CNS-3 status remains an independent adverse prognosis factor in children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: Results of EORTC Children Leukemia Group study 58951.

AIM: To evaluate the prognostic significance of initial central nervous system (CNS) involvement of children with acute lymphoblastic leukemia (ALL) enrolled in the EORTC 58951 trial. PATIENTS AND METHODS: From 1998 to 2008, 1930 ALL patients were included in the randomized EORTC 58951 trial. Overall treatment intensity was adjusted according to known prognostic factors including the level of minimal residual disease after induction treatment. CNS-directed therapy comprised four to 11 courses of i.v. methotrexate (5g/m2), and 10 to 19 intrathecal chemotherapy injections, depending on risk group and CNS status. Cranial irradiation was omitted for all patients. RESULTS: The overall 8-year event-free survival (EFS) and overall survival (OS) rates were 81.3% and 88.1%, respectively. In the CNS-1, TPL+, CNS-2, and CNS-3 groups, the 8-year EFS rates were 82.1%, 77.1%, 78.3%, and 57.4%, respectively. Multivariable analysis indicated that initial CNS-3 status, but not CNS-2 or TLP+, was an independent adverse predictor of outcome. The 8-year incidence of isolated CNS relapse was 1.7% and of isolated or combined CNS relapse it was 3.7%. NCI high-risk group, male sex, CNS-2 and CNS-3 status were independent predictors for a higher incidence of any CNS relapse. CONCLUSIONS: CNS-3 status remains associated with poor prognosis and requires intensification of both systemic and CNS-directed therapy. This trial was registered at https://clinicaltrials.gov/under/NCT00003728.

Evaluation of Stereotactic Radiotherapy of the Resection Cavity After Surgery of Brain Metastases Compared to Postoperative Whole-Brain Radiotherapy (ESTRON)-A Single-Center Prospective Randomized Trial.

BACKGROUND: Neurosurgical resection is recommended for symptomatic brain metastases, in oligometastatic patients or for histology acquisition. Without adjuvant radiotherapy, roughly two-thirds of the patients relapse at the resection site within 24 mo, while the risk of new metastases in the untreated brain is around 50%. Adjuvant whole-brain radiotherapy (WBRT) can reduce the risk of both scenarios of recurrence significantly, although the associated neurocognitive toxicity is substantial, while stereotactic radiotherapy (SRT) improves local control at comparably low toxicity. OBJECTIVE: To compare locoregional control and treatment-associated toxicity for postoperative SRT and WBRT after the resection of 1 brain metastasis in a single-center prospective randomized study. METHODS: Fifty patients will be randomized to receive either hypofractionated SRT of the resection cavity and single- or multisession SRT of all unresected brain metastases (up to 10 lesions) or WBRT. Patients will be followed-up regularly and the primary endpoint of neurological progression-free survival will be assessed by magnetic resonance imaging (MRI). Quality of life and neurocognition will be assessed in 3-mo intervals using standardized tests and EORTC questionnaires. EXPECTED OUTCOMES: We expect to show that postoperative SRT of the resection cavity and further unresected brain metastases is a valid means of improving locoregional control over observation at less neurocognitive toxicity than caused by WBRT. DISCUSSION: The present study is the first to compare locoregional control as well as neurocognitive toxicity for postoperative SRT and WBRT in patients with up to 10 metastases, while utilizing a highly sensitive and standardized MRI protocol for treatment planning and follow-up.

Radiobiology and radiotherapy of brain metastases.

Brain metastases are the most common intracranial tumors in adults, accounting for more than 50% of all such cases. The approach to and management of brain metastases have evolved significantly in recent years due to several reasons. These include advances in neurosurgical and radiotherapeutic techniques, improved systemic therapy options offering better systemic and intracranial disease control and prolongation of survival as a result of these improvements, making side-effects of proposed therapies (e.g. neurocognitive decline from whole brain radiotherapy) an important consideration. In this article, we review the the primary therapeutic approaches to the management of brain metastases, namely, surgery, stereotactic radiosurgery, and whole brain radiation therapy and the primary factors dictating choice.

A prospective study of corpus callosum regional volumes and neurocognitive outcomes following cranial radiation for pediatric brain tumors.

