Comparison of Neuropsychologic Functioning and Clinical Indicators of Neurotoxicity in Long-Term Survivors of Childhood Leukemia Given Cranial Radiation or Parenteral Methotrexate: A Prospective Study By Judith Ochs, Raymond Mulhern, Diane Fairclough, Louis Parvey, John Whitaker, Lawrence Ch'ien, Alvin Mauer, and Joseph Simone We prospectively compared neuropsychologic functioning and clinical indicators of neurotoxicity in 49 consecutive childhood leukemia patients in long-term continuous complete remission (CR) who had received two different regimens of CNS prophylaxis by random assignment. Twenty-three patients were treated with 1,800 cGy cranial radiation and intrathecal methotrexate (RT group) and 26 with parenteral methotrexate only (MTX group). Over half of the RT group had somnolence syndrome, and four developed cerebral calcifications late in their clinical course. Abnormal electroencephalograms (EEGs) were seen in 15 patients in the MTX group, and six had early, transient white-matter hypodensities apparent on computed tomographic (CT) scans. Mean scores on standard tests of intelligence and academic achievement, admin-
istered after remission induction and again at a median of 6 years after treatment cessation, did not differ significantly between the two groups. However, statistically significant decreases in overall and verbal intelligence quotients (lQs) and in arithmetic achievement were found within both treatment groups. Sixteen of 26 in the MTX group and 14 of the 23 in the RT group had clinically important decreases ( 15 points) on one or more neuropsychologic measures. These changes did not correlate with findings on CT scans, EEGs, or other clinical signs of neurotoxicity. We conclude that 1,800 cGy cranial radiation and parenteral methotrexate, as used in this study, are associated with comparable decreases in neuropsychologic function. J Clin Oncol 9:145-151. © 1991 by American Society of Clinical Oncology.
RECOGNITION of the CNS as a major site of
continuous complete remission, we devised a prospective comparative study that paralleled our therapeutic trial.
relapse in children with acute lymphoblastic leukemia (ALL) stimulated the development of effective preventive CNS therapy." 3 During the 1960s and 1970s, the most widely used approach was the administration of 2,400 cGy cranial radiation combined with intrathecal (IT) methotrexate shortly after induction of complete remission (CR). However, retrospective reports consistently linking radiation therapy to CNS structural changes4 and significantly lower scores on neuropsychologic tests5'6 led clinical oncologists to assume a causative role for this modality, and to modify or avoid its use in CNS prophylactic regimens. Two current approaches involve the combination of a lower dose of cranial radiation (1,800 cGy) with IT methotrexate' and the use of parenteral methotrexate alone.8 In a randomized study begun at our institution in 1979, 1,800 cGy cranial irradiation and parenteral methotrexate were shown to be equally effective in preventing CNS relapse, although radiation was superior to methotrexate in cases of poor-prognosis ALL.' To assess and compare the long-term effects of CNS
prophylaxis, with and without cranial irradiation, in consecutive
survivors of childhood ALL in
MATERIALS AND METHODS
PatientSample Between June 1979 and December 1983, 330 consecutive children with newly diagnosed ALL were enrolled in a randomized clinical trial on the basis of certain risk factors at the time of diagnosis." These were (1) an initial leukocyte 9 count less than 100 x 10 /L, (2) no mediastinal mass, (3) an absence of blast cells in CSF, and (4) blast cells lacking surface immunoglobulin and receptors for sheep RBCs.
