.1 months vs 5.2 months). Patients with triple negative disease had a median survival of 4.0 months, compared with 11.2 months for all other patients. Additional predictors of improved survival on univariate analysis included ≤3 BM, controlled or absent systemic disease, and controlled local disease. On multivariate analysis, only HER‐2 status, number of BM, and local disease status remained independent predictors of survival.

CONCLUSIONS

HER‐2 status is a strong predictor of survival after the diagnosis of BM. The survival of breast cancer patients with BM appears to be improving, but a better understanding of both the predictors of brain recurrence and the delayed effects of treatment is needed to properly counsel patients regarding the risk‐benefit ratio of various treatment modalities. Cancer 2008. © 2008 American Cancer Society.     

Discrepancies between biomarkers of primary breast cancer and subsequent brain metastases: an international multicenter study

Purpose

Discordances between the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), expression between primary breast tumors and their subsequent brain metastases (BM) were investigated in breast cancer patients.

Methods

We collected retrospective data from 11 institutions in 8 countries in a predefined-standardized format. Receptor status (positive or negative) was determined according to institutional guidelines (immunohistochemically and/or fluorescence in situ hybridization). The study was subject to each institution’s ethical research committee.

Results

A total of 167 breast cancer patients with BM were included. 25 patients out of 129 with a complete receptor information from both primary tumor and BM (ER, PR, HER2) available, had a change in receptor status: 7 of 26 (27%) ER/PR-positive/HER2-negative primaries (3 gained HER2; 4 lost expression of ER/PR); 10 of 31 (32%) ER/PR-positive/HER2-positive primaries (4 lost ER/PR only; 3 lost HER2 only; 3 lost both ER/PR and HER2); one of 33 (3%) ER/PR-negative receptor/HER2-positive primaries (gained ER); and 7 of 39 (18%) triple-negative primaries (5 gained ER/PR and 2 gained HER2).

Conclusions

The majority of breast cancer patients with BM in this series had primary HER2-enriched tumors, followed by those with a triple-negative profile. One out of 5 patients had a receptor discrepancy between the primary tumor and subsequent BM. Therefore, we advise receptor status assessment of BM in all breast cancer patients with available histology as it may have significant implications for therapy.

     

Real-world data on patterns and outcomes of radiation therapy for brain metastases in a population-based cohort of lung cancer patients in Victoria

Introduction

We evaluated real-world data on the patterns and outcomes of radiotherapy (RT) for brain metastases (BM) in a population-based cohort of patients with lung cancer (LC) in Victoria.

Methods

The Victorian Radiotherapy Minimum Data set (VRMDS) and the Victorian Cancer Registry (VCR) were linked to identify patients with LC who underwent RT for BM between 2013 and 2016. We determined: (i) proportion of patients treated with stereotactic radiosurgery (SRS); (ii) overall survival (OS); and (iii) 30-day mortality (30M) following RT for BM.

Results

Of the 1001 patients included in the study, 193 (19%) had SRS. There was no significant increase in SRS use over time – from 18% in 2013 to 21% in 2016 (P-trend = 0.8). In multivariate analyses, increased age (P = 0.03) and treatment in regional centres (P < 0.001) were independently associated with lower likelihood of SRS treatment. The median OS following RT for BM was 3.6 months. Patients who had SRS had better OS than those who did not have SRS (median OS 8.9 months vs. 3 months, P < 0.01). SRS use, age, sex and year of treatment were independently associated with OS in multivariate analyses. A total of 184 (18%) patients died within 30 days of RT for BM, and the proportion was higher in older (P = 0.001) and male patients (P = 0.004).

Conclusion

One-in-five LC patients who received RT for BM had SRS. The improved OS with SRS is likely confounded by patient selection. It is important to reduce 30M by better selecting patients who may not benefit from RT for BM.     

Prediction of postoperative disease-free survival and brain metastasis for HER2-positive breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab using a machine learning algorithm

Purpose

This study aimed to develop mathematical tools to predict the likelihood of recurrence after neoadjuvant chemotherapy (NAC) plus trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer.

Methods

Data of 776 patients from a multicenter retrospective cohort study were collected. All patients had HER2-positive breast cancer and received NAC plus trastuzumab between 2001 and 2010. Two mathematical tools using a machine learning method were developed to predict the likelihood of disease-free survival (DFS) (DFS model) and brain metastasis (BM) (BM model) within 5 years after surgery. For validation, bootstrap analyses were conducted. The area under the receiver operating characteristics curve (AUC) was calculated to examine the discrimination.

