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© 2001 American Society for Clinical Oncology Recombinant Urate Oxidase for the Prophylaxis or Treatment of Hyperuricemia in Patients With Leukemia or LymphomaFrom the St Jude Children’s Research Hospital and University of Tennessee, Memphis, TN; Midwest Children’s Cancer Center, Milwaukee, WI; University of North Carolina, Chapel Hill, NC; Children’s Mercy Hospital, Kansas City, MO; Hôpital Armand Trousseau, Paris, France; Children’s Hospital Medical Center of Northern California, Oakland, CA; Texas Children’s Cancer Center/Baylor College of Medicine, Houston, TX; and Children’s National Medical Center, Washington, DC. Address reprint requests to Ching-Hon Pui, MD, St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105; email: ching-hon.pui{at}stjude.org
PURPOSE: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys. PATIENTS AND METHODS: We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied. RESULTS: At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P = .0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P = .0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P = .0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P = .0003 and P = .02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 ± 6.3 (SD) hours and 21.1 ± 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme. CONCLUSION: Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.
HYPERURICEMIA, a well-recognized complication of leukemia and lymphoma and their treatment, has been associated with acute renal failure and delays in chemotherapy, especially in patients with B-cell or T-cell neoplasia and a large tumor burden.1-6 In North America, the standard prophylaxis or treatment of hyperuricemia consists of allopurinol, urinary alkalinization, hydration, and osmotic diuresis.2-5,7 By inhibiting the enzyme xanthine oxidase, allopurinol blocks uric acid formation but increases the renal load of uric acid precursors (hypoxanthine and xanthine).8 Unlike hypoxanthine, xanthine is actually less soluble than uric acid in urine.9 In fact, occasional cases of xanthine nephropathy and calculi have been reported in patients treated with allopurinol.10-13 Moreover, patients still need to excrete preexisting uric acid, which is not affected by allopurinol. Urate oxidase acts as a catalyst in the enzymatic oxidation of uric acid to allantoin, a readily excreted metabolite that is five- to 10-fold more soluble than uric acid.14 It is an endogenous enzyme in most mammals, but not in humans.15 A nonrecombinant form of urate oxidase (Uricozyme; Sanofi-Synthelabo, Inc, Paris, France), purified from cultures of Aspergillus flavus, has been shown to be a more effective agent than allopurinol in correcting hyperuricemia.16,17 However, this preparation is associated with an approximately 5% rate of acute hypersensitivity reactions (manifested as bronchospasm and hypoxemia), even in patients without a history of allergy, and with methemoglobinemia or hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.17 In this study, we evaluated the efficacy, safety and pharmacokinetics of Rasburicase (SR29142; Sanofi-Synthelabo), a newly developed recombinant urate oxidase product, in a group of patients with leukemia or lymphoma who presented with hyperuricemia or were at very high risk for this complication.
Study Cohort Between March 1996 and October 1997, 131 patient 20 years old or younger from 22 institutions, who had hyperuricemia as a result of leukemia or lymphoma or were judged to be at high risk for this complication, were enrolled onto the study. The eligibility criteria included a recent diagnosis of B-cell acute lymphoblastic leukemia (ALL), ALL with an initial leukocyte count of at least 50 x 109/L or a lymphomatous presentation and a large tumor burden, stage III or IV small noncleaved-cell (B-cell) or lymphoblastic non-Hodgkin’s lymphoma (NHL) with a large tumor burden, or any leukemia or NHL with a plasma uric acid concentration of at least 8 mg/dL and either a serum creatinine or lactate dehydrogenase concentration exceeding twice the upper limit of normal. Patients were excluded from the study if they had a history of clinically significant atopic allergy, bronchial asthma, or glucose-6-phosphate dehydrogenase deficiency, had received one dose of allopurinol within 24 hours or two doses or more within the preceding 7 days, or were pregnant or lactating. The study was approved by the institutional review board of each participating institution. Informed consent was obtained from the patients, parents, or legal guardians for the treatment of newly diagnosed cancer and for participation in the study.
