Adverse Effect of Radiation Therapy, Brain Necrosis, Nasopharyngeal Carcinoma
Conditions
Keywords
radiation-induced brain necrosis, nasopharyngeal carcinoma, Bevacizumab, Methylprednisolone
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.
Interventions
DRUGbevacizumab
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.
DRUGCorticosteroid
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.
Sponsors
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Treatment Response | At 2 months. | 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
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Radiological Measures of Lesion Volume | Change from baseline to evaluation at 2 months. | 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). |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab 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.
bevacizumab: 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. | 58 |
| Corticosteroid Patients in the corticosteroid group were treated with 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.
Corticosteroid: Patients in the corticosteroid group were treated with 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. | 54 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Bevacizumab | Corticosteroid | Total |
|---|---|---|---|
| Age, Continuous | 49.3 years STANDARD_DEVIATION 7 | 50.5 years STANDARD_DEVIATION 8.6 | 50.1 years STANDARD_DEVIATION 8.5 |
| Conventional radiotherapy | 41 Participants | 36 Participants | 77 Participants |
| Dose of nasopharyngeal radiation | 69.4 Gy STANDARD_DEVIATION 5.2 | 71.1 Gy STANDARD_DEVIATION 2.4 | 70.3 Gy STANDARD_DEVIATION 4.1 |
| Dose of neck radiation | 58.9 Gy STANDARD_DEVIATION 8.1 | 40.7 Gy STANDARD_DEVIATION 10.3 | 49.7 Gy STANDARD_DEVIATION 13 |
| IMRT(intensity modulated radiation therapy) | 17 Participants | 18 Participants | 35 Participants |
| Region of Enrollment China | 58 participants | 54 participants | 112 participants |
| Sex: Female, Male Female | 20 Participants | 15 Participants | 35 Participants |
| Sex: Female, Male Male | 38 Participants | 39 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 58 | 0 / 54 |
| other Total, other adverse events | 25 / 58 | 26 / 54 |
| serious Total, serious adverse events | 1 / 58 | 1 / 54 |
Outcome results
Primary
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.
Time frame: At 2 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab | Number of Participants With a Treatment Response | 38 Participants |
| Corticosteroid | Number of Participants With a Treatment Response | 17 Participants |
Secondary
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).
Time frame: Change from baseline to evaluation at 2 months.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bevacizumab | Percentage Change in Radiological Measures of Lesion Volume | Percentage Change in FLAIR | -51.8 percentage | Standard Deviation 39.9 |
| Bevacizumab | Percentage Change in Radiological Measures of Lesion Volume | Percentage Change in enhancement | -25.5 percentage | Standard Deviation 45.2 |
| Corticosteroid | Percentage Change in Radiological Measures of Lesion Volume | Percentage Change in FLAIR | -19.3 percentage | Standard Deviation 42.5 |
| Corticosteroid | Percentage Change in Radiological Measures of Lesion Volume | Percentage Change in enhancement | -5.0 percentage | Standard Deviation 44.2 |