Radiation Therapy With Concomitant and Adjuvant Temozolomide Versus Radiation Therapy With Adjuvant PCV Chemotherapy in Patients With Anaplastic Glioma or Low Grade Glioma
Phase III Intergroup Study of Radiotherapy With Concomitant and Adjuvant Temozolomide Versus Radiotherapy With Adjuvant PCV Chemotherapy in Patients With 1p/19q Co-deleted Anaplastic Glioma or Low Grade Glioma
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. It is not yet known whether giving
radiation with concomitant and adjuvant temozolomide versus radiation with adjuvant PCV is
more effective in treating anaplastic glioma or low grade glioma.
This study will be a randomized phase III for patients with newly diagnosed co-deleted
1p/19q anaplastic glioma or high risk low grade glioma. The trial will only enroll patients
with 1p/19q co-deletion. This study includes two arms as described in the "Arms" section. A
dynamic allocation procedure will be used to allocate an equal number of patients to
different arms (Arms A:B = 1:1). This procedure will balance the marginal distributions of
the stratification factors among arms. The stratification factors that will be used are
cooperative groups (EORTC vs. all North American groups), age (≤ 50 vs. > 50), performance
score (ECOG 0-1 vs. 2), and tumor grade (anaplastic glioma vs. low grade glioma).
The primary goal is to determine whether patients who receive radiotherapy with concomitant
temozolomide (TMZ) followed by adjuvant temozolomide (RT + TMZ --> TMZ) (Arm B) have a
marginally better progression free survival (PFS) as compared with patients who receive
radiotherapy followed by PCV chemotherapy (RT --> PCV)(Arm A).
1. Time to Progression - To determine whether patients who receive (RT + TMZ --> TMZ) have
a significantly longer time to progression (clinical or radiographic progression) as
compared with patients who receive radiotherapy followed by adjuvant PCV chemotherapy
(RT --> PCV).
2. Correlation between exploratory biomarkers and survival - To determine whether there is
a difference in survival based on t(1;19)(q10, p10) translocation status and MGMT
promoter hypermethylation status.
3. Descriptive Comparisons of Additional Secondary Endpoints - To perform descriptive
comparisons of additional secondary outcome endpoints, including overall survival,
objective tumor response, prognostic factor analysis and quality of life.
4. Toxicity - To determine the toxicity of the treatment in each arm and perform
5. Neurocognitive and Quality of Life (QOL) Effects - To determine the neurocognitive and
QOL effects in patients treated on this protocol and correlate these results with
6. Banking of Biospecimens and Neuroimaging Studies - To store blood products (i.e.,
plasma, DNA and buffy coat), tumor tissue and MRI/CT images for future scientific
After completion of study treatment, patients are followed every 12 weeks for 1 year, then
every 4 months for 2 years and then every 6 months until progressive disease or until the
end of study participation.
Pre-Registration Inclusion Criteria:
Central Pathology Review Submission: This review is mandatory prior to registration to
confirm eligibility. Patients must be willing to submit tissue samples for mandatory
central pathology review submission and deletion status determination. It should be
initiated as soon after surgery as possible.
Registration Inclusion Criteria:
1. Age ≥ 18 years
2. Newly diagnosed and ≤ 3 months from surgical diagnosis
3. Histological confirmation of anaplastic glioma (oligodendroglioma, mixed, or
astrocytoma [WHO grade 2 or 3] or low grade glioma [WHO grade 2], as determined by
pre-registration central pathology review. Note: Mixed gliomas are eligible,
regardless of the degree of astrocytic or oligodendrocytic predominance, as long as
the tumor is also co-deleted for 1p and 19q.
4. Patients with codeleted low grade gliomas must also be considered "high risk" by
clinical criteria utilized in RTOG 9802 and must be either: age ≥ 40 and any surgical
therapy or age < 40 and subtotal resection or biopsy.
5. Tumor tissue must show co-deletion for the relevant portions of chromosomes 1p and
19q by FISH analysis, as defined by the testing laboratory.
6. Surgery (partial or gross total resection or biopsy) must be performed ≥ 2 weeks
prior to registration. Patient must have recovered from the effects of surgery.
7. The following laboratory values obtained ≤ 21 days prior to registration.
1. Absolute neutrophil count (ANC) ≥ 1500/mm^3
2. Platelet (PLTs) count ≥ 100,000/mm^3
3. Hemoglobin (Hgb) > 9.0g/dL
4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
5. Serum glutamic oxaloacetic transaminase (SGOT) aspartate transaminase (AST) ≤ 3
6. Creatinine ≤ 1.5 x ULN
8. Negative serum or urine pregnancy test done ≤ 7 days prior to registration for women
of childbearing potential only.
9. Willing and able to complete neurocognitive testing without assistance and the
Quality of Life (QOL) questionnaires with or without assistance
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
11. Provide informed written consent.
12. Willing to return to enrolling institution for follow-up during the Active Monitoring
Phase (ie, active treatment and observation portion) of the study
13. Mandatory Tissue Samples for Correlative Research -Patient willing to provide tissue
samples for correlative research purposes
Registration Exclusion Criteria:
1. Fetal/Newborn Toxicity: Any of the following because this study involves an agent
that has known genotoxic, mutagenic and teratogenic effects: Pregnant women, nursing
women, men or women of childbearing potential who are unwilling to employ adequate
contraception during this study and for up to 6 months following the completion of
2. Received any prior surgery, radiation therapy or chemotherapy for any central nervous
system (CNS) neoplasm. Note: Patients who have had a prior low grade glioma with or
without surgery and who now have anaplastic glioma with no prior radiation or
chemotherapy are eligible for the study.
3. Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens.
4. Concomitant serious immunocompromised status (other than that related to concomitant
steroids) that would compromise the safety of the patient on the study.
5. Patients known to be Human Immunodeficiency Virus (HIV) positive and currently
receiving retroviral therapy. Note: Patients known to be HIV positive, but without
clinical evidence of an immunocompromised state, are eligible for the study.
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
7. Receiving any other investigational agent which would be considered as a treatment
for the primary neoplasm.
8. Other active malignancy within 5 years of registration. Exceptions:
Non-melanotic skin cancer or carcinoma in situ of the cervix. Note: If there is a
history of prior malignancy, the patient must not be receiving other specific
treatment (other than hormonal therapy) for their cancer.
9. History of myocardial infarction ≤ 6 months, or congestive heart failure requiring
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
10. Recent history of hepatitis infection or treating physician determined that the
patient would be at significant risk of reactivation of hepatitis.