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Effect of Bevacizumab on Radiation-induced Brain Necrosis in Patients With Nasopharyngeal Carcinoma (BRAIN)

Primary Purpose

Nasopharyngeal Carcinoma, Adverse Effect of Radiation Therapy, Brain Necrosis

Status
Completed
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
bevacizumab
Corticosteroid
Sponsored by
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Nasopharyngeal Carcinoma focused on measuring radiation-induced brain necrosis, nasopharyngeal carcinoma, Bevacizumab, Methylprednisolone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must have received radiotherapy for histologically confirmed nasopharyngeal carcinoma.
  • Prior irradiation >/= 6 months prior to study entry.
  • Radiographic evidence to support the diagnosis of radiation-induced brain necrosis without tumor recurrence.
  • Age>/= 18 years. Because on dosing or adverse event data are currently not available on the use of bevacizumab in patients <18years old.
  • No prior bevacizumab therapy.
  • No evidence of very high intracranial pressure that suggests brain hernia and needs surgery.
  • Fertile women who are willing to take contraception during the trial.
  • Routine laboratory studies with bilirubin </=upper limits of normal (ULN), aspartate aminotransferase (AST or SGOT) < ULN, creatinine <ULN, red-cell count >/= 4,000 per cubic millimeter; white-cell count >/=1500 per cubic millimeter, platelets >/= 75,000 per cubic millimeter; Hb >/=9.0. PT, APTT, INR in a normal range.
  • If with history of seizures, patients should be on anticonvulsant therapy. However, preference will be enzyme-non-inducing anticonvulsants.
  • Ability to understand and willingness to sign a written informed consent document.
  • The patient has no active bleeding or pathological condition that carries a high risk of bleeding; there is no evidence of serious or non-healing wound, ulcer or bone fracture.

Exclusion Criteria:

  • Patients with any of the following should be excluded: 1) evidence of metastatic disease; 2)evidence of tumor invasion to major vessels(e.g. the carotid); 3) history of bleeding related to tumor or radiotherapy during or after the completion of radiation.
  • Evidence of active central nervous system hemorrhage.
  • History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to study enrollment.
  • inadequately controlled hypertension (systolic blood pressure (SBP) > 140 mmHg and/or diastolic blood pressure (DBP) > 90 mmHg despite antihypertensive medication)
  • Severe complications: 1) History of large vessel cerebrovascular accident (CVA) within 6 months; 2) Myocardial infarction or unstable angina within 6 months; 3) New York heart association grade II or greater congestive heart failure; 4) Serious and inadequately controlled cardiac arrhythmia; 5) Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection); 6) Clinically significant peripheral vascular disease; 7) severe infection.
  • Evidence of bleeding diathesis or coagulopathy.
  • Patients who have received steroid therapy for radiation-induced brain necrosis before the study.
  • History of anaphylactic response to bevacizumab.

Sites / Locations

  • Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Bevacizumab

Corticosteroid

Arm Description

Patients receive bevacizumab 5mg/kg intravenously over 30-90 minutes on day1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients in the corticosteroid group were treated with intravenous pulsed-steroid therapy: methylprednisolone 500 mg daily intravenously for three consecutive days followed by oral prednisone 60 mg for five days and gradually tapered 15mg every 5 days. When the prednisone dose reached 30mg per day, it was tapered down more slowly (tapered 5mg every week), until a maintenance dose of 10mg per day was reached. The entire intervention lasted two months. At 2 months, prednisone was stopped.

Outcomes

Primary Outcome Measures

Number of Participants With a Treatment Response
The primary outcome of the trial was the treatment response rate at two months. The definitions of response and progressive disease were based on both the radiographic changes and clinical symptoms. We defined response as both (1)a reduction in edema volume on FLAIR images by ≥25% and (2)no deteriorating symptoms. Progressive disease was defined as either (1)larger than 10% increase in the volume of the lesions; (2)appearance of any new lesion/site; or (3)clear clinical worsening.

Secondary Outcome Measures

Percentage Change in Radiological Measures of Lesion Volume
T1 post-gadolinium imaging was used to measure the enhancement and T2-weighted FLAIR to measure the edema. For lesion measurements, radiologists used manual and semiautomatic approaches to identify the outline of the lesion, and the total volume was estimated with Volume Viewer 2 software(GE Healthcare, AW Suite2.0 6.5.1.z).

Full Information

First Posted
June 14, 2012
Last Updated
December 19, 2018
Sponsor
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
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1. Study Identification