From the Departments of Hematology-Oncology, Psychology, Biostatisticsand Information Services, Diagnostic Imaging, and Neurology, St Jude Children'sResearch Hospital; and Departmentsof Pediatricsand Neurology, Universityof Tennessee, Memphis, College of Medicine, Memphis, TN. Submitted March 13, 1990; acceptedJune 25, 1990. Supported by Grants CA 21765 and CA 20180 from the National Cancer Institute, and by the American Lebanese Syrian AssociatedCharities. Address reprint requests to Judith Ochs, MD, St Jude Children'sResearchHospital,332 N Lauderdale,PO Box 318, Memphis, TN38101. © 1991 by American Society of ClinicalOncology. 0732-183X/91/0901-0007$3.00/0
Journal of Clinical Oncology, Vol 9, No 1 (January), 1991: pp 145-151
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
145
146
OCHS ET AL
Within 2 weeks of diagnosis, 113 consecutive patients were asked to participate in a prospective study evaluating CNS toxicity; 108 agreed. One hundred two achieved CR and were randomized to receive either cranial radiation or parenteral methotrexate as CNS prophylaxis. Fifty-three were excluded from final data assessment because of relapse (n = 42), congenital disorders such as trisomy 21 with neurologic impairment (n = 8), noncompliance (n = 2), or hepatic toxicity requiring a change in therapy (n = 1). Forty-nine patients remained in continuous CR for > 4 years after cessation of therapy and were fully assessable for neurotoxicity; this total includes 23 patients in the cranial radiation group (RT group) and 26 in the methotrexate group (MTX group). The two cohorts were comparable with regard to age at diagnosis, age at final testing, intervals between first and last neuropsychologic evaluations, initial leukocyte count, sex, and family socioeconomic status (Table 1). Treatment Details of the treatment protocol are presented elsewhere.' 0 Briefly, the 4-week, three-drug induction regimen (prednisone, vincristine, and intravenous [IV] asparaginase) was the same for all patients. IT methotrexate (12 mg/m2, maximum of 12 mg) was administered as preventive CNS therapy on days 15 and 29. Patients achieving CR were randomized on the basis of age and initial leukocyte count to receive either cranial radiation plus IT methotrexate (RT group) followed by sequentially administered drug pairs plus IT methotrexate or IV infusions of methotrexate (1 2 g/m ) plus IT methotrexate (MTX group). The RT group received 1,800 cGy cranial irradiation in 12 fractions over 2.5 weeks with five concurrent doses of IT methotrexate given twice weekly. Systemic therapy consisted of the following drug pairs: mercaptopurine/methotrexate, cyclophosphamide/doxorubicin, and teniposide/ cytarabine. IT methotrexate was administered approximately every 3 months during the 120 weeks of continuation therapy. Each patient in the RT group thus received a total of 16 doses, or 192 g/m 2, of IT methotrexate and 2.35 g/m 2 oral methotrexate during the 120-week continuation period. The MTX group was given this agent with leucovorin rescue as 3 weekly 24-hour IV infusions of 1 g/m 2, followed by a total of 12 infusions administered once every 6 weeks for the
first 72 weeks; IT methotrexate was given every 3 months. Daily mercaptopurine and weekly methotrexate were given throughout the 120-week continuation therapy except on weeks when methotrexate infusions were given. Each patient in the MTX group received a total of 15 doses or 180 mg/m 2 of IT methotrexate, 2.7 g/m 2 of oral methotrexate through the 120-week continuation period, and 15 g/m2 of IV methotrexate during the first 75 weeks of continuation. Methods of Evaluation Neuropsychologic tests were scheduled to be administered as soon as possible after the date of remission induction, at yearly intervals until cessation of therapy, and every other year over the next 5 years. Patients who had reached 4 years of age were initially tested with the complete age-appropriate version of the Wechsler Preschool Scale (n = 14), Primary Scale of Intelligence (n = 33), or the Wechsler Intelligence Scale for Children-Revised (WISC-R; n = 2); the WISC-R was used for all final assessments.""12 Academic performance was uniformly assessed with the Wide Range Achievement Test, which provided standard scores for reading (word recognition), spelling, and arithmetic.1 3 Intelligence quotient (IQ) and achievement test scores were converted to age-corrected standard scores based on the general population norms in order to adjust for normally expected increased performance with increasing age. The present analysis includes only the initial and final neuropsychologic test scores since no significant differences were found in various interval scores between groups. In addition, data from analyses of scores obtained at various intervals of the study period did not add to the description of ultimate change (R. Mulhern, unpublished findings). Clinical neurologic examinations and electroencephalograms (EEGs) were interpreted by a board-certified pediatric neurologist. Cranial computed tomographic (CT) scans were performed with a General Electric 8800 CT-T scanner without contrast. A 9.8-second scan time with a 10-mm collimetor was the standard technique, except for very young children for whom a 5-mm collimetor was used. Standards for ventricular size and cortical, sulcal, and fissural widths were based on the findings of Bentson et al.14 Criteria for significant differences in white-gray matter densities were obtained by reviewing cranial CT scans for
Table 1. Descriptive Characteristics of Study Groups MTX (n = 26) Median
Feature
Age at diagnosis (year)
3.6
Male:female ratio
Range
1.8-12.1
16:10 9
Initial leukocyte count (x 10 /L) Age at final neuropsychologic testing interval (year) Time between first and last WISC (year) Time between first and last WRAT (year) Family socioeconomic statust
crRT (n =23) Median
4.6 10:13
Range
P*
2.0-14.5
0.13
-
0.26
6.0
1.4-73.9
8.3
1.9-95.0
0.60
10.6 5.7 3.1 4
5.2-18.5 1.1-8.3 0.9-8.3 1-5
11.8 6.0 4.2 3
9.0-21.0 3.6-7.8 1.0-7.8 1-7
0.23 0.57 0.35 0.19
Abbreviations: crRT, cranial radiation; WRAT, Wide Range Achievement Test. *By two-tailed Wilcoxon or Fisher's exact test. 3 tData from Hollingshead. "
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
147
NEUROPSYCHOLOGIC FUNCTION, NEUROTOXICITY IN ALL over 200 children, including those in this study, who were treated at this center and had had cranial CT scans performed for a variety of reasons. The mean difference between gray and white matter was calculated to be 6.5 Hounsfield units (2 SE = 3.0 units). White-gray matter differences greater than 10 Hounsfield units were used to designate significant white-matter hypodensity. These evaluations were done during remission induction, 6 weeks after either the completion of radiotherapy or the third weekly course of methotrexate, and again at 6, 12, 18, and 24 months during continuation therapy. After elective cessation of therapy, they were alternated with yearly neuropsychologic tests during the 5 years following completion of therapy. Myelin basic protein was measured in CSF at the time of scheduled diagnostic procedures, therapeutic lumbar punctures, or both (ie, approximately eight times during the first year, four times during the second, and three times during the third)." All examiners were unaware of the method of CNS prophylaxis; protein samples were assigned code numbers. More than 80% of scheduled evaluations were completed.
