Daniel N. Cagney

Glioproliferative Lesion of the Spinal Cord as a Complication of “Stem-Cell Tourism”

A primitive neoplasm composed predominantly of nonhost cells was detected in the thoracic spinal cord and thecal sac of a 66-year-old man who had received experimental stem-cell treatment from commercial clinics.

Brain Metastases in Newly Diagnosed Breast Cancer: A Population-Based Study.

Importance Population-based estimates of the incidence and prognosis of brain metastases at diagnosis of breast cancer are lacking. Objective To characterize the incidence proportions and median survivals of patients with breast cancer and brain metastases at the time of cancer diagnosis. Design, Setting, and Participants Patients with breast cancer and brain metastases at the time of diagnosis were identified using the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. Data were stratified by subtype, age, sex, and race. Multivariable logistic and Cox regression were performed to identify predictors of the presence of brain metastases at diagnosis and factors associated with all-cause mortality, respectively. For incidence, we identified a population-based sample of 238 726 adult patients diagnosed as having invasive breast cancer between 2010 and 2013 for whom the presence or absence of brain metastases at diagnosis was known. Patients diagnosed at autopsy or with an unknown follow-up were excluded from the survival analysis, leaving 231 684 patients in this cohort. Main Outcomes and Measures Incidence proportion and median survival of patients with brain metastases and newly diagnosed breast cancer. Results We identified 968 patients with brain metastases at the time of diagnosis of breast cancer, representing 0.41% of the entire cohort and 7.56% of the subset with metastatic disease to any site. A total of 57 were 18 to 40 years old, 423 were 41 to 60 years old, 425 were 61-80 years old, and 63 were older than 80 years. Ten were male and 958 were female. Incidence proportions were highest among patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive (1.1% among entire cohort, 11.5% among patients with metastatic disease to any distant site) and triple-negative (0.7% among entire cohort, 11.4% among patients with metastatic disease to any distant site) subtypes. Median survival among the entire cohort with brain metastases was 10.0 months. Patients with HR-positive HER2-positive subtype displayed the longest median survival (21.0 months); patients with triple-negative subtype had the shortest median survival (6.0 months). Conclusions and Relevance The findings of this study provides population-based estimates of the incidence and prognosis for patients with brain metastases at time of diagnosis of breast cancer. The findings lend support to consideration of screening imaging of the brain for patients with HER2-positive or triple-negative subtypes and extracranial metastases.

Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study

Background Brain metastases are associated with significant morbidity and mortality. Population-level data describing the incidence and prognosis of patients with brain metastases are lacking. The aim of this study was to characterize the incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy using recently released data from the Surveillance, Epidemiology, and End Results (SEER) program. Methods We identified 1302166 patients with diagnoses of nonhematologic malignancies originating outside of the CNS between 2010 and 2013 and described the incidence proportion and survival of patients with brain metastases. Results We identified 26430 patients with brain metastases at diagnosis of cancer. Patients with small cell and non-small cell lung cancer displayed the highest rates of identified brain metastases at diagnosis; among patients presenting with metastatic disease, patients with melanoma (28.2%), lung adenocarcinoma (26.8%), non-small cell lung cancer not otherwise specified/other lung cancer (25.6%), small cell lung cancer (23.5%), squamous cell carcinoma of the lung (15.9%), bronchioloalveolar carcinoma (15.5%), and renal cancer (10.8%) had an incidence proportion of identified brain metastases of >10%. Patients with brain metastases secondary to prostate cancer, bronchioloalveolar carcinoma, and breast cancer displayed the longest median survival (12.0, 10.0, and 10.0 months, respectively). Conclusions In this study we provide generalizable estimates of the incidence and prognosis for patients with brain metastases at diagnosis of a systemic malignancy. These data may allow for appropriate utilization of brain-directed imaging as screening for subpopulations with cancer and have implications for clinical trial design and counseling of patients regarding prognosis.

Immunotherapy and Symptomatic Radiation Necrosis in Patients With Brain Metastases Treated With Stereotactic Radiation

This study investigates the association between immunotherapy and symptomatic radiation necrosis in patients with melanoma, non–small-cell lung cancer, or renal cell carcinoma and newly diagnosed brain metastases treated with stereotactic radiation therapy.

Radiation and PD-1 inhibition: Favorable outcomes after brain-directed radiation

BACKGROUND AND PURPOSE Patients with metastatic melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune checkpoint blockade targeting the programed death (PD)-1 receptor, often with palliative radiation therapy. Outcome data are limited in this population. MATERIAL AND METHODS We retrospectively reviewed consecutive patients with metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy at four centers. RESULTS We identified 137 patients who received radiation and PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and 121days for NSCLC, melanoma, and RCC patients. Among 59 patients who received radiation following the start of PD-1 blockade, 25 continued to receive PD-1 inhibition for a median of 179days and survived for a median of 238 additional days. Median survival following first course of radiation for brain metastases was 634days. Melanoma patients received brain directed radiation relatively less frequently following the start of PD-1 inhibitor treatment. CONCLUSIONS Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls.