Treatment Design The study was divided into a dose-validation phase (to determine the effective dose) and an accrual phase (to confirm the efficacy and safety of the drug). The starting dosage in the first phase was 0.15 mg/kg of body weight, based on a phase I trial in which all healthy volunteers treated with more than 0.10 mg/kg had uric acid levels below the limits of assay detection within 4 hours.18 It was also based on the equivalent effective dose of the nonrecombinant enzyme, as determined in vitro (data not shown). The dosage was then increased by increments of 0.05 mg/kg to one that corrected hyperuricemia (plasma uric acid concentration more than 6.5 mg/dL in patients younger than 13 years or more than 7.5 mg/dL in older patients) within 48 ± 2 hours after the start of treatment and prevented hyperuricemia for up to 24 hours after treatment in 14 consecutive patients. Once the validated dosage was identified, the accrual phase began (with at least 76 patients treated) and no further dose escalations were allowed. By using this dosage, the failure rate in this phase was predicted to be less than 20%.
Laboratory Determinations Urine was collected daily (over 24 hours) during and after treatment for up to 8 days in patients who were toilet trained. Urinary concentrations of allantoin were determined by a validated liquid chromatography–mass spectroscopy/mass spectroscopy method; the limit of quantification was 14.6 µg/mL.20
Pharmacokinetic Studies
Antibodies to Rasburicase
Statistical Analysis
Of the 131 patients (88 boys and 43 girls) who were treated, 17 had stage III and three had stage IV small noncleaved-cell (B-cell) NHL, five had B-cell ALL, 33 had T-cell ALL, 62 had B-cell precursor ALL, one had acute myeloid leukemia, and four had stage III and six had stage IV NHL. Each case was characterized by a massive tumor burden, as indicated by high serum lactate dehydrogenase concentrations or hyperleukocytosis (Table 1). Notably, hyperuricemia was present at diagnosis in 65 patients (50%), and renal impairment (abnormally high serum creatinine level) was present in 28 (21%). Fourteen patients had previously received allopurinol; seven of them had hyperuricemia (6.9 to 16.3 mg/dL) before Rasburicase treatment.
Rasburicase, administered at 0.15 mg/kg, effectively corrected or prevented hyperuricemia in the first 11 patients treated. The median plasma uric acid concentration at diagnosis, 5.2 mg/dL (range, 3.1 to 8.6 mg/dL), decreased to 0.9 mg/dL (range, 0.5 to 8.3 mg/dL) by 4 hours after the first Rasburicase treatment (P < .0001). Uric acid concentrations remained low during the entire course of treatment, with the median and maximum values not exceeding 2.3 and 5.5 mg/dL, respectively, on any day. However, the 12th patient, a 13-year-old boy with stage III small noncleaved-cell NHL and a presenting uric acid of 21.1 mg/dL, had a transient increase in uric acid concentration (from 9.7 mg/dL at 4 hours to 10.7 mg/dL at 48 hours), decreasing to 1.2 mg/dL by 60 hours. According to the study design, the dosage of Rasburicase was increased to 0.20 mg/kg, which proved effective in the 14 subsequently treated patients and hence was used in the accrual phase. During this treatment, a 12-year-old girl with small noncleaved-cell NHL and a 6-year-old boy with T-cell ALL had hyperuricemia (7.4 and 8.7 mg/dL, respectively) at 48 hours, which resolved 24 hours later. Beyond 48 hours, there were two cases of transient hyperuricemia, neither lasting more than 24 hours: 7.5 mg/dL at 60 hours in an 11-year-old girl with B-cell precursor ALL and 6.9 mg/dL at 132 hours in an 8-year-old girl with T-cell ALL. At either dose, the recombinant enzyme produced rapid, dramatic decreases in uric acid concentrations in all 131 patients, regardless of whether they presented with hyperuricemia: median, 5.7 mg/dL (range, 2.6 to 33.8 mg/dL) at diagnosis, decreasing to 0.5 mg/dL (0.08 to 15.4 mg/dL) by 4 hours after the first Rasburicase treatment (P < .0001). The median level decreased from 9.7 to 1 mg/dL in the 65 patients who presented with hyperuricemia (P = .0001, Fig 1A) and from 4.3 to 0.5 mg/dL in the remaining 66 patients (P = .0001, Fig 1B). Despite intensive cytoreductive chemotherapy, the median uric acid concentration remained at or near 0.5 mg/dL in both groups throughout the treatment course. Repeated dose at 12 hours was given to only one patient in the dose-validation phase and 10 patients in the accrual phase (two of latter required repeated dose twice).
