Dose-Escalated Photon IMRT or Proton Beam Radiation Therapy Versus Standard-Dose Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma
- Conditions
- Glioblastoma
- Interventions
- Radiation: 3-Dimensional Conformal Radiation TherapyRadiation: Intensity-Modulated Radiation TherapyRadiation: Proton Beam Radiation TherapyOther: Laboratory Biomarker AnalysisRadiation: Photon Beam Radiation TherapyOther: Quality-of-Life AssessmentOther: Questionnaire Administration
- Registration Number
- NCT02179086
- Lead Sponsor
- NRG Oncology
- Brief Summary
This randomized phase II trial studies how well dose-escalated photon intensity-modulated radiation therapy (IMRT) or proton beam radiation therapy works compared with standard-dose radiation therapy when given with temozolomide in patients with newly diagnosed glioblastoma. Radiation therapy uses high-energy x-rays and other types of radiation to kill tumor cells and shrink tumors. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs, such as temozolomide, may make tumor cells more sensitive to radiation therapy. It is not yet known whether dose-escalated photon IMRT or proton beam radiation therapy is more effective than standard-dose radiation therapy with temozolomide in treating glioblastoma.
- Detailed Description
PRIMARY OBJECTIVE:
I. To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and adjuvant temozolomide improves overall survival, as compared to standard-dose photon irradiation with concomitant and adjuvant temozolomide.
SECONDARY OBJECTIVES:
I. To indirectly compare dose-escalated and -intensified photon IMRT to dose-escalated and -intensified proton beam therapy in terms of overall survival.
II. To indirectly compare and record toxicities of dose-escalated and -intensified photon IMRT versus dose-escalated and -intensified proton beam therapy and directly compare the toxicities of these approaches versus standard-dose photon irradiation on the backbone of concomitant and adjuvant temozolomide.
III. To determine if dose-escalated and -intensified IMRT or proton beam therapy (using a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and adjuvant temozolomide improves perceived cognitive symptom severity, as compared to standard-dose photon irradiation with concomitant and adjuvant temozolomide.
IV. To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and adjuvant temozolomide improves neurocognitive function, as compared to standard-dose photon irradiation with concomitant and adjuvant temozolomide.
V. To indirectly determine if dose-escalated and -intensified proton beam therapy with concomitant and adjuvant temozolomide improves perceived cognitive symptom severity, as compared to dose-escalated and -intensified photon IMRT, and to directly compare symptom burden with these approaches versus standard-dose photon irradiation on the backbone of concomitant and adjuvant temozolomide.
VI. To indirectly determine if dose-escalated and -intensified proton beam therapy with concomitant and adjuvant temozolomide improves neurocognitive function, as compared to dose-escalated and -intensified photon IMRT, and to directly compare neurocognitive function with these approaches versus standard-dose photon irradiation on the backbone of concomitant and adjuvant temozolomide.
EXPLORATORY OBJECTIVES:
I. Tissue banking for future translational science projects that will be determined based on the state of the science at the time the primary endpoint is reported and will be submitted to National Cancer Institute (NCI) for review and approval.
II. To prospectively compare CD4 lymphopenia between dose-escalated and intensified proton beam therapy, dose-escalated and -intensified photon IMRT, and standard-dose photon irradiation and determine whether CD4 lymphopenia impacts overall survival.
III. To explore the most appropriate and clinically relevant technological parameters to ensure quality and effectiveness throughout radiation therapy processes, including imaging, simulation, patient immobilization, target and critical structure definition, treatment planning, image guidance and delivery.
IIIa. To establish feasibility and clinical relevancy of quality assurance guidelines.
IIIb. To evaluate efficacy of quality assurance tools. IV. To explore the most appropriate and clinically relevant advanced and standard magnetic resonance imaging (MRI) imaging parameters.
IVa. To evaluate the feasibility of differentiating pseudo-progression and true progression in a multi institutional setting using magnetic resonance (MR) diffusion and perfusion imaging.
IVb. To evaluate for early, imaging biomarkers of response and overall survival.
OUTLINE: Patients are assigned to 1 of 2 groups depending on enrolling institution. Within each group, patients will be randomized 1:2 in favor of the experimental arms.
GROUP I (PHOTON IMRT CENTERS): Patients are randomized to 1 of 2 treatment arms.