StatisticalAnalysis Statistical comparisons between groups were based on the two-tailed Fisher's exact test for dichotomous variables, the Wilcoxon rank-sum test for continuous patient characteristics, and t-test analysis for the psychometric measures. The sample size was sufficient to detect statistically significant differences where the true difference between groups exceeded 0.8 standard deviation for the respective outcomes (a = 0.05; 1-P = 0.8). Analysis of change in the psychometric measures between the first and last evaluations was based on one-tailed, paired t-tests. The association of significant declines in neuropsychologic performance with clinical signs of neurotoxicity was tested with the one-tailed Fisher's exact test. Longitudinal analyses of all psychometric measures, as well as analysis of potential risk factors, will be included in a separate report. Children were considered to have clinically important changes in test performance if the difference between their first and last scores was 15 points or greater. This 15-point criterion is equal to one standard deviation of the test norms and approximately three times the error of measurement of the test.) .3
16U
140 4,
Verbal MTX CrRT
Performance CrRT
MTX
120 100
0
80 60
p=0.045
p=0.016
p 50 x 109/L) irradiation is the preferred method of CNS prophylaxis pending randomized trials comparing its efficacy with that of aggressive IT therapy.3
ACKNOWLEDGMENT The authors thank the following for their contributions over the past 10 years: W.P. Bowman, M. Abromowitch, and C.-H. Pui (Hematology-Oncology); I. Igurashi and E. Kovnar (Neurology); T. Coburn (Radiology); R. Berg and R. Ragland (Psychology); and M. Campbell, K. Davis, and numerous other examiners in the Neuropsychology Department. The authors also acknowledge the medical editorship of John Gilbert and Christy Wright, the patience and cooperation of the children and their parents who participated in this study, the long-term investment of time and resources made by St Jude Children's Research Hospital, and the manuscript typing of Peggy Vandiveer.
REFERENCES 1. Aur RJA, Simone JV, Hustu HO, et al: Central nervous system therapy and combination chemotherapy of childhood lymphocytic leukemia. Blood 37:272-281, 1971 2. Aur RJA, Hustu HO, Verzosa MS, et al: Comparison of two methods of preventing central nervous system leukemia. Blood 43:349-357, 1973 3. Sullivan MP, Chan T, Dyment PK, et al: Equivalence of intrathecal chemotherapy and radiotherapy as central nervous system prophylaxis in children with acute lymphatic leukemia: A Pediatric Oncology Group study. Blood 60:948958, 1982 4. Ochs J, Mulhern R: Late effects of antileukemic treatment, in D Poplack (ed): Childhood Acute Lymphoblastic Leukemia. Pediatric Clinics, Philadelphia, PA, Saunders, 1988, pp 815-835 5. Williams MJ, Davis KS: Central nervous system prophylactic treatment for childhood leukemia: Neuropsychological outcome studies. Cancer Res 13:113-127, 1986
6. Fletcher JM, Copeland DR: Neurobehavioral effects of central nervous system treatment of cancer in children. J Clin Exp Neuropsych 10:495-538, 1988 7. Nesbit ME, Sather HN, Robison LL, et al: Presymptomatic central nervous system therapy in previously untreated childhood acute lymphoblastic leukemia: Comparison of 1,800 rad and 2,400 rad. A report of the Children's Cancer Study Group. Lancet 1:461-466, 1981 8. Poplack DG, Reaman GH, Bleyer WA, et al: Successful prevention of central nervous system (CNS) leukemia without cranial radiation in children with high-risk acute lymphoblastic leukemia (ALL): A preliminary report. Proc Am Soc Clin Oncol 8:213, 1989 (abstr) 9. Abromowitch M, Ochs J, Pui C-H, et al: Efficacy of high-dose methotrexate in childhood acute lymphoblastic leukemia: Analysis by contemporary risk classifications. Blood 71:866-869, 1988 10. Bowman WP, Ochs J, Pui C-H, et al: New directions
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
