Unresectable Multiple Brain Metastases
Conditions
Keywords
cancer, brain, arginine, radiation
Brief summary
This study evaluates the nutritional supplement arginine as supportive measure for patients with unresectable metastatic brain tumors that receive radiation therapy with palliative intent
Detailed description
Brain metastasis, the most common intracranial tumor, is associated with neurological disability and short survival time. For selected patients this outcome can be improved by achieving greater local control. Virtually all cancer patients with brain metastases receive radiotherapy; a majority as part of their primary treatment while others in connection with surgery or palliation. Agents that increase the sensitivity of cancer cells to radiation may improve the control of the disease. Previous data indicates that arginine supplementation can modify the metabolism of cancer and immune cells making tumors more susceptible to standard treatments liked radiation. In this phase 1/2 comparative study the investigators will investigate whether 10 mg of arginine oral supplementation (compared to placebo administration) administered twice a day prior to the radiation therapy can modify tumor metabolism, immune response and effect of radiation. The primary end-points are safety and toxicity of arginine, quality-of-life and clinical response. The secondary end-points are imaging response and neurological progression-free survival. Additional exploratory end-points include intensity of radiation administered, effects on tumor metabolism by magnetic resonance spectroscopy, immune response by cytokine pattern in serum, body composition and nutritional parameters , overall survival and progression free survival
Interventions
DIETARY_SUPPLEMENTL-arginine hydrochloride solution
Patients with unresectable brain metastases from solid tumors that are candidates from twice-daily fractionated radiation therapy will be randomized to receive either oral arginine supplementation one-hour prior to each fraction of radiation. Radiation therapy consist in whole-brain treated by two lateral fields to a total dose of 32 Gy in 20 fractions of 1.6 Gy each two times a day with a 6 hours interval between treatments (10 days), followed by a 22.4 Gy boost over the evident lesions with the same fractionation schedule (7 days). The spinal cord dose will be limited to 40 Gy
OTHERPlacebo
Patients with unresectable brain metastases from solid tumors that are candidates from twice-daily fractionated radiation therapy will be randomized to receive oral placebo one-hour prior to each fraction of radiation. Radiation therapy consist in whole-brain treated by two lateral fields to a total dose of 32 Gy in 20 fractions of 1.6 Gy each two times a day with a 6 hours interval between treatments (10 days), followed by a 22.4 Gy boost over the evident lesions with the same fractionation schedule (7 days). The spinal cord dose will be limited to 40 Gy
Sponsors
Instituto de Oncología Ángel H. Roffo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients with pathology-confirmed diagnostic of solid cancer and measurable brain metastases by CT scan and/or MRI Inclusion Criteria: * Unresectable criteria by neurosurgeon * Recursive partitioning analysis (RPA) -Radiation Therapy Oncology Group (RTOG) class II (Karnofsky's performance score ≥ 70 and extracranial metastases and/or non-controlled primary tumor) * Measurable brain lesion/s by contrast-enhanced CT or MRI * Absolute granulocyte count more or equal than 2000/mm3 * Hemoglobin more or equal than 9 g/L (patients with lower levels were transfused before the randomization) * Normal renal laboratory (serum creatinine \<1.5 mg/dL and 24-h creatinine clearance \>60 mL/min) * Normal hepatic function (aspartate aminotransferase and alanine aminotransferase \<2.5 times the upper limit of normal) * Stable body weight and composition for at least one month prior enrollment
Exclusion criteria
* Prior treatment for brain metastases and/or brain tumor. * Primary brain tumor * Hematologic malignancies * Solid tumors of germinal origin * Contraindication for external radiation therapy. * Allergy to L-arginine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in signs and symptoms of neurological disease | Baseline and at 4 weeks counted from the last day of treatment | Signs and symptoms of neurological disease will be evaluated by caregiver and investigator according to response criteria evaluation guidelines. Clinical response will be considered as the changes in signs and symptoms that occur between baseline state and 30 days counted from the last day of treatment |
| Change from baseline of the scoring form NCI CTCAE v3 for detecting and quantifying potential adverse events | Baseline and thereafter every 7 days starting from day 1 of L-arginine or placebo administration and through study completion, an average of 1 year | NCI CTCAE v3 form will be completed baseline and every 7 days starting from day 1 of L-arginine or placebo administration thereafter. This form will detect adverse events including clinical laboratory alterations associated with the administration of of L-arginine or placebo including those that may exacerbate the adverse events expected from the radiation therapy |
| Change from baseline of quality of life questionnaire | Baseline and thereafter every 7 days starting from day 1 of L-arginine or placebo administration and through study completion, an average of 1 year | Quality of life questionnaire with assessment of the Karnofsky's index will be completed baseline and every 7 days starting from day 1 of L-arginine or placebo administration thereafter |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Imaging response | One month after the last day of radiation and one month after the first response assessment | The investigators will follow the R.E.C.I.S.T. criteria for imaging and overall response evaluation |
| Neurological progression-free survival | Time with no radiological or symptomatic progression counted from the first of radiation therapy until the day of first documented neurological progression or date of death from any cause, whichever came first, assessed up to 50 months | The investigators will follow the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for imaging (CT and MRI) response evaluation based on measurable disease, assessed up to 50 months |
Other
| Measure | Time frame | Description |
|---|---|---|
| Intensity of radiation administered | From the first of radiation therapy through study completion, an average of 1 year | Actual daily and total dose of radiation administered as fractional product of the planned (proposed) daily and total dose of radiation |
| Overall survival | Survival time counted from the first of radiation therapy until the date of death from any cause or lost of follow-up, assessed up to 50 months | Survival time counted from the day 1 of radiation therapy to death or lost of follow-up, assessed up to 50 months |
| effects on tumor metabolism by magnetic resonance spectroscopy | Before and one hour after the first dose of L-arginine (or placebo) administration without radiation therapy | Before and one hour after the first dose of L-arginine (or placebo) administration without radiation therapy |
| Change from baseline in cytokine pattern in serum | Before treatment (baseline), at 4 weeks after the last of treatment and at 8 weeks after the last of treatment | The investigators will determine levels of circulating (serum) cytokines in a sub-group of patients from both arms to determine immune effects of L-arginine. Comments \[5\] : |
| Change from baseline in body weight | Baseline and thereafter every 7 days starting from day 1 of L-arginine or placebo administration and through study completion, an average of 1 year | Body weight (kg) will be determined baseline and every 7 days starting from day 1 of L-arginine or placebo administration thereafter. The reported value will be number of patients with change of 10% or higher in any value at any time point from baseline |
| Progression free survival | Time with no radiological or symptomatic progression in any site of disease counted from the first of radiation therapy until the day of first documented disease progression or date of death from any cause, whichever came first, assessed up to 50 months | The investigators will follow the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for imaging (CT and MRI) response evaluation based on measurable disease assessed up to 50 months |
Outcome results
None listed