Neoplasms

Symptoms and General Pathology

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Nervous System Diseases

Neoplasm Metastasis

Brain Neoplasms

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

30 Gy in 10 fractions hippocampal sparing whole brain radiotherapy will be administered by Helical Tomotherapy, IMRT, or VMAT

30 Gy in 10 fractions conventional whole brain radiotherapy will be administered

Hippocampal sparing whole brain radiotherapy

Conventional whole brain radiotherapy

Gillian Whitfield, MA,MB BS,PhD

The purpose of this study is to evaluate whether sparing the hippocampi during whole brain radiotherapy following neurosurgery or stereotactic radiosurgery in patients with brain metastases from a systemic tumour helps preserve brain function.

Hippocampal Sparing Whole Brain Radiotherapy vs Conventional Whole Brain Radiotherapy in Patients With Brain Metastases

A Randomized Phase II Trial of Hippocampal Sparing Versus Conventional Whole Brain Radiotherapy After Surgical Resection or Radiosurgery in Favourable Prognosis Patients With 1-10 Brain Metastases

A decline in total recall will be assessed as being clinically significant if there is at least a 5 point decrease in total recall score at 4 months, compared to baseline \[Jacobson 1991, Brandt 1998\]

NCF, using a 30-60 min test battery (Memory - HVLT-R, Wechsler Memory Scale (logical memory subtest), Rey figure test, Wechsler digit span; Attention - Test of Everyday Attention (map search subtest), Trail Making Test (Parts A and B); Language - Graded Naming Test); this may be revised in the light of forthcoming recommendations on NCF assessment in brain metastases trials by the RANO (Revised Assessment in Neuro-oncology) working party

Quality of life will be assessed using EORTC QLQ C30 and BN20 and EuroQol EQ-5D questionnaires

The duration of functional independence will be assessed as the time for which the Karnofsky Performance Status ≥ 70

Incidence of metastases within the perihippocampal region, local control, and intracranial control will be assessed on the basis of MRI imaging

Date of death will be determined from the medical records, or from the GP

Steroid and antiepileptic medication use will be recorded in patient diaries and assessed at clinic visits

Acute and late side effects of radiotherapy will be assessed using NCI CTCAE scale v4.03

Cancer Research UK

The Brain Tumour Charity

University College, London

Respiratory Tract (Lung and Bronchial) Diseases

Skin and Connective Tissue Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Behaviors and Mental Disorders

Rare Diseases

Lung Neoplasms

Carcinoma

Breast Neoplasms

Recurrence

Melanoma

Carcinoma, Renal Cell

Kidney Neoplasms

Neoplasms, Second Primary

Quality of Life

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

* MRI will be performed prior to radiation is administered
* A hippocampal sparing approach will be used when possible
* Dose will be 30 Gy in 10 fractions

* MRI will be performed prior to radiation is administered
* Radiation will be given in 1-5 fractions (dose depends on the size of the tumor that will be treated)

Treatment of the whole brain with radiation. When possible the hippocampus will be spared from radiation.

Whole brain radiation

Focused radiation to each individual brain metastasis without treatment of the remainder of the brain.

Stereotactic radiation (SRS)

Ayal Aizer, MD

Ivy Ricca, BA

Ayal Aizer, MD MHS

This research study is studying two different types of radiation as treatment for brain metastases (tumors in the brain that spread from a cancer that originated elsewhere in the body)

This research study is a Phase III clinical trial. Phase III clinical trials examine the safety and effectiveness of a treatment, often comparing it to another known treatment. In this case, the investigators are specifically looking at differences between two forms of radiation treatment in terms of subsequent quality of life.

In this research study, the investigators are comparing stereotactic (focused, pinpoint) radiation (in which each tumor is narrowly targeted) against whole brain radiation (radiation targeting the entire brain) in the treatment of brain metastases. Currently whole brain radiation is the standard option for patients with 5-20 brain metastases. Stereotactic radiation is the standard option for patients with 1-4 brain metastases. Among patients with 1-4 brain metastases, recently published studies suggest that stereotactic radiation results in fewer neurologic side effects than whole brain radiation. It also yields better quality of life in this population. It remains unknown whether stereotactic radiation improves quality of life in patients with 5-20 brain metastases relative to whole brain radiation. In this study, the investigators seek to determine which of the two methods of study treatment results in a better subsequent quality of life for patients with 5-20 brain metastases.

