Methotrexate (MTX), a classic antifol, is one of the most widely. High-Dose Methotrexate-Induced Nephrotoxicity in Patients with Osteosarcoma

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1 2222 High-Dose Methotrexate-Induced Nephrotoxicity in Patients with Osteosarcoma Incidence, Treatment, and Outcome Brigitte C. Widemann, M.D. 1 Frank M. Balis, M.D. 1 Beate Kempf-Bielack, M.D. 2 Stefan Bielack, M.D. 2 Charles B. Pratt, M.D. 3 * Stefano Ferrari, M.D. 4 Gaetano Bacci, M.D. 4 Alan W. Craft, M.D. 5 Peter C. Adamson, M.D. 6 1 Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland. 2 Department of Pediatric Hematology and Oncology, University Children s Hospital Muenster, Muenster, Germany. 3 Department of Hematology/Oncology, St. Jude Children s Research Hospital, Memphis, Tennessee. 4 Istituto Ortopedico Rizzoli, Bologna, Italy. 5 Department of Child Health, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom. 6 Division of Clinical Pharmacology and Therapeutics, Children s Hospital of Philadelphia, Philadelphia, Pennsylvania. The authors thank Dr. James Balow at the National Institute of Diabetes, and Digestive, and Kidney Disorders for helpful suggestions during the preparation of this article. This article is dedicated to the memory of Dr. Charles Pratt, who devoted his extraordinary career to the treatment of children with cancer and the development of more effective therapies for childhood cancers. *Deceased. Address for reprints: Brigitte C. Widemann, M.D., Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Building 10, Room 13C103, Bethesda, MD ; Fax: (301) ; bw42y@nih.gov Received January 14, 2004; revision received February 19, 2004; accepted March 4, BACKGROUND. High-dose methotrexate (HDMTX)-induced renal dysfunction can be life threatening, because it delays methotrexate (MTX) excretion, thereby exacerbating the other toxicities of MTX. HDMTX-induced nephrotoxicity has been managed with high-dose leucovorin, dialysis-based methods of MTX removal, thymidine, and with the recombinant enzyme, carboxypeptidase-g 2 (CPDG 2 ), which cleaves MTX to inactive metabolites. The objectives of the current study were to estimate the current incidence of HDMTX-induced renal dysfunction in patients with osteosarcoma and to compare the efficacy and recovery of renal function for dialysis-based methods of MTX removal with treatment using CPDG 2. METHODS. The literature was reviewed for osteosarcoma trials, use of dialysisbased methods for MTX removal, and reports of MTX-induced nephrotoxicity, including information regarding recovery of renal function. Clinical trial databases of select osteosarcoma studies were reviewed. The efficacy of CPDG 2 and renal recovery after CPDG 2 rescue was obtained from the database of a compassionaterelease trial. RESULTS. Approximately 1.8% of patients with osteosarcoma (68 of 3887 patients) who received HDMTX developed nephrotoxicity Grade 2. The mortality rate among those patients was 4.4% (3 of 68 patients). Dialysis-based methods of MTX removal were used frequently but had limited effectiveness in removing MTX compared with the rapid reductions 98% in plasma MTX concentrations achieved with CPDG 2. CPDG 2 did not appear to increase the time to recovery of renal function compared with supportive treatment that included dialysis-based methods. CONCLUSIONS. HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma who are treated on clinical protocols with optimal supportive care. For patients with delayed MTX excretion and high plasma MTX concentrations, CPDG 2 should be considered over hemodialysis to lower plasma MTX concentrations rapidly and efficiently. Cancer 2004;100: American Cancer Society. KEYWORDS: methotrexate toxicity, renal dysfunction, hemodialysis, hemoperfusion, carboxypeptidase-g 2, high-dose methotrexate. Methotrexate (MTX), a classic antifol, is one of the most widely used and well studied anticancer agents. The administration of MTX doses 1000 mg/m 2 combined with leucovorin (LV) rescue is defined as high-dose methotrexate (HDMTX). HDMTX is an important component of treatment for a variety of malignancies, including acute lymphoblastic leukemia (ALL), lymphoma, osteosarcoma, breast carcinoma, and head and neck carcinoma. 1 5 HDMTX with LV rescue is tolerated well by the majority of pa American Cancer Society DOI /cncr Published online 19 April 2004 in Wiley InterScience (