Serum phosphorus concentrations did not change significantly during the first 3 days of treatment in either group (Fig 1C and 1D) and in fact had decreased significantly by day 4 of treatment in the hyperuricemic group (P = .0003); the concentrations were normal in all patients 48 hours after the end of treatment. Serum potassium concentrations were relatively stable throughout the treatment course, with a peak of 6.3 meq/L. More importantly, serum creatinine concentrations decreased significantly after 1 day of treatment in both the hyperuricemic (P = .0003, Fig 1E) and nonhyperuricemic (P = .02, Fig 1F) groups and were within the normal range in all patients by day 6 of treatment. A 16-year-old boy with T-cell ALL presented with a high creatinine level (2.4 mg/dL), oliguria, hypertension, and fluid overload on day 1 of treatment. With diuretic treatment, his signs and symptoms resolved a day later and his renal function gradually improved. None of the patients required dialysis after the start of Rasburicase therapy. Treatment with Rasburicase was well tolerated. One patient had mild nausea and vomiting. The other patient, a 13-year-old girl with B-cell precursor ALL who presented with a leukocyte count of 160 x 109/L, with 82% eosinophils and pneumonia, developed bronchospasm and hypoxemia 3 hours after completion of the first Rasburicase infusion. She had also received triple intrathecal treatment with methotrexate, hydrocortisone, and cytarabine 5 hours and a dose of vincristine 1 hour before the event. She required treatment with oxygen and bronchodilator, and recovered completely in 3 days. She did not receive additional Rasburicase treatment. Figure 2 shows mean plasma concentration-versus-time plots for Rasburicase administered on days 1 and 5 of treatment in 11 patients treated at 0.15 mg/kg and 19 at 0.20 mg/kg; the day 5 data from 2 patients treated with Rasburicase at 0.20 mg/kg were excluded because they required a repeated dose beyond day 1. The values of AUC0-24 on day 5 were not significantly greater than those on day 1. The estimated ratio (geometric mean) of day 5 to day 1 AUC0-24 values was 1.08 (90% confidence interval, 0.96 to 1.22), indicating a lack of accumulation of Rasburicase. The mean plasma terminal half-lives were 16.0 ± 6.3 (SD) hours in 11 patients treated at a dosage of 0.15 mg/kg, and 21.1 ± 12.0 hours in 19 treated with the higher dosage ( Table 2).
The urinary allantoin excretion rate increased during the first 3 days of treatment, peaked at day 3, and declined thereafter ( Fig 3). It should be noted that the amount of allantoin in the urine was less than would have been predicted from the decrease in plasma uric acid level because of incomplete urine collection in some patients as a result of their young age or clinical condition. Nonetheless, the excretion rate was significantly higher in the 46 patients who presented with hyperuricemia at diagnosis than in the remaining 42 patients over each of the first 4 days of the treatment (P  .01 for all comparisons).
