Brain and Central Nervous System Tumors
Conditions
Keywords
adult anaplastic oligodendroglioma, adult anaplastic astrocytoma
Brief summary
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with temozolomide may kill more tumor cells. It is not yet known whether giving temozolomide during and/or after radiation therapy is more effective than radiation therapy alone in treating anaplastic glioma. PURPOSE: This randomized phase III trial is studying giving temozolomide during and/or after radiation therapy to see how well it works compared to radiation therapy alone in treating patients with anaplastic glioma.
Detailed description
OBJECTIVES: Primary * To assess whether concurrent radiotherapy with daily temozolomide improves overall survival as compared to no daily temozolomide in patients with non-1p/19q deleted anaplastic glioma. * To assess whether adjuvant temozolomide improves survival as compared to no adjuvant temozolomide in patients with non-1p/19q deleted anaplastic glioma. Secondary * To assess whether concurrent and adjuvant temozolomide prolongs progression-free survival and neurological deterioration-free survival in patients with non-1p/19q deleted anaplastic glioma. * To assess the safety of concurrent and adjuvant temozolomide in patients with non-1p/19q deleted anaplastic glioma, including late effects on cognition. * To assess the impact of concurrent and adjuvant temozolomide on the quality of life of patients with non-1p/19q deleted anaplastic glioma. OUTLINE: This is a multicenter study. Patients are stratified according to institution, World Health Organization (WHO) performance status (0 vs \> 0), age (≤ 50 vs \> 50), presence of 1p LOH only (yes vs no), presence of oligodendroglial elements (yes vs no), and O6-methylguanine-DNA methyltransferase promoter methylation status (methylated vs unmethylated vs indeterminate). Patients are randomized to 1 of 4 treatment arms. * Arm I: Patients undergo radiotherapy\* once daily, 5 days a week, for 6.5 weeks (total of 33 fractions). * Arm II: Patients undergo radiotherapy\* once daily, 5 days a week and receive oral temozolomide once daily for 6.5 weeks (total of 33 fractions of radiotherapy). * Arm III: Patients undergo radiotherapy\* once daily, 5 days a week for 6.5 weeks (total of 33 fractions). Beginning 4 weeks after completion of radiotherapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses. * Arm IV: Patients undergo radiotherapy\* once daily, 5 days a week and receive oral temozolomide once daily for 6.5 weeks (total of 33 fractions of radiotherapy). Beginning 4 weeks after completion of radiotherapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses. * Patients must begin radiotherapy within 8 days after randomization and within 7 weeks after surgery. In all arms, treatment continues in the absence of disease progression or unacceptable toxicity. Patients complete quality-of-life questionnaires, including EORTC core quality of life questionnaire (QLQ-C30) version 3, EORTC brain cancer module (BCM20), and the Mini Mental Status Exam at baseline, 4 weeks after the completion of radiotherapy, and then every 3 months for 5 years. Tissue samples are collected at baseline for histology review, 1p/19q analysis, methylation status of the O6-methylguanine-DNA methyltransferase promoter, and isocitrate dehydrogenase mutation analysis. After completion of study treatment, patients are followed every 3 months.
Interventions
DRUGtemozolomide
Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.
GENETICDNA methylation analysis
O6-Methylguanine-DNA Methyltransferase (MGMT) methylation status is used for stratification at randomization.
OTHERlaboratory biomarker analysis
Prognostic factor analyses
PROCEDUREadjuvant therapy
Patients randomized to adjuvant temozolomide will start adjuvant temozolomide after a 4 week resting period after the end of radiotherapy.