Hippocampal Sparing Whole Brain Radiation Versus Stereotactic Radiation in Patients With 5-20 Brain Metastases: A Phase III, Randomized Trial

Hippocampal Sparing Whole Brain Radiation Versus Stereotactic Radiation (SRS) in Patients With 5-20 Brain Metastases: A Phase III, Randomized Clinical Trial

Questionnaire - MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT)

Clinical parameter to be assessed via review of study visits and medical records indicating cause of death (neurologic versus systemic)

Radiographic assessment of first appearance of new brain metastases

Radiographic assessment of first local recurrence in the 5-20 brain metastases that were initially treated with radiation

Radiographic assessment of first appearance of radiation necrosis

Radiographic assessment of first appearance of leptomeningeal disease

Clinical assessment of first use of neurosurgical resection as salvage therapy

Clinical assessment of first use of salvage brain-directed radiation

Clinical assessment of first post-treatment seizure as assessed during routine study visits and via medical record review

Questionnaire - Karnofsky performance status

Brigham and Women's Hospital

Dana-Farber Cancer Institute

Principal Investigator

Small Cell Lung Carcinoma

Carcinoma, Small Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Small Cell Lung Cancer

Five eligible patients will undergo WBRT with reduced dose to the hippocampi and will be evaluated prospectively by neuro cognitive testing, MRI scans and blood tests.

VMAT plan to treat the whole brain while reducing the dose to the hippocampi.

Whole brain radiotherapy with reduced dose to the hippocampi

Leor Zach, MD

Small cell lung cancer (SCLC) harbors a high risk for brain metastases. Prophylactic whole brain radiotherapy (PCI)) is the standard treatment for these patients after completing chemo-radiotherapy to the chest, with a 5% survival advantage. Recent data suggest minimal risk for hippocampal involvement in these patients. There is no published data thus far testing the effect of hippocampal sparing during WBRT on the patient's neuro-cognitive function, QOL, and survival.., The goals of the proposed study are to assess prospectively the neurocognitive changes in patients with LD SCLC who are candidates for PCI before, and periodically after PCI

Background and rational Prophylactic cranial irradiation Small cell lung cancer (SCLC) is an aggressive type of lung cancer, with high sensitivity to chemotherapy and radiotherapy but with high incidence of local and distant recurrences. The brain is a common site of metastases from SCLC with a risk of up to 70% for brain involvement \[1\]. Prophylactic cranial irradiation (PCI) is the standard treatment for patients with limited disease (LD) SCLC after completing chemo-radiotherapy to the chest. The treatment includes whole brain radiotherapy (WBRT), reduces the incidence of brain metastases and improves overall survival (OS) by 5% \[1\]. The down side of WBRT is that the central nervous system (CNS) is vulnerable to radiotherapy (RT) and its related toxicity may be associated with irreversible cognitive dysfunction \[2\].

Radiotherapy and neuro-cognitive function It has been demonstrated that there are two main regions of human containing multipotent neural stem cells (NSCs): the subgranular zone (SGZ) within the dentate gyrus of the hippocampus, and the subventricular zone (SVZ) on the lateral aspect of the lateral ventricles \[3,4,5,6,7,8\]. These NSCs are capable of replacing adult neuron loss caused by various forms of harm (e.g. local ischemia, brain trauma, and radiation exposure and neurodegenerative diseases). However, they are extremely sensitive to X-rays, and thus reduction of NSCs may play an important role in radiation-induced neurocognitive impairment \[6,7,8\]. Neurocognitive function (NCF) has a major impact on QOL and has been actively studied in brain tumor patients treated with radiotherapy. Many studies have evaluated the neurocognitive outcome of patients treated with radiation for brain metastases and primary brain tumors \[9,10,11,12,13,14\]. Radiation primarily causes coagulation necrosis of the white matter tracts and cerebral vasculature by axonal demyelination and damage to vascular endothelial cells. Radiation has been shown to negatively affect various neuropsychological domains. WBRT has been shown to have greater neuropsychological impairment than focused radiation treatment \[14\]. Correlation, between radiation dosage to the bilateral hippocampi and impairment of NCF, was found in adult patients with benign or low-grade brain tumors treated with fractionated stereotactic radiotherapy (FSRT) \[14\].

An ongoing clinical trial of the radiation oncology group (RTOG) is testing the applicability of hippocampal sparing and its impact on neurocognitive changes in cancer patients with brain metastases.

Neuro-cognitive function testing Even though many studies have evaluated NCF in relation to radiation, there is no consensus regarding standardization of tests selection, time points for evaluation and correlations with biomarkers. Many studies use the Folstein Mini-Mental State Examination (MMSE) to assess neurocognitive function \[15,16\]. The MMSE is not a sensitive tool for detecting cognitive impairment and does not measure the cognitive functions affected by radiation. The NeuroTrax system is described elsewhere \[17\]. In brief, Mindstreams consists of custom software that resides on the local testing computer and serves as a platform for interactive cognitive tests that produce accuracy and reaction time (millisecond time-scale) data. In case of conducting several trails for a single patient, Mindstreams uses a different version of the tests in each trial, in order to avoid a learning bias. Tests are available in multiple languages, and equivalence among English and Hebrew versions has been shown \[17\]. After tests are run on the local computer, data are automatically uploaded to a central server, where calculation of outcome parameters from raw single-trial data and report generation occurs. All responses are made with the mouse or with the number pad on the keyboard. Participants are familiarized with these input devices at the beginning of the battery, and practice sessions prior to the individual tests instruct them regarding the particular responses required for each test.