ARM A1: Patients undergo standard-dose photon irradiation using 3-dimensional conformal radiation therapy (3D-CRT) or IMRT once daily (QD), 5 days a week for 23 fractions plus a boost of 7 additional fractions.
ARM B: Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a total of 30 fractions.
GROUP II (PROTON CENTERS): Patients are randomized to 1 of 2 treatment arms.
ARM A2: Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1.
ARM C: Patients undergo dose-escalated and -intensified proton beam radiation therapy QD, 5 days a week for a total of 30 fractions.
In all treatment arms, patients receive temozolomide orally (PO) QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 606
-
PRIOR TO STEP 1 REGISTRATION
-
A diagnostic contrast-enhanced MRI (no other scan type allowed) of the brain must be performed postoperatively; the residual enhancing tumor and/or resection cavity must have a maximal diameter of 5 cm or less; the tumor diameter will be the greatest diameter as measured on the contrast-enhanced postoperative MRI and will include residual disease and/or the postoperative surgical cavity as appropriate
- The postoperative brain MRI should be obtained within 72 hours of resection; if it is not obtained within 72 hours post-resection, then an MRI obtained 2 weeks or longer after surgery is required and can be utilized to ensure maximal diameter of residual tumor and/or resection cavity is 5 cm or less
- For cases where a gross total resection of enhancing tumor is performed, but postoperative surgical cavity is NOT identifiable, the patient will be excluded from the trial
-
Tumor tissue must be available for submission for central pathology review
-
Timing requirements:
-
If MGMT has been assessed locally by LabCorps or MD Anderson Cancer Center Molecular Diagnostics Lab (MDACC-MDL):
- Tissue for central pathology review and central MGMT assessment and the official LabCorps or MDACC-MDL MGMT result must be received by the NRG Oncology Biospecimen Bank on or before postoperative calendar day 40
- The site's local MGMT report from LabCorp or MDACC-MDL will then be used to stratify the patient; a post-stratification MGMT central review will be performed, but step 2 registration and protocol treatment can proceed without central review of MGMT
- Patients whose tissue for central pathology review and official LabCorps or MDACC-MDL MGMT result cannot be received by NRG Oncology Biospecimen Bank on or before 40 calendar days after surgery may NOT enroll on this trial, as central pathology review and stratification will not be complete in time for the patient to start treatment within 49 calendar days following surgery
-
If MGMT has not been assessed locally by LabCorps or MDACC-MDL:
- Tissue for central pathology review and central MGMT assessment must be received by the NRG Oncology Biospecimen Bank on or before postoperative calendar day 30
- Central MGMT analysis will be performed at MDACC-MDL and used for patient stratification; results will be conveyed to NRG Oncology within 10 business days of receipt of the tissue
- Patients who have not had local MGMT assessment by LabCorps or MDACC-MDL and whose tissue for central pathology review cannot be received by NRG Oncology Biospecimen Bank on or before 30 calendar days after surgery may NOT enroll on this trial, as central pathology review and stratification will not be complete in time for the patient to start treatment within 49 calendar days following surgery
-
-
Tissue Requirements:
- Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; in total, at least 1 cubic centimeter of tissue composed primarily of tumor must be present
- Submission of an accompanying hematoxylin and eosin H&E slide(s) is MANDATORY
- Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy and cavitronic ultrasonic surgical (CUSA) techniques are not allowed
-
-
The tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed)
-
Patients must provide study-specific informed consent prior to step 1 registration
-
PRIOR TO STEP 2 REGISTRATION
-
Histologically proven diagnosis of glioblastoma (World Health Organization [WHO] grade IV) confirmed by central review prior to step 2 registration
-
Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient quantity for central analysis of MGMT status
-
History/physical examination within 28 days prior to step 2 registration
-
The patient must have recovered from effects of surgery, postoperative infection, and other complications within 28 days prior to step 2 registration
-
Documentation of steroid doses within 28 days prior to step 2 registration
-
Karnofsky performance status >= 70 within 28 days prior to step 2 registration
-
Age >= 18
-
Complete blood count (CBC)/differential obtained within 28 days prior to step 2 registration
-
Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (obtained within 28 days prior to step 2 registration)
-
Platelets >= 100,000 cells/mm^3 (obtained within 28 days prior to step 2 registration)
-
Hemoglobin >= 10.0 g/dl (obtained within 28 days prior to step 2 registration) (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable)
-
Bilirubin =< 1.5 upper limit of normal (ULN) (within 28 days prior to step 2 registration)
-
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (within 28 days prior to step 2 registration)
-
Negative serum pregnancy test obtained for females of child-bearing potential within 28 days prior to step 2 registration
-
As of Amendment 2, if the registering site is a photon center (registering patients to group I), the patient must agree to participate in the advanced imaging sub-study
-
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease-free for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
-
Recurrent or multifocal malignant gliomas
-
Any site of distant disease (for example, drop metastases from the GBM tumor site)
-
Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide)
