Neoplasms

Symptoms and General Pathology

All Conditions

Nervous System Diseases

Neoplasm Metastasis

Brain Neoplasms

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

All studied patients should undergo a computed tomography (CT) simulation scan encompassing the entire head region with 1.25-mm slice thickness using a thermoplastic mask for immobilization. To achieve conformal hippocampal sparing during the delivery of whole brain radiation (WBRT), the technique of volumetric modulated arc therapy (VMAT) via Linac-based RapidArc®.In terms of dose prescription, a dose of 30 Gy in 12 fractions was prescribed to whole-brain planning target volume (PTV) if the role of RT was considered either adjuvant following craniotomy with tumor removal or therapeutic for treating oligometastatic brain disease.

hippocampal-sparing WBRT

Chi-Cheng Chuang, M.D.

Shinn-Yn Lin, M.D.

Whole brain radiotherapy (WBRT) has long been a practical and effective therapeutic modality for various settings of management in radiation oncology. For example, the indications for WBRT should include brain metastasis or metastases, the setting of prophylactic cranial irradiation (PCI) used mainly for patients with limited-stage small cell lung cancer, and even some patients with extensive-stage small cell lung cancer. The rationales for WBRT are essentially based on that it can target both microscopic and gross intracranial disease.

In addition to providing rapid alleviation of neurologic symptoms and enhanced intracranial disease control, WBRT might also prolong the time to develop neurocognitive function (NCF) decline. However, paradoxically NCF decline can also occur due to a sequel of WBRT. In terms of the time course of WBRT-induced NCF decline, it might vary considerably according to the specific domains which are selected to be measured. Early neurocognitive decline occurs within the first 1 - 4 months after WBRT for brain metastases. The domains of early neurocognitive decline principally involve verbal and short-term memory recall.

Since several decades ago, it has been understood that hippocampus plays an essential role in memory function. Not little evidence supports that radiation-induced damage to hippocampus should be strongly associated with NCF impairment. Furthermore, several studies have shown that isodose distribution in hippocampus is closely related to neurocognitive function in patients with benign or low-grade brain tumors. As a consequence, it is hypothesized that conformal hippocampal sparing during the course of WBRT (HS-WBRT) might provide significant preservation in terms of cognitive function.

This prospective cohort study aims to explore and evaluate the impact of the delivery of HS-WBRT on the pattern of NCF change and the extent of NCF decline in patients receiving prophylactic or therapeutic WBRT. As compared with previous related and relevant studies, it will also be investigated whether neurocognitive functional preservation can be achieved via the integration of hippocampal sparing with the course of WBRT.

A Prospective Study of the Impact of Hippocampal Avoidance During Whole Brain Radiotherapy on Neurocognitive Function Decline

Neurocognitive assessment: including memory, executive functions, and psychomotor speed. This neurocognitive outcome was delayed recall, as determined by the change/decline in either verbal memory \[Wechsler Memory Scale - 3rd edition (WMS III) - Word List score\] or non-verbal memory (WMS III- Visual Reproduction score) from the baseline assessment to 4 months after the start of the course of WBRT with hippocampus sparing (HS-WBRT). Additionally, the follow-up of neurocognitive assessment will also be administered at 12 months and up to 18 months after the start of HS-WBRT.

Chang Gung Memorial Hospital

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Lung Neoplasms

Small Cell Lung Carcinoma

Small Cell Lung Cancer

All Drugs and Chemicals

Immunomodulating Agents

hippocampal-sparing WBRT combined with SRS will be used to treat SCLC patients with baseline brain metastases during standard first-line chemotherapy combined with immunotherapy.

hippocampal-avoidance whole brain radiotherapy (WBRT) followed by stereotactic body radiotherapy (SBRT)

HA-WBRT plus SBRT

zhengfei zhu

Xiao Chu

Zhengfei Zhu, MD

This study aims to evaluate the safety and efficacy of hippocampal-sparing WBRT combined with SRS as first-line treatment for SCLC patients with brain metastases.

At present, the standard treatment for SCLC brain metastases is whole brain radiotherapy (WBRT). However, WBRT is palliative in nature due to its low dose and poor long-term control rate of intracranial lesions. At the same time, with the advent of the era of immunotherapy, a variety of PD-1/PD-L1 monoclonal antibodies combined with chemotherapy have become the standard first-line treatment for extensive-stage SCLC(ES-SCLC). Studies have shown that the survival time of SCLC patients with brain metastases is expected to be further prolonged in the era of chemotherapy and immunotherapy. Therefore, it is particularly important to further improve the control rate of intracranial lesions.