Results

The AUC values were 0.785 (95% CI 0.740–0.831, P?<?0.001) for the DFS model and 0.871 (95% CI 0.830–0.912, P?<?0.001) for the BM model. Patients with low-risk DFS or BM events, as predicted by the models, showed better 5-year DFS and BM rates than those with high-risk DFS or BM events (89% vs. 61% for the DFS model, P?<?0.001; 99% vs. 87% for the BM model, P?<?0.001). These models maintained discrimination abilities in both luminal and non-luminal subtypes, providing prognostic information independent of pathological response. Bootstrap validation confirmed the high generalization abilities of the models.

Conclusions

The DFS and BM models have a high accuracy to predict prognosis among HER2-positive patients treated with NAC plus trastuzumab. Our models can help optimize adjuvant therapy and postoperative surveillance.

     

Exit of pediatric pre-B acute lymphoblastic leukaemia cells from the bone marrow to the peripheral blood is not associated with cell maturation or alterations in gene expression

Background  

Childhood pre-B acute lymphoblastic leukemia (ALL) is a bone marrow (BM) derived disease, which often disseminates out of the BM cavity, where malignant cells to a variable degree can be found circulating in the peripheral blood (PB). Normal pre-B cells are absolutely dependent on BM stroma for survival and differentiation. It is not known whether transformed pre-B ALL cells retain any of this dependence, which possibly could impact on drug sensitivity or MRD measurements.     

If it is in the marrow,is it also in the blood? An analysis of 1,000 paired samples from patients with B-cell non-Hodgkin lymphoma

Background  

Staging of B-cell non Hodgkin's lymphoma (NHL) routinely involves bone marrow (BM) examination by trephine biopsy (BM-TB). The evidence of disease in the BM-TB results in a clinical stage IV classification affecting therapeutic strategies for NHL patients. BM immunophenotyping by flow cytometry (FC) is also used, although its clinical value is still under debate.     

Epidermal growth factor receptor mutation predicts favorable outcomes in non-small cell lung cancer patients with brain metastases treated with stereotactic radiosurgery

Purpose

The impact of epidermal growth factor receptor (EGFR) mutations on radiotherapy for brain metastases (BM) is undetermined. We evaluated the effects of EGFR mutation status on responses and outcomes in non-small cell lung cancer (NSCLC) patients with BM, treated with upfront or salvage stereotactic radiosurgery (SRS).

Anaemia and thrombocytopenia in patients with prostate cancer and bone metastases

Background  

The purpose of this study was to determine the incidence, risk factors and prognostic impact of anaemia and thrombocytopenia in patients with bone metastases (BM) from prostate cancer.     

Impact of preexisting tumor necrosis on the efficacy of stereotactic radiosurgery in the treatment of brain metastases in women with breast cancer

BACKGROUND:

Breast cancer is the second most common source of brain metastasis. Stereotactic radiosurgery (SRS) can be an effective treatment for some patients with brain metastasis (BM). Necrosis is a common feature of many brain tumors, including BM; however, the influence of tumor necrosis on treatment efficacy of SRS in women with breast cancer metastatic to the brain is unknown.

METHODS:

A cohort of 147 women with breast cancer and BM treated consecutively with SRS over 10 years were studied. Of these, 80 (54.4%) had necrosis identified on pretreatment magnetic resonance images and 67 (46.4%) did not. Survival times were computed using the Kaplan‐Meier method. Log‐rank tests were used to compare groups with respect to survival times, Cox proportional hazards regression models were used to perform univariate and multivariate analyses, and chi‐square and Fisher exact tests were used to compare clinicopathologic covariates.

RESULTS:

Neurological survival (NS) and survival after SRS were decreased in BM patients with necrosis at the time of SRS compared with patients without necrosis by 32% and 27%, respectively (NS median survival, 25 vs 17 months [log‐rank test, P = .006]; SRS median survival, 15 vs 11 months [log‐rank test, P = .045]). On multivariate analysis, HER2 amplification status and necrosis influenced NS and SRS after adjusting for standard clinical features, including BM number, size, and volume as well as Karnofsky performance status.

CONCLUSION:

Neuroimaging evidence of necrosis at the time of SRS significantly diminished the efficacy of therapy and was a potent prognostic marker. Cancer 2012. © 2011 American Cancer Society.     

Detection of mammaglobin mRNA in peripheral blood is associated with high grade breast cancer: Interim results of a prospective cohort study

Background  

We sought to examine the detection rate of cancer cells in peripheral blood (PBL) and in bone marrow (BM) using an established 7-gene marker panel and evaluated whether there were any definable associations of any individual gene with traditional predictors of prognosis.