2 HDMTX Nephrotoxicity in Osteosarcoma/Widemann et al tients. However, the development of HDMTX-induced acute renal dysfunction, which is mediated by the precipitation of MTX and its metabolites in the renal tubules, 6 8 is a potentially life-threatening complication. MTX is cleared primarily by renal excretion, 9 and renal dysfunction results in delayed MTX excretion and sustained, elevated plasma MTX concentrations, which may lead to a marked enhancement of the other toxicities of MTX, especially myelosuppression, mucositis, hepatitis, and dermatitis. 2,3,9 11 Nephrotoxicity secondary to HDMTX was responsible primarily for its morbidity and mortality observed during the 1970s. In a single-institution study of 64 patients, there were 3 deaths secondary to renal dysfunction, 12 and 29 of 498 patients who were treated on National Cancer Institute protocols died secondary to HDMTX, for a mortality rate of 6%. 13 Uniform institution of aggressive hydration, alkalinization, and pharmacokinetically guided LV rescue reduced the morbidity rate significantly in patients receiving HDMTX. 14 However, reports of significant morbidity and mortality secondary to HDMTX-induced renal dysfunction have continued to appear in the literature. 11,15 19 Because there is no centralized reporting mechanism for MTX nephrotoxicity, to our knowledge the current incidence of HDMTX-induced renal dysfunction is unknown. Conventional treatment for HDMTX-induced renal dysfunction includes a prompt increase in the LV dose based on plasma MTX concentrations 9,20 and the continuation of hydration and alkalinization, provided adequate urine output can be maintained. Hemodialysis-based methods of MTX removal have been described for over 20 years More recently, carboxypeptidase-g 2 (CPDG 2 ), a recombinant bacterial enzyme 30,31 that hydrolyzes MTX to the inactive metabolite 2,4-diamino-N 10 -methylpteroic acid (DAMPA), 32,33 has become available as an investigational new drug for the treatment of HDMTX-induced renal dysfunction. When administered to patients with MTX-induced renal dysfunction, CPDG 2 lowers plasma MTX concentrations within 15 minutes of administration by a median of 98.7% (range, %). 27,34 36 With the advent of new therapeutic strategies for patients with HDMTX-induced renal dysfunction, a reassessment of the incidence, treatment, and outcome of MTX-induced nephrotoxicity is needed. Patients with osteosarcoma usually receive single-agent HDMTX as a short, intravenous infusion during a chemotherapy cycle and, thus, represent an ideal population to study this toxicity, because their development of renal dysfunction can be attributed to the HDMTX. The objectives of the current study were 1) to determine the current incidence of HDMTX-induced renal dysfunction in patients with osteosarcoma, 2) to review the use and efficacy of dialysis-based methods of MTX removal in patients with HDMTX-induced renal dysfunction, 3) to determine the time to recovery of renal function in patients with HDMTX-induced renal dysfunction after treatment with supportive and dialysis-based methods, and 4) to compare the efficacy of dialysis-based methods and the time to renal recovery after supportive treatment with the efficacy and renal recovery after treatment with CPDG 2. MATERIALS AND METHODS Current Incidence of HDMTX-Induced Renal Dysfunction in Osteosarcoma Databases from the Cooperative German-Swiss-Austrian Osteosarcoma Study (COSS), 15,37 44 the European Osteosarcoma Intergroup (EOI), the Rizzoli Institute (Italy), and the St. Jude Children s Research Center (St. Jude) were reviewed. Information regarding the number of patients in which renal dysfunction after HDMTX was reported, the severity and treatment of renal dysfunction, and the time to recovery of renal dysfunction was collected. COSS screened their database for patients with renal toxicity Grade 2, the Rizzoli Institute screened their database for patients with serum creatinine levels greater than the upper limit of normal (ULN), and the EOI and St. Jude screened their databases for patients with serious and significant renal toxicity. Renal toxicity was graded using World Health Organization criteria (Grade 1, serum creatinine levels 1.5 ULN; Grade 2, ULN; Grade 3, ULN; and Grade 4, 6.0 ULN). The literature was reviewed using the MEDLINE and CancerLit databases ( ). Publications of clinical osteosarcoma trials that contained HDMTX that were performed after 1980, a time during which hydration and alkalinization were administered routinely as part of HDMTX treatment, were identified. Data were included only from those studies in which the number of patients entered and the number of HDMTX-related nephrotoxic events were reported. Use and Effectiveness of Dialysis-Based Methods for MTX Removal The literature was reviewed using MEDLINE and CancerLit databases ( ) for reports or case series describing the use of dialysis-based methods for MTX removal in patients with MTX-induced renal dysfunction.