NEUROPSYCHOLOGIC FUNCTION, NEUROTOXICITY IN ALL of St Jude total therapy protocol: Study X for standard-risk childhood acute lymphoblastic leukemia, in, Murphy SB, Gilbert JR (eds): Leukemia Research: Advances in Cell Biology and Treatment, New York, NY, Elsevier Biomedical, 1983, p 203 11. Wechsler D: Manual for the Wechsler Preschool and Primary Scale of Intelligence. San Antonio, TX, Psychological Corporation, 1967 12. Wechsler D: Manual for the Wechsler Intelligence Scale for Children-Revised. San Antonio, TX, The Psychological Corporation, 1974 13. Jastak JS, Jastak S: The Wide Range Achievement Test. Wilmington, DE, Jastak Associates, 1984 14. Bentson J, Reza M, Winter J, et al: Steroids and apparent atrophy on computed tomography scans. J Comp Assist Tomogr 2:16-23, 1978 15. Whitaker JN, Lisak RP, Bashir RM, et al: Immunoreactive myelin basic protein in the cerebrospinal fluid in neurologic disorders. Ann Neurol 7:58-64, 1980 16. Ochs J, Parvey LS, Whitaker JN, et al: Serial cranial computed tomography scans in children with leukemia given two different forms of central nervous system therapy. J Clin Oncol 1:793-798, 1983 17. Eiser C: Intellectual abilities among survivors of childhood leukemia as a function of CNS irradiation. Arch Dis Child 53:391-395, 1978 18. Obetz SW, Smithson WA, Groover RV, et al: Neurologic follow-up study of children with ALL. Am J Pediatr Hematol Oncol 11:207-313, 1979 19. Meadows T, Massari DJ, Fergussion J, et al: Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukemia treated with cranial irradiation. Lancet 2:1015-1018, 1983 20. Rowland JH, Glidewell DJ, Sibley RF, et al: Effects of different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia. J Clin Oncol 2:1327-1335, 1984 21. Pfefferbaum-Levine B, Copeland DR, Fletcher JM, et al: Neuropsychological assessment of long-term survivors of childhood leukemia. Am J Pediatr Hematol Oncol 6:123-128, 1984 22. Whitt JK, Wells RJ, Lauria MM, et al: Cranial irradiation in childhood acute lymphocytic leukemia. Am J Dis Child 138:730-736, 1984 23. Pavlosky S, Fisman N, Arizoga, et al: Neuropsychologic study in patients with ALL: Two different CNS prevention therapies-cranial irradiation plus IT methotrexate versus IT methotrexate alone. Am J Pediatr Hematol Oncol 5:79-86, 1983
151
24. Lansky SB, Cairns SV, Lansky L, et al: Central nervous system prophylaxis studies showing impairment in verbal skills and academic achievement. Am J Pediatr Hematol 6:183-190, 1984 25. Stehbens JA, Kisker CR, Wilson BK: Achievement and intellectual test-retest performance in pediatric cancer patients at diagnosis and one year later. N Pediatr Psycho 8:47-56, 1983 26. Moss HA, Nannis ED, Poplack DG: The effects of prophylactic treatment of the CNS on the intellectual functioning of children with ALL. Am J Med 71:47-52, 1981 27. Soni SS, Martin G, Pitner SE, et al: Effects of CNS irradiation on neuropsychologic functioning of children with acute lymphoblastic leukemia. N Engl J Med 293:113118, 1975 28. Riehm H, Feckert H-S, Lampert F: Acute lymphoblastic leukemia, in, Voute PA, Barrett A, Bloom J, et al (eds): UICC Cancer in Children: Clinical Management (ed 2). New York, NY, Springer-Verlag, 1986, pp 101-118 29. Freeman JE, Johnson PG, Wohe JM: Somnolence after prophylactic cranial irradiation in children with acute lymphoblastic leukemia. Br Med J 4:523-525, 1973 30. Carli M, Perilongi G, Laverda AM, et al: Risk factors of central nervous system prophylaxis in successfully treated children with acute lymphocytic leukemia. Med Pediatr Oncol 13:334-340, 1985 31. Brouers P, Riccardi R, Fedio P, et al: Long-term neuropsychologic sequelae of childhood leukemia: Correlation with CT scan abnormalities. J Pediatr 106:723-728, 1985 32. Mahoney DH, Fernbach DJ, Glaze DG, et al: Elevated myelin basic protein levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia. 2:58-61, 1984 33. Kent SP, Pickering JE: Neoplasms in monkeys (Macaca Mulatta): Spontaneous and irradiation induced. Cancer 11:138-147, 1958 34. Ron E, Modan B, Boice JD, et al: Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 391:1033-1039, 1988 35. Crist W, Boyett J, Jackson J: Prognostic importance of the pre-B-cell immunophenotype and other presenting features in B-lineage childhood acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood 74(4):12521259, 1989 36. Hollingshead AB: Four Factor Index of Social Position. New Haven, CT, Yale University, 1975
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
istered after remission induction and again at a median of 6 years after treatment cessation, did not differ significantly between the two groups. However, statistically significant decreases in overall and verbal intelligence quotients (lQs) and in arithmetic achievement were found within both treatment groups. Sixteen of 26 in the MTX group and 14 of the 23 in the RT group had clinically important decreases ( 15 points) on one or more neuropsychologic measures. These changes did not correlate with findings on CT scans, EEGs, or other clinical signs of neurotoxicity. We conclude that 1,800 cGy cranial radiation and parenteral methotrexate, as used in this study, are associated with comparable decreases in neuropsychologic function. J Clin Oncol 9:145-151. © 1991 by American Society of Clinical Oncology.
