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© 1999 American Society for Clinical Oncology High-Dose Leucovorin as Sole Therapy for Methotrexate ToxicityFrom the Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Carlos D. Flombaum, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.
PURPOSE: Hemodialysis, hemoperfusion, thymidine, and carboxypeptidase have been recommended together with high-dose (HD) leucovorin (LV) to treat patients at risk for methotrexate (MTX) toxicity. To elucidate the efficacy of high LV rescue as the sole salvage modality for severe MTX intoxication, we studied 13 patients who were treated in this fashion at Memorial Sloan-Kettering Cancer Center (New York, NY). PATIENTS AND METHODS: To identify patients at high risk for severe MTX toxicity, we performed a retrospective review of all patients with MTX levels greater than 100 µmol/L at 24 hours and greater than 10 µmol/L at 48 hours after HD MTX. RESULTS: A total of 13 patients were identified. The median MTX concentration was 164 µmol/L at 24 hours (range, 102 to 940 µmol/L), 16.3 µmol/L at 48 hours (range, 10.5 to 190 µmol/L), and 6.2 µmol/L at 72 hours (range, 1.35 to 39 µmol/L). MTX levels remained greater than 0.1 µmol/L for an average of 11 ± 3 days (mean ± SD) (range, 7 to 17 days). In addition to supportive treatment with hydration and sodium bicarbonate administration, all patients were treated solely with HD LV, which was started within the first 24 hours in nine patients, 48 hours in three patients, and 72 hours in one patient in doses that varied from 0.24 to 8 g/d. Significant neutropenia (neutrophil count < 1,000/µL) occurred in eight patients and lasted for 1 to 5 days. Thrombocytopenia (platelet count < 100,000/µL) occurred in seven patients and lasted for 5 to 10 days. Other toxic manifestations included mucositis of varying degrees, diarrhea, and neutropenic fever, but all patients recovered. CONCLUSION: In the range of MTX levels observed, HD LV can be used as a sole therapy for MTX toxicity without the need for extracorporeal removal and with tolerable morbidity.
HIGH-DOSE (HD) methotrexate (MTX) with leucovorin (LV) rescue has demonstrated activity in a variety of tumors and is routinely used in patients with osteosarcoma and CNS lymphomas.1-3 Although HD MTX is generally well tolerated, unpredictable life-threatening toxicity still occurs.4,5 Toxicity after HD MTX is usually the consequence of delayed MTX excretion and persistently high plasma MTX levels resulting from MTX-induced acute renal dysfunction.6-10 For patients who have markedly delayed clearance of MTX secondary to acute renal dysfunction, increasing the dose and rate of LV administration has been the routine therapeutic maneuver used to avert severe systemic toxicity.11-14 Although this therapy can prevent certain tissue toxicity, experimental studies have shown the inability of high extracellular concentrations of LV to rescue cells exposed to extremely high MTX levels.15 Thus, it is unknown whether patients exposed to extremely high MTX concentrations for prolonged periods of time can be adequately treated with HD LV alone without experiencing life-threatening myelosuppression and gastrointestinal toxicity. Because of this concern, the following alternative rescue techniques have been used in an attempt to minimize systemic toxicity in these patients: (1) extracorporeal removal of the drug by means of peritoneal dialysis,16 hemodialysis,17-22 hemoperfusion,23-30 and/or hemodiafiltration31; (2) administration of LV in combination with thymidine32; and (3) carboxypeptidase administration.33 In most of the studies reported, increased LV rescue was also used in addition to the aforementioned salvage maneuvers. Therefore, the beneficial effects of each therapy alone cannot be clearly discerned. We recently encountered two patients who experienced markedly delayed clearance of MTX and extremely high MTX levels as a consequence of MTX-induced renal failure. These two patients were successfully treated with supportive therapy and HD LV rescue alone and survived with tolerable morbidity. To elucidate the efficacy of HD LV rescue as the sole salvage modality for severe MTX intoxication, we reviewed 13 patients who were treated in a similar fashion during the past 10 years at our institution, Memorial Sloan-Kettering Cancer Center (New York, NY).