Two (17%) of the 12 patients receiving Rasburicase at 0.15 mg/kg and 15 (14%) of 109 receiving the 0.20 mg/kg, developed antibodies against Rasburicase or its epitopes after the completion of Rasburicase treatment. No relationship could be demonstrated between the detection of antibodies and the clinical status of the patients. Antibodies were not detectable before Rasburicase treatment in the patient who had bronchospasm but were not tested after the event.
This study demonstrates that Rasburicase is a highly effective, fast-acting, and safe uricolytic agent. All of the patients either presented with hyperuricemia or had lymphoid malignancies with large tumor cell burdens, placing them at high risk for this complication. The urinary excretion of allantoin, a product of uric acid degradation, increased sharply during the first 3 days of treatment, commensurate with tumor cell lysis caused by intensive chemotherapy and with rapid breakdown of uric acid by Rasburicase. Patients presenting with hyperuricemia had a higher allantoin excretion rate than did those without hyperuricemia at diagnosis. Virtually all patients had low blood uric acid concentrations during the entire treatment course. Transient hyperuricemia, lasting for less than 24 hours, was observed in only five patients during Rasburicase treatment, none of whom had uric acid concentrations above 10.7 mg/dL. In fact, uric acid was undetectable in approximately half of the plasma samples. Rasburicase has a relatively long plasma half-life (16 to 22 hours). One of the 12 patients treated with the recombinant enzyme at a daily dosage of 0.15 mg/kg had transient hyperuricemia during remission induction. In view of the relatively unpredictable course of tumor cell lysis after initial cytoreductive chemotherapy, we suggest that the higher dosage of this agent, 0.20 mg/kg, be used in future trials, especially for patients with a large tumor cell burden. This recommendation is supported by the higher rate of urinary excretion of allantoin in patients receiving Rasburicase at 0.20 mg/kg, compared with those treated at the lower dosage (data not shown) and by the apparent lack of additional side effects with use of the higher dosage. The treatment duration should depend on the type of malignancy and anticancer treatment, and, hence the duration of tumor cell lysis. Hyperphosphatemia with consequent hyperphosphaturia is another important cause of acute renal failure due to tumor cell lysis.5,22 Strikingly, in this study, serum phosphorus levels did not change significantly during the first 3 days of chemotherapy, when tumor cell lysis was most pronounced, and in patients who presented with hyperuricemia, these levels had decreased significantly by day 4 of treatment. We attribute this result partly to the use of Rasburicase, which obviated the need to alkalinize the urine, hence facilitating the excretion of phosphorus because of its greater solubility in acidic urine. The decreased precipitation of uric acid or its precursor xanthine in renal tubules might also have improved the excretion of phosphorus. Most important, perhaps, was the steady improvement of renal function during treatment of our patients, none of whom required dialysis or developed acute renal failure, defined as doubling of the serum creatinine concentration or an increase in the serum creatinine level of greater than 1 mg/dL.23 This finding is remarkable, considering that 25 patients in this study had stage III or IV B-cell NHL or B-cell ALL, malignancies associated with a high rate of renal complications. In this regard, acute renal failure prompting hemodialysis developed in 10 (25%) of 40 patients treated for stage III or IV B-cell NHL or B-cell ALL by Stapleton et al,23 and in 28 (21%) of 133 similar patients recently treated by members of the Pediatric Oncology Group (six patients died of complications).24 Thus, judicious use