3 2224 CANCER May 15, 2004 / Volume 100 / Number 10 Recovery of Renal Function after MTX-Induced Renal Dysfunction To define the time course of recovery of renal function after MTX-induced renal dysfunction in patients who were treated with supportive and hemodialysis/filtration-based methods or with the addition of CPDG 2, publications and clinical trial database data were analyzed that provided a definition for recovery of renal function and included the number of days to recovery of renal function. MTX Pharmacokinetics and Recovery of Renal Function after CPDG 2 Administration Information regarding MTX pharmacokinetics and clinical outcome after the administration of CPDG 2 for HDMTX-induced renal dysfunction was obtained from the database of an ongoing, compassionate-release trial of CPDG 2 sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute and was published previously. 34,35 RESULTS Current Incidence of HDMTX-Induced Renal Dysfunction in Osteosarcoma Twenty published clinical trials, which accrued patients after 1980, contained data that included the number of patients entered and the incidence of renal toxicity (Table 1). The median incidence of reported renal toxicity in the individual studies was 1.5% (range, %). When renal events were described as cases or cycles, the assumption was made that each cycle or case corresponded to an individual patient. When combined with additional data provided in this report (Table 1), there were 3887 patients enrolled on osteosarcoma trials in which renal toxicity data were available. Sixty-eight of those 3887 patients (1.8%) developed nephrotoxicity that was either Grade 2 or significant enough to be reported, and 23 patients (0.6%) developed Grade 3 or 4 toxicity. The management of HDMTX-induced renal dysfunction was described for 24 patients. Three patients received CPDG 2, 1 patient was treated with hemoperfusion (1 death), 1 patient was treated with plasmapheresis, 2 patients received CPDG 2 and underwent high-flux hemodialysis or hemodialysis, and 17 patients were treated with supportive measures that included alkalinization, hydration, and LV rescue only. There were 3 deaths attributable to HDMTX-induced renal dysfunction in 68 patients, for a 4.4% mortality rate (0.08% mortality in all patients who received HDMTX). Use of Dialysis-Based Methods to Remove MTX The efficacy of mechanical methods of MTX removal is summarized in Table 2. Over the past 20 years, 30 publications reported results of dialysis-based methods of MTX removal in 49 patients. The most frequently utilized single methods used were hemodialysis (10 patients), high-flux hemodialysis (nine patients), and charcoal hemoperfusion or charcoal hemofiltration (seven patients). Sixteen patients were treated with multiple modalities and therefore are referenced more than once in Table 2. Peritoneal dialysis alone resulted in a minimal decrease in plasma MTX concentrations. 21,22 The use of other single-modality methods of MTX removal resulted in a median decrease in plasma MTX concentrations of 52% (range, 26 82%). Dialysis-based methods were used for up to 14 days. The use of high-flux hemodialysis resulted in the greatest decrease in plasma MTX concentrations (median, 75.7%; range, 42 94%) within the shortest time (median, 4 hours; range, 4 12 hours). Only 3 patients had a decrease 90% in MTX concentrations with the use of a single method in 1 dialysis session. 28,69,70 Increases in MTX plasma concentrations after the completion of dialysis-based methods were reported and quantified in seven reports. Rebound increases in postdialysis plasma MTX concentrations by % of the postprocedure MTX levels 21,71,72 and to % of the preprocedure MTX levels were reported. 