Case Reports Patient no. 1. A 12-year-old girl was diagnosed with osteosarcoma in April 1994. She received her second course of HD MTX (10 g/m2 administered over 4 hours) on May 31, 1994. When she was examined 24 hours later, her MTX level was markedly elevated (297 µmol/L) to a concentration well above our criteria for toxic MTX concentration (10 µmol/L at 24 hours). In addition, her serum creatinine level had increased from 0.6 mg/dL before administration of HD MTX to 1.7 mg/dL. The patient was hospitalized and hemoperfusion was initiated but discontinued a few minutes later because of abdominal pain, nausea, vomiting, hypotension, and loss of consciousness. Because of the extremely high MTX level, a second attempt at hemoperfusion was begun 10 minutes later, but once again it was followed by similar symptoms and the procedure was terminated. A sample of blood obtained just before the initiation of hemoperfusion (approximately 32 hours after HD MTX administration) showed that the MTX level had already decreased spontaneously to 94 µmol/L. At this point, it was decided to treat the patient with a combination of hydration, alkalinization of the urine, and supportive therapy with intensive LV rescue (8 g/d as a continuous intravenous infusion for 3 days, after which the dose was gradually decreased and continued for the next 6 days). The patient's renal function slowly improved, but her serum creatinine levels remained elevated for more than 2 weeks. Her MTX levels also decreased (Table 1) but remained greater than 0.1 µmol/L for 10 days. The serum bilirubin and AST levels, which had been normal before HD MTX, increased to 4.5 mg/dL (normal, 0 to 1 mg/dL) and 813 U/L (normal, 10 to 37 U/L), respectively, at 48 hours. The ALT level peaked at 1,362 U/L (normal, 5 to 37 U/L) on the third day. Her hospital course was complicated by intermittent nausea and vomiting and an episode of hematemesis, which subsided after treatment with ranitidine. Mucositis, which lasted for 3 days and required narcotic analgesia, abated as her MTX levels decreased. Her WBC and platelet counts remained normal throughout her hospital stay. The patient was discharged from the hospital on the 10th day with normal hematologic and biochemical parameters and with a serum creatinine level of 1.2 mg/dL. The patient received further therapy with HD MTX without incident.
Patient no. 2. A 12-year-old girl was diagnosed with osteosarcoma in November 1995. She received her second dose of HD MTX (12 g/m2 administered over 4 hours) on December 26, 1995. She was hospitalized 24 hours later with persistent nausea, vomiting, and diarrhea. She was found to be experiencing acute renal failure (her serum creatinine level had increased from 0.7 mg/dL to 2.6 mg/dL), and her MTX level was 940 µmol/L. In view of the successful treatment of patient no. 1 with HD LV alone, we considered it safe to treat this patient in a similar fashion. Intensive hydration and forced alkaline diuresis were performed as with patient no. 1. LV treatment was begun 30 hours after HD MTX as a 1-g/d intravenous (IV) infusion and continued for the next 8 days. Her serum creatinine level peaked at 3 mg/dL on the third hospital day and then decreased slowly over the next 7 days. Her serum MTX levels were 190 µmol/L and 39 µmol/L at 48 and 72 hours, respectively, and continued to decrease but remained greater than 0.1 µmol/L for a total of 10 days. Her hospital course was complicated by intermittent nausea, vomiting, diarrhea, abdominal pain, and mucositis. Neutropenia lasted 3 days and thrombocytopenia 7 days. Liver function abnormalities consisted of a peak serum bilirubin level of 1.7 mg/dL, AST level of 436 U/L, and ALT level of 596 U/L. Fever appeared in association with neutropenia but resolved after administration of broad-spectrum antibiotics. The patient was discharged on the 10th hospital day with normal serum transaminase levels and a serum creatinine level of 1.1 mg/dL. She received further courses of HD MTX, which she tolerated well.