-
Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted
-
Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
-
Severe, active co-morbidity, defined as follows:
- Unstable angina at step 2 registration
- Transmural myocardial infarction within the last 6 months prior to step 2 registration
- Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 28 days prior to step 2 registration (Note: EKG to be performed only if clinical suspicion of cardiac issue)
- New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
- Serious and inadequately controlled arrhythmia at step 2 registration
- Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for surgical resection
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration
- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
- Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is because the treatments involved in this protocol may be significantly immunosuppressive with potentially fatal outcomes in patients already immunosuppressed
- Any other severe immunocompromised condition
- Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
- End-stage renal disease (ie, on dialysis or dialysis has been recommended)
- Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy
-
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic
-
Patients treated on any other therapeutic clinical protocols within 30 days prior to step 2 registration
-
Inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker, or severe claustrophobia)
-
Postoperative tumor plus surgical bed size exceeds 5 cm in maximum diameter
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A1 (control) 3-Dimensional Conformal Radiation Therapy Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT QD, 5 days a week for 23 fractions plus a boost of 7 additional fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A1 (control) Intensity-Modulated Radiation Therapy Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT QD, 5 days a week for 23 fractions plus a boost of 7 additional fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A1 (control) Laboratory Biomarker Analysis Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT QD, 5 days a week for 23 fractions plus a boost of 7 additional fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A1 (control) Quality-of-Life Assessment Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT QD, 5 days a week for 23 fractions plus a boost of 7 additional fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A1 (control) Questionnaire Administration Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT QD, 5 days a week for 23 fractions plus a boost of 7 additional fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A1 (control) Temozolomide Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT QD, 5 days a week for 23 fractions plus a boost of 7 additional fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A2 (control) 3-Dimensional Conformal Radiation Therapy Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A2 (control) Intensity-Modulated Radiation Therapy Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A2 (control) Laboratory Biomarker Analysis Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A2 (control) Quality-of-Life Assessment Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A2 (control) Questionnaire Administration Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm A2 (control) Temozolomide Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm B (photon IMRT) Intensity-Modulated Radiation Therapy Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm B (photon IMRT) Laboratory Biomarker Analysis Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm B (photon IMRT) Photon Beam Radiation Therapy Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm B (photon IMRT) Quality-of-Life Assessment Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm B (photon IMRT) Questionnaire Administration Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm B (photon IMRT) Temozolomide Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm C (proton beam radiation therapy) Laboratory Biomarker Analysis Patients undergo dose-escalated and -intensified proton beam therapy QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm C (proton beam radiation therapy) Proton Beam Radiation Therapy Patients undergo dose-escalated and -intensified proton beam therapy QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm C (proton beam radiation therapy) Quality-of-Life Assessment Patients undergo dose-escalated and -intensified proton beam therapy QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm C (proton beam radiation therapy) Questionnaire Administration Patients undergo dose-escalated and -intensified proton beam therapy QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Arm C (proton beam radiation therapy) Temozolomide Patients undergo dose-escalated and -intensified proton beam therapy QD, 5 days a week for a total of 30 fractions. In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Overall survival Date of randomization to the date of death due to any cause, assessed up to 5 years Will be compared between dose-escalated and -intensified photon intensity-modulated radiation therapy or proton beam therapy with concomitant and adjuvant temozolomide and the standard-dose photon irradiation with concomitant and adjuvant temozolomide. OS rate will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested in a stratified log-rank test, consistent with the stratified randomization. The overall survival rates by MGMT, recursive partitioning analysis class and other prognostic factors will be estimated by Kaplan-Meier methods and compared using the log-rank test. Multivariate analyses with the Cox proportional hazard model for overall survival will be performed to assess the treatment effect adjusting for patient-specific risk factors.