PURPOSE/OBJECTIVE(S): Cranial radiation therapy (CRT) may disrupt the corpus callosum (CC), which plays an important role in basic motor and cognitive functions. The aim of this prospective longitudinal study was to assess changes in CC mid-sagittal areas, CC volumes, and performance on neuropsychological (NP) tests related to the CC in children following CRT. MATERIALS/METHODS: Twelve pediatric patients were treated with CRT for primary brain malignancies. Thirteen age-matched healthy volunteers served as controls. Brain MRIs and NP assessment emphasizing motor dexterity, processing speed, visuomotor integration, and working memory (visual and verbal) were performed at baseline and at 6, 15, and 27 months following completion of CRT. Linear mixed effects (LME) analyses were used to evaluate patient NP performance and changes in regional CC volumes (genu, anterior body, mid-body, posterior body, and splenium) and mid-sagittal areas over time and with radiation doses, correcting for age at CRT start. RESULTS: The mean age at CRT was 9.41 (range 1.2-15.7) years. The median prescription dose was 54 (range 18-59.4) Gy. LME analysis revealed a significant decrease in overall CC volumes over time (p < 0.00001), with no overall effect of radiation dose. Analysis of individual CC regions demonstrated a significant decrease in all regional volumes over time (p < 0.00001) in patients, with no effect of radiation dose. Only in the splenium was there a trend toward a dose-dependent effect (p = 0.093). Patients had significantly reduced NP performance across visits-most notably in motor dexterity and visual working memory (both p < 0.0001). CONCLUSIONS: These prospective data demonstrate a significant decrease in CC regional volumes after CRT, with associated decline in neurocognitive function, most notably in manual dexterity, attention, and working memory. Further prospective study of larger cohorts of patients is needed to establish the relationship between CRT dose, neuroanatomical, and functional changes in the CC.

Development of cystic malacia after high-dose cranial irradiation of pediatric CNS tumors in long-term follow-up.

PURPOSE: The purpose of this study is to investigate the incidence of cystic malacia in long-term survivors of pediatric brain tumors treated with high-dose cranial irradiation. MATERIALS AND METHODS: Between 1997 and 2015, we treated 41 pediatric patients (26 males, 15 females; age ranging from 3.3 to 15.7 years, median 9-year-old) of pediatric brain tumors [17 medulloblastomas, 7 primitive neuroectodermal tumors (PNET), 3 pineoblastomas, 6 non-germinomatous germ cell tumors (NGGCT), 8 gliomas (including 4 ependymomas, 1 anaplastic astrocytoma, 1 oligodendroglioma, 1 pilocytic astrocytoma, 1 astroblastoma)] with high-dose craniospinal irradiation. Follow-up ranged from 14.0 to 189.2 months (median 86.0 months, mean 81.5 months), the irradiation dose to the whole neural axis ranged from 18 to 41.4 Gy, and the total local dose from 43.2 to 60.4 Gy. All patients underwent follow-up magnetic resonance imaging (MRI) studies at least once a year. Diagnosis of cystic malacia was based solely on MRI findings. Of the 41 patients, 31 were censored during their follow-up due to recurrence of the primary disease (n = 5), detection of secondary leukemia after development of cystic malacia (n = 1), or the absence of cystic malacia on the last follow-up MRI study (n = 25). We also evaluated the development of post-irradiation cavernous angioma and white matter changes. RESULTS: Following irradiation treatment, 11 patients developed 19 cystic malacia during a median course of 30.8 months (range 14.9 to 59.3 months). The site of predilection for cystic malacia was white matter around trigone of lateral ventricles with an incidence of 47.4% (9 of 19 lesions, 7 in 11 patients). Patients with supratentorial tumors developed cystic malacia statistically earlier than the patients with infratentorial tumors (P = 0.0178, log-rank test). Among the same patient group, incidence of post-irradiation cavernous angioma increased progressively, while the incidence of post-irradiation cystic malacia did not increase after 5 years. White matter degeneration developed earlier than cystic malacia or cavernous angioma, and these three clinical entities developed mutually exclusive of each other. CONCLUSION: We attribute the higher incidence of post-irradiation cystic malacia, in our long-term follow-up study, to the cranial irradiation for pediatric brain tumors, particularly supratentorial brain tumors, and recommend a regular, long-term follow-up of brain tumor patients treated with cranial irradiation.

Treatment trends for patients with brain metastases: Does practice reflect the data?

