Background: High-dose methotrexate (HD-MTX) is widely used as a standard chemotherapeutic agent in pediatric cancers. Most research studies have confirmed the therapeutic efficacy of HD-MTX; however, strategies to prevent side effects vary among institutions, especially in developing countries, with limited monitoring of plasma methotrexate level.
Objective: To evaluate the effect of intravenous hydration during HD-MTX administration on plasma methotrexate clearance in pediatric oncology patients.
Materials and methods: This study retrospectively reviewed 165 courses of HD-MTX administered to children with acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), or osteosarcoma. Demographic data of patients were collected. Adverse complications related to HD-MTX and 72-hour plasma methotrexate level were analyzed between patients receiving intravenous hydration ≥3,000 mL/m2/day and those receiving hydration <3,000 mL/m2/day.
Results: Among 56 HD-MTX (1.5 g/m2) courses in ALL, delayed methotrexate clearance was only found in one course administered with hydration <3,000 mL/m2/day. However, no correlation was observed between adverse complications and methotrexate levels. Of 34 HD-MTX (1.5–3 g/m2) courses in NHL, no significant correlation was observed between methotrexate levels and intravenous hydration. However, increased adverse complications were found in the course with delayed methotrexate clearance. Interestingly, among 75 HD-MTX (10–12 g/m2) courses in osteosarcoma, normal methotrexate clearance was successfully achieved in all courses administered with hydration ≥3,000 mL/m2/day compared with those administered with hydration <3,000 mL/m2/day (P=0.007). Furthermore, the courses administered with hydration <3,000 mL/m2/day and had delayed methotrexate clearance were more likely to develop adverse complications.
Conclusion: Intravenous hydration of ≥3,000 mL/m2/day during HD-MTX administration is essentially required in osteosarcoma and can be considered as optional in ALL with HD-MTX <1.5 g/m2, especially in developing countries with limited monitoring of plasma methotrexate level.
Keywords: high-dose methotrexate, hydration, children, cancer, osteosarcoma, leukemia, lymphoma
Methotrexate is a chemotherapeutic agent that is practically used in cancer treatment, with additional indications for autoimmune and rheumatological diseases.1,2 A methotrexate dose of >500 mg/m2 is generally considered a high dose, for which careful monitoring of drug clearance and extended supportive care to prevent adverse complications are essentially needed.3–6 In the pediatric oncology population, high-dose methotrexate (HD-MTX) is commonly used as a part of treatment protocols among patients with acute lymphoblastic leukemia (ALL),7–9 non-Hodgkin’s lymphoma (NHL),10,11 and osteosarcoma,12–15 with the dose ranging from 1 to 12 g/m2. With the integration of HD-MTX in standard chemotherapeutic regimens, the current survival rates of those patients with ALL, NHL, and osteosarcoma have dramatically improved compared with those reported previously.
Methotrexate is a synthetic folate antimetabolite and cell cycle specific for S phase which inhibits DNA synthesis, repair, and cellular replication. The action of methotrexate is caused by irreversible competitive inhibition of the dihydrofolate reductase enzyme, resulting in the interference of active tetrahydrofolate synthesis and later in inhibited purine and thymidylic acid synthesis, and thus inhibiting DNA synthesis, repair, and cellular replication.16–19 Therefore, actively proliferative tissues are more susceptible to the effects of this chemotherapeutic agent. When methotrexate is used in a higher dose, the drug produces several serious complications. The most common adverse complications of high-dose treatment include mucositis or ulcerative stomatitis, hepatotoxicity, nephrotoxicity, and bone marrow suppression, predisposing to severe infection and bleeding complications.20 An additional rare but important complication is the reaction of the central nervous system to methotrexate, especially when it is administered using an intrathecal route, including leukoencephalopathies and myelopathies.21
The risk of developing adverse toxicities of HD-MTX can be prevented by careful monitoring of plasma methotrexate level, aggressive intravenous hydration with alkalinization of urine, and concurrent use of leucovorin or folinic acid at the appropriate timing according to plasma methotrexate level nomogram.3,4 Since methotrexate can penetrate third-space fluids, such as pleural effusion or ascites, and exits slowly from these compartments as well as excretes through urine, delayed methotrexate clearance can cause serious adverse complications among patients with kidney dysfunction or third-space fluid accumulation or those receiving inadequate hydration. Evidence suggests that a less aggressive hydration regimen (1,500 mL/m2/day) was associated with higher plasma methotrexate levels at the end of infusion of HD-MTX (8 g/m2) among patients with osteosarcoma compared with a higher aggressive hydration regimen (2,000 mL/m2/day); however, there was no difference in the incidence of late eliminated methotrexate between the two hydration regimens.22 Many of the current pediatric protocols recommend a higher hydration strategy during HD-MTX administration, with at least 2 hours of aggressive hydration of a minimum of 200 mL/m2 hourly or 2,400–3,600 mL/m2/day beginning 12 hours before the start of HD-MTX and continuing for 24–48 hours or longer;3 however, the benefits of this aggressive hydration remain unclear.
Although most research studies have focused on the efficacy of HD-MTX in cancer treatment, only a few reports have described the hydration strategy in preventing adverse complications of this chemotherapy.22–25 The strategies for intravenous hydration among patients receiving HD-MTX vary among different institutions and treatment protocols. In addition, some institutions, especially in developing countries, have limited monitoring of plasma methotrexate level, making the intravenous hydration management difficult, which, in turn, results in clinical symptoms of volume overload due to overhydration or HD-MTX-related toxicities due to underhydration. Our study aimed to evaluate the effect of intravenous hydration during HD-MTX administration on plasma methotrexate clearance, as well as adverse complications of HD-MTX among pediatric oncology patients. In addition, potential adverse events from aggressive hydration, including clinical symptoms of volume overload, were also reviewed.