RECOGNITION of the CNS as a major site of
continuous complete remission, we devised a prospective comparative study that paralleled our therapeutic trial.
relapse in children with acute lymphoblastic leukemia (ALL) stimulated the development of effective preventive CNS therapy." 3 During the 1960s and 1970s, the most widely used approach was the administration of 2,400 cGy cranial radiation combined with intrathecal (IT) methotrexate shortly after induction of complete remission (CR). However, retrospective reports consistently linking radiation therapy to CNS structural changes4 and significantly lower scores on neuropsychologic tests5'6 led clinical oncologists to assume a causative role for this modality, and to modify or avoid its use in CNS prophylactic regimens. Two current approaches involve the combination of a lower dose of cranial radiation (1,800 cGy) with IT methotrexate' and the use of parenteral methotrexate alone.8 In a randomized study begun at our institution in 1979, 1,800 cGy cranial irradiation and parenteral methotrexate were shown to be equally effective in preventing CNS relapse, although radiation was superior to methotrexate in cases of poor-prognosis ALL.' To assess and compare the long-term effects of CNS
prophylaxis, with and without cranial irradiation, in consecutive
survivors of childhood ALL in
MATERIALS AND METHODS
PatientSample Between June 1979 and December 1983, 330 consecutive children with newly diagnosed ALL were enrolled in a randomized clinical trial on the basis of certain risk factors at the time of diagnosis." These were (1) an initial leukocyte 9 count less than 100 x 10 /L, (2) no mediastinal mass, (3) an absence of blast cells in CSF, and (4) blast cells lacking surface immunoglobulin and receptors for sheep RBCs.
From the Departments of Hematology-Oncology, Psychology, Biostatisticsand Information Services, Diagnostic Imaging, and Neurology, St Jude Children'sResearch Hospital; and Departmentsof Pediatricsand Neurology, Universityof Tennessee, Memphis, College of Medicine, Memphis, TN. Submitted March 13, 1990; acceptedJune 25, 1990. Supported by Grants CA 21765 and CA 20180 from the National Cancer Institute, and by the American Lebanese Syrian AssociatedCharities. Address reprint requests to Judith Ochs, MD, St Jude Children'sResearchHospital,332 N Lauderdale,PO Box 318, Memphis, TN38101. © 1991 by American Society of ClinicalOncology. 0732-183X/91/0901-0007$3.00/0
Journal of Clinical Oncology, Vol 9, No 1 (January), 1991: pp 145-151
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
145
146
OCHS ET AL
Within 2 weeks of diagnosis, 113 consecutive patients were asked to participate in a prospective study evaluating CNS toxicity; 108 agreed. One hundred two achieved CR and were randomized to receive either cranial radiation or parenteral methotrexate as CNS prophylaxis. Fifty-three were excluded from final data assessment because of relapse (n = 42), congenital disorders such as trisomy 21 with neurologic impairment (n = 8), noncompliance (n = 2), or hepatic toxicity requiring a change in therapy (n = 1). Forty-nine patients remained in continuous CR for > 4 years after cessation of therapy and were fully assessable for neurotoxicity; this total includes 23 patients in the cranial radiation group (RT group) and 26 in the methotrexate group (MTX group). The two cohorts were comparable with regard to age at diagnosis, age at final testing, intervals between first and last neuropsychologic evaluations, initial leukocyte count, sex, and family socioeconomic status (Table 1). Treatment Details of the treatment protocol are presented elsewhere.' 0 Briefly, the 4-week, three-drug induction regimen (prednisone, vincristine, and intravenous [IV] asparaginase) was the same for all patients. IT methotrexate (12 mg/m2, maximum of 12 mg) was administered as preventive CNS therapy on days 15 and 29. Patients achieving CR were randomized on the basis of age and initial leukocyte count to receive either cranial radiation plus IT methotrexate (RT group) followed by sequentially administered drug pairs plus IT methotrexate or IV infusions of methotrexate (1 2 g/m ) plus IT methotrexate (MTX group). The RT group received 1,800 cGy cranial irradiation in 12 fractions over 2.5 weeks with five concurrent doses of IT methotrexate given twice weekly. Systemic therapy consisted of the following drug pairs: mercaptopurine/methotrexate, cyclophosphamide/doxorubicin, and teniposide/ cytarabine. IT methotrexate was administered approximately every 3 months during the 120 weeks of continuation therapy. Each patient in the RT group thus received a total of 16 doses, or 192 g/m 2, of IT methotrexate and 2.35 g/m 2 oral methotrexate during the 120-week continuation period. The MTX group was given this agent with leucovorin rescue as 3 weekly 24-hour IV infusions of 1 g/m 2, followed by a total of 12 infusions administered once every 6 weeks for the