PROCEDUREquality-of-life assessment
Quality of Life analysis will also be used to assess neurological deterioration free progression
RADIATIONradiation therapy
Radiotherapy will consist of a conventionally fractionated regimen for 6.5 weeks in a once daily schedule
Sponsors
NCIC Clinical Trials Group
Radiation Therapy Oncology Group
Medical Research Council
Merck Sharp & Dohme LLC
European Organisation for Research and Treatment of Cancer - EORTC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed diagnosis of 1 of the following: * Anaplastic oligodendroglioma * Anaplastic oligoastrocytoma * Anaplastic astrocytoma * Newly diagnosed disease * Prior surgery for a low grade tumor is allowed, provided histological confirmation of an anaplastic tumor is present at the time of progression * Absence of combined 1p/19q loss * Tumor material available for central 1p/19q assessment, central O6-methylguanine-DNA methyltransferase promoter methylation status assessment, isocitrate dehydrogenase mutation analysis, and central pathology review * Patients must be on a stable or decreasing dose of steroids for at least two weeks prior to randomization PATIENT CHARACTERISTICS: * WHO performance status 0-2 * Absolute Neutrophil Count (ANC) ≥ 1.5 x 10\^9 cells/L * Platelet count ≥ 100 x 10\^9 cells/L * Bilirubin \< 1.5 x upper limit of normal (ULN) * Alkaline phosphatase \< 2.5 x ULN * Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) \< 2.5 x ULN * Serum creatinine \< 1.5 x ULN * Not pregnant or nursing * Fertile patients must use effective contraception * No known HIV infection or chronic hepatitis B or hepatitis C infection * No other serious medical condition that would interfere with follow-up * No medical condition that could interfere with oral medication intake (e.g., frequent vomiting or partial bowel obstruction) * No other prior malignancies except for any malignancy which was treated with curative intent more than 5 years prior to registration and adequately controlled limited basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix * No prior or concurrent malignancies at other sites except for surgically cured carcinoma in situ of the cervix or nonmelanoma skin cancer * No psychological, familial, sociological, or geographical condition that would potentially hamper compliance with the study protocol and follow-up schedule PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior chemotherapy, including carmustine-containing wafers (Gliadel®) * No prior radiotherapy to the brain * No concurrent growth factors unless vital for the patient * No other concurrent investigational treatment * No other concurrent anticancer agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival as Measured From the Day of Randomization | from date from enrollment till the date of death (time till death is up to 10.9 years after patient enrollment in the study) | The duration of survival is the time interval between randomization and the date of death due to any cause. Patients not reported dead or lost to follow up will be censored at the date of the last follow up examination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | from randomization till the date of disease progression or death (time till death is up to 10.9 years after patient enrollment in the study) | Disease progression is defined as radiological or neurological/clinical progression (whichever occurs first); progression free survival (PFS) is the time interval between the date of randomization and the date of disease progression or death whichever occurs first. If neither event has been observed, the patient is censored at the date of the last follow up examination. Radiological progression was defined as increase of contrast enhancing area on MRI or CT scans of more than 25% as measured by two perpendicular diameters compared to the smallest measurements ever recorded for the same lesion by the same technique. The appearance of new lesions with or without contrast enhancement Neurological/clinical progression was defined as:decrease in WHO performance status,deterioration of neurological functions,appearance of signs/symptoms of increased intracranial pressure,and/or start of corticosteroid or increase of corticosteroid dosage by 50% for control of neurological symptoms. |
| Quality of Life of the Patient | from 14 days prior to randomization till five years or death (time till death is up to 10.9 years after patient enrollment in the study) | Quality of life was assessed by the EORTC Quality of Life Questionnaire (QLQ-C30) version 3 and the Brain Cancer Module-20 |
| Neurological Deterioration Free Survival | within 2 weeks of randomization; during radiotherapy at week 4 and 6; 4 weeks after the end of radiotherapy; Six monthly after the end of radiotherapy; Prior to each cycle of adjuvant therapy; Every six months after the documentation of first progression. | Neurological deterioration is defined as a decrease in WHO performance status as follows: decrease in WHO performance status * for patients with baseline WHO performance status 0: deterioration to WHO performance status 2 or worse for which no other explanation is present, and which is maintained for at least three months * for patients with baseline WHO performance status 1 or 2: deterioration to WHO performance status 3 or worse for which no other explanation is present and which is maintained for at least three months The date of neurological deterioration will be the first date the persistent decrease in performance status was diagnosed. Neurological deterioration free progression is the time interval between the date of randomization and the date of neurological deterioration or death whichever occurs first. If neither event has been observed, the patient is censored at the date of the last follow up examination |
Countries
Australia, Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
After registration step was completed, eligible patients were randomized into the trial within 8 days from the start of radiotherapy; at this time, all baseline requirements for the study had to be fulfilled.