23,24,26,73 Reported complications from the various dialysis methods included cardiac arrest in one patient after plasma exchange, 23 bleeding from the catheter exit site, 24 anemia, 24,25 thrombocytopenia, 24,74 and hypokalemia and severe hypophosphatemia, 70 but the incidence of these complications could not be estimated accurately. Recovery of Renal Function with Current Supportive Treatment For 31 patients described in 13 publications and 9 additional patients treated on COSS trials who received treatment with supportive measures (including LV), and thymidine administration or dialysis-based removal of MTX in some patients, but not CPDG 2, sufficient data regarding recovery of renal function were available (Table 3). The studies defined recovery of renal function differently as recovery of function (1 patient), serum creatinine 1.5 times the baseline level (20 patients), serum creatinine 1.7 times the baseline level (1 patient), the ability to discontinue dialysis (2 patients), normal serum creatinine levels (7 patients), or a return of serum creatinine to pretreatment (baseline) levels (9 patients). The reported peak serum creatinine concentrations were higher for the 12 patients who underwent dialysis-based methods (median serum creatinine, 3.9 mg/dl; range, mg/dl) compared with 20 patients who did not undergo dial-

4 HDMTX Nephrotoxicity in Osteosarcoma/Widemann et al TABLE 1 Incidence of High-Dose Methotrexate-Induced Nephrotoxicity in Patients with Osteosarcoma Study/yrs of study MTX dose (g/m 2 ) No. of patients on HDMTX No. of planned courses/ patient HDMTX renal toxicity No. % Details of renal toxicity Mortality (no. of deaths) Reference(s) Results of a review of the literature ( ) COSS a 14 2 patients a 1.0 Death, delayed MTX elimination 2 b 15, 37, a 14 7 cycles a 5.0 Delay 7 days in subsequent CT for delayed MTX 39 elimination (3 patients), elevated serum creatinine (4 patients) France , 12.0, patients 8.5 Delayed MTX elimination but no severe MTX toxicity 77 Scandinavia Sarcoma Group cycles 5.2 Grade 1 2 (3 patients), Grade 3 (2 patients), all transient 78, 79 Norwegian Radium Hospital patients 1.9 Moderate increase in creatinine, no further MTX (1 patient), 1 80 fatal HDMTX toxicity (1 patient) EOI total 5 patients 3.6 Grade 2 (3 patients), Grade 3 (2 patients) 45 (8/patient) patients 3.1 Severe renal impairment (2 patients) c 48 Rizzoli Institute / patient 0.9 One patient on MTX 2.0 g/m 2 had renal failure with 1 50 pancytopenia / OS a , 53, 56, 64, 81, 82 OS a 5 5 patients a 5.0 Delayed MTX elimination with nephrotoxicity, no further MTX 58, 63 OS a 6 15 cycles a 12.4 Grade , a 5 1 patient a 3.6 Delayed MTX clearance 65 POG/DFCI Moderate, 1%; severe, 2% c 83 TIOS , 85 TIOS , 85 TIOS , 85 OGS patients 4.2 c 86, Results of a review of clinical trial data COSS ,000 total 24 patients 1.1 Grade 2 toxicity (11 patients), Grade 3 (9 patients), Grade 4 (4 1 d patients); CPDG 2 (3 patients), plasmapheresis (1 patient), hemodialysis CPDG 2 (2 patients), supportive (2 patients) St. Jude s Children s Research Center patient 0.9 Grade 3 toxicity: hemodialysis, charcoal hemoperfusion, 24 thymidine Rizzoli Institute patients 3.0 Grade 2 toxicity (14 patients), Grade 3 (1 patients); all patients received LV, hydration, alkalinization, no dialysis, no more MTX MTX: methotrexate; HDMTX: high-dose methotrexate; COSS: Cooperative German-Swiss-Austrian Osteosarcoma Study; CT: chemotherapy; EOI: European Osteosarcoma Intergroup; OS-2, OS-3, OS-4: Rizzoli Institute osteosarcoma studies 2, 3, and 4, respectively; POG: Pediatric Oncology Group/Dana Farber Cancer Institute; TIOS: Treatment and Investigation of Sarcoma; OGS: Osteogenic Sarcoma Studies; CPDG 2 : carboxypeptidase-g 2 ; LV: leucovorin. a Included in clinical trial data review. b Reanalysis by study principal investigator determined that only one death was related to high-dose methotrexate-induced renal dysfunction. c Not related conclusively to methotrexate. d Death in patient with Grade 4 renal toxicity who underwent hemoperfusion.