first 72 weeks; IT methotrexate was given every 3 months. Daily mercaptopurine and weekly methotrexate were given throughout the 120-week continuation therapy except on weeks when methotrexate infusions were given. Each patient in the MTX group received a total of 15 doses or 180 mg/m 2 of IT methotrexate, 2.7 g/m 2 of oral methotrexate through the 120-week continuation period, and 15 g/m2 of IV methotrexate during the first 75 weeks of continuation. Methods of Evaluation Neuropsychologic tests were scheduled to be administered as soon as possible after the date of remission induction, at yearly intervals until cessation of therapy, and every other year over the next 5 years. Patients who had reached 4 years of age were initially tested with the complete age-appropriate version of the Wechsler Preschool Scale (n = 14), Primary Scale of Intelligence (n = 33), or the Wechsler Intelligence Scale for Children-Revised (WISC-R; n = 2); the WISC-R was used for all final assessments.""12 Academic performance was uniformly assessed with the Wide Range Achievement Test, which provided standard scores for reading (word recognition), spelling, and arithmetic.1 3 Intelligence quotient (IQ) and achievement test scores were converted to age-corrected standard scores based on the general population norms in order to adjust for normally expected increased performance with increasing age. The present analysis includes only the initial and final neuropsychologic test scores since no significant differences were found in various interval scores between groups. In addition, data from analyses of scores obtained at various intervals of the study period did not add to the description of ultimate change (R. Mulhern, unpublished findings). Clinical neurologic examinations and electroencephalograms (EEGs) were interpreted by a board-certified pediatric neurologist. Cranial computed tomographic (CT) scans were performed with a General Electric 8800 CT-T scanner without contrast. A 9.8-second scan time with a 10-mm collimetor was the standard technique, except for very young children for whom a 5-mm collimetor was used. Standards for ventricular size and cortical, sulcal, and fissural widths were based on the findings of Bentson et al.14 Criteria for significant differences in white-gray matter densities were obtained by reviewing cranial CT scans for
Table 1. Descriptive Characteristics of Study Groups MTX (n = 26) Median
Feature
Age at diagnosis (year)
3.6
Male:female ratio
Range
1.8-12.1
16:10 9
Initial leukocyte count (x 10 /L) Age at final neuropsychologic testing interval (year) Time between first and last WISC (year) Time between first and last WRAT (year) Family socioeconomic statust
crRT (n =23) Median
4.6 10:13
Range
P*
2.0-14.5
0.13
-
0.26
6.0
1.4-73.9
8.3
1.9-95.0
0.60
10.6 5.7 3.1 4
5.2-18.5 1.1-8.3 0.9-8.3 1-5
11.8 6.0 4.2 3
9.0-21.0 3.6-7.8 1.0-7.8 1-7
0.23 0.57 0.35 0.19
Abbreviations: crRT, cranial radiation; WRAT, Wide Range Achievement Test. *By two-tailed Wilcoxon or Fisher's exact test. 3 tData from Hollingshead. "
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
147
NEUROPSYCHOLOGIC FUNCTION, NEUROTOXICITY IN ALL over 200 children, including those in this study, who were treated at this center and had had cranial CT scans performed for a variety of reasons. The mean difference between gray and white matter was calculated to be 6.5 Hounsfield units (2 SE = 3.0 units). White-gray matter differences greater than 10 Hounsfield units were used to designate significant white-matter hypodensity. These evaluations were done during remission induction, 6 weeks after either the completion of radiotherapy or the third weekly course of methotrexate, and again at 6, 12, 18, and 24 months during continuation therapy. After elective cessation of therapy, they were alternated with yearly neuropsychologic tests during the 5 years following completion of therapy. Myelin basic protein was measured in CSF at the time of scheduled diagnostic procedures, therapeutic lumbar punctures, or both (ie, approximately eight times during the first year, four times during the second, and three times during the third)." All examiners were unaware of the method of CNS prophylaxis; protein samples were assigned code numbers. More than 80% of scheduled evaluations were completed.