Pre-assignment details
The patients were first registered to the trial by authorized sites. For all patients, tumor and blood samples had to be sent for histology review, 1p/19q analysis and O6-Methylguanine-DNA Methyltransferase (MGMT) assay. If inclusion was based on central pathology and 1p/19q diagnosis the patient could be randomized into the trial once found eligible at central assessment.
Participants by arm
| Arm | Count |
|---|---|
| RT Alone radiation therapy alone
DNA methylation analysis: MGMT methylation status is used for stratification at randomization.
laboratory biomarker analysis: Prognostic factor analyses
quality-of-life assessment: Quality of Life analysis will also be used to assess neurological deterioration free progression
radiation therapy: Radiotherapy will consist of a conventionally fractionated regimen for 6.5 weeks in a once daily schedule | 189 |
| RT & Concurrent CT Radiotherapy and concurrent temozolomide chemotherapy
temozolomide: Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.
DNA methylation analysis: MGMT methylation status is used for stratification at randomization.
laboratory biomarker analysis: Prognostic factor analyses
quality-of-life assessment: Quality of Life analysis will also be used to assess neurological deterioration free progression
radiation therapy: Radiotherapy will consist of a conventionally fractionated regimen for 6.5 weeks in a once daily schedule | 188 |
| RT + Adjuvant CT Radiotherapy plus adjuvant temozolomide chemotherapy
temozolomide: Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.
DNA methylation analysis: MGMT methylation status is used for stratification at randomization.
laboratory biomarker analysis: Prognostic factor analyses
adjuvant therapy: Patients randomized to adjuvant temozolomide will start adjuvant temozolomide after a 4 week resting period after the end of radiotherapy.
quality-of-life assessment: Quality of Life analysis will also be used to assess neurological deterioration free progression
radiation therapy: Radiotherapy will consist of a conventionally fractionated regimen for 6.5 weeks in a once daily schedule | 186 |
| RT & Concurrent CT + Adjuvant CT Radiotherapy and concurrent chemotherapy plus adjuvant temozolomide chemotherapy
temozolomide: Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.
DNA methylation analysis: MGMT methylation status is used for stratification at randomization.
laboratory biomarker analysis: Prognostic factor analyses
adjuvant therapy: Patients randomized to adjuvant temozolomide will start adjuvant temozolomide after a 4 week resting period after the end of radiotherapy.
quality-of-life assessment: Quality of Life analysis will also be used to assess neurological deterioration free progression
radiation therapy: Radiotherapy will consist of a conventionally fractionated regimen for 6.5 weeks in a once daily schedule | 188 |
| Total | 751 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 7 | 14 | 28 |
| Overall Study | Death | 0 | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 6 | 7 | 49 | 40 |
| Overall Study | Protocol Violation | 0 | 1 | 1 | 0 |
| Overall Study | Various different reasons/missing | 4 | 8 | 8 | 16 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 5 | 11 |
Baseline characteristics
| Characteristic | Total | RT & Concurrent CT + Adjuvant CT | RT Alone | RT & Concurrent CT | RT + Adjuvant CT |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 55 Participants | 8 Participants | 15 Participants | 20 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 696 Participants | 180 Participants | 174 Participants | 168 Participants | 174 Participants |
| Age, Continuous | 42.2 years | 42.8 years | 42 years | 43.1 years | 40 years |
| MGMT Methylation status Methylated | 239 Participants | 56 Participants | 62 Participants | 55 Participants | 66 Participants |