BACKGROUND: Published guidelines regarding the optimal treatment strategies for brain metastases focus on patients with ≤3 lesions. As delivery techniques for stereotactic radiosurgery (SRS) improve, radiation oncologists are increasingly using it for patients with >3 metastases. In the current study, the authors sought to characterize practice patterns among practitioners to identify areas of controversy. METHODS: A survey of practicing radiation oncologists was distributed via e-mail. Responses were collected from April 1 to May 5, 2016. Survey data were analyzed. RESULTS: A total of 711 currently practicing radiation oncologists responded, for a response rate of 12.5%. Specialists in central nervous system tumors (CNS specialists) were more likely to treat higher numbers of patients with brain metastases with SRS. There was a significant difference in the optimal "cutoff number" used when deciding how many lesions to treat with SRS versus whole-brain radiotherapy. Cutoff numbers were significantly higher for high-volume CNS specialists (≥10 patients/month) than for either low-volume CNS specialists (5-9 patients/month) or high-volume, non-CNS specialists (8.1 vs 5.6 and 5.1, respectively; P<.001). A majority of respondents (56%) identified patients with 4 to 6 brain metastases as being the most challenging patients to treat. CONCLUSIONS: To the authors' knowledge, there appears to be no consensus regarding the optimal treatment strategy among patients with >3 brain metastases, and practice patterns are heterogeneous. Radiation oncologists, especially high-volume CNS specialists, are treating significantly more brain metastases with SRS than what currently is recommended by published consensus guidelines. Providers struggle with patients with a moderate intracranial disease burden. Further prospective studies are needed to support these practice patterns and guide decision making. Cancer 2017;123:2274-2282. © 2017 American Cancer Society.

Therapies in the pipeline for small-cell lung cancer.

INTRODUCTION OR BACKGROUND: Small-cell lung cancer (SCLC) represents ~15% of all cases of lung cancer and is characterized by a rapid tumour doubling time, early onset disease dissemination and high sensitivity to chemotherapy. SOURCES OF DATA: We searched MEDLINE and OVID databases for articles in English published from January 1980 to February 2015. AREAS OF AGREEMENT: Platinum-based chemotherapy, thoracic radiotherapy and prophylactic cranial irradiation are standard of care. Benefit from second-line chemotherapy is limited. AREAS OF CONTROVERSY: The role of platinum/irinotecan chemotherapy in the Western population and the role of maintenance therapies remain to be established. GROWING POINTS: Knowledge of the biology of SCLC has expanded exponentially and many potential therapeutic targets have been identified. AREAS TIMELY FOR DEVELOPING RESEARCH: The use of circulating tumour cells can help investigating molecular alterations occurring within tumour cells, understanding drug resistance mechanisms and evaluating new treatments.

Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy.

BACKGROUND: This study compared prophylactic cranial irradiation (PCI) with observation in patients with resected stage IIIA-N2 non-small-cell lung cancer (NSCLC) and high risk of cerebral metastases after adjuvant chemotherapy. PATIENTS AND METHODS: In this open-label, randomized, phase III trial, patients with fully resected postoperative pathologically confirmed stage IIIA-N2 NSCLC and high cerebral metastases risk without recurrence after postoperative adjuvant chemotherapy were randomly assigned to receive PCI (30 Gy in 10 fractions) or observation. The primary end point was disease-free survival (DFS). The secondary end points included the incidence of brain metastases, overall survival (OS), toxicity and quality of life. RESULTS: This trial was terminated early after the random assignment of 156 patients (81 to PCI group and 75 to control group). The PCI group had significantly lengthened DFS compared with the control group, with a median DFS of 28.5 months versus 21.2 months [hazard ratio (HR), 0.67; 95% confidence interval (CI) 0.46-0.98; P = 0.037]. PCI was associated with a decrease in risk of brain metastases (the actuarial 5-year brain metastases rate, 20.3% versus 49.9%; HR, 0.28; 95% CI 0.14-0.57; P < 0.001). The median OS was 31.2 months in the PCI group and 27.4 months in the control group (HR, 0.81; 95% CI 0.56-1.16; P = 0.310). While main toxicities were headache, nausea/vomiting and fatigue in the PCI group, they were generally mild. CONCLUSION: In patients with fully resected postoperative pathologically confirmed stage IIIA-N2 NSCLC and high risk of cerebral metastases after adjuvant chemotherapy, PCI prolongs DFS and decreases the incidence of brain metastases.

The Liege Acromegaly Survey (LAS): a new software tool for the study of acromegaly.