StatisticalAnalysis Statistical comparisons between groups were based on the two-tailed Fisher's exact test for dichotomous variables, the Wilcoxon rank-sum test for continuous patient characteristics, and t-test analysis for the psychometric measures. The sample size was sufficient to detect statistically significant differences where the true difference between groups exceeded 0.8 standard deviation for the respective outcomes (a = 0.05; 1-P = 0.8). Analysis of change in the psychometric measures between the first and last evaluations was based on one-tailed, paired t-tests. The association of significant declines in neuropsychologic performance with clinical signs of neurotoxicity was tested with the one-tailed Fisher's exact test. Longitudinal analyses of all psychometric measures, as well as analysis of potential risk factors, will be included in a separate report. Children were considered to have clinically important changes in test performance if the difference between their first and last scores was 15 points or greater. This 15-point criterion is equal to one standard deviation of the test norms and approximately three times the error of measurement of the test.) .3
16U
140 4,
Verbal MTX CrRT
Performance CrRT
MTX
120 100
0
80 60
p=0.045
p=0.016
p 50 x 109/L) irradiation is the preferred method of CNS prophylaxis pending randomized trials comparing its efficacy with that of aggressive IT therapy.3
ACKNOWLEDGMENT The authors thank the following for their contributions over the past 10 years: W.P. Bowman, M. Abromowitch, and C.-H. Pui (Hematology-Oncology); I. Igurashi and E. Kovnar (Neurology); T. Coburn (Radiology); R. Berg and R. Ragland (Psychology); and M. Campbell, K. Davis, and numerous other examiners in the Neuropsychology Department. The authors also acknowledge the medical editorship of John Gilbert and Christy Wright, the patience and cooperation of the children and their parents who participated in this study, the long-term investment of time and resources made by St Jude Children's Research Hospital, and the manuscript typing of Peggy Vandiveer.
REFERENCES 1. Aur RJA, Simone JV, Hustu HO, et al: Central nervous system therapy and combination chemotherapy of childhood lymphocytic leukemia. Blood 37:272-281, 1971 2. Aur RJA, Hustu HO, Verzosa MS, et al: Comparison of two methods of preventing central nervous system leukemia. Blood 43:349-357, 1973 3. Sullivan MP, Chan T, Dyment PK, et al: Equivalence of intrathecal chemotherapy and radiotherapy as central nervous system prophylaxis in children with acute lymphatic leukemia: A Pediatric Oncology Group study. Blood 60:948958, 1982 4. Ochs J, Mulhern R: Late effects of antileukemic treatment, in D Poplack (ed): Childhood Acute Lymphoblastic Leukemia. Pediatric Clinics, Philadelphia, PA, Saunders, 1988, pp 815-835 5. Williams MJ, Davis KS: Central nervous system prophylactic treatment for childhood leukemia: Neuropsychological outcome studies. Cancer Res 13:113-127, 1986
6. Fletcher JM, Copeland DR: Neurobehavioral effects of central nervous system treatment of cancer in children. J Clin Exp Neuropsych 10:495-538, 1988 7. Nesbit ME, Sather HN, Robison LL, et al: Presymptomatic central nervous system therapy in previously untreated childhood acute lymphoblastic leukemia: Comparison of 1,800 rad and 2,400 rad. A report of the Children's Cancer Study Group. Lancet 1:461-466, 1981 8. Poplack DG, Reaman GH, Bleyer WA, et al: Successful prevention of central nervous system (CNS) leukemia without cranial radiation in children with high-risk acute lymphoblastic leukemia (ALL): A preliminary report. Proc Am Soc Clin Oncol 8:213, 1989 (abstr) 9. Abromowitch M, Ochs J, Pui C-H, et al: Efficacy of high-dose methotrexate in childhood acute lymphoblastic leukemia: Analysis by contemporary risk classifications. Blood 71:866-869, 1988 10. Bowman WP, Ochs J, Pui C-H, et al: New directions
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