- Secondary Outcome Measures
Name Time Method Overall survival Date of randomization to the date of death, assessed up to 5 years Will be compared between dose-escalated and -intensified photon intensity-modulated radiation therapy to dose-escalated and -intensified proton beam therapy. If the instrumental variable assumptions hold, overall survival rate will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested in the log-rank test.
Progression-free survival Date of randomization to the date of progression or death, assessed up to 5 years Progression-free survival rates will be estimated using the Kaplan-Meier method and comparisons between treatment arms will be made in the same manner as for overall survival.
Incidence of treatment-related toxicity, as measured by the Common Terminology Criteria for Adverse Events version 4 Up to 5 years Differences in observed severities of toxicities (grade 3+) between groups will be estimated using an exact binomial distribution together with 95% confidence interval. The difference between the 2 groups will be tested using a chi square test. If the instrumental variable assumptions hold the experimental arms will also be compared.
Change in perceived cognitive function, as measured by M.D. Anderson Symptom Inventory Brain Tumor Baseline to up to 60 weeks The change from baseline to each follow-up time point for the perceived cognitive symptom severity score will each be compared using a t-test with alpha=0.05, or Wilcoxon test if the data is not normally distributed, between treatment arms within each group. If the instrumental variable assumptions hold and the perceived cognitive function is significantly different within both groups, a test will be performed to compare between the 2 experimental arms.
Change in neurocognitive function, as measured by Hopkins' Verbal Learning Test-Revised, Trail Making Test Parts A and B, and Controlled Oral Word Association Test Baseline to up to 60 weeks The change from baseline to each follow-up time point for the perceived Clinical Trial Battery composite score will each be compared using a t-test with alpha=0.05, or Wilcoxon test if the data is not normally distributed, between treatment arms within each group. If the instrumental variable assumptions hold and the Clinical Trial Battery composite score is significantly different within both groups, a test will be performed to compare between the 2 experimental arms.
Change in CD4 lymphopenia count Baseline to up to 5 years The change from baseline to the completion of radiation will be compared between the control and experimental arms in each group using a t-test. If the instrumental variable assumptions hold, then it will be compared between the experimental arms. A repeated measures analysis, using a mixed effects model, will be used to assess the change of CD4 lymphopenia across time. CD4 count at 2 months after beginning therapy (dichotomized at 200) was shown to be prognostic of overall survival. This will be assessed here based on the CD4 count at the completion of chemoradiation which matches best to 2-months.
Use of magnetic resonance diffusion and perfusion imaging to differentiate between tumor progression and pseudo-progression Baseline up to prior to cycle 4 Will be determined retrospectively following central review by an experienced neuro-radiologist blinded to the patient's outcome.
Use of magnetic resonance diffusion and perfusion imaging as early predictors of overall survival Baseline up to 12 months Cox proportional hazard model will be used to analyze the effect of imaging markers on overall survival. Known prognostic factors and patient baseline characteristics will be included in the multivariate analyses as covariates. Response rate at 3 months post-radiation treatment (prior to cycle 4) as well as overall survival at 12 months will be analyzed in separate logistic regression models, and predictors will be changes in the magnetic resonance imaging parameters between baseline and specific early time points in the study. Known prognostic factors and patient baseline characteristics will be included in the regression models. Leave-one-out cross validation will be employed for predictive assessment of the imaging parameters.
