Supplementation of L-arginine in Patients With Non-resectable Brain Metastases

Oral L-arginine Supplementation in Patients With Non-resectable Brain Metastases Treated With Radiation Therapy With Palliative Intent

This study evaluates the nutritional supplement arginine as supportive measure for patients with unresectable metastatic brain tumors that receive radiation therapy with palliative intent

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

In the Arginine arm patients will receive 10 mg of L-arginine hydrochloride solution oral supplementation (in 200 ml of flavoured drinking water solution) administered twice a day prior to the radiation therapy fraction

In the Placebo arm patients will receive 200 ml of flavoured drinking water oral solution administered twice a day prior to the radiation therapy fraction

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

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

Change from baseline of the scoring form NCI CTCAE v3 for detecting and quantifying potential adverse events

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

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

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

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

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

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

Actual daily and total dose of radiation administered as fractional product of the planned (proposed) daily and total dose of radiation

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

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] :

Before treatment (baseline), at 4 weeks after the last of treatment and at 8 weeks after the last of treatment

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

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

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

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

Survival time counted from the day 1 of radiation therapy to death or lost of follow-up, assessed up to 50 months

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

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.

Castillo L, Beaumier L, Ajami AM, Young VR. Whole body nitric oxide synthesis in healthy men determined from [15N] arginine-to-[15N]citrulline labeling. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11460-5. doi: 10.1073/pnas.93.21.11460.

Cho-Chung YS, Clair T, Bodwin JS, Berghoffer B. Growth arrest and morphological change of human breast cancer cells by dibutyryl cyclic AMP and L-arginine. Science. 1981 Oct 2;214(4516):77-9. doi: 10.1126/science.6269181.

Bode-Boger SM, Boger RH, Galland A, Tsikas D, Frolich JC. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol. 1998 Nov;46(5):489-97. doi: 10.1046/j.1365-2125.1998.00803.x.

Kang K, Shu XL, Zhong JX, Yu TT. Effect of L-arginine on immune function: a meta-analysis. Asia Pac J Clin Nutr. 2014;23(3):351-9. doi: 10.6133/apjcn.2014.23.3.09.

Cerchietti LC, Bonomi MR, Navigante AH, Castro MA, Cabalar ME, Roth BM. Phase I/II study of selective cyclooxygenase-2 inhibitor celecoxib as a radiation sensitizer in patients with unresectable brain metastases. J Neurooncol. 2005 Jan;71(1):73-81. doi: 10.1007/s11060-004-9179-x.