Dose-Escalated Photon IMRT or Proton Beam Radiation Therapy Versus Standard-Dose Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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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
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PRIMARY OBJECTIVES: 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 photon 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. TERTIARY 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. To establish feasibility and clinical relevancy of quality assurance guidelines. To evaluate efficacy of quality assurance tools. IV. To explore the most appropriate and clinically relevant advanced and standard MRI imaging parameters. To evaluate the feasibility of differentiating pseudo-progression and true progression in a multi institutional setting using MR diffusion and perfusion imaging. 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.

Official Title
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Randomized Phase II Trial of Hypofractionated Dose-Escalated Photon IMRT or Proton Beam Therapy Versus Conventional Photon Irradiation With Concomitant and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma

Conditions
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Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

Intervention / Treatment
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* Radiation: 3-dimensional conformal radiation therapy
* Radiation: intensity-modulated radiation therapy
* Radiation: photon beam radiation therapy
* Radiation: intensity-modulated radiation therapy
* Radiation: proton beam radiation therapy
* Drug: temozolomide
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRIOR TO STEP 1 REGISTRATION A diagnostic contrast-enhanced magnetic resonance imaging (MRI) (no other scan type allowed) of the brain must be performed postoperatively within 72 hours of resection; the enhancing tumor must have a maximal diameter of 5 cm; 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; for cases where residual disease or postoperative surgical cavity is NOT identifiable (e.g., polar glioblastomas [GBMs] where a polar lobectomy is performed), the patient will be excluded from the trial The GBM 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 analysis of O6-methylguanin-DNA-methyltransferase (MGMT) status Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; at least 1 cubic centimeter of tissue composed primarily of tumor must be present Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy or cavitron ultrasonic suction aspirator (CUSA) technique are not allowed 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 Absolute neutrophil count (ANC) >= 1,800 cells/mm^3 Platelets >= 100,000 cells/mm^3 Hemoglobin >= 10.0 g/dl (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) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN Negative serum pregnancy test obtained for females of child-bearing potential within 28 days prior to step 2 registration Exclusion Criteria: 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 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 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 Patents 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A1 (control)<br>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 courses in the absence of disease progression or unacceptable toxicity. | Radiation: 3-dimensional conformal radiation therapy<br>* Undergo standard-dose 3D-CRT<br>* Other names: 3D-CRT;Radiation: intensity-modulated radiation therapy<br>* Undergo standard-dose IMRT<br>* Other names: IMRT;Drug: temozolomide<br>* Given PO<br>* Other names: TMZ;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm B (photon IMRT)<br>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 courses in the absence of disease progression or unacceptable toxicity. | Radiation: photon beam radiation therapy<br>* Undergo dose-escalated and -intensified photon IMRT<br>Radiation: intensity-modulated radiation therapy<br>* Undergo dose-escalated and -intensified photon IMRT<br>* Other names: IMRT;Drug: temozolomide<br>* Given PO<br>* Other names: TMZ;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Active Comparator: Arm A2 (control)<br>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 courses in the absence of disease progression or unacceptable toxicity. | Radiation: 3-dimensional conformal radiation therapy<br>* Undergo standard-dose 3D-CRT<br>* Other names: 3D-CRT;Radiation: intensity-modulated radiation therapy<br>* Undergo standard-dose IMRT<br>* Other names: IMRT;Drug: temozolomide<br>* Given PO<br>* Other names: TMZ;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm C (proton beam radiation therapy)<br>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 courses in the absence of disease progression or unacceptable toxicity. | Radiation: proton beam radiation therapy<br>* Undergo dose-escalated and -intensified proton beam radiation therapy<br>Drug: temozolomide<br>* Given PO<br>* Other names: TMZ;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) compared between dose-escalated and -intensified photon IMRT 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 OS rates by MGMT, recursive partitioning analysis (RPA) 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 OS will be performed to assess the treatment effect adjusting for patient-specific risk factors. | Date of randomization to the date of death due to any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS when compared between dose-escalated and -intensified photon IMRT to dose-escalated and -intensified proton beam therapy | If the instrumental variable assumptions hold, OS rate will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested in the log-rank test. | Date of randomization to the date of death, assessed up to 5 years | 
| Progression-free survival (PFS) | PFS rates will be estimated using the Kaplan-Meier method and comparisons between treatment arms will be made in the same manner as for OS. | Date of randomization to the date of progression or death, assessed up to 5 years | 
| Incidence of treatment-related toxicity, as measured by the Common Terminology Criteria for Adverse Events version 4 | 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. | Up to 5 years | 
| Change in perceived cognitive function, as measured by M.D. Anderson Symptom Inventory Brain Tumor | 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. | Baseline to up to 60 weeks | 
| 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 | The change from baseline to each follow-up time point for the perceived Clinical Trial Battery (CTB) 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 CTB composite score is significantly different within both groups, a test will be performed to compare between the 2 experimental arms. | Baseline to up to 60 weeks | 
| Change in CD4 lymphopenia count | 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 OS. This will be assessed here based on the CD4 count at the completion of chemoradiation which matches best to 2-months. | Baseline to up to 5 years | 
| Use of magnetic resonance diffusion and perfusion imaging to differentiate between tumor progression and pseudo-progression | Retrospective analysis will be performed to evaluate and refine the method and the threshold cut-off point determined from our previous single institute data set to determine progression using the first one-third of the patient data collected in this trial. If the initial analysis supports our preliminary results with sufficient high sensitivity and specificity, e.g., 80% specificity and 90% sensitivity or higher, results will be validated using the remaining two-thirds of the imaging data. | Up to 5 years |