Trial Locations
- Locations (237)
Mayo Clinic in Arizona
🇺🇸Scottsdale, Arizona, United States
Virtua Voorhees
🇺🇸Voorhees, New Jersey, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
New York-Presbyterian/Brooklyn Methodist Hospital
🇺🇸Brooklyn, New York, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
🇺🇸Orange, California, United States
Palo Alto Medical Foundation Health Care
🇺🇸Palo Alto, California, United States
Riverside Methodist Hospital
🇺🇸Columbus, Ohio, United States
Mercy Cancer Center-Elyria
🇺🇸Elyria, Ohio, United States
Ephrata Cancer Center
🇺🇸Ephrata, Pennsylvania, United States
Cleveland Clinic Cancer Center Independence
🇺🇸Independence, Ohio, United States
Sanford Roger Maris Cancer Center
🇺🇸Fargo, North Dakota, United States
Cleveland Clinic Akron General
🇺🇸Akron, Ohio, United States
UHHS-Chagrin Highlands Medical Center
🇺🇸Beachwood, Ohio, United States
Geauga Hospital
🇺🇸Chardon, Ohio, United States
University of Cincinnati Cancer Center-UC Medical Center
🇺🇸Cincinnati, Ohio, United States
Case Western Reserve University
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic Cancer Center/Fairview Hospital
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
North Coast Cancer Care
🇺🇸Sandusky, Ohio, United States
Hillcrest Hospital Cancer Center
🇺🇸Mayfield Heights, Ohio, United States
UH Seidman Cancer Center at Lake Health Mentor Campus
🇺🇸Mentor, Ohio, United States
UH Seidman Cancer Center at Southwest General Hospital
🇺🇸Middleburg Heights, Ohio, United States
University Hospitals Parma Medical Center
🇺🇸Parma, Ohio, United States
UH Seidman Cancer Center at Firelands Regional Medical Center
🇺🇸Sandusky, Ohio, United States
Cleveland Clinic Cancer Center Strongsville
🇺🇸Strongsville, Ohio, United States
University of Toledo
🇺🇸Toledo, Ohio, United States
University of Cincinnati Cancer Center-West Chester
🇺🇸West Chester, Ohio, United States
UHHS-Westlake Medical Center
🇺🇸Westlake, Ohio, United States
Northeast Radiation Oncology Center
🇺🇸Dunmore, Pennsylvania, United States
Cleveland Clinic Wooster Family Health and Surgery Center
🇺🇸Wooster, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Willamette Valley Cancer Center
🇺🇸Eugene, Oregon, United States
Legacy Mount Hood Medical Center
🇺🇸Gresham, Oregon, United States
Legacy Good Samaritan Hospital and Medical Center
🇺🇸Portland, Oregon, United States
Saint Luke's University Hospital-Bethlehem Campus
🇺🇸Bethlehem, Pennsylvania, United States
Adams Cancer Center
🇺🇸Gettysburg, Pennsylvania, United States
University of Alabama at Birmingham Cancer Center
🇺🇸Birmingham, Alabama, United States
Saint Joseph's Hospital and Medical Center
🇺🇸Phoenix, Arizona, United States
UPMC Pinnacle Cancer Center/Community Osteopathic Campus
🇺🇸Harrisburg, Pennsylvania, United States
Mayo Clinic Hospital in Arizona
🇺🇸Phoenix, Arizona, United States
Arizona Oncology Associates-West Orange Grove
🇺🇸Tucson, Arizona, United States
Sechler Family Cancer Center
🇺🇸Lebanon, Pennsylvania, United States
University of Pennsylvania/Abramson Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Jefferson Torresdale Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Reading Hospital
🇺🇸West Reading, Pennsylvania, United States
WellSpan Health-York Cancer Center
🇺🇸York, Pennsylvania, United States
Prisma Health Cancer Institute - Spartanburg
🇺🇸Boiling Springs, South Carolina, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Prisma Health Cancer Institute - Faris
🇺🇸Greenville, South Carolina, United States
Prisma Health Cancer Institute - Eastside
🇺🇸Greenville, South Carolina, United States
Self Regional Healthcare
🇺🇸Greenwood, South Carolina, United States
Prisma Health Cancer Institute - Greer
🇺🇸Greer, South Carolina, United States
Prisma Health Cancer Institute - Seneca
🇺🇸Seneca, South Carolina, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
Tennessee Cancer Specialists-Dowell Springs
🇺🇸Knoxville, Tennessee, United States
Dell Seton Medical Center at The University of Texas
🇺🇸Austin, Texas, United States
Austin Cancer Centers-Central Austin