It has been confirmed in previous studies that WBRT combined with stereotactic radiotherapy for visible intracranial lesions (SRS/SRT) can effectively improve the control rate of intracranial lesions. However, most of the previous studies of WBRT combined with SRT for brain metastases did not include or only included a very small number of patients with SCLC. Studies on thoracic radiotherapy for limited-stage small cell lung cancer have found that an increase in radiotherapy dose can significantly improve the prognosis of patients with SCLC, which was previously considered to be highly radiosensitive. It is reasonable to think that SRS combined with WBRT for SCLC brain metastases may improve the prognosis of patients.

WBRT is known to cause severe cognitive impairment, which has also led to the reluctance of some patients to undergo WBRT. In the era of chemotherapy, the NRG-CC001 study showed that Hippocampal avoidance WBRT (HA-WBRT) could better protect the cognitive function of patients without affecting the prognosis of patients. The 2022 ASTRO guidelines have clearly recommended the use of hippocampal protection techniques in WBRT. Considering the lack of previous literature on the use of SRS combined with WBRT in SCLC patients in the chemo-immunotherapy era, The aim of this study is to adopt the dose fractionation of SRS combined with WBRT, which has been proven to be safe in the treatment of brain metastases from NSCLC, and to evaluate the safety of this treatment mode in SCLC patients with brain metastases receiving standard first-line chemoimmunotherapy.

In summary, this study aims to evaluate the safety and efficacy of hippocampal-sparing WBRT combined with SRS in the first-line treatment of SCLC patients with baseline brain metastases who are suitable for SRS treatment during the standard first-line chemotherapy combined with immunotherapy.

For ES-SCLC patients with baseline brain metastasis enrolled in this study, standard chemo-immunotherapy will be delivered every 3 weeks.

Simulation for radiotherapy should be performed at baseline, and WBRT should be completed no later than the start of the third course of systemic treatment. The WBRT dose is 30Gy/10Fx. For patients without brain metastases within 1cm of the hippocampus, hippocampal avoidance technology should be employed. After WBRT, the treating physician will perform another simulation for subsequent SRS treatment to the brain lesions. SRS should be completed no later than the start of the fourth course of drug treatment. Specific SRS dose should be as follows: 16Gy for tumors with a diameter ≤ 2cm; 12Gy for tumors with a diameter of between 2cm and 3cm. WBRT and SRS should be performed during the interval between two systemic drug treatments, concurrent (on the same day) brain radiotherapy with chemo-immunotherapy treatment should be avoided.

WBRT With Hippocampal-avoidance Technique Followed by SRT for Extensive-stage SCLC With Baseline Brain Metastases

A Phase I/II Study to Evaluate the Safety and Efficacy of Hippocampal-avoidance Whole Brain Radiotherapy Followed by Stereotactic Radiotherapy for Extensive-stage Small Cell Lung Cancer With Baseline Brain Metastases

dose-limiting toxicities(DLTs) were assessed according to CTCAE 5.0 criteria and included the following three conditions, with the exception of asymptomatic biochemical abnormalities: (1) grade 3 toxicity lasting for more than 7 consecutive days; (2) Grade 4 toxicity excluding neutropenia and thrombocytopenia; (3) Treatment-related grade 5 adverse events could not be excluded.

1-year intracranial progression-free survival (iPFS) rate was defined as proportion of patients without intracranial disease progression or death at 1 year of follow-up

overall survival(OS) was defined as the time from the date of enrollment until death by any cause. Participants still alive at the time of data analysis were censored at the date of last follow-up.

Time to intracranial progression was defined as the time from enrollment for treatment to the observation of progression of intracranial disease.

learning and memory function was assessed at 2, 4, 6, and 12 months from the first day of radiotherapy using the Hopkins Verbal Learning Test (HVLT-R)

processing speed and executive function was assessed at 2, 4, 6, and 12 months from the first day of radiotherapy using the trail making test (TMT-Part A, to assess processing speed, and TMT-Part B, to assess executive function).

Fudan University

Professor

Carcinoma, Non-Small-Cell Lung

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

100 mg as a once daily oral dose, 21 days

ZD6474 (Vandetanib)

Whole Brain Radiotherapy (WBRT)

200 mg as a once daily oral dose, 21 days

ZD6474

300 mg as a once daily oral dose, 21 days

Clinical Sciences & Operations

A clinical study to investigate the maximum tolerated dose of Vandetanib and concurrent WBRT in patients with NSCLC and brain metastases. All patients will receive WBRT, 10 fractions of 3 Gy. Patients will start 7 days prior to start of radiation treatment with Vandetanib. Total treatment time with Vandetanib is 3 weeks (21 days). Patients will have the opportunity to continue Vandetanib until progression at a dose of 300 mg. This multi-centre study will be conducted in a minimum of 9 patients and a maximum of 18 patients at 3 sites.