NEUROPSYCHOLOGIC FUNCTION, NEUROTOXICITY IN ALL of St Jude total therapy protocol: Study X for standard-risk childhood acute lymphoblastic leukemia, in, Murphy SB, Gilbert JR (eds): Leukemia Research: Advances in Cell Biology and Treatment, New York, NY, Elsevier Biomedical, 1983, p 203 11. Wechsler D: Manual for the Wechsler Preschool and Primary Scale of Intelligence. San Antonio, TX, Psychological Corporation, 1967 12. Wechsler D: Manual for the Wechsler Intelligence Scale for Children-Revised. San Antonio, TX, The Psychological Corporation, 1974 13. Jastak JS, Jastak S: The Wide Range Achievement Test. Wilmington, DE, Jastak Associates, 1984 14. Bentson J, Reza M, Winter J, et al: Steroids and apparent atrophy on computed tomography scans. J Comp Assist Tomogr 2:16-23, 1978 15. Whitaker JN, Lisak RP, Bashir RM, et al: Immunoreactive myelin basic protein in the cerebrospinal fluid in neurologic disorders. Ann Neurol 7:58-64, 1980 16. Ochs J, Parvey LS, Whitaker JN, et al: Serial cranial computed tomography scans in children with leukemia given two different forms of central nervous system therapy. J Clin Oncol 1:793-798, 1983 17. Eiser C: Intellectual abilities among survivors of childhood leukemia as a function of CNS irradiation. Arch Dis Child 53:391-395, 1978 18. Obetz SW, Smithson WA, Groover RV, et al: Neurologic follow-up study of children with ALL. Am J Pediatr Hematol Oncol 11:207-313, 1979 19. Meadows T, Massari DJ, Fergussion J, et al: Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukemia treated with cranial irradiation. Lancet 2:1015-1018, 1983 20. Rowland JH, Glidewell DJ, Sibley RF, et al: Effects of different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia. J Clin Oncol 2:1327-1335, 1984 21. Pfefferbaum-Levine B, Copeland DR, Fletcher JM, et al: Neuropsychological assessment of long-term survivors of childhood leukemia. Am J Pediatr Hematol Oncol 6:123-128, 1984 22. Whitt JK, Wells RJ, Lauria MM, et al: Cranial irradiation in childhood acute lymphocytic leukemia. Am J Dis Child 138:730-736, 1984 23. Pavlosky S, Fisman N, Arizoga, et al: Neuropsychologic study in patients with ALL: Two different CNS prevention therapies-cranial irradiation plus IT methotrexate versus IT methotrexate alone. Am J Pediatr Hematol Oncol 5:79-86, 1983
151
24. Lansky SB, Cairns SV, Lansky L, et al: Central nervous system prophylaxis studies showing impairment in verbal skills and academic achievement. Am J Pediatr Hematol 6:183-190, 1984 25. Stehbens JA, Kisker CR, Wilson BK: Achievement and intellectual test-retest performance in pediatric cancer patients at diagnosis and one year later. N Pediatr Psycho 8:47-56, 1983 26. Moss HA, Nannis ED, Poplack DG: The effects of prophylactic treatment of the CNS on the intellectual functioning of children with ALL. Am J Med 71:47-52, 1981 27. Soni SS, Martin G, Pitner SE, et al: Effects of CNS irradiation on neuropsychologic functioning of children with acute lymphoblastic leukemia. N Engl J Med 293:113118, 1975 28. Riehm H, Feckert H-S, Lampert F: Acute lymphoblastic leukemia, in, Voute PA, Barrett A, Bloom J, et al (eds): UICC Cancer in Children: Clinical Management (ed 2). New York, NY, Springer-Verlag, 1986, pp 101-118 29. Freeman JE, Johnson PG, Wohe JM: Somnolence after prophylactic cranial irradiation in children with acute lymphoblastic leukemia. Br Med J 4:523-525, 1973 30. Carli M, Perilongi G, Laverda AM, et al: Risk factors of central nervous system prophylaxis in successfully treated children with acute lymphocytic leukemia. Med Pediatr Oncol 13:334-340, 1985 31. Brouers P, Riccardi R, Fedio P, et al: Long-term neuropsychologic sequelae of childhood leukemia: Correlation with CT scan abnormalities. J Pediatr 106:723-728, 1985 32. Mahoney DH, Fernbach DJ, Glaze DG, et al: Elevated myelin basic protein levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia. 2:58-61, 1984 33. Kent SP, Pickering JE: Neoplasms in monkeys (Macaca Mulatta): Spontaneous and irradiation induced. Cancer 11:138-147, 1958 34. Ron E, Modan B, Boice JD, et al: Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 391:1033-1039, 1988 35. Crist W, Boyett J, Jackson J: Prognostic importance of the pre-B-cell immunophenotype and other presenting features in B-lineage childhood acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood 74(4):12521259, 1989 36. Hollingshead AB: Four Factor Index of Social Position. New Haven, CT, Yale University, 1975
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