🇺🇸Austin, Texas, United States
Texas Oncology-Austin Midtown
🇺🇸Austin, Texas, United States
Texas Oncology - Central Austin Cancer Center
🇺🇸Austin, Texas, United States
Banner University Medical Center - Tucson
🇺🇸Tucson, Arizona, United States
Texas Oncology - South Austin Cancer Center
🇺🇸Austin, Texas, United States
Austin Cancer Centers-North
🇺🇸Austin, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
Texas Oncology - Denison Cancer Center
🇺🇸Denison, Texas, United States
Texas Oncology-Flower Mound
🇺🇸Flower Mound, Texas, United States
Texas Oncology - Fort Worth Cancer Center
🇺🇸Fort Worth, Texas, United States
University of Texas Medical Branch
🇺🇸Galveston, Texas, United States
Memorial Hermann Memorial City Medical Center
🇺🇸Houston, Texas, United States
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
UTMB Cancer Center at Victory Lakes
🇺🇸League City, Texas, United States
Covenant Medical Center-Lakeside
🇺🇸Lubbock, Texas, United States
Texas Oncology-Seton Williamson
🇺🇸Round Rock, Texas, United States
Texas Oncology - Round Rock Cancer Center
🇺🇸Round Rock, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Texas Oncology Cancer Center Sugar Land
🇺🇸Sugar Land, Texas, United States
Texas Oncology - Tyler
🇺🇸Tyler, Texas, United States
Logan Regional Hospital
🇺🇸Logan, Utah, United States
Intermountain Medical Center
🇺🇸Murray, Utah, United States
McKay-Dee Hospital Center
🇺🇸Ogden, Utah, United States
Utah Valley Regional Medical Center
🇺🇸Provo, Utah, United States
Saint George Regional Medical Center
🇺🇸Saint George, Utah, United States
Huntsman Cancer Institute/University of Utah
🇺🇸Salt Lake City, Utah, United States
Central Vermont Medical Center/National Life Cancer Treatment
🇺🇸Berlin, Vermont, United States
University of Vermont Medical Center
🇺🇸Burlington, Vermont, United States
Dartmouth Cancer Center - North
🇺🇸Saint Johnsbury, Vermont, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
FHCC at Northwest Hospital
🇺🇸Seattle, Washington, United States
FHCC Proton Therapy Center
🇺🇸Seattle, Washington, United States
University of Washington Medical Center - Montlake
🇺🇸Seattle, Washington, United States
Compass Oncology Vancouver
🇺🇸Vancouver, Washington, United States
Legacy Salmon Creek Hospital
🇺🇸Vancouver, Washington, United States
Wheeling Hospital/Schiffler Cancer Center
🇺🇸Wheeling, West Virginia, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
Sutter Cancer Centers Radiation Oncology Services-Auburn
🇺🇸Auburn, California, United States
AIS Cancer Center at San Joaquin Community Hospital
🇺🇸Bakersfield, California, United States
Alta Bates Summit Medical Center-Herrick Campus
🇺🇸Berkeley, California, United States
Langlade Hospital and Cancer Center
🇺🇸Antigo, Wisconsin, United States
Gundersen Lutheran Medical Center
🇺🇸La Crosse, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸Madison, Wisconsin, United States
Froedtert Menomonee Falls Hospital
🇺🇸Menomonee Falls, Wisconsin, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
UW Cancer Center at ProHealth Care
🇺🇸Waukesha, Wisconsin, United States
Aspirus Regional Cancer Center
🇺🇸Wausau, Wisconsin, United States
BCCA-Vancouver Island Cancer Centre
🇨🇦Victoria, British Columbia, Canada
Ottawa Hospital and Cancer Center-General Campus
🇨🇦Ottawa, Ontario, Canada
Windsor Regional Cancer Centre
🇨🇦Windsor, Ontario, Canada
CHUM - Centre Hospitalier de l'Universite de Montreal
🇨🇦Montreal, Quebec, Canada
The Research Institute of the McGill University Health Centre (MUHC)
🇨🇦Montreal, Quebec, Canada
CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ)
🇨🇦Quebec City, Quebec, Canada
Saskatoon Cancer Centre
🇨🇦Saskatoon, Saskatchewan, Canada
Sutter Cancer Centers Radiation Oncology Services-Cameron Park
🇺🇸Cameron Park, California, United States
Eden Hospital Medical Center
🇺🇸Castro Valley, California, United States
Fresno Cancer Center
🇺🇸Fresno, California, United States
Marin General Hospital
🇺🇸Greenbrae, California, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Los Angeles General Medical Center