Acromegaly is a chronic rare disease associated with negative pathological effects on multiple systems and organs. We designed a new informatics tool to study data from patients with acromegaly, the Liege Acromegaly Survey (LAS). This relational database permits the inclusion of anonymous historical and prospective data on patients and includes pathophysiology, clinical features, responses to therapy and long term outcomes of acromegaly. We deployed the LAS in a validation study at a single center in order to study the characteristics of patients with acromegaly diagnosed at our center from 1970-2011. A total of 290 patients with acromegaly were included (147 males and 143 females). There was a linear relationship between age at diagnosis and the date of diagnosis, indicating that older patients are being diagnosed with acromegaly more frequently. A majority presented with macroadenomas (77.5%) and the median diameter was 14 mm. Patients with macroadenomas were significantly younger than patients with microadenomas (P=0.01). GH values at diagnosis decreased with the age of the patients (P=0.01) and there was a correlation between GH values and tumor size at diagnosis (P=0.02). No correlation existed between insulin-like growth factor 1 (IGF-1) levels and tumor characteristics. The prevalence of diabetes was 21.4% in this population and 41.0% had hypertension. The presence of hypertension and diabetes were significantly associated with one another (P<0.001). There was a linear relation between initial GH and IGF-1 levels at diagnosis and those obtained during SSA analog treatment and the lowest GH and IGF-1 values following SSA therapy were obtained in older patients (GH: P<0.001; IGF-1: P<0.001). The LAS is a new relational database that is feasible to use in the clinical research setting and permits ready pooling of anonymous patient data from multiple study sites to undertake robust statistical analyses of clinical and therapeutic characteristics.

Whole-brain radiation therapy of brain metastasis.

The purpose of this report was to review the role of whole brain radiotherapy (WBRT) in the management of brain metastases. In particular, we review the role of WBRT as a prophylactic therapy, and the role of surgery and stereotactic radiousurgery (SRS) with respect to WBRT, by discussing the relevant randomized controlled trials. WBRT is associated with toxicities and this may influence the decision to use WBRT and, therefore, we review both the acute side effects of WBRT and the more serious late side effects of neurocognitive impairment and leukoencephalopathy. As patients are living longer with brain metastases the role of WBRT is moving forward; however, using modern radiation technology we may be able to reduce the morbidity of this therapy. We present an extreme case of re-re-treatment WBRT with hippocampal sparing and simultaneous integrated boosts to multiple lesions as one of the future directions under evaluation.

Advances in radiation therapy of brain metastasis.

The traditional treatment for brain metastases is to administer whole-brain radiation therapy using two-dimensional techniques. Owing to the short survival duration of patients historically treated, most patients with brain metastases did not survive long enough to manifest neurologic/neuropsychologic complications. With improved systemic therapy, and more aggressive focal treatment options, longer survival times are now becoming observed along with late effects of cancer treatment. Recently, advances in radiation therapy for brain metastases have taken shape in an attempt to improve the therapeutic ratio of improving intracranial disease control while reducing neurotoxicities. This review provides an overview of advances in the radiotherapeutic management of brain metastases.

Current strategies in whole-brain radiation therapy for brain metastases.

Whole-brain radiation therapy (WBRT) has been the primary treatment for patients with brain metastases for more than 50 years and provides effective palliative relief in most patients. Although advancements in radiotherapeutic technique continue to improve local and locoregional control, median survival for patients treated with WBRT monotherapy remains fixed at approximately 4 to 6 months. Key issues in the use of WBRT include optimizing its efficacy when it is used in conjunction with surgery, radiosurgery, radiosensitizers, and new chemotherapeutic agents. These multimodal approaches to brain metastases have resulted in significant increases in the median survival time in many patients. Radiosurgery is part of a continuing effort to improve the effects of radiation therapy, especially in brain metastases. The optimal combination of WBRT and radiosurgery remains to be elucidated, including appropriate timing or sequence and use in conjunction with other modalities. Newer radiosensitizing agents (e.g., efaproxiral [RSR-13] and motexafin gadolinium) have shown promise in the treatment of brain tumors, especially in specific patient subsets. Recently developed systemic chemotherapy agents, such as temozolomide, which crosses the blood-brain barrier, have a synergistic effect on brain metastases when used in conjunction with radiation. In addition, the use of interstitial chemotherapy agents provides highly focused local chemotherapy in the brain without increasing systemic toxicity; carmustine polymer wafer, in combination with WBRT, has shown promising results in treating brain metastases.

New technologies in radiation therapy for pediatric brain tumors: the rationale for proton radiation therapy.

BACKGROUND: Pediatric brain tumors are frequently treated with radiation therapy and often cured. The long-term side effects of treatment with high-energy X-rays (photons) can be substantial. Proton radiation therapy may limit these late effects. PROCEDURE: The physical difference between photon and proton irradiation is compared. The clinical benefits of the superior physical properties of proton beam radiation therapy are explained for children with brain tumors. RESULTS: At biologically equivalent doses, proton radiation therapy offers tumor control similar to photon radiation therapy. The superior physical properties of proton beams make this mode of radiation therapy less likely to cause late effects. CONCLUSIONS: For many children with brain tumors, proton beam radiation therapy may limit the late effects of radiation therapy and therefore offer an advantage over techniques using photons.