Hyper-alkalinization without hyper-hydration for the prevention of high-dose methotrexate acute nephrotoxicity in patients with osteosarcoma

Abstract

(204 words)Purpose: To evaluate the reliability and renal safety of an original schedule of high-dose methotrexate (HDMTX) administration with hyper-alkalinization, and without hyperhydration.Methods: Osteosarcoma patients received HDMTX (8-12 g/m²) as a 4-hour infusion.Hypertonic 8.4% sodium bicarbonate was infused prior to HDMTX, then once daily for 3 days. Methotrexate serum concentrations was measured at hour 4 (Cmax), hour 24, hour 48 and hour 72. Urinary pH was measured on each miction. Serum creatinine was assessed on days 1, 3 and 8.Results: Twenty-six patients (median age: 18 years, range: 15-25) received a total of 344 cycles of HDMTX, including 16 patients treated in an outpatient basis. Urinary pH remained constantly higher than 7.5 in all patients. Grade 1 creatininemia toxicity was observed in 31 cycles (9%), and grade 2 creatinine toxicity was observed in one patient. No episode of acute severe nephrotoxicity was observed. No significant worsening was observed in serum creatinine and calculated creatinine clearance from baseline to the end of therapy (p = 0.74).The main extra-renal toxicity was alkalinization-related hypokalemia from H48. No rehospitalisation was required. Conclusion:Hyper-alkalinization appears an efficient and reliable method to prevent the acute renal toxicity of HDMTX, and allows its safe administration in the outpatient setting.

Use of sodium bicarbonate to promote weight gain, maintain body temperature, normalize renal functions and minimize mortality in rodents receiving the chemotherapeutic agent cisplatin

“…Human studies have reported beneficial effects of sodium bicarbonate in reducing blood acidosis and kidney toxicity in chemotherapy patients [7,21]. Therefore, we developed a new preclinical method to minimize damage to renal functions (assessed by measurements of creatinine levels, kidney weight ratio and urine pH) and improve general health (weight gain, normal body temperature and reduced mortality) in rodent subjects.…”

“…Cisplatin is partially metabolized into toxic species [30], promoting an acidic environment that produces nephrotoxicity and changes in renal functions, documented by increases in creatinine (normal creatinine between 0.2 –1.36 mg/dL) and kidney weight ratio [13,15] in our study. A change in the body pH (normal blood pH: 7.35–7.45; normal urine pH ~7.00) toward acidity (below pH 7.0) favours oxygen to be driven out of the body, thereby facilitating cancer cell survival [10,12,21]. Thus, urine, but not blood, pH would be expected to be increased by alkaline and decreased by acidic diets/treatments, as observed in our study and elsewhere [21].…”

“…A change in the body pH (normal blood pH: 7.35–7.45; normal urine pH ~7.00) toward acidity (below pH 7.0) favours oxygen to be driven out of the body, thereby facilitating cancer cell survival [10,12,21]. Thus, urine, but not blood, pH would be expected to be increased by alkaline and decreased by acidic diets/treatments, as observed in our study and elsewhere [21]. Cancerous tissue is acidic because cells spill lactic acid, causing an acidic pH [29].…”

Salvianolic acid B suppresses cell proliferation and induces apoptosis in osteosarcoma through p38-mediated reactive oxygen species generation

“…Levels of malignancy in osteosarcoma are high, patient prognosis is poor, and patients may exhibit lung metastases within several months. Subsequent to amputation, the 3-5-year survival rates are only 60% (19). The present study observed that salvianolic acid B suppressed cell proliferation, induced apoptosis and activated cleaved caspase 3 of the osteosarcoma MG63 cell.…”

Contribution of tumoral and host solute carriers to clinical drug response

“…Antifolates have been used in cancer treatment since 1948 when aminopterin was first shown to cause temporary remission of disease in children with acute lymphoblastic leukemia (ALL) (Farber and Diamond, 1948). Today, the most widely used antifolate, methotrexate (MTX), is used in the treatment of multiple diseases including ALL, osteosarcomas, lymphomas, head and neck, bladder, and breast cancer (Catto and Hamdy, 2010; Mikkelsen et al, 2011; Mir et al, 2010; Tobias et al, 2010). …”