🇺🇸Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Fremont - Rideout Cancer Center
🇺🇸Marysville, California, United States
Memorial Medical Center
🇺🇸Modesto, California, United States
Kaiser Permanente Oakland-Broadway
🇺🇸Oakland, California, United States
Saint Joseph Hospital - Orange
🇺🇸Orange, California, United States
Pomona Valley Hospital Medical Center
🇺🇸Pomona, California, United States
Kaiser Permanente-Rancho Cordova Cancer Center
🇺🇸Rancho Cordova, California, United States
Rohnert Park Cancer Center
🇺🇸Rohnert Park, California, United States
Sutter Cancer Centers Radiation Oncology Services-Roseville
🇺🇸Roseville, California, United States
The Permanente Medical Group-Roseville Radiation Oncology
🇺🇸Roseville, California, United States
Sutter Medical Center Sacramento
🇺🇸Sacramento, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
South Sacramento Cancer Center
🇺🇸Sacramento, California, United States
California Pacific Medical Center-Pacific Campus
🇺🇸San Francisco, California, United States
Palo Alto Medical Foundation-Santa Cruz
🇺🇸Santa Cruz, California, United States
Kaiser Permanente Cancer Treatment Center
🇺🇸South San Francisco, California, United States
Palo Alto Medical Foundation-Sunnyvale
🇺🇸Sunnyvale, California, United States
John Muir Medical Center-Walnut Creek
🇺🇸Walnut Creek, California, United States
UCHealth Memorial Hospital Central
🇺🇸Colorado Springs, Colorado, United States
Poudre Valley Hospital
🇺🇸Fort Collins, Colorado, United States
Hartford Hospital
🇺🇸Hartford, Connecticut, United States
Boca Raton Regional Hospital
🇺🇸Boca Raton, Florida, United States
University of Florida Health Science Center - Gainesville
🇺🇸Gainesville, Florida, United States
Baptist MD Anderson Cancer Center
🇺🇸Jacksonville, Florida, United States
University of Florida Health Science Center - Jacksonville
🇺🇸Jacksonville, Florida, United States
Baptist Medical Center South
🇺🇸Jacksonville, Florida, United States
Miami Cancer Institute
🇺🇸Miami, Florida, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Emory Proton Therapy Center
🇺🇸Atlanta, Georgia, United States
Emory University Hospital Midtown
🇺🇸Atlanta, Georgia, United States
Emory University Hospital/Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States
Lewis Cancer and Research Pavilion at Saint Joseph's/Candler
🇺🇸Savannah, Georgia, United States
Saint Alphonsus Cancer Care Center-Boise
🇺🇸Boise, Idaho, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
John H Stroger Jr Hospital of Cook County
🇺🇸Chicago, Illinois, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
Decatur Memorial Hospital
🇺🇸Decatur, Illinois, United States
Northwestern Medicine Cancer Center Kishwaukee
🇺🇸DeKalb, Illinois, United States
Northwestern Medicine Cancer Center Delnor
🇺🇸Geneva, Illinois, United States
UC Comprehensive Cancer Center at Silver Cross
🇺🇸New Lenox, Illinois, United States
Advocate Lutheran General Hospital
🇺🇸Park Ridge, Illinois, United States
OSF Saint Francis Medical Center
🇺🇸Peoria, Illinois, United States
Springfield Memorial Hospital
🇺🇸Springfield, Illinois, United States
Northwestern Medicine Cancer Center Warrenville
🇺🇸Warrenville, Illinois, United States
Radiation Oncology Associates PC
🇺🇸Fort Wayne, Indiana, United States
Parkview Hospital Randallia
🇺🇸Fort Wayne, Indiana, United States
Parkview Regional Medical Center
🇺🇸Fort Wayne, Indiana, United States
IU Health Methodist Hospital
🇺🇸Indianapolis, Indiana, United States
Community Cancer Center East
🇺🇸Indianapolis, Indiana, United States
Community Cancer Center South
🇺🇸Indianapolis, Indiana, United States
Community Cancer Center North
🇺🇸Indianapolis, Indiana, United States
IU Health Ball Memorial Hospital
🇺🇸Muncie, Indiana, United States
Mercy Hospital
🇺🇸Cedar Rapids, Iowa, United States
Iowa Methodist Medical Center
🇺🇸Des Moines, Iowa, United States
University of Kansas Cancer Center
🇺🇸Kansas City, Kansas, United States
University of Kansas Cancer Center-Overland Park
🇺🇸Overland Park, Kansas, United States
Norton Hospital Pavilion and Medical Campus
🇺🇸Louisville, Kentucky, United States
