Glioma
Conditions
Brief summary
This is a study to determine the safety and effectiveness of high-dose radiation therapy (RT) with concurrent temozolomide in patients with newly diagnosed glioblastoma.
Detailed description
After analysis demonstrated the improved prognostic value of identifying both hypercellular tumor (TVHCV) based on high b-value diffusion-weighted magnetic resonance imaging (DW-MRI) and hyperperfused tumor (TVCBV) based on dynamic contrast-enhanced MRI (DCE-MRI), the study was amended and later-enrolled patients boosted to both TVHCV and TVCBV.
Interventions
RADIATIONHigh Dose Radiation
Radiation will be delivered once daily for a total of 30 fractions, five days per week.
DRUGTemozolomide
Patients will receive concurrent temozolomide (75 mg/m\^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m\^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Newly diagnosed histologically-confirmed supratentorial World Health Organization (WHO) grade IV gliomas including glioblastoma multiforme and gliosarcoma * Age 18 or older * Karnofsky performance status (a measure to quantify general well being and activities of daily life; scale ranges from 0 to 100 where 100 is perfect health) of greater than or equal to 70 * Life expectancy of at least 12 weeks * Adequate bone marrow reserve (hemoglobin greater than or equal to 10, absolute neutrophil count greater than or equal to 1500, platelets greater than or equal to 100,000); acceptable liver function (total bilirubin less than or equal to 2.0 mg/dl, ALT (Alanine Aminotransferase)/AST (Aspartate Aminotransferase) less than or equal to 5 times the normal range); acceptable renal function (serum creatinine less than or equal to 2.0 mg/dl). Eligibility level for hemoglobin may be reached by transfusion. * Maximal contiguous volume of tumor based on high b-value diffusion MRI \< 1/3 volume of brain * Patients must be registered within 6 weeks of most recent resection. * Patients must have signed a study-specific informed consent.
Exclusion criteria
* Recurrent glioma, or tumor involving the brainstem or cerebellum. Prior low-grade glioma without prior RT, now with malignant progression are eligible. * Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment is not permitted. Prior chemotherapy for a different cancer is allowable, except for Temozolomide or Bevacizumab. * Evidence of cerebrospinal fluid dissemination (positive cerebrospinal fluid cytology for malignancy or MRI findings consistent with CSF dissemination) * Evidence of severe concurrent disease requiring treatment * Prior invasive malignancy (except non-melanoma skin cancer) unless disease-free for a minimum of 3 years (for example, carcinoma in situ of breast, oral cavity or cervix are all permissible) * Patients unable to undergo Magnetic Resonance Imaging exams (MRI) (i.e. patients with non-compatible devices such as cardiac pacemakers, other implanted electronic devices, metallic prostheses, or ferromagnetic prostheses (e.g. pins in artificial joints and surgical pins/clips) or unable to receive gadolinium for MRI, as per the standard UM Department of Radiology MRI screening criteria) * Patients treated with previous cranial or head/neck radiotherapy leading to radiation field overlap * Females of child-bearing potential must have a negative pregnancy test within 14 days prior to registration. Patients with reproductive potential must agree to use an effective contraceptive method during treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival at 12 Months | 12 months after completion of chemoradiation | Percentage of patients alive at 12 months after completion of chemoradiation |
| Median Overall Survival | Median follow-up time was 26 months | Median overall survival in months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-free Survival | Median follow-up time was 26 months | From start of RT until disease progression or death, or until date of last imaging follow-up, estimated using Kaplan-Meier. Progression is defined by any of the following: \>= 25% increase in sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR non-enhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; appearance of any new lesions; clear progression of non-measurable lesions; or definite clinical deterioration not attributable to causes other than tumor, or to decrease in corticosteroid dose. When pathologic confirmation was unavailable, progression was defined as worsening enhancement based on imaging with or without adjunctive advanced imaging including perfusion MRI or magnetic resonance spectroscopy, when clinically indicated. |
| Median Change in Tumor Volume From Baseline to Mid-radiation Treatment (Week 4) | Baseline to Week 4 | Tumor volume will be measured by diffusion MRI and perfusion MRI before treatment start and at mid-treatment. |
| Percentage of Patients That Experienced Deterioration in Quality of Life (QOL) | Baseline to 1 and 7 months | Percentage of patients that experienced deterioration in QOL per the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire (EORTC QLQ-C30). EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score=better level of physical functioning. |