Investigate the Maximum Tolerated Dose of Vandetanib and Concurrent Whole Brain Radiotherapy (WBRT) in Patients With Non-small Cell Lung Cancer (NSCLC) and Brain Metastases

A Phase I Study of ZD6474 (Vandetanib) Concurrent With Whole Brain Radiotherapy for the Treatment of Brain Metastases in Patients With Non-small Cell Lung Cancer (NSCLC)

Sanofi

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

Dexamethasone

Dexamethasone acetate

Sorafenib

Proton Pump Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

This is a single institution, open label, prospective, phase I clinical trial using standard 3+3 design. Histologically confirmed metastatic adenocarcinoma of the breast with radiologic evidence of new and/or progressive brain metastases (BM) with a clinical indication for WBRT will be enrolled.

WBRT (30 Gy) will be delivered in 10 fractions. Standard opposed lateral fields with multileaf collimation blocking will be used. Treatment will be administered on business days and delivered over an approximate 2 week period. Dexamethasone may be given at the discretion of the treating physician but the dose cannot exceed greater than 16mg daily as it is a strong CYP3A4 inducer. Patients will also receive a proton pump inhibitor with dexamethasone.

The proposed three dose levels of sorafenib during dose escalation are 200 mg, 400mg, and 600 mg administered daily orally. Patients will be enrolled in cohorts of 3.The first three subjects will take sorafenib 200 mg daily within a few hours after the first RT fraction. Sorafenib will be continued concurrently with WBRT (1 fraction /day x 10 fractions) without breaks and then continued after WBRTfor a total of 21 days. If no dose limiting toxicity (DLT) is observed in a cohort of 3 patients until two weeks after completion of WBRT, the next dose level will be evaluated.

Andrew Seidman, MD

Sorafenib is a new type of anti-cancer drug. It belongs to a new class of medications known as tyrosine kinase inhibitors. Sorafenib is thought to work against cancer in many ways. It helps decrease blood supply to the tumor. It also blocks some proteins that help the tumor cells to grow." Sorafenib is approved by the Food and Drug administration (FDA) for treatment for other cancers like liver and kidney cancer. Sorafenib has also been studied in the treatment of breast cancer that has spread but is not specifically approved for the treatment of breast cancer. It has been studied both as a single agent and also in combination with other anti-cancer therapies for breast cancer. In laboratory models and in some patients with other cancers, sorafenib has been studied in tumors in the brain.

In this study, sorafenib will be given together with whole brain radiation therapy (WBRT). Overall this research study is designed to answer 2 main questions:

1. What dose of sorafenib should be used together with WBRT?
2. What are the side effects of sorafenib and WBRT when given together?

Whole Brain Radiotherapy (WBRT) With Sorafenib for Breast Cancer Brain Metastases (BCBM)

Whole Brain Radiotherapy (WBRT) With Sorafenib for Breast Cancer Brain Metastases (BCBM): A Phase I Study

Dose-escalation Phase: The proposed three dose levels of sorafenib during dose escalation are 200 mg, 400mg, and 600 mg administered daily orally. The dose-escalation phase is for 3-6 patients to be treated at each dose level. Assuming 3 dose levels during this phase, it will require a minimum of 2 and a maximum of 18 patients.

using the active version of the CTCAE version 4.0

CNS-PFS is defined as the interval between the date of study entry and the date of intracranial tumor progression or death from any cause. We will evaluate this during follow-up MRI scans that will be performed as a standard of care using the Macdonald criteria.

Bayer

Memorial Sloan Kettering Cancer Center

High-resolution contrast-enhanced post-operative MRI imaging in preparation for Cyberknife SRS. Cyberknife SRS of the resection cavity and all potential additional metastases diagnosed in the treatment planning MRI (up to 10 lesions)

Resection cavity:

7 x 5 Gy @ 95%-isodose

Potential additional brain metastases:

20 Gy @ 70%-isodose (lesions \< 2 cm max. diameter) 18 Gy @ 70%-isodose (lesions 2 - 3 cm max. diameter) 6 x 5 Gy @ 70%-isodose (lesions \> 3 cm max. diameter)

Post-operative WBRT will be performed according to the following dose regimen: 10 x 3 Gy

For radiosurgery, patients will be immobilized. Treatment planning including the MRI and planning CT should be performed 1 -2 weeks before SRT and treatment finished at latest 3-4 weeks after surgery. Planning should be as close to SRT as possible.