Unique Protocol Identification Number
NCT01621880
Brief Title
Effect of Bevacizumab on Radiation-induced Brain Necrosis in Patients With Nasopharyngeal Carcinoma
Acronym
BRAIN
Official Title
Effect of Bevacizumab on Radiation-induced Brain Necrosis in Patients With Nasopharyngeal Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
December 2018
Overall Recruitment Status
Completed
Study Start Date
June 2012 (Actual)
Primary Completion Date
August 2015 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Bevacizumab may have a better effect on brain necrosis caused by radiotherapy.This randomized trial aims to investigate whether bevacizumab may alleviate radiation-induced brain necrosis in patients with nasopharyngeal carcinoma. The effect will be compared with outcomes in patients receiving steroid therapy.
Detailed Description
Radiation-induced brain necrosis is a severe complication of radiotherapy in patients with Nasopharyngeal carcinoma. Current neuroprotective therapies show limited benefit in ameliorating this complication of radiotherapy. This study is a randomized, single blind clinical study. The primary aim of this study is to determine whether bevacizumab can alleviate radiation-induced brain necrosis in patients with nasopharyngeal carcinoma, and to compare the treating effect between bevacizumab and steroid.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nasopharyngeal Carcinoma, Adverse Effect of Radiation Therapy, Brain Necrosis
Keywords
radiation-induced brain necrosis, nasopharyngeal carcinoma, Bevacizumab, Methylprednisolone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
112 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bevacizumab
Arm Type
Active Comparator
Arm Description
Patients receive bevacizumab 5mg/kg intravenously over 30-90 minutes on day1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Arm Title
Corticosteroid
Arm Type
Active Comparator
Arm Description
Patients in the corticosteroid group were treated with intravenous pulsed-steroid therapy: methylprednisolone 500 mg daily intravenously for three consecutive days followed by oral prednisone 60 mg for five days and gradually tapered 15mg every 5 days. When the prednisone dose reached 30mg per day, it was tapered down more slowly (tapered 5mg every week), until a maintenance dose of 10mg per day was reached. The entire intervention lasted two months. At 2 months, prednisone was stopped.
Intervention Type
Drug
Intervention Name(s)
bevacizumab
Other Intervention Name(s)
Bevacizumab（Avastin）
Intervention Description
Patients receive bevacizumab 5mg/kg intravenously over 30-90 minutes on day1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Corticosteroid
Other Intervention Name(s)
methylprednisolone
Intervention Description
Patients in the corticosteroid group were treated with intravenous pulsed-steroid therapy: methylprednisolone 500 mg daily intravenously for three consecutive days followed by oral prednisone 60 mg for five days and gradually tapered 15mg every 5 days. When the prednisone dose reached 30mg per day, it was tapered down more slowly (tapered 5mg every week), until a maintenance dose of 10mg per day was reached. The entire intervention lasted two months. At 2 months, prednisone was stopped.
Primary Outcome Measure Information:
Title
Number of Participants With a Treatment Response
Description
The primary outcome of the trial was the treatment response rate at two months. The definitions of response and progressive disease were based on both the radiographic changes and clinical symptoms. We defined response as both (1)a reduction in edema volume on FLAIR images by ≥25% and (2)no deteriorating symptoms. Progressive disease was defined as either (1)larger than 10% increase in the volume of the lesions; (2)appearance of any new lesion/site; or (3)clear clinical worsening.
Time Frame
At 2 months.
Secondary Outcome Measure Information:
Title
Percentage Change in Radiological Measures of Lesion Volume
Description
T1 post-gadolinium imaging was used to measure the enhancement and T2-weighted FLAIR to measure the edema. For lesion measurements, radiologists used manual and semiautomatic approaches to identify the outline of the lesion, and the total volume was estimated with Volume Viewer 2 software(GE Healthcare, AW Suite2.0 6.5.1.z).
Time Frame
Change from baseline to evaluation at 2 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have received radiotherapy for histologically confirmed nasopharyngeal carcinoma. Prior irradiation >/= 6 months prior to study entry. Radiographic evidence to support the diagnosis of radiation-induced brain necrosis without tumor recurrence. Age>/= 18 years. Because on dosing or adverse event data are currently not available on the use of bevacizumab in patients <18years old. No prior bevacizumab therapy. No evidence of very high intracranial pressure that suggests brain hernia and needs surgery. Fertile women who are willing to take contraception during the trial. Routine laboratory studies with bilirubin </=upper limits of normal (ULN), aspartate aminotransferase (AST or SGOT) < ULN, creatinine <ULN, red-cell count >/= 4,000 per cubic millimeter; white-cell count >/=1500 per cubic millimeter, platelets >/= 75,000 per cubic millimeter; Hb >/=9.0. PT, APTT, INR in a normal range. If with history of seizures, patients should be on anticonvulsant therapy. However, preference will be enzyme-non-inducing anticonvulsants. Ability to understand and willingness to sign a written informed consent document. The patient has no active bleeding or pathological condition that carries a high risk of bleeding; there is no evidence of serious or non-healing wound, ulcer or bone fracture. Exclusion Criteria: Patients with any of the following should be excluded: 1) evidence of metastatic disease; 2)evidence of tumor invasion to major vessels(e.g. the carotid); 3) history of bleeding related to tumor or radiotherapy during or after the completion of radiation. Evidence of active central nervous system hemorrhage. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to study enrollment. inadequately controlled hypertension (systolic blood pressure (SBP) > 140 mmHg and/or diastolic blood pressure (DBP) > 90 mmHg despite antihypertensive medication) Severe complications: 1) History of large vessel cerebrovascular accident (CVA) within 6 months; 2) Myocardial infarction or unstable angina within 6 months; 3) New York heart association grade II or greater congestive heart failure; 4) Serious and inadequately controlled cardiac arrhythmia; 5) Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection); 6) Clinically significant peripheral vascular disease; 7) severe infection. Evidence of bleeding diathesis or coagulopathy. Patients who have received steroid therapy for radiation-induced brain necrosis before the study. History of anaphylactic response to bevacizumab.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yamei Tang, Ph.D
Organizational Affiliation
Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
510120
Country
China

12. IPD Sharing Statement

Citations:
PubMed Identifier
29885994
Citation
Xu Y, Rong X, Hu W, Huang X, Li Y, Zheng D, Cai Z, Zuo Z, Tang Y. Bevacizumab Monotherapy Reduces Radiation-induced Brain Necrosis in Nasopharyngeal Carcinoma Patients: A Randomized Controlled Trial. Int J Radiat Oncol Biol Phys. 2018 Aug 1;101(5):1087-1095. doi: 10.1016/j.ijrobp.2018.04.068. Epub 2018 May 2.
Results Reference
derived

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Effect of Bevacizumab on Radiation-induced Brain Necrosis in Patients With Nasopharyngeal Carcinoma

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