Dose-Escalated Photon IMRT or Proton Beam Radiation Therapy Versus Standard-Dose Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma
Purpose
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.
Conditions
- Adult Giant Cell Glioblastoma
- Adult Glioblastoma
- Adult Gliosarcoma
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
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 O(6)-methylguanine-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.
Study Design
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Active Comparator Arm A1 (control) |
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. |
|
|
Experimental Arm B (photon IMRT) |
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. |
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|
Active Comparator Arm A2 (control) |
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. |
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|
Experimental Arm C (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 courses in the absence of disease progression or unacceptable toxicity. |
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Recruiting Locations
More Details
- NCT ID
- NCT02179086
- Status
- Active, not recruiting
- Sponsor
- NRG Oncology
Detailed Description
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.