| Percentage of Patients With Failure; Central or In-field vs. Marginal or Distant | Median 26 months | Failures will be classified as central or in-field, marginal or distant based on previously published criteria. 1) central, in which 95% or more of the recurrent tumor volume (Vrecur) was within D95, the region treated to high dose (95% of the prescription dose); 2) in-field, in which 80% or more of Vrecur was within the D95 isodose surface; 3) marginal, when between 20 and 80% of Vrecur was inside the D95 surface; 4) outside, in which less than 20% of Vrecur was inside the D95 surface. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High Dose Chemoradiation Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. High Dose Radiation: Radiation will be delivered once daily for a total of 30 fractions, five days per week. Temozolomide: Patients will receive concurrent temozolomide (75 mg/m\^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m\^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy. | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | High Dose Chemoradiation |
|---|---|
| Age, Continuous | 62 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 21 / 26 |
| other Total, other adverse events | 25 / 26 |
| serious Total, serious adverse events | 8 / 26 |
Outcome results
Primary
Median Overall Survival
Median overall survival in months
Time frame: Median follow-up time was 26 months
Population: all eligible patients who completed dose-intensified chemo-radiation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| High Dose Chemoradiation | Median Overall Survival | all eligible patients who completed dose-intensified chemo-radiation | 20 months |
| High Dose Chemoradiation | Median Overall Survival | only patients who were boosted to both diffusion and perfusion | 20 months |
Primary
Overall Survival at 12 Months
Percentage of patients alive at 12 months after completion of chemoradiation
Time frame: 12 months after completion of chemoradiation
Population: all eligible patients who completed dose-intensified chemo-radiation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| High Dose Chemoradiation | Overall Survival at 12 Months | all eligible patients who completed dose-intensified chemo-radiation | 74 percentage of participants |
| High Dose Chemoradiation | Overall Survival at 12 Months | only patients who were boosted to both diffusion and perfusion | 92 percentage of participants |
p-value: 0.031-sided binomial test
Secondary
Median Change in Tumor Volume From Baseline to Mid-radiation Treatment (Week 4)
Tumor volume will be measured by diffusion MRI and perfusion MRI before treatment start and at mid-treatment.
Time frame: Baseline to Week 4
Population: All enrolled patients had available imaging were included in this analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High Dose Chemoradiation | Median Change in Tumor Volume From Baseline to Mid-radiation Treatment (Week 4) | -2.9 cubic centimeters |
Secondary
Median Progression-free Survival
From start of RT until disease progression or death, or until date of last imaging follow-up, estimated using Kaplan-Meier. Progression is defined by any of the following: \>= 25% increase in sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR non-enhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; appearance of any new lesions; clear progression of non-measurable lesions; or definite clinical deterioration not attributable to causes other than tumor, or to decrease in corticosteroid dose. When pathologic confirmation was unavailable, progression was defined as worsening enhancement based on imaging with or without adjunctive advanced imaging including perfusion MRI or magnetic resonance spectroscopy, when clinically indicated.
Time frame: Median follow-up time was 26 months
Population: all eligible patients who completed dose-intensified chemo-radiation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| High Dose Chemoradiation | Median Progression-free Survival | all eligible patients who completed dose-intensified chemo-radiation | 10 months |
| High Dose Chemoradiation | Median Progression-free Survival | only patients who were boosted to both diffusion and perfusion | 12 months |
Secondary
Percentage of Patients That Experienced Deterioration in Quality of Life (QOL)
Percentage of patients that experienced deterioration in QOL per the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire (EORTC QLQ-C30). EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score=better level of physical functioning.
Time frame: Baseline to 1 and 7 months
Population: all eligible patients who completed dose-intensified chemo-radiation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| High Dose Chemoradiation | Percentage of Patients That Experienced Deterioration in Quality of Life (QOL) | at 1 month | 26 percentage of participants |
| High Dose Chemoradiation | Percentage of Patients That Experienced Deterioration in Quality of Life (QOL) | at 7 months | 33 percentage of participants |
Secondary
Percentage of Patients With Failure; Central or In-field vs. Marginal or Distant
Failures will be classified as central or in-field, marginal or distant based on previously published criteria. 1) central, in which 95% or more of the recurrent tumor volume (Vrecur) was within D95, the region treated to high dose (95% of the prescription dose); 2) in-field, in which 80% or more of Vrecur was within the D95 isodose surface; 3) marginal, when between 20 and 80% of Vrecur was inside the D95 surface; 4) outside, in which less than 20% of Vrecur was inside the D95 surface.
Time frame: Median 26 months
Population: all eligible patients who completed dose-intensified chemo-radiation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| High Dose Chemoradiation | Percentage of Patients With Failure; Central or In-field vs. Marginal or Distant | central or in-field | 31 percentage of participants |
| High Dose Chemoradiation | Percentage of Patients With Failure; Central or In-field vs. Marginal or Distant | non-central/non-in-field (marginal or distant) | 69 percentage of participants |