Organs at risk such as the brain stem, optic nerves, chiasm and spinal cord will be contoured. The Clinical Target Volume 1 (CTV1) will be defined as the resection cavity based on MRI and CT including T1 contrast enhanced changes around the resection cavity. The Clinical Target Volume 2 (CTV2) will be defined as a 3mm margin added to CTV1 by isotropic expansion and slightly adjusted as deemed appropriated by the experienced contouring physician. The Planning Target Volume (PTV) will be an additional margin of 1mm added to CTV2 by isotropic expansion.

Treatment planning will be performed using Accuray's Multiplan or subsequent approved treatment planning systems for Cyberknife.

post-operative stereotactic radiosurgery (SRS)

For WBRT, an individual head fixation mask is manufactured for each patient, and treatment planning is performed as virtual simulation or 3D-conformal RT planning based on CT-imaging. The portals include the whole brain with special focus as including the skull base areas and lamina cribrosa. For low infratentorial lesions, the treatment volume may include the whole brain down to the second cervical vertbra.

RT will be applied with two portals (e.g. 87°and 273°) using a 6 MeV linear accelerator.

For WBRT, a total dose of 30 Gy in 3 Gy fractions will be applied.

Whole brain radiotherapy (WBRT)

Juergen Debus, Prof. Dr. Dr.

In advanced cancer disease brain metastases are common, difficult to treat, and are associated with a poor prognosis. As new local and systemic therapies are eventually resulting in improved survival and quality of life for patients with brain metastases, negative neurocognitive effects of radiation therapy are becoming increasingly important as well as good loco-regional disease control of brain metastases.

Concerning treatment, brain metastases remain a major clinical problem and a multidisciplinary approach to management should be adopted. Neurosurgical resection with postoperative whole brain radiotherapy (WBRT) is one major treatment option in solitary or symptomatic brain metastases. Furthermore, WBRT is recommended for multiple brain metastases. For a limited number of brain metastases stereotactic radiosurgery (SRS) has been established as a highly effective treatment alternative.

Recently, a new treatment approach combing neurosurgery with postoperative stereotactic radiotherapy (SRT) of the resection cavity is emerging. Based on available evidence, postoperative SRT of the resection cavity improves local control following surgery, reduces the number of patients who require whole brain radiotherapy, and is well tolerated (1).

This protocol is aimed at primarily evaluating the safety and toxicity profile of SRT to the resection cavity following neurosurgical resection combined with SRT of potentially further unresected brain metastases, compared to postoperative whole-brain radiotherapy (WBRT). Secondary, the local effect of SRT in patients with brain metastases will be assessed by measuring time to local recurrence (LR), local and loco-regional progression-free survival (PFS).

Additional systemic treatment will be carried out according to the standards of the National Center for Tumor Therapy (NCT).

Scientific Background: Brain metastases (BM) represent a significant healthcare problem. It is estimated that 20% to 40% of patients with cancer will develop metastatic cancer to the brain during the course of their illness 1. The most common primary sites are lung, melanoma, renal, breast and colorectal cancer 2. Options for patients with brain metastases had been limited to whole brain radiotherapy (WBRT) or supportive care alone, and systemic chemotherapy was often discontinued. Historically, the best possible supportive care or whole-brain radiotherapy (WBRT) were the standard of care 1 aiming at temporary symptom relief. For WBRT, efficacy in symptom relief but also in prolongation of the median survival time by 3-6 months is well documented. To date, microsurgical approaches and SRS, both proved to be safe and efficient, offer alternative treatment options that potentially meet these concerns 6,7. After proving its efficacy in achieving local tumor control in the treated volume, SRS was used as a stand-alone treatment option in patients with oligometastases (one to four metastases) in the brain. There is a rapidly expanding recent body of literature on outcomes of single-fraction SRS or hypofractionated SRS targeting the resection cavity after surgical resection of BM. Several retrospective series assessed the efficacy and safety of postoperative SRS to the resection cavity 9 aiming at an enhanced local tumor control but also at avoidance of the neurotoxic late effects of WBRT. WBRT followed by SRS of the tumor bed leads to 1-year local control rates of 70-93 %, which is comparable to results after surgery followed by WBRT. Median survival was 12-18 months with a 1-year incidence of new metastases in the brain of 45-60 %.