| MGMT Methylation status Undetermined/invalid | 185 Participants | 45 Participants | 44 Participants | 54 Participants | 42 Participants |
| MGMT Methylation status Unmethylated | 327 Participants | 87 Participants | 83 Participants | 79 Participants | 78 Participants |
| Presence of 1p LOH Loss | 53 Participants | 13 Participants | 14 Participants | 12 Participants | 14 Participants |
| Presence of 1p LOH No loss | 698 Participants | 175 Participants | 175 Participants | 176 Participants | 172 Participants |
| Presence of oligodendroglial elements No | 577 Participants | 144 Participants | 146 Participants | 144 Participants | 143 Participants |
| Presence of oligodendroglial elements Yes | 174 Participants | 44 Participants | 43 Participants | 44 Participants | 43 Participants |
| Procedure for pathology and genetic testing by central laboratory assessment | 487 Participants | 134 Participants | 119 Participants | 118 Participants | 116 Participants |
| Procedure for pathology and genetic testing by local site laboratory assessment | 262 Participants | 54 Participants | 70 Participants | 70 Participants | 68 Participants |
| Procedure for pathology and genetic testing Unknown | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — | — | — |
| Region of Enrollment Australia | 82 participants | 25 participants | 14 participants | 22 participants | 21 participants |
| Region of Enrollment Belgium | 73 participants | 18 participants | 19 participants | 20 participants | 16 participants |
| Region of Enrollment Canada | 23 participants | 6 participants | 6 participants | 5 participants | 6 participants |
| Region of Enrollment France | 93 participants | 22 participants | 26 participants | 23 participants | 22 participants |
| Region of Enrollment Germany | 70 participants | 18 participants | 22 participants | 13 participants | 17 participants |
| Region of Enrollment Italy | 50 participants | 11 participants | 13 participants | 10 participants | 16 participants |
| Region of Enrollment Netherlands | 72 participants | 14 participants | 19 participants | 20 participants | 19 participants |
| Region of Enrollment Spain | 14 participants | 3 participants | 4 participants | 6 participants | 1 participants |
| Region of Enrollment Switzerland | 26 participants | 7 participants | 5 participants | 7 participants | 7 participants |
| Region of Enrollment Turkey | 4 participants | 2 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United Kingdom | 143 participants | 34 participants | 31 participants | 39 participants | 39 participants |
| Region of Enrollment United States | 101 participants | 28 participants | 30 participants | 22 participants | 21 participants |
| Sex: Female, Male Female | 307 Participants | 82 Participants | 75 Participants | 68 Participants | 82 Participants |
| Sex: Female, Male Male | 444 Participants | 106 Participants | 114 Participants | 120 Participants | 104 Participants |
| World Health Organization (WHO) Performance Status ECOG performance status 0 (good prognosis) | 441 Participants | 112 Participants | 111 Participants | 110 Participants | 108 Participants |
| World Health Organization (WHO) Performance Status ECOG performance status >0 (poorer prognosis) | 310 Participants | 76 Participants | 78 Participants | 78 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 107 / 189 | 97 / 188 | 78 / 186 | 74 / 188 |
| other Total, other adverse events | 182 / 186 | 183 / 185 | 182 / 183 | 185 / 185 |
| serious Total, serious adverse events | 13 / 186 | 27 / 185 | 32 / 183 | 32 / 185 |
Outcome results
Primary
Overall Survival as Measured From the Day of Randomization
The duration of survival is the time interval between randomization and the date of death due to any cause. Patients not reported dead or lost to follow up will be censored at the date of the last follow up examination.