Ochsner Medical Center Jefferson
🇺🇸New Orleans, Louisiana, United States
Willis-Knighton Medical and Cancer Center
🇺🇸Shreveport, Louisiana, United States
Maryland Proton Treatment Center
🇺🇸Baltimore, Maryland, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸Baltimore, Maryland, United States
UM Upper Chesapeake Medical Center
🇺🇸Bel Air, Maryland, United States
Central Maryland Radiation Oncology in Howard County
🇺🇸Columbia, Maryland, United States
UM Baltimore Washington Medical Center/Tate Cancer Center
🇺🇸Glen Burnie, Maryland, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital Cancer Center
🇺🇸Boston, Massachusetts, United States
Boston Medical Center
🇺🇸Boston, Massachusetts, United States
Mass General/North Shore Cancer Center
🇺🇸Danvers, Massachusetts, United States
Lowell General Hospital
🇺🇸Lowell, Massachusetts, United States
Trinity Health Saint Joseph Mercy Hospital Ann Arbor
🇺🇸Ann Arbor, Michigan, United States
University of Michigan Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
McLaren Cancer Institute-Bay City
🇺🇸Bay City, Michigan, United States
Corewell Health Dearborn Hospital
🇺🇸Dearborn, Michigan, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
McLaren Cancer Institute-Flint
🇺🇸Flint, Michigan, United States
Corewell Health Grand Rapids Hospitals - Butterworth Hospital
🇺🇸Grand Rapids, Michigan, United States
Trinity Health Grand Rapids Hospital
🇺🇸Grand Rapids, Michigan, United States
West Michigan Cancer Center
🇺🇸Kalamazoo, Michigan, United States
McLaren Cancer Institute-Lapeer Region
🇺🇸Lapeer, Michigan, United States
Trinity Health Saint Mary Mercy Livonia Hospital
🇺🇸Livonia, Michigan, United States
McLaren Cancer Institute-Macomb
🇺🇸Mount Clemens, Michigan, United States
McLaren Cancer Institute-Central Michigan
🇺🇸Mount Pleasant, Michigan, United States
McLaren Cancer Institute-Owosso
🇺🇸Owosso, Michigan, United States
McLaren Cancer Institute-Northern Michigan
🇺🇸Petoskey, Michigan, United States
Trinity Health Saint Joseph Mercy Oakland Hospital
🇺🇸Pontiac, Michigan, United States
Corewell Health William Beaumont University Hospital
🇺🇸Royal Oak, Michigan, United States
Corewell Health Lakeland Hospitals - Saint Joseph Hospital
🇺🇸Saint Joseph, Michigan, United States
Corewell Health Beaumont Troy Hospital
🇺🇸Troy, Michigan, United States
Sanford Joe Lueken Cancer Center
🇺🇸Bemidji, Minnesota, United States
Saint Luke's Hospital of Duluth
🇺🇸Duluth, Minnesota, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States
Coborn Cancer Center at Saint Cloud Hospital
🇺🇸Saint Cloud, Minnesota, United States
Regions Hospital
🇺🇸Saint Paul, Minnesota, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
North Kansas City Hospital
🇺🇸Kansas City, Missouri, United States
University of Kansas Cancer Center - North
🇺🇸Kansas City, Missouri, United States
ProCure Proton Therapy Center-Somerset
🇺🇸Somerset, New Jersey, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Billings Clinic Cancer Center
🇺🇸Billings, Montana, United States
Comprehensive Cancer Centers of Nevada
🇺🇸Las Vegas, Nevada, United States
Renown Regional Medical Center
🇺🇸Reno, Nevada, United States
Saint Mary's Regional Medical Center
🇺🇸Reno, Nevada, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸Lebanon, New Hampshire, United States
Memorial Sloan Kettering Basking Ridge
🇺🇸Basking Ridge, New Jersey, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
Capital Health Medical Center-Hopewell
🇺🇸Pennington, New Jersey, United States
Memorial Sloan Kettering Commack
🇺🇸Commack, New York, United States
Memorial Sloan Kettering Westchester
🇺🇸Harrison, New York, United States
Northwell Health/Center for Advanced Medicine
🇺🇸Lake Success, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸New York, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Mission Hospital
🇺🇸Asheville, North Carolina, United States
Novant Health Forsyth Medical Center
🇺🇸Winston-Salem, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Sanford Bismarck Medical Center
🇺🇸Bismarck, North Dakota, United States