5 2226 CANCER May 15, 2004 / Volume 100 / Number 10 TABLE 2 Efficacy of Methotrexate Removal Methods a Method No. of patients reported No. of sessions Preprocedure MTX ( M) (range) Postprocedure MTX decrease (%) Procedure duration Postprocedure MTX rebound increase Reference(s) Hemodialysis ( ) 0.8 ( ) 50 (3 90) 1 Session (4 hrs to 14 days) Hemodiafiltration ( ) 0.45 ( ) 82 (44 98) 3.5 Days (1 session to 5 days) 20% of postprocedure to 100% of preprocedure levels (2 patients) b 21, 23, 24, 26, 27, 69, % of postprocedure levels c 73, 96, 97 High-flux hemodialysis ( ) 42.0 ( ) 75.5 ( ) 4 Hrs (4 12 hrs) 50% of postprocedure levels h 28, 70 Charcoal-hemoperfusion or hemofiltration ( ) 0.75 ( ) 53 (14 95) 1 Session (3 hrs to 7 days) 20% of postprocedure (3 patients) to 90% of preprocedure levels d 20, 23, 69, 71, , 74, 93, 96, Plasma resin perfusion Hrs 93% of preprocedure levels (1 patient) e Peritoneal dialysis ( ) Minimal decrease Minimal decrease 4.5 Days (2 7 days) 21, 22 Exchange transfusion or ( ) 2.3 ( ) 26 (0 72) 1 Session (5 hrs 20% of postprocedure plasma exchange to 1 session) levels (3 patients) f 97, 99, 100 Charcoal-hemoperfusion/ hemofiltration and hemodialysis ( ) 2.2 ( ) 78 (38 98) 1.0 Day (6 hrs to 6.25 days) 10% and % (1 patient each) of postprocedure levels g 20, 23 26, 72, 92, 101 MTX: methotrexate. a Published literature from 1977 to 2002 on methods and their efficacy used to remove methotrexate from patients with renal dysfunction after methotrexate administration. The median values for plasma methotrexate concentrations preprocedure and postprocedure, % decrease in methotrexate concentration, and dialysis session duration are reported with the range shown in parenthesis. b See Hande et al. 21 and Bouffet et al. 23 c See Jambou et al. 73 d See Bouffet et al. 23 and Gibson et al. 71 e See Greil et al. 72 f See Bouffet et al. 23 g See Relling et al. 24 and Kawabata et al. 26 h See Wall et al. 28 ysis (median serum creatinine, 2.2 mg/dl; range, mg/dl). Patients with osteosarcoma who were treated on COSS studies had a greater degree of renal dysfunction compared with the patients reported by Flobaum and Meyers, 20 with 5 of 9 patients and 1 of 11 patients, respectively, reported to have renal toxicity Grade 3. The median time to recovery of renal function for the 40 patients, as defined by the individual studies, was 16 days (range, 4 48 days). MTX Pharmacokinetics and Recovery of Renal Function after CPDG 2 Administration In patients with HDMTX-induced renal dysfunction, CPDG 2 was tolerated well. Four of 20 patients described mild symptoms associated with CPDG 2 administration, including a feeling of warmth, tingling fingers, head pressure, flushing, shaking, and burning of face and extremities. CPDG 2 administration resulted in a rapid % reduction (median, 98.7%) in plasma MTX concentrations, as measured by high-pressure liquid chromatography due to the interference of MTX metabolites with commercially available immunoassays. Plasma MTX concentrations decreased from a median of 89 mol/l and 6.4 mol/l to a median of 1 mol/l and 0.05 mol/l within 15 minutes of CPDG 2 administration for patients with osteosarcoma and non-hodgkin lymphoma (NHL) or ALL, respectively. A rebound increase in plasma MTX concentrations was observed in 60% of patients who were treated with CPDG 2, which reached 2.8%, 8.8%, and 2.5% of the MTX concentration prior to administration of CPDG 2 for patients with osteosarcoma (n 7 patients), NHL or ALL (n 5 patients), and gastric carcinoma (n 1 patient), respectively. For 17 patients with complete data regarding renal recovery, serum creatinine levels peaked at a median of 3.4 mg/dl (range, from 0.8 mg/dl in an infant age 3 months to 12.5 mg/dl) and returned to values within