Trial Objectives: This protocol is primarily aimed at evaluating the safety and toxicity profile of SRS following neurosurgical resection and compares it to that of WBRT as the established standard of care. Secondary, the local effect of radiation therapy in patients with brain metastases will be assessed by measuring time to local and loco-regional recurrence, local and loco-regional PFS and overall survival at 12 months after treatment.

Patients´Selection: Patients with the diagnosis of brain metastases from solid tumors that have undergone neurosurgical resection of one brain metastasis will be evaluated and screened for the protocol. All patients fulfilling the inclusion and exclusion criteria will be informed about the study and included into the study if they declare informed consent. Registration for the study must be performed before the start of RT.

Trial Design: The trial will be performed as a single-center two-armed prospective randomized Phase II study. Patients will be randomized into an experimental arm and a control arm. All patients will receive post-operative contrast-enhanced cranial MRI imaging and imaging will be assessed by a radiologist. All available MRI sequences, including SPACE will be taken into consideration for the definition of treatment target lesions. Patients for whom the post-operative MRI reveals more than 10 suspect intracranial lesions (all sequences taken into account) will not be included in the trial.

Stereotactic Radiotherapy of the Resection Cavity of Brain Metastases vs. Post-operative Whole-brain Radiotherapy

Evaluation of Stereotactic Radiotherapy of the Resection Cavity After Surgery of Brain Metastases Compared to Post-operative Whole-brain Radiotherapy

Neurologic progression-free survival in follow-up imaging is the primary endpoint of the study. The duration is defined as the time interval between the date start of RT and the date of local and loco-regional progression or death, or the date of leaving the study without local and loco-regional progression (e.g., lost to follow up non-local progression) whatever occurs first. Patients not reported local and loco-regional progressive or dead, or lost to follow-up or non-local progressive will be censored at the date of the last follow-up examination where no signs of local and loco-regional progression were observed.

Time interval (days) between the date of RT begin and the date of death or date of leaving the study e.g., lost to follow up) whatever occurs first. Patients not reported dead or lost to follow-up will be censored at the date of the last follow-up or the time when last seen alive.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Prospective Study of the Impact of Hippocampal Avoidance During Whole Brain Radiotherapy on Neurocognitive Function Decline	NCT02504788	Brain Metastasi... Brain Metastase...	hippocampal-spa...	18 Years - 84 Years	Chang Gung Memorial Hospital
WBRT With Hippocampal-avoidance Technique Followed by SRT for Extensive-stage SCLC With Baseline Brain Metastases	NCT06243003	SCLC,Extensive ... Brain Metastase...	HA-WBRT plus SB...	18 Years -	Fudan University
Investigate the Maximum Tolerated Dose of Vandetanib and Concurrent Whole Brain Radiotherapy (WBRT) in Patients With Non-small Cell Lung Cancer (NSCLC) and Brain Metastases	NCT00807170	Non-small Cell ...	ZD6474 (Vandeta... Whole Brain Rad... ZD6474 ZD6474	18 Years -	Sanofi
Whole Brain Radiotherapy (WBRT) With Sorafenib for Breast Cancer Brain Metastases (BCBM)	NCT01724606	Breast Cancer Brain Metastase...	Whole Brain Rad... Sorafenib	18 Years -	Memorial Sloan Kettering Cancer Center
Investigate the Maximum Tolerated Dose of Vandetanib and Concurrent Whole Brain Radiotherapy (WBRT) in Patients With Non-small Cell Lung Cancer (NSCLC) and Brain Metastases	NCT00807170	Non-small Cell ...	ZD6474 (Vandeta... Whole Brain Rad... ZD6474 ZD6474	18 Years -	Sanofi
Stereotactic Radiotherapy of the Resection Cavity of Brain Metastases vs. Post-operative Whole-brain Radiotherapy	NCT03285932	Brain Metastase...	post-operative ... Whole brain rad...	18 Years -	University Hospital Heidelberg
WBRT With Hippocampal-avoidance Technique Followed by SRT for Extensive-stage SCLC With Baseline Brain Metastases	NCT06243003	SCLC,Extensive ... Brain Metastase...	HA-WBRT plus SB...	18 Years -	Fudan University
Whole Brain Radiotherapy (WBRT) With Sorafenib for Breast Cancer Brain Metastases (BCBM)	NCT01724606	Breast Cancer Brain Metastase...	Whole Brain Rad... Sorafenib	18 Years -	Memorial Sloan Kettering Cancer Center

Spots Global Cancer Trial Database for whole brain radiotherapy (wbrt)