Methods
For the purpose of identifying patients at high risk of developing severe MTX toxicity, we performed a retrospective review of all patients with toxic MTX levels after HD MTX chemotherapy. To help determine patients at risk for developing severe MTX toxicity, various cutoff points were established. At our institution, patients with 24-hour serum MTX levels greater than 10 µmol/L, 48-hour levels greater than 1 µmol/L, and 72-hour levels greater than 0.1 µmol/L are considered to be at high risk of impending toxicity.12 Using the computer in the Department of Chemistry at our institution, we identified all patients treated between December 1988 and February 1996 who had a serum MTX level of
The present report includes the two patients described in Case Reports, nine other patients identified by retrospective review, and two other similar patients treated in the last 2 years at our institution. Clinical data for all patients is listed in Table 1. All nine patients with osteosarcoma received MTX at doses of 8 to 12 g/m2 given by infusion over 4 hours. The three patients with CNS lymphoma received an MTX dose of 3.5 g/m2 administered over 4 hours. Two of these patients also received vincristine and procarbazine as part of their chemotherapy regimen. One patient with Burkitt's lymphoma received MTX at a dose of 6.7 g/m2 administered as continuous infusion over 24 hours. As shown in Table 1, MTX concentrations greatly exceeded published levels indicating a high risk of toxicity (> 5 to 20 µmol/L at 24 hours, 0.5 to 2 µmol/L at 48 hours, and 0.1 to 0.2 µmol/L at 72 hours).2,3 The median MTX concentration was 164 µmol/L at 24 hours (range, 102 to 940 µmol/L), 16.3 µmol/L at 48 hours (range, 10.5 to 190 µmol/L), and 6.2 µmol/L at 72 hours (range, 1.35 to 39 µmol/L). The highest MTX levels at 24 hours were observed in patients no. 2, 5, and 11. The details on patient no. 2 are given in Case Reports. Patient no. 5 was a 71-year-old man who received MTX at a dose of 3.5 g/m2. His serum creatinine level increased from 1.1 to 2.6 mg/dL on the third day after HD MTX. LV 80 mg/d was started 24 hours after MTX administration and was increased to 240 mg/d IV the next day. Systemic toxicity consisted of transient neutropenia (5 days), thrombocytopenia (6 days), mild mucositis, and transient elevation of liver enzymes (maximum AST, 136 U/L; ALT, 210 U/L; and normal alkaline phosphatase and bilirubin levels). Patient no. 11 was a 10-year-old boy with osteosarcoma who received MTX at a dose of 12 g/m2. His serum creatinine level increased from 0.7 to 2.0 mg/dL 2 days later. Intensive LV rescue at a dose of 1 g/d IV was started on the first day, as soon as the toxic MTX levels were reported. MTX levels remained greater than 0.1 µmol/L for a total of 14 days, but the patient recovered without developing myelosuppression or mucositis. Delayed excretion of MTX resulted in MTX levels remaining greater than 0.1 µmol/L for an average of 11 ± 3 days (range, 7 to 17 days). There seemed to be a correlation between the number of days that the serum creatinine level remained greater than 50% of the initial level and the number of days of elevated MTX levels.
MTX-induced acute renal dysfunction, as evidenced by a Significant neutropenia (absolute neutrophil count <1,000/µL) occurred in eight patients (two of whom had also received procarbazine) and lasted for 1 to 5 days. Five patients in this group received filgrastim (Neupogen; Amgen Inc, Thousand Oaks, CA), with rapid resolution of the neutropenia. Severe thrombocytopenia (platelet count <100,000/µL) developed in seven patients and lasted for 5 to 10 days. Stomatitis of varying degrees occurred in six patients and diarrhea in four. No patients died. All patients received supportive treatment with intensive hydration and administration of sodium bicarbonate–containing IV fluids. In addition, acetazolamide was administered to some patients in an attempt to alkalinize the urine when systemic alkalosis developed secondary to the administration of bicarbonate in the presence of renal failure. LV administration, given in high doses, was begun within the first 24 hours after detection of the first toxic MTX level in nine patients, within the first 48 hours in three patients, and at 72 hours in one patient. HD LV was administered intravenously by continuous infusion or intermittently in total daily doses that varied between 240 mg and 8 g. In addition to supportive therapy with IV hydration, sodium bicarbonate, and increased LV administration, two patients also received hemoperfusion. These two patients are included in the report because hemoperfusion was performed once the levels had decreased significantly before the procedure or because this treatment did not alter the MTX concentration. In patient no. 12, the serum creatinine level increased from 0.6 mg/dL to 2.4 mg/dL 24 hours after administration of HD MTX. Concomitant with the development of acute renal failure, the serum MTX level was markedly elevated at 24 hours (164 µmol/L) and stayed in the same range for the next 24 hours. HD LV was initiated 24 hours after chemotherapy, initially at a dose of 1 g/d IV, and progressively increased to 10 g/d. On the third hospital day, combined hemodialysis and hemoperfusion was performed, but a blood sample obtained just before the initiation of the procedure showed that the MTX level had spontaneously decreased to 28.1 µmol/L, with a decrease in the serum creatinine level from 2.7 mg/dL to 2.4 mg/dL. Soon thereafter, both the MTX and serum creatinine levels continued to decrease without further interventions, and the patient recovered after suffering a transient period of thrombocytopenia and neutropenia. Patient no. 13 developed nonoliguric renal failure after his first course of HD MTX for Burkitt's lymphoma. Hemoperfusion was started on the sixth hospital day when the serum creatinine level had peaked to 7.5 mg/dL from a baseline level of 0.9 mg/dL. The serum MTX level at the start of hemoperfusion was 2.2 µmol/L and decreased minimally to 1.9 µmol/L after 2 hours. Forty-eight hours after HD MTX, the patient was treated with HD LV to a maximum of 2 g/d by continuous infusion. He recovered after a period of transient bone marrow suppression and mucositis.