6 HDMTX Nephrotoxicity in Osteosarcoma/Widemann et al TABLE 3 Recovery of Renal Function after Methotrexate-Induced Renal Dysfunction a Study Year No. of patients b Peak serum Cr Time to renal renal levels (mg/dl) Treatment c recovery (days) Definition of recovery Hande et al Dialysis 20 Recovery of function Abelson et al , 2.2, 1.1, 4.1, Thymidine 21, 10, 9, 15, 17, 11, 7, 8 Serum Cr 1.5 baseline 5.2, 1.35, 2.1, 0.9 Molina et al Charcoal hemoperfusion 20 Serum Cr WNL Relling et al Hemodialysis hemoperfusion 24 Serum Cr WNL Stark et al Supportive 19, 12 Serum Cr WNL Thierry et al Hemodialysis/plasma exchange 15 Hemodialysis stopped Grimes et al Charcoal hemoperfusion 17 Serum Cr WNL McIvor Charcoal hemoperfusion 28 Serum Cr WNL Kawabata et al Plasma perfusion hemodialysis 29 Hemodialysis stopped Benezet et al Exchange transfusion 23 Serum Cr WNL Flobaum and Meyers , 3.0, 1.8, 2.6, 1.9, Hemoperfusion (2 patients) 16, 10, 6, 10, 8, 4, 5, 25, 3, Serum Cr 1.5 baseline 2.0, 1.7, 2.5, 2.0, 2.7, , 21 van den Bongard et al Thymidine 17 Serum Cr 1.7 baseline Shinozaki et al Plasma exchange, cholestyramine 20 Serum Cr 1.5 baseline Bielack (trial survey) WHO G2 and G3 (4 patients each), G4 (1 patient) Plasmapheresis (1 patient) 38, 16, 40, 8, 34, 21, 14, 48, 16 Serum Cr 1.0 baseline ( ) d Cr: creatinine; WNL: within normal limits; WHO: World Health Organization; G2 G4: Grade 2 4. a Treatment of patients did not include carboxypeptidase-g 2. Published literature was reviewed from 1977 to 2002 on recovery of renal function in patients with methotrexate-induced renal dysfunction. b Patients were included only if days to recovery data were available. c Treatment included leucovorin for all patients. d Numbers indicate median, with ranges shown in parentheses normal limits (median, 1.1 mg/dl; range, mg/ dl), corresponding to a median of 1.4 times the baseline creatinine level at a median of 22 days (range, 5 40 days) after the initiation of the MTX infusion. Additional MTX infusions were administered to 5 patients after recovery of renal function (full dose, n 1 patient; 20 75% of the protocol-prescribed dose, n 4 patients) without recurrence of nephrotoxicity. DISCUSSION Based on our literature review and information available from our databases (see Table 1), approximately 1.8% of patients with osteosarcoma who are treated with HDMTX develop significant nephrotoxicity at some time during treatment, and the mortality among these patients is estimated at 4.4%. Limitations of this estimate include the following: nephrotoxicity was not defined uniformly across studies, trials were not designed to capture data concerning nephrotoxicity comprehensively, and few published studies included a comprehensive description of MTX-related toxicities. In addition, only patients entered on clinical trials, who may be more likely to receive optimal supportive care, were included in the estimate. Therefore, the incidence of MTX-induced renal dysfunction among all patients receiving HDMTX may be higher. Although the incidence and mortality of HDMTX-induced renal dysfunction appear to have decreased significantly since the 1970s, 13 nephrotoxicity continues to occur and may be fatal. The cornerstone of successful treatment for patients with HDMTX-induced renal dysfunction includes early recognition of this toxicity and prompt institution of increased doses of LV. 9,20 However, patients are at greater risk for the development of lifethreatening MTX toxicities if MTX renal excretion is delayed and plasma MTX concentrations remain elevated, even though they are receiving high doses of LV. The large number of publications describing invasive methods that attempt to address the underlying problem of impaired MTX elimination (Table 2) reflects the necessity to provide an alternative route of MTX elimination in patients with renal dysfunction. This review suggests that these mechanical methods have variable and limited effectiveness in removing MTX. Rebound increases in MTX concentrations to levels approaching those that existed prior to institution of the dialysis-based method have been reported. The most effec-

7 2228 CANCER May 15, 2004 / Volume 100 / Number 10 tive dialysis-based methods for MTX removal currently in use are charcoal hemoperfusion in combination with hemodialysis or high-flux hemodialysis. 24,25,28,70 Such methods of mechanical MTX removal, however, may not be available readily outside of major medical centers and include the risks associated with the insertion of vascular-access devices, the transfusion of blood products, electrolyte imbalances, and the risk of bleeding secondary to heparinization, thrombocytopenia, and anemia. 24,25,70,74 Compared with dialysis-based methods, the use of CPDG 2 is tolerated well and results in a more profound, rapid, and consistent decrease in plasma MTX concentrations, and rebounds 10% in plasma MTX concentrations were observed in only 60% of patients who were treated with CPDG 2. 