of Rasburicase may not only decrease initial rates of morbidity and mortality but also lead to improved long-term survival, owing to timely delivery of chemotherapy, a particularly important consideration in the treatment of patients with advanced B-cell malignancies.25 Rasburicase was very well tolerated. One child developed nausea and vomiting. Another patient developed bronchospasms and hypoxemia, but it was not clear whether the uricolytic agent was the underlying cause. First, in our experience with the nonrecombinant urate oxidase, the hypersensitivity reactions occurred rapidly during infusion of the agent: median time of onset, 6 minutes (range, 1 to 17 minutes),17 as compared with 3 hours after treatment in the present case. Second, the patient presented with hypereosinophilia and pneumonia and had received cancer chemotherapy, including vincristine and intrathecal methotrexate, hydrocortisone, and cytarabine, immediately preceding the onset of symptoms. Conceivably, the symptoms were related to the release of cytokines from eosinophils caused by chemotherapy. Even if the symptoms did result from Rasburicase therapy, the incidence (one in 131 patients) is substantially lower than the six in 134 incidence associated with the nonrecombinant product.17 Additional studies are needed to determine the safety of Rasburicase in patients with a history of allergy or bronchial asthma. Antibodies against Rasburicase or its epitopes were detected in 17 (14%) of the 121 patients tested, raising the question of whether subsequent administration of the enzyme would enhance hypersensitivity reactions and limit clinical efficacy. These possibilities notwithstanding, any clinical impact of Rasburicase-induced immunogenicity would be small. First, the antibody formation rate was relatively low in our study. Second, only one course of treatment is usually needed in patients with leukemia or lymphoma, who are at high risk for tumor lysis syndrome at diagnosis caused by a large tumor burden and drug-sensitive disease. For the few patients who suffer a relapse, their disease at relapse is relatively drug-resistant and therefore poses a much lower risk for tumor lysis syndrome. To this end, a second course of treatment was given to six patients, 16 to 80 days after the initial treatment, one of whom also received a third course. These repeated administrations were effective, reducing plasma uric acid to undetectable levels in all patients and were not associated with drug-related adverse reactions (data on file, Sanofi-Synthelabo, Inc). Additional cases needed to be assessed. We conclude that Rasburicase is a safe and highly effective uricolytic agent in patients with leukemia or lymphoma. Its ability to ameliorate hyperuricemia in patients receiving intensive chemotherapy may prove useful in treatment of other conditions marked by excessive accumulation of uric acid.
APPENDIX
Supported in part by grants no. CA-21765, CA-20180, CA-51001, CA-23099, CA-31566, and CA-32053 from the National Cancer Institute, a grant from the Sanofi-Synthelabo, Inc, a Center of Excellence Grant from the State of Tennessee, and American Lebanese Syrian Associated Charities. We thank John Gilbert for scientific editing, Richard Czerniak for pharmacokinetic studies, Joel Weiner, Fabienne Flory, Francine High, James M. Grabicki, and Kim Juneau for data managing and monitoring, Conrad Tou and Carol Gleason for statistical analysis, and Pediatric Oncology Group and Children’s Cancer Group for identifying institutions to participate in this study.
1. Rieselbach RE, Bentzel CJ, Cotlove E, et al: Uric acid excretion and renal function in the acute hyperuricemia of leukemia: Pathogenesis and therapy or uric acid nephropathy. Am J Med 37: 872-884, 1964[Medline] 2. Holland P, Holland NH: Prevention and management of acute hyperuricemia in childhood leukemia. J Pediatr 72: 358-366, 1968[Medline]
3.