Time frame: from date from enrollment till the date of death (time till death is up to 10.9 years after patient enrollment in the study)
Population: This trial studied 2 questions 1) effect of concomitant Temozolomide (TMZ) 2) effect of adjuvant TMZ. The 4 randomized arms were combined. Absence of concomitant TMZ including Arm Radiotherapy (RT) alone \& Arm RT followed by adjuvant TMZ. Presence of concomitant TMZ including Arm TMZ/RT \& Arm TMZ/RT followed by adjuvant TMZ. Absence of adjuvant TMZ including Arm RT alone \& Arm TMZ/RT. Presence of adjuvant TMZ including Arm RT followed by adjuvant TMZ \& Arm TMZ/RT followed by adjuvant TMZ
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Absence of Concomitant Temozolomide (TMZ) | Overall Survival as Measured From the Day of Randomization | 60.42 Months |
| Presence of Concomitant Temozolomide (TMZ) | Overall Survival as Measured From the Day of Randomization | 66.92 Months |
| Absence of Adjuvant Temozolomide (TMZ) | Overall Survival as Measured From the Day of Randomization | 46.92 Months |
| Presence of Adjuvant Temozolomide (TMZ) | Overall Survival as Measured From the Day of Randomization | 82.33 Months |
p-value: 0.7699.1% CI: [0.73, 1.28]Regression, Cox
p-value: <0.000195% CI: [0.52, 0.79]Regression, Cox
Secondary
Neurological Deterioration Free Survival
Neurological deterioration is defined as a decrease in WHO performance status as follows: decrease in WHO performance status * for patients with baseline WHO performance status 0: deterioration to WHO performance status 2 or worse for which no other explanation is present, and which is maintained for at least three months * for patients with baseline WHO performance status 1 or 2: deterioration to WHO performance status 3 or worse for which no other explanation is present and which is maintained for at least three months The date of neurological deterioration will be the first date the persistent decrease in performance status was diagnosed. Neurological deterioration free progression is the time interval between the date of randomization and the date of neurological deterioration or death whichever occurs first. If neither event has been observed, the patient is censored at the date of the last follow up examination
Time frame: within 2 weeks of randomization; during radiotherapy at week 4 and 6; 4 weeks after the end of radiotherapy; Six monthly after the end of radiotherapy; Prior to each cycle of adjuvant therapy; Every six months after the documentation of first progression.
Secondary
Progression-free Survival
Disease progression is defined as radiological or neurological/clinical progression (whichever occurs first); progression free survival (PFS) is the time interval between the date of randomization and the date of disease progression or death whichever occurs first. If neither event has been observed, the patient is censored at the date of the last follow up examination. Radiological progression was defined as increase of contrast enhancing area on MRI or CT scans of more than 25% as measured by two perpendicular diameters compared to the smallest measurements ever recorded for the same lesion by the same technique. The appearance of new lesions with or without contrast enhancement Neurological/clinical progression was defined as:decrease in WHO performance status,deterioration of neurological functions,appearance of signs/symptoms of increased intracranial pressure,and/or start of corticosteroid or increase of corticosteroid dosage by 50% for control of neurological symptoms.
Time frame: from randomization till the date of disease progression or death (time till death is up to 10.9 years after patient enrollment in the study)
Population: This trial studied separately two questions 1) effect of concomitant TMZ 2) effect of adjuvant TMZ. The 4 randomized arms were combined before analysis. Absence of concomitant TMZ including Arm RT alone \& Arm RT followed by adjuvant TMZ. Presence of concomitant TMZ including Arm TMZ/RT \& Arm TMZ/RT followed by adjuvant TMZ. Absence of adjuvant TMZ including Arm RT alone \& Arm TMZ/RT. Presence of adjuvant TMZ including Arm RT followed by adjuvant TMZ \& Arm TMZ/RT followed by adjuvant TMZ
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Absence of Concomitant Temozolomide (TMZ) | Progression-free Survival | 20.9 Months |
| Presence of Concomitant Temozolomide (TMZ) | Progression-free Survival | 33.02 Months |
| Absence of Adjuvant Temozolomide (TMZ) | Progression-free Survival | 19.09 Months |
| Presence of Adjuvant Temozolomide (TMZ) | Progression-free Survival | 42.81 Months |
p-value: 0.1195% CI: [0.72, 1.03]Regression, Cox
p-value: <0.000195% CI: [0.49, 0.7]Regression, Cox
Secondary
Quality of Life of the Patient
Quality of life was assessed by the EORTC Quality of Life Questionnaire (QLQ-C30) version 3 and the Brain Cancer Module-20
Time frame: from 14 days prior to randomization till five years or death (time till death is up to 10.9 years after patient enrollment in the study)