34,35 A retrospective comparison of the recovery of renal function after supportive therapy that included dialysis versus CPDG 2 in patients with HDMTX-induced renal dysfunction is limited by the varying degrees of renal damage and the differing of definitions used in the literature to define renal recovery. In the majority of patients included in our literature review, recovery of renal function was defined not as a return of serum creatinine to pretreatment (baseline) levels but as a return to a serum creatinine levels within 1.5 baseline levels or as the ability to discontinue dialysis-based methods. With this definition, the median time to recovery of renal function in patients with HDMTX-induced renal dysfunction who were treated with supportive measures, including dialysis-based methods but not CPDG 2, was 16 days. A theoretic concern regarding the use of CPDG 2 is that the rapid formation of the MTX metabolite, DAMPA, which is approximately 10-fold less soluble than MTX, could lead to further renal toxicity by precipitation in the renal tubules. 75 In 17 patients who received CPDG 2 for MTX-induced renal dysfunction, serum creatinine declined to levels below the upper limit of normal, corresponding to a median serum creatinine level 1.4 times the pre-hd- MTX level at a median of 22 days after the administration of CPDG 2. 34,35 The severity of renal injury in these CPDG 2 -treated patients, as measured by the peak serum creatinine level (median, 3.4 mg/dl), was worse compared with the severity in patients who were treated with supportive measures without CPDG 2 or dialysis (median peak creatinine level, 2.1 mg/dl) but less compared with the severity in patients who underwent dialysis-based methods but did not receive CPDG 2 (median peak creatinine level, 3.9 mg/dl). For patients with osteosarcoma who received CPDG 2 (n 11 patients) 34,35 for MTXinduced nephrotoxicity and delayed MTX clearance, the median plasma MTX concentration 44 hours after the initiation of the HDMTX infusion was 485 M, compared with 16.3 M at 48 hours for patients with osteosarcoma (n 13 patients) who received LV as the only rescue agent, according to a report by Flobaum and Meyers. 20 The median peak serum creatinine level was 5.0 mg/dl (range, mg/ dl) for the CPDG 2 -treated patients and 2.0 mg/dl ( mg/dl) for patients who received only LV. This indicates that patients with osteosarcoma who received CPDG 2 had experienced a greater degree of renal injury prior to CPDG 2 administration compared with the patients with osteosarcoma reported by Flobaum and Meyers, which may account for the prolonged time to renal recovery in patients who were treated with CPDG 2. The degree of renal injury (Grade 3 4 toxicity in 5 of 9 patients) and the time to recovery of renal function (median, 21 days) for patients who were entered on COSS trials and who did not receive CPDG 2 appears more comparable to those of the patients who received CPDG 2. These data suggest that the administration of CPDG 2 does not result in prolonged renal recovery compared with patients who had similar degrees of renal toxicity and were treated with supportive or dialysis-based methods. The potential benefits of the administration of CPDG 2 over the use of dialysis-based methods to lower plasma MTX concentrations in the treatment of HDMTX-induced renal dysfunction include the more rapid and profound lowering of plasma MTX concentrations, the ease of use (single intravenous infusion), the potential ready availability at the treating institutions, and the lack of a need for the insertion of a new vascular-access device and its associated risks. HDMTX-induced renal dysfunction continues to occur with an approximate frequency of 1.8% in patients with osteosarcoma who are treated on clinical protocols. Dialysis-based methods of MTX removal are used frequently but have variable and limited effectiveness compared with the rapid and marked decrease in plasma MTX concentrations after the administration of CPDG 2. CPDG 2 is tolerated well and does not appear to delay renal recovery compared with patients who have comparable renal toxicity and are treated with supportive treatment or dialysis-based methods. Therefore, the use of CPDG 2 instead of dialysis-based methods is recommended to reduce plasma MTX concentrations in patients with HDMTXinduced renal dysfunction.

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