Although intensive hydration and urinary alkalinization have decreased the incidence of MTX-induced nephrotoxicity, this complication can still occur in patients treated with HD MTX. Increased LV rescue has been the main maneuver to counteract the consequences of prolonged exposure to high MTX levels resulting from delayed MTX excretion. Nevertheless, in vitro data demonstrate the inability of high extracellular concentrations of LV to rescue cells exposed to extremely high MTX levels. In a study by Pinedo et al,15 toxicity of MTX concentrations of 0.1 µmol/L was completely reversed by equimolar concentrations of LV, but as MTX concentrations were increased, progressively higher levels of LV were required. When cells were exposed to MTX concentrations of 100 µmol/L, rescue of the toxic effects was not observed.15 Because of the possibility that increasing the doses of LV may not avoid systemic MTX toxicity in patients with acute renal dysfunction, alternative rescue techniques have been attempted. Removal of MTX by peritoneal dialysis or hemodialysis is ineffective because the drug is extensively protein-bound. Charcoal hemoperfusion removes the drug more effectively, but its efficacy is limited by rebounds in MTX levels and the fact that the hemoperfusion cartridges become rapidly saturated and must be repeatedly changed during the procedure.23-30 Hemoperfusion can produce thrombocytopenia, and as shown in patient no. 1, severe complications may occur. Most recently, high-flux hemodialysis21 and hemodiafiltration31 have been used successfully. However, hemodialysis and hemoperfusion are invasive procedures, requiring the insertion of large-bore vascular catheters and anticoagulation, and result in only transient and small decreases in MTX levels, necessitating their combined or repeated daily use to effectively lower MTX concentration. Although the study by Pinedo et al15 was conducted with mouse bone marrow cells, the findings have been extrapolated to humans, resulting in the concern that even increased doses of LV may not be sufficient to prevent systemic toxicity when MTX levels are greatly elevated. Our findings show that if therapy with HD LV is initiated early, as soon as acute renal dysfunction is diagnosed, patients can be treated effectively with tolerable morbidity and without resorting to extracorporeal removal. The levels of MTX present in our patients were in the range of the concentrations reported in previous studies in which extracorporeal removal of the drug was performed16-31 or when thymidine32 or carboxypeptidase33 was used. The success of HD LV rescue alone may be related to the high levels of reduced folates obtained in patients with decreased renal function. After administration, LV (5-formyltetrahydrofolate) is partially excreted by the kidneys and undergoes rapid conversion to 5-methyltetrahydrofolate, which is eliminated almost exclusively by renal excretion.36-38 As both LV and 5-methyltetrahydrofolate are eliminated by the kidneys, it can be anticipated that when renal failure is present, the half-life of these compounds should be significantly prolonged, and repeated LV doses should result in their accumulation in plasma and tissues. In fact, in the study by Relling et al,29 the administration of HD LV resulted in extremely high LV and 5-methyltetrahydrofolate levels, which increased progressively with time becauseof delayed excretion in the presence of MTX-induced renal failure. Both compounds share with MTX the same high-affinity transport system that facilitates their entry into cells.39 As each compound inhibits the influx of the other,39 it is conceivable that if 5-methyltetrahydrofolate and LV are present in vast excess, as observed when HD LV is administered to patients with renal failure, then competition for uptake is virtually eliminated. This phenomenon could explain the beneficial effects observed in our patients. Because toxicity is determined by the duration of exposure, therapy with HD LV should start within the first 24 to 48 hours after HD MTX. Thymidine and carboxypeptidase have been used to treat MTX intoxication. The simultaneous administration of LV in these studies makes it difficult to conclude that beneficial effects are solely a result of these interventions. In the report by Widemann et al,33 the median MTX level at 46 hours (201 µmol/L) was higher than the median level observed in our patients at 48 hours (16.3 µmol/L). Therefore, a direct comparison with our group of patients cannot be made. Nevertheless, in the range of MTX levels observed in our study, and if it is started early, increased LV rescue alone seems to be safe as the mainstay therapy when given according to published guidelines.11-14
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
100 µmol/L 24 hours after MTX administration. From this group, we selected for inclusion in this study only patients who also had an MTX level of 