Hippocampal sparing during PCI Recent data suggest minimal risk for hippocampal involvement in patients with SCLC and brain metastases suggesting that reduced radiation dose to these areas during PCI would not significantly compromise the control in the brain \[18\]. There is no published data thus far testing the effect of hippocampal sparing during PCI on the patient's neuro-cognitive function, QOL, and survival. Volumetric arc radiotherapy (VMAT) and intensity modulated radiotherapy (IMRT) use advanced radiation planning software with computerized algorithms of inverse planning to allow differential radiation dose distribution within the same radiation field. A preliminary dosimetric work in the radiation oncology unit at Sheba medical center has proved the feasibility of generating WBRT plans using these techniques while reducing the dose to the hippocampi. The investigators compared 3 radiotherapy plans (standard 2 lateral field plan, IMRT plan and a VMAT plan) aiming to give 30Gy to the brain, with 40Gy integrated boost to evident brain metastases (using magnetic resonance imaging - MRI scan) and reduced dose to the hippocampi (\<10Gy) according to RTOG 0933 protocol. IMRT achieved better results in general then the VMAT plans, especially in patients with brain metastases located closer to the hippocampi. The work has been presented in the EANS European Association of Neuro-Surgeonsmeeting last year.

Serum biomarkers for CNS damage Neuron-specific enolase (NSE) and S100 are two serum tumor markers that may be used as a potential screening tool for brain injury caused by radiation \[19-27\]. NSE is a glycolytic enzyme found in the CNS, expressed by neural and neuroendocrine cells. Elevated levels of NSE have been found in patients with brain metastases from NSCLC. A multi-center retrospective study involving 231 NSCLC patients demonstrated that high serum levels of NSE indicated shorter survival and was a specific marker of metastases. It is thought that the rise in NSE in brain metastasis patients reflects the extent of neuronal damage, as seen following a cerebral stroke. S100 protein is a nervous-system-specific cytoplasmic protein found in astrocytes and released into the serum when the blood brain barrier (BBB) is breached. Brain metastases were shown to be associated with elevated levels of S100 in several malignancies. Serum S-100B has also been demonstrated to be useful in determining brain damage related to stroke.

Imaging biomarkers for CNS damage Although brain radiotherapy induces white matter changes which can be depicted in standard MRI scans, no correlation was found between these changes and cognitive impairment. BBB disruption is an early, readily recognizable pathophysiological event occurring after radiation injury. It is detectable in vivo/in vitro by MRI and other imaging modalities, and appears to precede white matter necrosis. Micro-vascular leakage (MVL), calculated from perfusion MRI, is more sensitive than conventional contrast-enhanced MRI to subtle BBB opening, reflecting abnormal permeability of immature vessels. Treatment response assessment maps (TRAM) is a novel methodology, based on T1-MRI acquired up to 90 min after contrast injection, which allows depiction of subtle BBB disruption \[28\]. The resulting calculated maps, depict BBB functioning of the full brain, with high spatial resolution and high sensitivity to subtle BBB abnormalities. Results in \>200 patients with primary and metastatic brain tumors demonstrate the high sensitivity for subtle BBB disruption and the ability of the investigators maps to depict and differentiate various BBB disruption patterns within the tumor and the irradiated area.

Neurocognitive Function After Prophylactic Cranial Irradiation & Hippocampal Sparing in LD SCLC Patients - a Pilot Study

Neurocognitive Function Changes in Patients With LD Small Cell Lung Cancer Undergoing Prophylactic Whole Brain Radiotherapy With Hippocampal Sparing - a Pilot Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Hippocampal Sparing Whole Brain Radiotherapy vs Conventional Whole Brain Radiotherapy in Patients With Brain Metastases	NCT02147028	Brain Metastase...	Hippocampal spa... Conventional wh...	16 Years -	University College, London
Hippocampal Sparing Whole Brain Radiation Versus Stereotactic Radiation in Patients With 5-20 Brain Metastases: A Phase III, Randomized Trial	NCT03075072	Brain Metastase...	Whole brain rad... Stereotactic ra...	18 Years - 80 Years	Dana-Farber Cancer Institute
Neurocognitive Function After Prophylactic Cranial Irradiation & Hippocampal Sparing in LD SCLC Patients - a Pilot Study	NCT02366741	Carcinoma, Smal...	Whole brain rad...	18 Years -	Sheba Medical Center

Spots Global Cancer Trial Database for hippocampal sparing