Krakoff IH, Murphy ML: Hyperuricemia in neoplastic disease in children: Prevention with allopurinol, a xanthine oxidase inhibitor. Pediatrics 41: 52-56, 1968 4. Jones DP, Mahmoud H, Chesney RW: Tumor lysis syndrome: Pathogenesis and management. Pediatr Nephrol 9: 206-212, 1995[Medline] 5. Cohen LF, Balow JE, Magrath IT, et al: Acute tumor lysis syndrome: A review of 37 patients with Burkitt’s lymphoma. Am J Med 68: 486-491, 1980[Medline] 6. Jones DP, Stapleton FB, Kalwinsky D, et al: Renal dysfunction and hyperuricemia at presentation and relapse of acute lymphoblastic leukemia. Med Pediatr Oncol 18: 283-286, 1990[Medline] 7. DeConti RC, Calabresi P: Use of allopurinol for prevention and control of hyperuricemia in patients with neoplastic disease. N Engl J Med 274: 481-486, 1966 8. Andreoli SP, Clark JH, McGuire WA, et al: Purine excretion during tumor lysis in children with acute lymphocytic leukemia receiving allopurinol: Relationship to acute renal failure. J Pediatr 109: 292-298, 1986[Medline] 9. Klinenberg JR, Goldfinger SE, Seegmiller JE: The effectiveness of the xanthine oxidase inhibitor allopurinol in the treatment of gout. Ann Intern Med 62: 639-647, 1965 10. Greene ML, Fujimoto WY, Seegmiller JE: Urinary xanthine stones: A rare complication of allopurinol therapy. N Engl J Med 280: 426-427, 1969 11. Band PR, Silverberg DS, Henderson JF, et al: Xanthine nephropathy in a patient with lymphosarcoma treated with allopurinol. N Engl J Med 283: 354-357, 1970 12. Ablin A, Stephens BG, Hirata T, et al: Nephropathy, xanthinuria, and orotic aciduria complicating Burkitt’s lymphoma treated with chemotherapy and allopurinol. Metabolism 21: 771-778, 1972[Medline] 13. Shohet I, Aladjem M, Lotan D, et al: Acute renal failure complicating Burkitt’s lymphoma treated with chemotherapy and allopurinol. Int J Pediatr Nephrol 1: 240-241, 1980 14. Brogard JM, Coumaros D, Franckhauser J, et al: Enzymatic uricolysis: A study of the effect of a fungal urate-oxydase. Rev Eur Etudes Clin Biol 17: 890-895, 1972[Medline] 15. Yeldandi AV, Yeldandi V, Kumar S, et al: Molecular evolution of the urate oxidase-encoding gene in hominoid primates: Nonsense mutations. Gene 109: 281-284, 1991[Medline] 16. Masera G, Jankovic M, Zurlo MG, et al: Urate-oxidase prophylaxis of uric acid-induced renal damage in childhood leukemia. J Pediatr 100: 152-155, 1982[Medline] 17. Pui C-H, Relling MV, Lascombes F, et al: Urate oxidase in prevention and treatment of hyperuricemia associated with lymphoid malignancies. Leukemia 11: 1813-1816, 1997[Medline] 18. Mahmoud HH, Leverger G, Patte C, et al: Advances in the management of malignancy-associated hyperuricemia. Br J Cancer 77: 18-20, 1998 (suppl 4) 19. Choukair MK: Blood chemistries/body fluids, in Siberry GK, Iannone R (eds): The Harriet Lane Handbook: A Manual for Pediatric House Officers ( ed 15 ). St Louis, MO, Mosby-Year Book Inc, 1996, pp 119-130 20. Berthemy A, Newton J, Wu D, et al: Quantitative determination of an extremely polar compound allantoin in human urine by LC-MS/MS based on the separation on a polymeric amino column. J Pharm Biomed Anal 19: 429-434, 1999[Medline] 21. Dussossoy D, Py ML, Pastor G, et al: Development of a two-site immunoassay of recombinant urate oxidase (SR 29142) and its use for determination of pharmacokinetic parameters in rats and baboons. J Pharm Sci 85: 955-959, 1996[Medline] 22. Tsokos GC, Balow JE, Spiegel RJ, et al: Renal and metabolic complications of undifferentiated and lymphoblastic lymphomas. Medicine 60: 218-229, 1981[Medline]
23.
Stapleton FB, Strother DR, Roy S III, et al: Acute renal failure at onset of therapy for advanced stage Burkitt lymphoma and B cell acute lymphoblastic lymphoma. Pediatrics 82: 863-869, 1988
24.
Bowman WP, Shuster JJ, Cook B, et al: Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: A Pediatric Oncology Group study. J Clin Oncol 14: 1252-1261, 1996
25.
Pui C-H, Evans WE: Acute lymphoblastic leukemia. N Engl J Med 339: 605-615, 1998 Submitted June 20, 2000; accepted September 13, 2000. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
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