The cost and value of glioblastoma therapy

Malignant brain tumors account for 1.4% of the total cancer cases, with glioblastoma (GBM) being the most common in adults, with approximately 17,000 new cases per year in the United States [1]. Patients with GBM face a frequently incurable illness with few efficacious therapies. Furthermore, GBM may cause significant neurological dysfunction and result in disproportionately high morbidity. Preserving quality of life remains a vital component of patients’ preferences and values. Current standard of care for newly diagnosed GBM was defined by the EORTC/NCIC CE.3 trial in 2005 to include maximal safe surgical resection, adjuvant chemoradiation with temozolomide (TMZ), followed by ongoing TMZ monotherapy [2]. While there are ongoing efforts to improve both radiotherapy and systemic therapy for GBM, median survival remains less than 18 months from diagnosis [2]. Sparse data exists examining the cost and value of various therapeutic strategies in GBM despite the associated high morbidity and mortality. Some studies have reported on direct medical and treatmentrelated costs, but a lack of data exists on indirect costs associated with premature death or years of productive life lost [3]. In an era of limited resources and rising healthcare costs, it is important to not only consider the direct and indirect costs to the patient but also the value of delivered treatments.

Impact of pemetrexed on intracranial disease control and radiation necrosis in patients with brain metastases from non-small cell lung cancer receiving stereotactic radiation

BACKGROUND Pemetrexed is a folate antimetabolite used in the management of advanced adenocarcinoma of the lung. We sought to assess the impact of pemetrexed on intracranial disease control and radiation-related toxicity among patients with adenocarcinoma of the lung who received stereotactic radiation for brain metastases. MATERIALS/METHODS We identified 149 patients with adenocarcinoma of the lung and newly diagnosed brain metastases without a targetable mutation receiving stereotactic radiation. Kaplan-Meier plots and Cox regression were employed to assess whether use of pemetrexed was associated with intracranial disease control and radiation necrosis. RESULTS Among the entire cohort, 105 patients received pemetrexed while 44 did not. Among patients who were chemotherapy-naïve, use of pemetrexed (n = 43) versus alternative regimens after stereotactic radiation (n = 24) was associated with a reduced likelihood of developing new brain metastases (HR 0.42, 95% CI 0.22-0.79, p = 0.006) and a reduced need for salvage brain-directed radiation therapy (HR 0.36, 95% CI 0.18-0.73, p = 0.005). Pemetrexed use was associated with increased radiographic necrosis. (HR 2.70, 95% CI 1.09-6.70, p = 0.03). CONCLUSIONS Patients receiving pemetrexed after brain-directed stereotactic radiation appear to benefit from improved intracranial disease control at the possible expense of radiation-related radiographic necrosis. Whether symptomatic radiation injury occurs more frequently in patients receiving pemetrexed requires further study.

Implications of Screening for Brain Metastases in Patients With Breast Cancer and Non–Small Cell Lung Cancer

This study analyzes the value of magnetic resonance imaging of the brain for patients with cancers that frequently metastasize to the brain.

Whole brain radiotherapy for non-small cell lung cancer

1394 www.thelancet.com Vol 389 April 8, 2017 brain radiotherapy (WBRT) versus optimal supportive care in patients with non-small cell lung cancer (NSCLC) and brain metastases. We commend the authors on undertaking this important study. This study validates the practice pattern of withholding WBRT in patients that will not live long enough to derive benefit from intracranial control. However, we caution against overgeneralisation of the results to all patients. This multicentre study randomised 538 patients between March, 2007, and August, 2014, from 72 centres in the UK and Australia. These numbers suggest that, on average, only one patient per centre was enrolled annually, and might reflect selection bias in which only patients with the poorest of expected outcomes were enrolled. This hypothesis is consistent with a median survival among the entire cohort of 2 months and that approximately 10% of patients assigned to WBRT either died before receiving WBRT or declined to the point that WBRT could no longer be given. Patients were enrolled on this trial if they were “unsuitable for surgical resection or stereotactic radiotherapy”, yet approximately two-thirds of patients had four lesions or fewer; recently published randomised trials indicate that few situations exist in which patients with four brain metastases or fewer should be treated with WBRT as opposed to stereotactic radiation. Had this study started enrolment in 2016, it is plausible that few patients would have met eligibility criteria. Despite the patient selection issues noted above, some groups of patients appeared to show potential survival benefit with WBRT, including patients younger than 70 years of age, those with a Karnofsky Performance Status of at least 70, and those with controlled systemic disease. Given that only 10–25% of patients with brain metastases die of neurological disease, an improvement in overall DFCI counts among its core values the pursuit of integrity “in all that we do, adhering always to the highest standards of conduct”. In holding its fundraiser at Mar-a-Lago, DFCI acted both cowardly and myopically without apparent consideration of the long-term implications of what will be interpreted by many as a symbolic endorsement of Trump. In doing so, DFCI lost a rare opportunity to lead and the respect of many of its advocates.

Rapid progression of intracranial melanoma metastases controlled with combined BRAF/MEK inhibition after discontinuation of therapy: a clinical challenge

Novel systemic therapies with anti-tumor activity in the brain including small molecules targeting BRAF and MEK, and immune checkpoint inhibition, offer the possibility of improved control of intracranial disease. A number of prospective trials support the judicious use of modern systemic therapies in patients with melanoma and limited brain metastases .The intracranial clinical course of patients who progress extracranially on BRAF/MEK inhibition remains poorly described in the literature. In this report, we highlight a series of clinical cases, with rapid progression of intracranial disease following discontinuation of dabrafenib/trametinib for extracranial disease progression or toxicity, a previously unreported finding in the medical literature with significant implications for patient care.